Datasets:

findzebra
/

corpus

Dataset card Data Studio Files Files and versions Community

Split (1)

train · 30.7k rows

text stringlengths 297 230k	title stringlengths 4 145	cui stringlengths 4 10	idx int64 0 30.7k	source stringclasses 6 values	source_url stringlengths 33 155	retrieved_date timestamp[s]	classification_map stringlengths 2 1.45k
A number sign (#) is used with this entry because of evidence that a retinitis pigmentosa-deafness syndrome is due to mutation in the MTTS2 gene (590085). Clinical Features Kumar-Singh et al. (1993) reported an extensive Irish kindred segregating retinitis pigmentosa and deafness. Affected members usually presented first with hearing difficulties in their teens. In their twenties, patients noted symptoms referable to impairment of night vision and loss of peripheral visual fields. Affected individuals showed abnormal electroretinographic responses before the onset of symptoms, however. Kenna et al. (1997) reported observations on the same large kindred segregating retinitis pigmentosa and sensorineural hearing impairment. The retinopathy in this kindred was typical of retinitis pigmentosa. Members of the pedigree who were examined also demonstrated a subclinical myopathy as evidenced by abnormal skeletal muscle histology, electromyography, and electrocardiography. None of the affected individuals had external ocular muscle movement disorders to suggest Kearns-Sayre syndrome (530000). Mapping Using polymorphic microsatellite markers, Kumar-Singh et al. (1993) excluded linkage of the retinitis pigmentosa-deafness syndrome in the Irish kindred to chromosome 3q (180380), 6q (608133), and the pericentric region of chromosome 8 (180100). They also excluded linkage to markers on Xp and to the region of chromosome 1q where Usher syndrome type II (276901) maps. In a report on the same family, Kumar-Singh et al. (1993) indicated that linkage to the 5 previously defined forms of autosomal dominant RP could be excluded. Kenna et al. (1997) found linkage of the disease locus in the same Irish kindred to markers D9S118, D9S122, and ASS (603470) on 9q34 with lod scores of 3.75 (theta = 0.10), 3.41 (theta = 0.10), and 3.25 (theta = 0.15). However, multipoint and haplotype analyses on this family by Mansergh et al. (1999) excluded linkage to this region of 9q. Molecular Genetics In the large Irish family reported by Kumar-Singh et al. (1993) and Kenna et al. (1997), Mansergh et al. (1999) identified a mutation in the mitochondrial genome, i.e., a 12258C-A change (590085.0001) in the MTTS2 gene. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	RETINITIS PIGMENTOSA-DEAFNESS SYNDROME	c0271097	6,400	omim	https://www.omim.org/entry/500004	2019-09-22T16:16:59	{"doid": ["0110829"], "mesh": ["D052245"], "omim": ["500004"], "orphanet": ["886", "231183"], "synonyms": ["Alternative titles", "RETINITIS PIGMENTOSA 8, FORMERLY", "RETINITIS PIGMENTOSA 21, FORMERLY"]}
A number sign (#) is used with this entry because progressive familial intrahepatic cholestasis-4 (PFIC4) is caused by homozygous or compound heterozygous mutation in the TJP2 gene (607709) on chromosome 9q21. For a phenotypic description and a discussion of genetic heterogeneity of progressive familial intrahepatic cholestasis, see PFIC1 (211600). Clinical Features Sambrotta et al. (2014) reported 12 patients from 8 families with early childhood onset of severe progressive liver disease. One child died at age 13 months, 9 patients required a liver transplant, and 2 had stable liver disease with mild portal hypertension at ages 4 and 7 years, respectively. Laboratory studies showed normal or mildly increased GGT levels. No additional clinical details were given. Most of the families were consanguineous. Zhou et al. (2015) reported 2 patients with PFIC4 who developed hepatocellular carcinoma (HCC). The first was a 26-month-old Caucasian female who had had intermittent jaundice of neonatal onset and normal GGT. She presented in acute liver failure. CT scan showed innumerable well-defined hepatic masses. Serum alpha-fetoprotein (AFP; 104150) was 171,000 ng/mL, and liver biopsy found moderately differentiated HCC in a background of chronic cholestatic hepatitis with cirrhosis. The patient died 3 weeks after admission. An autopsy confirmed multifocal HCC. The second patient was a 6-month-old Caucasian male referred for persistent cholestasis with near-normal GGT after hepatoportoenterostomy for presumed biliary atresia. Icterus resolved by 19 months, but a growing lesion in the right liver lobe, with rising serum AFP, prompted liver transplantation at 2 years of age. The explanted liver was cirrhotic, with multiple cholestatic nodules and a single, well-encapsulated 2-cm tumor that diffusely expressed AFP and glypican-3 (300037); a central region of well-differentiated HCC was found. The patient was well post 2 years transplantation. Zhou et al. (2015) concluded that mutations in TJP2 resulting in progressive intrahepatic cholestasis may predispose to hepatocellular carcinoma in early childhood, warranting close monitoring and early liver transplantation. Inheritance The transmission pattern of PFIC4 in the families reported by Sambrotta et al. (2014) was consistent with autosomal recessive inheritance. Molecular Genetics In 12 patients from 8 families with progressive familial intrahepatic cholestasis-4, Sambrotta et al. (2014) identified homozygous mutations in the TJP2 gene (see, e.g., 607709.0002-607709.0005). The mutations were identified by a combination of whole-exome sequencing and targeted sequencing of genes known to be associated with cholestasis. All mutations were predicted to abolish protein translation, consistent with a complete loss of function. Liver biopsy tissue available from several patients showed a lack of TJP2 protein expression. Patient liver tissue showed decreased localization of CLDN1 (603718) at tight junctions, although protein levels were normal; these findings suggested abnormal localization of CLDN1 in the absence of TJP2. Expression and localization of CLDN2 (300520) was normal. Transmission electron microscopy showed that the tight junctions between adjacent hepatocytes and biliary canaliculi in liver tissue were elongated and lacked the densest part of the zona occludens. Sambrotta et al. (2014) noted that homozygous loss of Zo2 in mice is embryonic lethal (Xu et al., 2008), indicating interspecies differences, and concluded that the lack of redundancy in humans must be restricted to the liver. Zhou et al. (2015) reported 2 patients with PFIC4 who developed hepatocellular carcinoma. One was compound heterozygous for TJP2 mutations (see 615878.0006); the other was homozygous for a frameshift mutation (615878.0008). INHERITANCE \- Autosomal recessive ABDOMEN Liver \- Intrahepatic cholestasis \- Liver failure \- Portal hypertension \- Elongated tight junctions between adjacent hepatocytes and biliary canaliculi seen on biopsy NEOPLASIA \- Hepatocellular carcinoma, childhood onset (reported in 2 patients) LABORATORY ABNORMALITIES \- Normal or mildly increased serum gamma-glutamyltransferase (GGT) MISCELLANEOUS \- Onset in childhood \- Progressive disorder \- Most patients require liver transplant in childhood MOLECULAR BASIS \- Caused by mutation in the tight junction protein 2 gene (TJP2, 607709.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 4	c0268312	6,401	omim	https://www.omim.org/entry/615878	2019-09-22T15:50:46	{"doid": ["0070224"], "omim": ["615878"], "orphanet": ["172", "79304", "480483"]}
Prion diseases are a group of rare transmissible disorders characterized by progressive debilitating neurological manifestations due to spongiform changes with an invariably fatal course. The disorders all involve accumulation of an abnormal prion protein in the central nervous system with no specific immunological response. Sporadic Creutzfeldt-Jakob disease (CJD; see this term) is the most frequent form accounting for about 85% of prion disease cases. The other forms of prion disease are genetic (5-15%) and include inherited CJD, fatal familial insomnia (FFI), and Familial Alzheimer-like prion disease (see these terms). Acquired forms (< 5%) include iatrogenic CJD and variant CJD (vCDJ). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Human prion disease	c0162534	6,402	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=56970	2021-01-23T17:27:03	{"mesh": ["D017096"], "umls": ["C0162534"], "icd-10": ["A81.0", "A81.1", "A81.8", "A81.9"], "synonyms": ["TSE", "Transmissible spongiform encephalopathy"]}
A rare frontonasal dysplasia characterized by median cleft of the upper lip (MCL), midline polyps of the facial skin, nasal mucosa, and pericallosal lipomas. Hypertelorism with ocular anomalies are also observed, generally with normal neuropsychological development. ## Epidemiology Pai syndrome (PS) has been reported in 67 patients to date, however, the incidence seems to be underestimated. ## Clinical description PS presents at birth with a variable phenotype ranging from mild facial dysmorphism to more severe anomalies resembling frontonasal dysplasia. Most patients present with a marked hypertelorism with downward slanting palpebral fissures and may include a bifid nose in the most extreme cases. Midline cleft lip with midline nasal and facial polyps manifest generally as a bifid uvula with high palate, polyps are located over the nasal septum or extend from the nostril from an attachment to the nasal septum. These anomalies may lead to respiratory impairment, increased respiratory infections, speech impediments or early childhood difficulties in eating solids. Skin lipomas containing cartilage may be seen on the forehead. Ocular anomalies may include anterior segment dysgenesis, persistent papillary membrane, corneal leukoma, microcornea, posterior lenticonus, heterochromia iris and conjunctival lipoma. Coloboma of the iris has been reported. Neuropsychological development is usually normal, but some patients may present with epilepsy and impaired neuropsychological development. Sacral dimples may be observed at birth, and hypospadias has been reported in some male patients. ## Etiology The etiology of PS is unknown. ## Diagnostic methods PS is diagnosed strictly by clinical signs, the presence of a congenital nasal polyp plus one or more of the three following traits: MCL (with or without cleft alveolus), mid-anterior alveolar process congenital polyp and pericallosal lipoma. MRI may reveal pericallosal lipomas and an abnormal configuration of the third ventricle. An ophthalomogical exam is recommended. ## Differential diagnosis Differential diagnoses include Loeys-Dietz syndrome, oculocerebrocutaneous syndrome, frontonasal dysplasia, Goldenhar syndrome, as well as a variety of chromosomal anomalies. ## Genetic counseling One case of father to son transmission has been reported to date, but no recurrence in sibs has ever been reported. Recurrence risk in families with no history of PS is therefore thought to be low. ## Management and treatment Detection of potential oral or respiratory difficulties in newborns must be treated immediately. Multistage craniofacial surgery may be necessary in many cases. Surgical restoration of orbicular muscle continuity and excision of skin lipomas may be performed early in childhood, correction of the nasal pyramid should be performed after the pubertal growth spurt. In patients presenting with ocular anomalies, corneal or cataract surgery may improve vision in some cases, and optical iridectomy may be necessary in cases presenting with corneal leukoma. All patients should be regularly monitored for increases in intraocular pressure. ## Prognosis Both cosmetic and functional restoration of buccal and nasal anomalies is feasible and the prognosis is good for most patients. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Pai syndrome	c1835087	6,403	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1993	2021-01-23T18:10:11	{"gard": ["3439"], "mesh": ["C536135"], "omim": ["155145"], "umls": ["C1835087"], "icd-10": ["Q87.8"], "synonyms": ["Median cleft of the upper lip-corpus callosum lipoma-midline facial cutaneous polyps syndrome"]}
Glycogen storage disease type I (also known as GSDI or von Gierke disease) is an inherited disorder caused by the buildup of a complex sugar called glycogen in the body's cells. The accumulation of glycogen in certain organs and tissues, especially the liver, kidneys, and small intestines, impairs their ability to function normally. Signs and symptoms of this condition typically appear around the age of 3 or 4 months, when babies start to sleep through the night and do not eat as frequently as newborns. Affected infants may have low blood sugar (hypoglycemia), which can lead to seizures. They can also have a buildup of lactic acid in the body (lactic acidosis), high blood levels of a waste product called uric acid (hyperuricemia), and excess amounts of fats in the blood (hyperlipidemia). As they get older, children with GSDI have thin arms and legs and short stature. An enlarged liver may give the appearance of a protruding abdomen. The kidneys may also be enlarged. Affected individuals may also have diarrhea and deposits of cholesterol in the skin (xanthomas). People with GSDI may experience delayed puberty. Beginning in young to mid-adulthood, affected individuals may have thinning of the bones (osteoporosis), a form of arthritis resulting from uric acid crystals in the joints (gout), kidney disease, and high blood pressure in the blood vessels that supply the lungs (pulmonary hypertension). Females with this condition may also have abnormal development of the ovaries (polycystic ovaries). In affected teens and adults, tumors called adenomas may form in the liver. Adenomas are usually noncancerous (benign), but occasionally these tumors can become cancerous (malignant). Researchers have described two types of GSDI, which differ in their signs and symptoms and genetic cause. These types are known as glycogen storage disease type Ia (GSDIa) and glycogen storage disease type Ib (GSDIb). Two other forms of GSDI have been described, and they were originally named types Ic and Id. However, these types are now known to be variations of GSDIb; for this reason, GSDIb is sometimes called GSD type I non-a. Many people with GSDIb have a shortage of white blood cells (neutropenia), which can make them prone to recurrent bacterial infections. Neutropenia is usually apparent by age 1. Many affected individuals also have inflammation of the intestinal walls (inflammatory bowel disease). People with GSDIb may have oral problems including cavities, inflammation of the gums (gingivitis), chronic gum (periodontal) disease, abnormal tooth development, and open sores (ulcers) in the mouth. The neutropenia and oral problems are specific to people with GSDIb and are typically not seen in people with GSDIa. ## Frequency The overall incidence of GSDI is 1 in 100,000 individuals. GSDIa is more common than GSDIb, accounting for 80 percent of all GSDI cases. ## Causes Mutations in two genes, G6PC and SLC37A4, cause GSDI. G6PC gene mutations cause GSDIa, and SLC37A4 gene mutations cause GSDIb. The proteins produced from the G6PC and SLC37A4 genes work together to break down a type of sugar molecule called glucose 6-phosphate. The breakdown of this molecule produces the simple sugar glucose, which is the primary energy source for most cells in the body. Mutations in the G6PC and SLC37A4 genes prevent the effective breakdown of glucose 6-phosphate. Glucose 6-phosphate that is not broken down to glucose is converted to glycogen and fat so it can be stored within cells. Too much glycogen and fat stored within a cell can be toxic. This buildup damages organs and tissues throughout the body, particularly the liver and kidneys, leading to the signs and symptoms of GSDI. ### Learn more about the genes associated with Glycogen storage disease type I * G6PC * SLC37A4 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Glycogen storage disease type I	c0017920	6,404	medlineplus	https://medlineplus.gov/genetics/condition/glycogen-storage-disease-type-i/	2021-01-27T08:25:35	{"gard": ["7864", "2515"], "mesh": ["D005953"], "omim": ["232200", "232220"], "synonyms": []}
Hemangioma Hemangioma SpecialtyOncology A hemangioma or haemangioma is a usually benign vascular tumor derived from blood vessel cell types. The most common form is infantile hemangioma, known colloquially as a "strawberry mark", most commonly seen on the skin at birth or in the first weeks of life. A hemangioma can occur anywhere on the body, but most commonly appears on the face, scalp, chest or back. They tend to grow for up to a year before gradually shrinking as the child gets older. A hemangioma may need to be treated if it interferes with vision or breathing or is likely to cause long-term disfigurement. In rare cases internal hemangiomas can cause or contribute to other medical problems. The first line treatment option is beta blockers, which are highly effective in the majority of cases. ## Contents * 1 Types * 1.1 Infantile hemangiomas * 1.2 Congenital hemangiomas * 2 Other types * 2.1 Cavernous liver hemangioma * 2.2 Drug-induced hemangioma * 3 Diagnosis * 4 Treatment * 5 References ## Types[edit] Hemangioma on a child's arm. Hemangiomas are benign (noncancerous) vascular tumors, and many different types occur. The correct terminology for these hemangioma types is constantly being updated by the International Society for the Study of Vascular Anomalies (ISSVA).[1] The most common are infantile hemangiomas, and congenital hemangiomas. ### Infantile hemangiomas[edit] Main article: Infantile hemangioma Infantile hemangiomas are the most common benign tumor found in children. They are made up of blood vessels, often called strawberry marks, and are more common in girls than in boys. They usually appear on the skin of infants in the days or weeks after birth. They tend to grow quickly for up to a year. Most then shrink or involute without further problem, however some can ulcerate and form scabs which can be painful.[2] Depending on their location and size, they may also be disfiguring. Rarely, they may be related to disorders of the central nervous system or spine. They may also occur in the internal organs of the body, such as the liver, airway or brain.[3] The color of the hemangioma depends on how deep it is in the skin: superficial (near the skin's surface) hemangiomas tend to be bright red; deep (furthest from the skin's surface) hemangiomas are often blue or purple; mixed hemangiomas may have colors of both superficial and deep.[4] ### Congenital hemangiomas[edit] Congenital hemangiomas are present on the skin at birth, unlike infantile hemangiomas, which appear later. They are fully formed at birth, meaning that they do not grow after a child is born, as infantile hemangiomas do. They are less common than infantile hemangiomas. Congenital hemangiomas can be coloured from pink to blue. Congenital hemangiomas are classified according to whether they shrink and go away, or do not shrink, and do not go away, or partially shrink. Those that shrink are known as rapidly involuting congenital hemangiomas (RICH) and go away quickly. Those that do not shrink, and remain are known as noninvoluting congenital hemangiomas (NICH). Others that partially shrink are known as partially involuting congenital hemangiomas (PICH).[5][6] ## Other types[edit] Main article: Vascular tumor Other types of hemangioma include cavernous hemangiomas such as cavernous hemangioma of the liver. ### Cavernous liver hemangioma[edit] Hemangioma of the liver as seen on ultrasound Main article: Cavernous liver haemangioma A cavernous liver hemangioma or hepatic hemangioma is a benign tumour of the liver composed of hepatic endothelial cells. It is the most common liver tumour, and is usually asymptomatic and diagnosed incidentally on radiological imaging. Liver hemangiomas are thought to be congenital in origin.[7] Several subtypes exist, including the giant hepatic hemangioma, which can cause significant complications. ### Drug-induced hemangioma[edit] Drug-induced hemangiomas are reported side-effects for some drugs in nonclinical toxicology animal models, studying carcinogenesis. For example, hemangiomas of the mesenteric lymph node were increased significantly at 700 mg/kg/day of Empagliflozin in male rats, or approximately 42 times the exposure from a 25 mg clinical dose. [8] It is inferred from nonclinical animal studies that some drugs can also produce hemangiomos in humans, and careful dosing during therapeutic drug design can ensure their safe use. ## Diagnosis[edit] Diagnosis is usually clinical. Paediatric Dermatologists are experts in diagnosing and treating hemangiomas. Depending on the location of the hemangioma, tests such as MRIs or ultrasounds can be done to see how far the hemangioma goes under the skin and whether it affects any internal organs.[9] ## Treatment[edit] Hemangiomas usually fade gradually over time, and many do not require treatment. However, Hemangiomas that may be disfiguring or that are located at sites that can cause impairment (eyelids, airway) require early treatment intervention, typically with beta blockers. Management options may include:[10] * Oral beta blockers such as propranolol or atenolol have been used since 2008 and are the first-line treatment of hemangiomas. Beta blockers have repeatedly been shown to be effective and safe in treating hemangiomas that cause complications.[11] Beta blockers work via multiple mechanisms including narrowing the hemangioma's blood vessels, stopping them from proliferating and bringing forward their natural cell death. These correspond with hemangiomas fading and shrinking. [2] Approximately 97% of hemangiomas respond to Propanalol, with patients under 2 months old showing the greatest improvement.[3] * Topical beta blockers such as timolol. These can also be used in conjunction with oral beta blockers for greater effect, which has shown to be effective and safe for compound hemangiomas.[4] * Corticosteroids * Laser surgery ## References[edit] 1. ^ "ISSVA Classification of Vascular Anomalies International Society for the Study of Vascular Anomalies" (PDF). Retrieved 11 August 2018. 2. ^ Chang LC, Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, Lucky AW, Mancini AJ, Metry DW, Nopper AJ, Frieden IJ; Hemangioma Investigator Group. Growth characteristics of infantile hemangiomas: implications for management. Pediatrics. 2008 Aug;122(2):360-7. doi: 10.1542/peds.2007-2767. 3. ^ Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med. 1999 Jul 15;341(3):173-81. 4. ^ "Infantile Hemangiomas". Retrieved 11 August 2018. 5. ^ Mulliken JB, Bischoff J, Kozakewich HP. Multifocal rapidly involuting congenital hemangioma: a link to chorangioma. Am J Med Genet A. 2007;143A(24):3038-3046. 6. ^ Funk T, Lim Y, Kulungowski AM, et al. Symptomatic Congenital Hemangioma and Congenital Hemangiomatosis Associated With a Somatic Activating Mutation in GNA11. JAMA Dermatol. 2016;152(9):1015-1020. 7. ^ Baron R. 'Liver: Masses Part I: detection and characterization'. The Radiology Assistant 2006 8. ^ Prescribing Information: JARDIANCE® (empagliflozin). Section 13.1. https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf 9. ^ "Hemangioma". 10. ^ "Hemangioma". 11. ^ [1] * v * t * e Tumours of blood vessels Blood vessel * Hemangiosarcoma * Blue rubber bleb nevus syndrome * Hemangioendothelioma * Composite * Endovascular papillary * Epithelioid * Kaposiform * Infantile * Retiform) * Spindle cell * Proliferating angioendotheliomatosis * Hemangiopericytoma * Venous lake * Kaposi's sarcoma * African cutaneous * African lymphadenopathic * AIDS-associated * Classic * Immunosuppression-associated * Hemangioblastoma * Hemangioma * Capillary * Cavernous * Glomeruloid * Microvenular * Targeted hemosiderotic * Angioma * Cherry * Seriginosum * Spider * Tufted * Universal angiomatosis * Angiokeratoma * of Mibelli * Angiolipoma * Pyogenic granuloma Lymphatic * Lymphangioma/lymphangiosarcoma * Lymphangioma circumscriptum * Acquired progressive lymphangioma * PEComa * Lymphangioleiomyomatosis * Cystic hygroma * Multifocal lymphangioendotheliomatosis * Lymphangiomatosis Either * Angioma/angiosarcoma * Angiofibroma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Hemangioma	c0018916	6,405	wikipedia	https://en.wikipedia.org/wiki/Hemangioma	2021-01-18T18:30:47	{"mesh": ["D006391"], "umls": ["C0018916"], "wikidata": ["Q861028"]}
Distal muscular dystrophy Other namesDistal myopathy DYSF SpecialtyNeurology Distal muscular dystrophy is a group of disorders characterized by onset in the hands or feet. Many types involve dysferlin, but it has been suggested that not all cases do.[1] ## Contents * 1 Types * 2 Cause * 3 Diagnosis * 4 Management * 5 References * 6 Further reading * 7 External links ## Types[edit] This section needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Distal muscular dystrophy" – news · newspapers · books · scholar · JSTOR (October 2018) Name OMIM Locus Miyoshi myopathy (in Japan)[2][3] 254130 DYSF at 2p13.3-p13.1(DYSF is also associated with limb-girdle muscular dystrophy type 2B.[4]) Distal myopathy with anterior tibial onset[5] 606768 DYSF at 2p13.3-p13.1 Welander distal myopathy 604454 TIA1[6] at 2p13[7] ## Cause[edit] The cause of this dystrophy is very hard to determine because it can be a mutation in any of at least eight genes and not all are known yet. These mutations can be inherited from one parent, autosomal dominant, or from both parents, autosomal recessive. Along with being able to inherit the mutated gene, distal muscular dystrophy has slow progress therefore the patient may not know that they have it until they are in their late 40s or 50s. There are eight known types of distal muscular dystrophy. They are Welander’s distal myopathy, Finnish (tibial) distal myopathy, Miyoshi distal myopathy, Nonaka distal myopathy, Gowers–Laing distal myopathy, Hereditary inclusion-body myositis type 1, Distal myopathy with vocal cord and pharyngeal weakness, and ZASP-related myopathy. All of these affect different regions of the extremities and can show up as early as 5 years of age to as late as 50 years old.[citation needed] ## Diagnosis[edit] In terms of diagnosis, Vocal cord and pharyngeal distal myopathy should be assessed via serum CK levels, as well as muscle biopsy of the individual suspected of being afflicted with this condition[8] ## Management[edit] This section is empty. You can help by adding to it. (October 2018) ## References[edit] 1. ^ Murakami N, Sakuta R, Takahashi E, et al. (December 2005). "Early onset distal muscular dystrophy with normal dysferlin expression". Brain Dev. 27 (8): 589–91. doi:10.1016/j.braindev.2005.02.002. PMID 16310593. S2CID 28957231. 2. ^ Soares CN, de Freitas MR, Nascimento OJ, da Silva LF, de Freitas AR, Werneck LC (December 2003). "Myopathy of distal lower limbs: the clinical variant of Miyoshi". Arq Neuropsiquiatr. 61 (4): 946–9. doi:10.1590/S0004-282X2003000600011. PMID 14762596. 3. ^ Aoki, Masashi (1 January 1993). "Dysferlinopathy". GeneReviews. PMID 20301480. Retrieved 10 May 2016. 4. ^ Illa I (March 2000). "Distal myopathies". J. Neurol. 247 (3): 169–74. doi:10.1007/s004150050557. PMID 10787109. S2CID 39723106. Archived from the original on 2013-02-13. 5. ^ "OMIM Entry - # 606768 - MYOPATHY, DISTAL, WITH ANTERIOR TIBIAL ONSET; DMAT". www.omim.org. Retrieved 31 May 2017. 6. ^ Hackman P, Sarparanta J, Lehtinen S, Vihola A, Evilä A, Jonson PH, Luque H, Kere J, Screen M, Chinnery PF, Åhlberg G, Edsröm L, Udd B (January 2013). "Welander Distal Myopathy Is Caused by a Mutation in the RNA-Binding Protein TIA1". Annals of Neurology. 73 (4): 500–509. doi:10.1002/ana.23831. PMID 23401021. S2CID 13908127. 7. ^ von Tell D, Bruder CE, Anderson LV, Anvret M, Ahlberg G (August 2003). "Refined mapping of the Welander distal myopathy region on chromosome 2p13 positions the new candidate region telomeric of the DYSF locus". Neurogenetics. 4 (4): 173–7. doi:10.1007/s10048-003-0154-z. PMID 12836053. S2CID 27539044. 8. ^ Udd, Bjarne (1 January 2011). "Distal muscular dystrophies". Muscular Dystrophies. Handbook of Clinical Neurology. 101. pp. 239–262. doi:10.1016/B978-0-08-045031-5.00016-5. ISBN 9780080450315. ISSN 0072-9752. PMID 21496636. – via ScienceDirect (Subscription may be required or content may be available in libraries.) ## Further reading[edit] * Udd, Bjarne (February 2007). "Molecular biology of distal muscular dystrophies—Sarcomeric proteins on top". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1772 (2): 145–158. doi:10.1016/j.bbadis.2006.08.005. PMID 17029922. ## External links[edit] Classification D * ICD-10: G71.0 * ICD-9-CM: 359.1 * OMIM: 254130 604454 606768 * MeSH: D049310 * DiseasesDB: 31977 * SNOMED CT: 58795000 External resources * GeneReviews: Dysferlinopathy * v * t * e Muscular dystrophy Types * Congenital * Dystrophinopathy * Becker's * Duchenne * Distal * Emery-Dreifuss * Facioscapulohumeral * Limb-girdle muscular dystrophy * Calpainopathy * Myotonic * Oculopharyngeal National/International Organizations * Muscular Dystrophy Association (USA) * Muscular Dystrophy Canada * Myotonic Dystrophy Foundation * Muskelsvindfonden (Denmark) National/International Events * MDA Muscle Walk (USA) * Labor Day Telethon (defunct; USA/Canada) * Décrypthon (France) * Grøn Koncert (Denmark) Clinical trials * Stamulumab (MYO-029) Category * v * t * e Diseases of muscle, neuromuscular junction, and neuromuscular disease Neuromuscular- junction disease * autoimmune * Myasthenia gravis * Lambert–Eaton myasthenic syndrome * Neuromyotonia Myopathy Muscular dystrophy (DAPC) AD * Limb-girdle muscular dystrophy 1 * Oculopharyngeal * Facioscapulohumeral * Myotonic * Distal (most) AR * Calpainopathy * Limb-girdle muscular dystrophy 2 * Congenital * Fukuyama * Ullrich * Walker–Warburg XR * dystrophin * Becker's * Duchenne * Emery–Dreifuss Other structural * collagen disease * Bethlem myopathy * PTP disease * X-linked MTM * adaptor protein disease * BIN1-linked centronuclear myopathy * cytoskeleton disease * Nemaline myopathy * Zaspopathy Channelopathy Myotonia * Myotonia congenita * Thomsen disease * Neuromyotonia/Isaacs syndrome * Paramyotonia congenita Periodic paralysis * Hypokalemic * Thyrotoxic * Hyperkalemic Other * Central core disease Mitochondrial myopathy * MELAS * MERRF * KSS * PEO General * Inflammatory myopathy * Congenital myopathy * v * t * e Cell membrane protein disorders (other than Cell surface receptor, enzymes, and cytoskeleton) Arrestin * Oguchi disease 1 Myelin * Pelizaeus–Merzbacher disease * Dejerine–Sottas disease * Charcot–Marie–Tooth disease 1B, 2J Pulmonary surfactant * Surfactant metabolism dysfunction 1, 2 Cell adhesion molecule IgSF CAM: * OFC7 Cadherin: * DSG1 * Striate palmoplantar keratoderma 1 * DSG2 * Arrhythmogenic right ventricular dysplasia 10 * DSG4 * LAH1 * DSC2 * Arrhythmogenic right ventricular dysplasia 11 Integrin: * cell surface receptor deficiencies Tetraspanin * TSPAN7 * X-Linked mental retardation 58 * TSPAN12 * Familial exudative vitreoretinopathy 5 Other * KIND1 * Kindler syndrome * HFE * HFE hereditary haemochromatosis * DYSF * Distal muscular dystrophy * Limb-girdle muscular dystrophy 2B See also other cell membrane proteins This article about a disease of musculoskeletal and connective tissue is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Distal muscular dystrophy	c1864706	6,406	wikipedia	https://en.wikipedia.org/wiki/Distal_muscular_dystrophy	2021-01-18T18:49:33	{"mesh": ["C566445", "D049310"], "umls": ["C1864706"], "icd-9": ["359.1"], "orphanet": ["5448", "59135", "63273", "599", "399096"], "wikidata": ["Q5282843"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by homozygous or compound heterozygous mutation in the LAMA2 gene (156225) on chromosome 6q22. Biallelic mutation in the LAMA2 gene can also cause congenital muscular dystrophy (MDC1A; 607855), which has overlapping but more severe features. Description Autosomal recessive limb-girdle muscular dystrophy-23 is characterized by slowly progressive proximal muscle weakness primarily affecting the lower limbs and resulting in gait difficulties. Age at onset generally ranges from childhood to mid-adulthood. Additional features include white matter abnormalities on brain imaging, increased serum creatine kinase, and dystrophic features, with partial LAMA2 deficiency on muscle biopsy. Some patients may have additional neurologic features, including executive deficits, seizures, and peripheral neuropathy. Patients remain ambulatory well into adulthood (summary by Gavassini et al., 2011 and Chan et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600). Clinical Features Gavassini et al. (2011) reported 5 patients from 4 families with LGMDR23. The phenotype was highly variable, but all patients remained ambulant between 17 and 65 years of age. Four patients had normal motor development, whereas 1 patient had delayed walking at 2 years of age. The age at onset was reported to be between 10 and 59 years, but 1 patient had onset at age 14 months. Features included proximal muscle weakness in the upper and lower limbs, difficulty climbing stairs and running, waddling gait, Gowers sign, and muscle cramps, as well as increased serum creatine kinase. Three patients had calf hypertrophy. Neurologic involvement was also variable: all patients had nonprogressive diffuse white matter abnormalities on brain imaging, 3 had deficits in executive function or cognition, 2 had controlled seizures, and 2 had possible seizures. Muscle biopsy showed partial and variably decreased immunostaining for LAMA2 as well as increased immunostaining for LAMA5 (601033). Chan et al. (2014) reported an 11-year-old girl with LGMDR23. She had normal early motor development, but had transient unilateral ptosis in early childhood. At age 5, she was noted to be clumsy and slow, and later showed difficulty running, jumping, climbing stairs and lifting heavy objects, but remained ambulatory. Her initial assessment, including electrophysiologic studies, was consistent with a demyelinating sensorimotor peripheral neuropathy. Physical examination showed proximal weakness of the upper and lower limbs, areflexia, distal hand wasting, Gowers sign, elbow contractures, and mild kyphosis. Sensation, proprioception, and vibration sensation were intact. She had decreased nerve conduction velocities as well as signs of chronic reinnervation and axonal degeneration. Muscle biopsy showed dystrophic features, including increased fiber size variation, increased fat and connective tissue, and internal nuclei. Immunostaining of skeletal muscle sample showed partial LAMA2 deficiency in both muscle fibers and intramuscular motor nerves. Serum creatine kinase was increased, and brain imaging showed white matter abnormalities. Lokken et al. (2015) reported 1 new patient (patient 7) with LGMDR23. This woman showed delayed motor development before 1 year of age, but presented with LGMD at age 32. She was able to walk and run and remained ambulatory as an adult, but she had a positive Gowers sign. Serum creatine kinase was increased, and muscle biopsy showed mild dystrophic and myopathic changes as well as partial LAMA2 deficiency. Brain imaging showed white matter abnormalities; cognition was normal. Inheritance The transmission pattern of LGMDR23 in the families reported by Gavassini et al. (2011) was consistent with autosomal recessive inheritance. Molecular Genetics In 5 patients from 4 families with LGMDR23, Gavassini et al. (2011) identified homozygous or compound heterozygous mutations in the LAMA2 gene (see, e.g., 156225.0016 and 156225.0017). There were 4 missense mutations, 1 splice site mutation, and 1 in-frame deletion. The mutations were located in both the globular and the rod-like domains of the protein. Functional studies of the variants were not performed, but the splice site mutation was confirmed to result in a frameshift in patient cells. Muscle biopsy showed partial LAMA2 deficiency in all patients. In a girl with LGMDR23, Chan et al. (2014) identified compound heterozygous mutations in the LAMA2 gene (Q131X, 156225.0018 and A1496V, 156225.0019). The mutations segregated with the disorder in the family. Functional studies of the variants were not performed. In a patient with LGMDR23, Lokken et al. (2015) identified compound heterozygous missense mutations in the LAMA2 gene (L12R and L1253R). Functional studies of the variants were not performed. Genotype/Phenotype Correlations In a comprehensive mutation update on LAMA2 mutations, Oliveira et al. (2018) stated that the most frequently reported genotypes are variants that create premature termination codons (PTC) in both disease alleles, are associated with complete deficiency of laminin in muscle biopsy, and cause a severe, congenital-onset muscular dystrophy (MDC1A). In contrast, missense variants, which are present in a smaller number of cases, usually correlate with partial laminin deficiency in muscle biopsy, and cause a milder, later-onset disorder (LGMDR23). INHERITANCE \- Autosomal recessive HEAD & NECK Neck \- Neck weakness MUSCLE, SOFT TISSUES \- Proximal muscle weakness, upper and lower limbs \- Difficulty climbing stairs \- Gower sign \- Gait difficulties \- Muscle cramps \- Calf hypertrophy \- Dystrophic changes seen on muscle biopsy \- Partial LAMA2 deficiency NEUROLOGIC Central Nervous System \- Delayed motor development \- Executive deficits (in some patients) \- Seizures (in some patients) \- White matter abnormalities seen on brain imaging Peripheral Nervous System \- Sensorimotor demyelinating neuropathy (in some patients) \- Areflexia LABORATORY ABNORMALITIES \- Increased serum creatine kinase MISCELLANEOUS \- Onset after walking is achieved \- Variable age at onset (range childhood to adult) \- Slowly progressive \- Variable severity \- Patients remain ambulatory MOLECULAR BASIS \- Caused by mutation in the laminin alpha-2 gene (LAMA2, 156225.0016 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 23	c1263858	6,407	omim	https://www.omim.org/entry/618138	2019-09-22T15:43:31	{"mesh": ["C537384"], "omim": ["618138"], "orphanet": ["258"], "genereviews": ["NBK97333"]}
For the scientific journals, see Carcinogenesis (journal) and Oncogenesis (journal). The formation of cancer Cancers and tumors are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat. Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by disrupting the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not. Variants of inherited genes may predispose individuals to cancer. In addition, environmental factors such as carcinogens and radiation cause mutations that may contribute to the development of cancer. Finally random mistakes in normal DNA replication may result in cancer causing mutations.[1] A series of several mutations to certain classes of genes is usually required before a normal cell will transform into a cancer cell.[2][3][4][5] On average, for example, 15 "driver mutations" and 60 "passenger" mutations are found in colon cancers.[2] Mutations in genes that regulate cell division, apoptosis (cell death), and DNA repair may result in uncontrolled cell proliferation and cancer. Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes that regulate cell growth and differentiation must be altered.[6] Genetic and epigenetic changes can occur at many levels, from gain or loss of entire chromosomes, to a mutation affecting a single DNA nucleotide, or to silencing or activating a microRNA that controls expression of 100 to 500 genes.[7][8] There are two broad categories of genes that are affected by these changes. Oncogenes may be normal genes that are expressed at inappropriately high levels, or altered genes that have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes that inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Finally Oncovirinae, viruses that contain an oncogene, are categorized as oncogenic because they trigger the growth of tumorous tissues in the host. This process is also referred to as viral transformation. ## Contents * 1 Causes * 1.1 Genetic and epigenetic * 1.2 DNA damage * 1.3 Contribution of field defects * 1.4 Genome instability * 1.5 Non-mainstream theories * 2 Cancer cell biology * 2.1 Clonal evolution * 2.2 Biological properties of cancer cells * 2.3 Cancer as a defect in cell interactions * 2.4 In fish * 3 Mechanisms * 3.1 Oncogenes * 3.2 Proto-oncogenes * 3.3 Tumor suppressor genes * 3.4 Multiple mutations * 3.5 Non-mutagenic carcinogens * 3.6 Role of infections * 3.6.1 Bacterial * 3.6.2 Viral * 3.6.3 Helminthiasis * 3.7 Epigenetics * 3.8 Cancer stem cells * 3.9 Clonal evolution * 4 See also * 5 References * 6 Further reading ## Causes[edit] ### Genetic and epigenetic[edit] There is a diverse classification scheme for the various genomic changes that may contribute to the generation of cancer cells. Many of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. There are also many epigenetic changes that alter whether genes are expressed or not expressed. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change that is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis. Large-scale mutations involve either the deletion or duplication of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal region, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase. Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants. ### DNA damage[edit] The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis DNA damage is considered to be the primary cause of cancer.[9] More than 60,000 new naturally-occurring instances of DNA damage arise, on average, per human cell, per day, due to endogenous cellular processes (see article DNA damage (naturally occurring)). Additional DNA damage can arise from exposure to exogenous agents. As one example of an exogenous carcinogenic agent, tobacco smoke causes increased DNA damage, and this DNA damage likely cause the increase of lung cancer due to smoking.[10] In other examples, UV light from solar radiation causes DNA damage that is important in melanoma,[11] Helicobacter pylori infection produces high levels of reactive oxygen species that damage DNA and contribute to gastric cancer,[12] and the Aspergillus flavus metabolite aflatoxin is a DNA damaging agent that is causative in liver cancer.[13] DNA damage can also be caused by substances produced in the body. Macrophages and neutrophils in an inflamed colonic epithelium are the source of reactive oxygen species causing the DNA damage that initiates colonic tumorigenesis,[14] and bile acids, at high levels in the colons of humans eating a high-fat diet, also cause DNA damage and contribute to colon cancer.[15] Such exogenous and endogenous sources of DNA damage are indicated in the boxes at the top of the figure in this section. The central role of DNA damage in progression to cancer is indicated at the second level of the figure. The central elements of DNA damage, epigenetic alterations and deficient DNA repair in progression to cancer are shown in red. A deficiency in DNA repair would cause more DNA damage to accumulate, and increase the risk for cancer. For example, individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) are at increased risk of cancer, with some defects causing an up to 100% lifetime chance of cancer (e.g. p53 mutations).[16] Such germline mutations are shown in a box at the left of the figure, with an indication of their contribution to DNA repair deficiency. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about one percent of cancers.[17] The majority of cancers are called non-hereditary or "sporadic cancers". About 30% of sporadic cancers do have some hereditary component that is currently undefined, while the majority, or 70% of sporadic cancers, have no hereditary component.[18] In sporadic cancers, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene; much more frequently, reduced or absent expression of DNA repair genes is due to epigenetic alterations that reduce or silence gene expression. This is indicated in the figure at the 3rd level from the top. For example, for 113 colorectal cancers examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).[19] When expression of DNA repair genes is reduced, this causes a DNA repair deficiency. This is shown in the figure at the 4th level from the top. With a DNA repair deficiency, DNA damage persists in cells at a higher than typical level (5th level from the top in figure); this excess damage causes an increased frequency of mutation and/or epimutation (6th level from top of figure). Experimentally, mutation rates increase substantially in cells defective in DNA mismatch repair[20][21] or in Homologous recombinational repair (HRR).[22] Chromosomal rearrangements and aneuploidy also increase in HRR-defective cells[23] During repair of DNA double-strand breaks, or repair of other DNA damage, incompletely-cleared repair sites can cause epigenetic gene silencing.[24][25] The somatic mutations and epigenetic alterations caused by DNA damage and deficiencies in DNA repair accumulate in field defects. Field defects are normal-appearing tissues with multiple alterations (discussed in the section below), and are common precursors to development of the disordered and over-proliferating clone of tissue in a cancer. Such field defects (second level from bottom of figure) may have numerous mutations and epigenetic alterations. It is impossible to determine the initial cause for most specific cancers. In a few cases, only one cause exists: for example, the virus HHV-8 causes all Kaposi's sarcomas. However, with the help of cancer epidemiology techniques and information, it is possible to produce an estimate of a likely cause in many more situations. For example, lung cancer has several causes, including tobacco use and radon gas. Men who currently smoke tobacco develop lung cancer at a rate 14 times that of men who have never smoked tobacco: the chance of lung cancer in a current smoker being caused by smoking is about 93%; there is a 7% chance that the smoker's lung cancer was caused by radon gas or some other, non-tobacco cause.[26] These statistical correlations have made it possible for researchers to infer that certain substances or behaviors are carcinogenic. Tobacco smoke causes increased exogenous DNA damage, and this DNA damage is the likely cause of lung cancer due to smoking. Among the more than 5,000 compounds in tobacco smoke, the genotoxic DNA-damaging agents that occur both at the highest concentrations, and which have the strongest mutagenic effects are acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide and isoprene.[10] Using molecular biological techniques, it is possible to characterize the mutations, epimutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting certain cancer patients' prognosis based on the spectrum of mutations. For example, up to half of all tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body. However, once a cancer is formed it continues to evolve and to produce sub-clones. It was reported in 2012 that a single renal cancer specimen, sampled in nine different areas, had 40 "ubiquitous" mutations, found in all nine areas, 59 mutations shared by some, but not all nine areas, and 29 "private" mutations only present in one area.[27] The lineages of cells in which all these DNA alterations accumulate are difficult to trace, but two recent lines of evidence suggest that normal stem cells may be the cells of origin in cancers.[28][29] First, there exists a highly positive correlation (Spearman's rho = 0.81; P < 3.5 × 10−8) between the risk of developing cancer in a tissue and the number of normal stem cell divisions taking place in that same tissue. The correlation applied to 31 cancer types and extended across five orders of magnitude.[30] This correlation means that if normal stem cells from a tissue divide once, the cancer risk in that tissue is approximately 1X. If they divide 1,000 times, the cancer risk is 1,000X. And if the normal stem cells from a tissue divide 100,000 times, the cancer risk in that tissue is approximately 100,000X. This strongly suggests that the main factor in cancer initiation is the fact that "normal" stem cells divide, which implies that cancer originates in normal, healthy stem cells.[29] Second, statistics show that most human cancers are diagnosed in older people. A possible explanation is that cancers occur because cells accumulate damage through time. DNA is the only cellular component that can accumulate damage over the entire course of a life, and stem cells are the only cells that can transmit DNA from the zygote to cells late in life. Other cells, derived from stem cells, do not keep DNA from the beginning of life until a possible cancer occurs. This implies that most cancers arise from normal stem cells.[28][29] ### Contribution of field defects[edit] Longitudinally opened freshly resected colon segment showing a cancer and four polyps. Plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. The diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors. The term "field cancerization" was first used in 1953 to describe an area or "field" of epithelium that has been preconditioned by (at that time) largely unknown processes so as to predispose it towards development of cancer.[31] Since then, the terms "field cancerization" and "field defect" have been used to describe pre-malignant tissue in which new cancers are likely to arise. Field defects have been identified in association with cancers and are important in progression to cancer.[32][33] However, it was pointed out by Rubin[34] that "the vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion…"[35] More than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells. It would also be expected that many of the epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects.[36] In the colon, a field defect probably arises by natural selection of a mutant or epigenetically altered cell among the stem cells at the base of one of the intestinal crypts on the inside surface of the colon. A mutant or epigenetically altered stem cell may replace the other nearby stem cells by natural selection. This may cause a patch of abnormal tissue to arise. The figure in this section includes a photo of a freshly resected and lengthwise-opened segment of the colon showing a colon cancer and four polyps. Below the photo there is a schematic diagram of how a large patch of mutant or epigenetically altered cells may have formed, shown by the large area in yellow in the diagram. Within this first large patch in the diagram (a large clone of cells), a second such mutation or epigenetic alteration may occur, so that a given stem cell acquires an advantage compared to its neighbors, and this altered stem cell may expand clonally, forming a secondary patch, or sub-clone, within the original patch. This is indicated in the diagram by four smaller patches of different colors within the large yellow original area. Within these new patches (sub-clones), the process may be repeated multiple times, indicated by the still smaller patches within the four secondary patches (with still different colors in the diagram) which clonally expand, until stem cells arise that generate either small polyps or else a malignant neoplasm (cancer). In the photo, an apparent field defect in this segment of a colon has generated four polyps (labeled with the size of the polyps, 6mm, 5mm, and two of 3mm, and a cancer about 3 cm across in its longest dimension). These neoplasms are also indicated (in the diagram below the photo) by 4 small tan circles (polyps) and a larger red area (cancer). The cancer in the photo occurred in the cecal area of the colon, where the colon joins the small intestine (labeled) and where the appendix occurs (labeled). The fat in the photo is external to the outer wall of the colon. In the segment of colon shown here, the colon was cut open lengthwise to expose its inner surface and to display the cancer and polyps occurring within the inner epithelial lining of the colon. If the general process by which sporadic colon cancers arise is the formation of a pre-neoplastic clone that spreads by natural selection, followed by formation of internal sub-clones within the initial clone, and sub-sub-clones inside those, then colon cancers generally should be associated with, and be preceded by, fields of increasing abnormality, reflecting the succession of premalignant events. The most extensive region of abnormality (the outermost yellow irregular area in the diagram) would reflect the earliest event in formation of a malignant neoplasm. In experimental evaluation of specific DNA repair deficiencies in cancers, many specific DNA repair deficiencies were also shown to occur in the field defects surrounding those cancers. The table below gives examples for which the DNA repair deficiency in a cancer was shown to be caused by an epigenetic alteration, and the somewhat lower frequencies with which the same epigenetically-caused DNA repair deficiency was found in the surrounding field defect. Frequency of epigenetic changes in DNA repair genes in sporadic cancers and in adjacent field defects Cancer Gene Frequency in Cancer Frequency in Field Defect Reference Colorectal MGMT 46% 34% [37] Colorectal MGMT 47% 11% [38] Colorectal MGMT 70% 60% [39] Colorectal MSH2 13% 5% [38] Colorectal ERCC1 100% 40% [40] Colorectal PMS2 88% 50% [40] Colorectal XPF 55% 40% [40] Head and Neck MGMT 54% 38% [41] Head and Neck MLH1 33% 25% [42] Head and Neck MLH1 31% 20% [43] Stomach MGMT 88% 78% [44] Stomach MLH1 73% 20% [45] Esophagus MLH1 77%–100% 23%–79% [46] Some of the small polyps in the field defect shown in the photo of the opened colon segment may be relatively benign neoplasms. In a 1996 study of polyps less than 10mm in size found during colonoscopy and followed with repeat colonoscopies for 3 years, 25% remained unchanged in size, 35% regressed or shrank in size and 40% grew in size.[47] ### Genome instability[edit] Cancers are known to exhibit genome instability or a "mutator phenotype".[48] The protein-coding DNA within the nucleus is about 1.5% of the total genomic DNA.[49] Within this protein-coding DNA (called the exome), an average cancer of the breast or colon can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be "driver" mutations, and the remaining ones may be "passenger" mutations.[36] However, the average number of DNA sequence mutations in the entire genome (including non-protein-coding regions) within a breast cancer tissue sample is about 20,000.[50] In an average melanoma tissue sample (melanomas have a higher exome mutation frequency),[36]) the total number of DNA sequence mutations is about 80,000.[51] These high frequencies of mutations in the total nucleotide sequences within cancers suggest that often an early alteration in the field defect giving rise to a cancer (e.g. yellow area in the diagram in the preceding section) is a deficiency in DNA repair. Large field defects surrounding colon cancers (extending to about 10 cm on each side of a cancer) are found[40] to frequently have epigenetic defects in two or three DNA repair proteins (ERCC1, ERCC4 (XPF) and/or PMS2) in the entire area of the field defect. When expression of DNA repair genes is reduced, DNA damage accumulates in cells at a higher than normal rate, and this excess damage causes an increased frequency of mutation and/or epimutation. Mutation rates strongly increase in cells defective in DNA mismatch repair[20][21] or in homologous recombinational repair (HRR).[22] A deficiency in DNA repair, itself, can allow DNA damage to accumulate, and error-prone translesion synthesis of some of the damaged areas may give rise to mutations. In addition, faulty repair of this accumulated DNA damage may give rise to epimutations. These new mutations and/or epimutations may provide a proliferative advantage, generating a field defect. Although the mutations/epimutations in DNA repair genes do not, themselves, confer a selective advantage, they may be carried along as passengers in cells when the cell acquires an additional mutation/epimutation that does provide a proliferative advantage. ### Non-mainstream theories[edit] There are a number of theories of carcinogenesis and cancer treatment that fall outside the mainstream of scientific opinion, due to lack of scientific rationale, logic, or evidence base. These theories may be used to justify various alternative cancer treatments. They should be distinguished from those theories of carcinogenesis that have a logical basis within mainstream cancer biology, and from which conventionally testable hypotheses can be made. Several alternative theories of carcinogenesis, however, are based on scientific evidence and are increasingly being acknowledged. Some researchers believe that cancer may be caused by aneuploidy (numerical and structural abnormalities in chromosomes)[52] rather than by mutations or epimutations. Cancer has also been considered as a metabolic disease, in which the cellular metabolism of oxygen is diverted from the pathway that generates energy (oxidative phosphorylation) to the pathway that generates reactive oxygen species.[53] This causes an energy switch from oxidative phosphorylation to aerobic glycolysis (Warburg's hypothesis), and the accumulation of reactive oxygen species leading to oxidative stress ("oxidative stress theory of cancer").[53] A number of authors have questioned the assumption that cancers result from sequential random mutations as oversimplistic, suggesting instead that cancer results from a failure of the body to inhibit an innate, programmed proliferative tendency.[54] A related theory suggests that cancer is an atavism, an evolutionary throwback to an earlier form of multicellular life.[55] The genes responsible for uncontrolled cell growth and cooperation between cancer cells are very similar to those that enabled the first multicellular life forms to group together and flourish. These genes still exist within the genomes of more complex metazoans, such as humans, although more recently evolved genes keep them in check. When the newer controlling genes fail for whatever reason, the cell can revert to its more primitive programming and reproduce out of control. The theory is an alternative to the notion that cancers begin with rogue cells that undergo evolution within the body. Instead, they possess a fixed number of primitive genes that are progressively activated, giving them finite variability.[56] Another evolutionary theory puts the roots of cancer back to the origin of the eukaryote (nucleated) cell by massive horizontal gene transfer, when the genomes of infecting viruses were cleaved (and thereby attenuated) by the host, but their fragments integrated into the host genome as immune protection. Cancer thus originates when a rare somatic mutation recombines such fragments into a functional driver of cell proliferation.[57] ## Cancer cell biology[edit] Tissue can be organized in a continuous spectrum from normal to cancer. Often, the multiple genetic changes that result in cancer may take many years to accumulate. During this time, the biological behavior of the pre-malignant cells slowly changes from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a distinctive appearance under the microscope. Among the distinguishing traits of a pre-malignant lesion are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation. The most severe cases of dysplasia are referred to as carcinoma in situ. In Latin, the term in situ means "in place"; carcinoma in situ refers to an uncontrolled growth of dysplastic cells that remains in its original location and has not shown invasion into other tissues. Carcinoma in situ may develop into an invasive malignancy and is usually removed surgically when detected. ### Clonal evolution[edit] Main article: Somatic evolution in cancer Just as a population of animals undergoes evolution, an unchecked population of cells also can undergo "evolution". This undesirable process is called somatic evolution, and is how cancer arises and becomes more malignant over time.[58] Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. However, once cancer begins, cancer cells undergo a process of natural selection: the few cells with new genetic changes that enhance their survival or reproduction multiply faster, and soon come to dominate the growing tumor as cells with less favorable genetic change are out-competed.[59] This is the same mechanism by which pathogenic species such as MRSA can become antibiotic-resistant and by which HIV can become drug-resistant), and by which plant diseases and insects can become pesticide-resistant. This evolution explains why a cancer relapse often involves cells that have acquired cancer-drug resistance or resistance to radiation from radiotherapy). ### Biological properties of cancer cells[edit] In a 2000 article by Hanahan and Weinberg, the biological properties of malignant tumor cells were summarized as follows:[60] * Acquisition of self-sufficiency in growth signals, leading to unchecked growth. * Loss of sensitivity to anti-growth signals, also leading to unchecked growth. * Loss of capacity for apoptosis, allowing growth despite genetic errors and external anti-growth signals. * Loss of capacity for senescence, leading to limitless replicative potential (immortality) * Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion. * Acquisition of ability to invade neighbouring tissues, the defining property of invasive carcinoma. * Acquisition of ability to seed metastases at distant sites, a late-appearing property of some malignant tumors (carcinomas or others). The completion of these multiple steps would be a very rare event without: * Loss of capacity to repair genetic errors, leading to an increased mutation rate (genomic instability), thus accelerating all the other changes. These biological changes are classical in carcinomas; other malignant tumors may not need to achieve them all. For example, given that tissue invasion and displacement to distant sites are normal properties of leukocytes, these steps are not needed in the development of leukemia. Nor do the different steps necessarily represent individual mutations. For example, inactivation of a single gene, coding for the p53 protein, will cause genomic instability, evasion of apoptosis and increased angiogenesis. Further, not all the cancer cells are dividing. Rather, a subset of the cells in a tumor, called cancer stem cells, replicate themselves as they generate differentiated cells.[61] ### Cancer as a defect in cell interactions[edit] Normally, once a tissue is injured or infected, damaged cells elicit inflammation by stimulating specific patterns of enzyme activity and cytokine gene expression in surrounding cells.[62][63] Discrete clusters ("cytokine clusters") of molecules are secreted, which act as mediators, inducing the activity of subsequent cascades of biochemical changes.[64] Each cytokine binds to specific receptors on various cell types, and each cell type responds in turn by altering the activity of intracellular signal transduction pathways, depending on the receptors that the cell expresses and the signaling molecules present inside the cell.[65][66] Collectively, this reprogramming process induces a stepwise change in cell phenotypes, which will ultimately lead to restoration of tissue function and toward regaining essential structural integrity.[67][68] A tissue can thereby heal, depending on the productive communication between the cells present at the site of damage and the immune system.[69] One key factor in healing is the regulation of cytokine gene expression, which enables complementary groups of cells to respond to inflammatory mediators in a manner that gradually produces essential changes in tissue physiology.[70][71][72] Cancer cells have either permanent (genetic) or reversible (epigenetic) changes to their genome, which partly inhibit their communication with surrounding cells and with the immune system.[73][74] Cancer cells do not communicate with their tissue microenvironment in a manner that protects tissue integrity; instead, the movement and the survival of cancer cells become possible in locations where they can impair tissue function.[75][76] Cancer cells survive by "rewiring" signal pathways that normally protect the tissue from the immune system. One example of tissue function rewiring in cancer is the activity of transcription factor NF-κB.[77] NF-κB activates the expression of numerous genes involved in the transition between inflammation and regeneration, which encode cytokines, adhesion factors, and other molecules that can change cell fate.[78] This reprogramming of cellular phenotypes normally allows the development of a fully functional intact tissue.[79] NF-κB activity is tightly controlled by multiple proteins, which collectively ensure that only discrete clusters of genes are induced by NF-κB in a given cell and at a given time.[80] This tight regulation of signal exchange between cells protects the tissue from excessive inflammation, and ensures that different cell types gradually acquire complementary functions and specific positions. Failure of this mutual regulation between genetic reprogramming and cell interactions allows cancer cells to give rise to metastasis. Cancer cells respond aberrantly to cytokines, and activate signal cascades that can protect them from the immune system.[77][81] ### In fish[edit] The role of iodine in marine fish (rich in iodine) and freshwater fish (iodine-deficient) is not completely understood, but it has been reported that freshwater fish are more susceptible to infectious and, in particular, neoplastic and atherosclerotic diseases, than marine fish.[82][83] Marine elasmobranch fishes such as sharks, stingrays etc. are much less affected by cancer than freshwater fishes, and therefore have stimulated medical research to better understand carcinogenesis.[84] ## Mechanisms[edit] In order for cells to start dividing uncontrollably, genes that regulate cell growth must be dysregulated.[85] Proto-oncogenes are genes that promote cell growth and mitosis, whereas tumor suppressor genes discourage cell growth, or temporarily halt cell division to carry out DNA repair. Typically, a series of several mutations to these genes is required before a normal cell transforms into a cancer cell.[5] This concept is sometimes termed "oncoevolution." Mutations to these genes provide the signals for tumor cells to start dividing uncontrollably. But the uncontrolled cell division that characterizes cancer also requires that the dividing cell duplicates all its cellular components to create two daughter cells. The activation of anaerobic glycolysis (the Warburg effect), which is not necessarily induced by mutations in proto-oncogenes and tumor suppressor genes,[86] provides most of the building blocks required to duplicate the cellular components of a dividing cell and, therefore, is also essential for carcinogenesis.[53] ### Oncogenes[edit] Oncogenes promote cell growth through a variety of ways. Many can produce hormones, a "chemical messenger" between cells that encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the cell nucleus to affect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with. Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive. One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours.[87] Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only is this gene present in the human genome but also, when ligated to a stimulating control element, it could induce cancers in cell line cultures.[88] ### Proto-oncogenes[edit] Proto-oncogenes promote cell growth in a variety of ways. Many can produce hormones, "chemical messengers" between cells that encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. Some are responsible for the signal transduction system and signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce mitogens, or are involved in transcription of DNA in protein synthesis, which create the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with. Mutations in proto-oncogenes can modify their expression and function, increasing the amount or activity of the product protein. When this happens, they become oncogenes, and, thus, cells have a higher chance of dividing excessively and uncontrollably. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, as they are critical for growth, repair and homeostasis of the body. It is only when they become mutated that the signals for growth become excessive. It is important to note that a gene possessing a growth-promoting role may increase the carcinogenic potential of a cell, under the condition that all necessary cellular mechanisms that permit growth are activated.[89] This condition also includes the inactivation of specific tumor suppressor genes (see below). If the condition is not fulfilled, the cell may cease to grow and can proceed to die. This makes identification of the stage and type of cancer cell that grows under the control of a given oncogene crucial for the development of treatment strategies. ### Tumor suppressor genes[edit] Many tumor suppressor genes effect signal transduction pathways that regulate apoptosis, also known as "programmed cell death". Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways that lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage. Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis. The Warburg hypothesis is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway.[90] However, a mutation can damage the tumor suppressor gene itself, or the signal pathway that activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer. Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer. Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would cause cancer only if another mutation event occurred later in the organism's life, inactivating the other allele of that tumor suppressor gene.[91] Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations. Knudson's two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.[92] ### Multiple mutations[edit] Multiple mutations in cancer cells In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control and tumor suppressor genes, first hypothesised by the Knudson hypothesis.[3] A mutation to only one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it, that cell growth quickly spirals out of control.[5] Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increases as one gets older, because DNA damage forms a feedback loop. Mutation of tumor suppressor genes that are passed on to the next generation of not merely cells, but their offspring, can cause increased likelihoods for cancers to be inherited. Members within these families have increased incidence and decreased latency of multiple tumors. The mode of inheritance of mutant tumor suppressors is that affected member inherits a defective copy from one parent, and a normal copy from another. Because mutations in tumor suppressors act in a recessive manner (note, however, there are exceptions), the loss of the normal copy creates the cancer phenotype. For instance, individuals that are heterozygous for p53 mutations are often victims of Li-Fraumeni syndrome, and that are heterozygous for Rb mutations develop retinoblastoma. In similar fashion, mutations in the adenomatous polyposis coli gene are linked to adenopolyposis colon cancer, with thousands of polyps in the colon while young, whereas mutations in BRCA1 and BRCA2 lead to early onset of breast cancer. A new idea announced in 2011 is an extreme version of multiple mutations, called chromothripsis by its proponents. This idea, affecting only 2–3% of cases of cancer, although up to 25% of bone cancers, involves the catastrophic shattering of a chromosome into tens or hundreds of pieces and then being patched back together incorrectly. This shattering probably takes place when the chromosomes are compacted during normal cell division, but the trigger for the shattering is unknown. Under this model, cancer arises as the result of a single, isolated event, rather than the slow accumulation of multiple mutations.[93] ### Non-mutagenic carcinogens[edit] Many mutagens are also carcinogens, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include alcohol and estrogen. These are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis increasingly leave fewer opportunities for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells' receiving the wrong number of chromosomes, which leads to aneuploidy and may lead to cancer. ### Role of infections[edit] #### Bacterial[edit] Helicobacter pylori can cause gastric cancer. Although the data varies between different countries, overall about 1% to 3% of people infected with Helicobacter pylori develop gastric cancer in their lifetime compared to 0.13% of individuals who have had no H. pylori infection.[94][95] H. pylori infection is very prevalent. As evaluated in 2002, it is present in the gastric tissues of 74% of middle-aged adults in developing countries and 58% in developed countries.[96] Since 1% to 3% of infected individuals are likely to develop gastric cancer,[97] H. pylori-induced gastric cancer is the third highest cause of worldwide cancer mortality as of 2018.[98] Infection by H. pylori causes no symptoms in about 80% of those infected.[99] About 75% of individuals infected with H. pylori develop gastritis.[100] Thus, the usual consequence of H. pylori infection is chronic asymptomatic gastritis.[101] Because of the usual lack of symptoms, when gastric cancer is finally diagnosed it is often fairly advanced. More than half of gastric cancer patients have lymph node metastasis when they are initially diagnosed.[102] The gastritis caused by H. pylori is accompanied by inflammation, characterized by infiltration of neutrophils and macrophages to the gastric epithelium, which favors the accumulation of pro-inflammatory cytokines and reactive oxygen species/reactive nitrogen species (ROS/RNS).[103] The substantial presence of ROS/RNS causes DNA damage including 8-oxo-2'-deoxyguanosine (8-OHdG).[103] If the infecting H. pylori carry the cytotoxic cagA gene (present in about 60% of Western isolates and a higher percentage of Asian isolates), they can increase the level of 8-OHdG in gastric cells by 8-fold, while if the H. pylori do not carry the cagA gene, the increase in 8-OHdG is about 4-fold.[104] In addition to the oxidative DNA damage 8-OHdG, H. pylori infection causes other characteristic DNA damages including DNA double-strand breaks.[105] H. pylori also causes many epigenetic alterations linked to cancer development.[106][107] These epigenetic alterations are due to H. pylori-induced methylation of CpG sites in promoters of genes[106] and H. pylori-induced altered expression of multiple microRNAs.[107] As reviewed by Santos and Ribeiro[108] H. pylori infection is associated with epigenetically reduced efficiency of the DNA repair machinery, which favors the accumulation of mutations and genomic instability as well as gastric carcinogenesis. In particular, Raza et al.[109] showed that expression of two DNA repair proteins, ERCC1 and PMS2, was severely reduced once H. pylori infection had progressed to cause dyspepsia. Dyspepsia occurs in about 20% of infected individuals.[110] In addition, as reviewed by Raza et al.,[109] human gastric infection with H. pylori causes epigenetically reduced protein expression of DNA repair proteins MLH1, MGMT and MRE11. Reduced DNA repair in the presence of increased DNA damage increases carcinogenic mutations and is likely a significant cause of H. pylori carcinogenesis. #### Viral[edit] Main article: Oncovirus Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but less so in humans. 12% of human cancers can be attributed to a viral infection.[111] The mode of virally induced tumors can be divided into two, acutely transforming or slowly transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly transforming viruses, the virus genome is inserted, especially as viral genome insertion is obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements, in turn, cause over-expression of that proto-oncogene, which, in turn, induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly transforming viruses have very long tumor latency compared to acutely transforming virus, which already carries the viral-oncogene. Viruses that are known to cause cancer such as HPV (cervical cancer), Hepatitis B (liver cancer), and EBV (a type of lymphoma), are all DNA viruses. It is thought that when the virus infects a cell, it inserts a part of its own DNA near the cell growth genes, causing cell division. The group of changed cells that are formed from the first cell dividing all have the same viral DNA near the cell growth genes. The group of changed cells are now special because one of the normal controls on growth has been lost. Depending on their location, cells can be damaged through radiation, chemicals from cigarette smoke, and inflammation from bacterial infection or other viruses. Each cell has a chance of damage. Cells often die if they are damaged, through failure of a vital process or the immune system, however, sometimes damage will knock out a single cancer gene. In an old person, there are thousands, tens of thousands, or hundreds of thousands of knocked-out cells. The chance that any one would form a cancer is very low.[citation needed] When the damage occurs in any area of changed cells, something different occurs. Each of the cells has the potential for growth. The changed cells will divide quicker when the area is damaged by physical, chemical, or viral agents. A vicious circle has been set up: Damaging the area will cause the changed cells to divide, causing a greater likelihood that they will suffer knock-outs. This model of carcinogenesis is popular because it explains why cancers grow. It would be expected that cells that are damaged through radiation would die or at least be worse off because they have fewer genes working; viruses increase the number of genes working. One thought is that we may end up with thousands of vaccines to prevent every virus that can change our cells. Viruses can have different effects on different parts of the body. It may be possible to prevent a number of different cancers by immunizing against one viral agent. It is likely that HPV, for instance, has a role in cancers of the mucous membranes of the mouth. #### Helminthiasis[edit] Certain parasitic worms are known to be carcinogenic.[112] These include: * Clonorchis sinensis (the organism causing Clonorchiasis) and Opisthorchis viverrini (causing Opisthorchiasis) are associated with cholangiocarcinoma.[113] * Schistosoma species (the organisms causing Schistosomiasis) is associated with bladder cancer. ### Epigenetics[edit] Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure. The theory of epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression. Normally, oncogenes are silent, for example, because of DNA methylation. Loss of that methylation can induce the aberrant expression of oncogenes, leading to cancer pathogenesis. Known mechanisms of epigenetic change include DNA methylation, and methylation or acetylation of histone proteins bound to chromosomal DNA at specific locations. Classes of medications, known as HDAC inhibitors and DNA methyltransferase inhibitors, can re-regulate the epigenetic signaling in the cancer cell. Epimutations include methylations or demethylations of the CpG islands of the promoter regions of genes, which result in repression or de-repression, respectively of gene expression.[114][115][116] Epimutations can also occur by acetylation, methylation, phosphorylation or other alterations to histones, creating a histone code that represses or activates gene expression, and such histone epimutations can be important epigenetic factors in cancer.[117][118] In addition, carcinogenic epimutation can occur through alterations of chromosome architecture caused by proteins such as HMGA2.[119] A further source of epimutation is due to increased or decreased expression of microRNAs (miRNAs). For example, extra expression of miR-137 can cause downregulation of expression of 491 genes, and miR-137 is epigenetically silenced in 32% of colorectal cancers>[8] ### Cancer stem cells[edit] Main article: Cancer stem cell A new way of looking at carcinogenesis comes from integrating the ideas of developmental biology into oncology. The cancer stem cell hypothesis proposes that the different kinds of cells in a heterogeneous tumor arise from a single cell, termed Cancer Stem Cell. Cancer stem cells may arise from transformation of adult stem cells or differentiated cells within a body. These cells persist as a subcomponent of the tumor and retain key stem cell properties. They give rise to a variety of cells, are capable of self-renewal and homeostatic control.[120] Furthermore, the relapse of cancer and the emergence of metastasis are also attributed to these cells. The cancer stem cell hypothesis does not contradict earlier concepts of carcinogenesis. The cancer stem cell hypothesis has been a proposed mechanism that contributes to tumour heterogeneity. ### Clonal evolution[edit] Main article: Somatic evolution in cancer While genetic and epigenetic alterations in tumor suppressor genes and oncogenes change the behavior of cells, those alterations, in the end, result in cancer through their effects on the population of neoplastic cells and their microenvironment.[58] Mutant cells in neoplasms compete for space and resources. Thus, a clone with a mutation in a tumor suppressor gene or oncogene will expand only in a neoplasm if that mutation gives the clone a competitive advantage over the other clones and normal cells in its microenvironment.[121] Thus, the process of carcinogenesis is formally a process of Darwinian evolution, known as somatic or clonal evolution.[59] Furthermore, in light of the Darwinistic mechanisms of carcinogenesis, it has been theorized that the various forms of cancer can be categorized as pubertal and gerontological. Anthropological research is currently being conducted on cancer as a natural evolutionary process through which natural selection destroys environmentally inferior phenotypes while supporting others. According to this theory, cancer comes in two separate types: from birth to the end of puberty (approximately age 20) teleologically inclined toward supportive group dynamics, and from mid-life to death (approximately age 40+) teleologically inclined away from overpopulated group dynamics.[citation needed] ## See also[edit] * Cancer cell ## References[edit] 1. ^ Tomasetti C, Li L, Vogelstein B (23 March 2017). "Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention". Science. 355 (6331): 1330–1334. Bibcode:2017Sci...355.1330T. doi:10.1126/science.aaf9011. PMC 5852673. PMID 28336671. 2. ^ a b Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, et al. (November 2007). "The genomic landscapes of human breast and colorectal cancers". Science. 318 (5853): 1108–13. Bibcode:2007Sci...318.1108W. CiteSeerX 10.1.1.218.5477. doi:10.1126/science.1145720. PMID 17932254. 3. ^ a b Knudson AG (November 2001). "Two genetic hits (more or less) to cancer". Nature Reviews. Cancer. 1 (2): 157–62. doi:10.1038/35101031. PMID 11905807. 4. ^ Fearon ER, Vogelstein B (June 1990). "A genetic model for colorectal tumorigenesis". Cell. 61 (5): 759–67. doi:10.1016/0092-8674(90)90186-I. PMID 2188735. 5. ^ a b c Belikov, Aleksey V. (22 September 2017). "The number of key carcinogenic events can be predicted from cancer incidence". Scientific Reports. 7 (1): 12170. Bibcode:2017NatSR...712170B. doi:10.1038/s41598-017-12448-7. PMC 5610194. PMID 28939880. 6. ^ Croce CM (January 2008). "Oncogenes and cancer". The New England Journal of Medicine. 358 (5): 502–11. doi:10.1056/NEJMra072367. PMID 18234754. 7. ^ Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM (February 2005). "Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs". Nature. 433 (7027): 769–73. Bibcode:2005Natur.433..769L. doi:10.1038/nature03315. PMID 15685193. 8. ^ a b Balaguer F, Link A, Lozano JJ, Cuatrecasas M, Nagasaka T, Boland CR, Goel A (August 2010). "Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis". Cancer Research. 70 (16): 6609–18. doi:10.1158/0008-5472.CAN-10-0622. PMC 2922409. PMID 20682795. 9. ^ Kastan MB (April 2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Molecular Cancer Research. 6 (4): 517–24. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632. 10. ^ a b Cunningham FH, Fiebelkorn S, Johnson M, Meredith C (November 2011). "A novel application of the Margin of Exposure approach: segregation of tobacco smoke toxicants". Food and Chemical Toxicology. 49 (11): 2921–33. doi:10.1016/j.fct.2011.07.019. PMID 21802474. 11. ^ Kanavy HE, Gerstenblith MR (December 2011). "Ultraviolet radiation and melanoma". Seminars in Cutaneous Medicine and Surgery. 30 (4): 222–8. doi:10.1016/j.sder.2011.08.003. PMID 22123420. 12. ^ Handa O, Naito Y, Yoshikawa T (2011). "Redox biology and gastric carcinogenesis: the role of Helicobacter pylori". Redox Report. 16 (1): 1–7. doi:10.1179/174329211X12968219310756. PMID 21605492. 13. ^ Smela ME, Hamm ML, Henderson PT, Harris CM, Harris TM, Essigmann JM (May 2002). "The aflatoxin B(1) formamidopyrimidine adduct plays a major role in causing the types of mutations observed in human hepatocellular carcinoma". Proceedings of the National Academy of Sciences of the United States of America. 99 (10): 6655–60. Bibcode:2002PNAS...99.6655S. doi:10.1073/pnas.102167699. PMC 124458. PMID 12011430. 14. ^ Katsurano M, Niwa T, Yasui Y, Shigematsu Y, Yamashita S, Takeshima H, Lee MS, Kim YJ, Tanaka T, Ushijima T (January 2012). "Early-stage formation of an epigenetic field defect in a mouse colitis model, and non-essential roles of T- and B-cells in DNA methylation induction". Oncogene. 31 (3): 342–51. doi:10.1038/onc.2011.241. PMID 21685942. 15. ^ Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, Zaitlin B, Bernstein H (August 2011). "Carcinogenicity of deoxycholate, a secondary bile acid". Archives of Toxicology. 85 (8): 863–71. doi:10.1007/s00204-011-0648-7. PMC 3149672. PMID 21267546. 16. ^ Malkin D (April 2011). "Li-fraumeni syndrome". Genes & Cancer. 2 (4): 475–84. doi:10.1177/1947601911413466. PMC 3135649. PMID 21779515. 17. ^ Fearon ER (November 1997). "Human cancer syndromes: clues to the origin and nature of cancer". Science. 278 (5340): 1043–50. Bibcode:1997Sci...278.1043F. doi:10.1126/science.278.5340.1043. PMID 9353177. 18. ^ Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (July 2000). "Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland". The New England Journal of Medicine. 343 (2): 78–85. doi:10.1056/NEJM200007133430201. PMID 10891514. 19. ^ Halford S, Rowan A, Sawyer E, Talbot I, Tomlinson I (June 2005). "O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions". Gut. 54 (6): 797–802. doi:10.1136/gut.2004.059535. PMC 1774551. PMID 15888787. 20. ^ a b Narayanan L, Fritzell JA, Baker SM, Liskay RM, Glazer PM (April 1997). "Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2". Proceedings of the National Academy of Sciences of the United States of America. 94 (7): 3122–7. Bibcode:1997PNAS...94.3122N. doi:10.1073/pnas.94.7.3122. PMC 20332. PMID 9096356. 21. ^ a b Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM, Glazer PM (December 2006). "Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6". Carcinogenesis. 27 (12): 2402–8. doi:10.1093/carcin/bgl079. PMC 2612936. PMID 16728433. 22. ^ a b Tutt AN, van Oostrom CT, Ross GM, van Steeg H, Ashworth A (March 2002). "Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation". EMBO Reports. 3 (3): 255–60. doi:10.1093/embo-reports/kvf037. PMC 1084010. PMID 11850397. 23. ^ German J (March 1969). "Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients". American Journal of Human Genetics. 21 (2): 196–227. PMC 1706430. PMID 5770175. 24. ^ O'Hagan HM, Mohammad HP, Baylin SB (August 2008). Lee JT (ed.). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLOS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723. PMID 18704159. 25. ^ Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV (July 2007). "DNA damage, homology-directed repair, and DNA methylation". PLOS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100. PMID 17616978. 26. ^ Villeneuve PJ, Mao Y (November 1994). "Lifetime probability of developing lung cancer, by smoking status, Canada". Canadian Journal of Public Health. 85 (6): 385–8. PMID 7895211. 27. ^ Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. (March 2012). "Intratumor heterogeneity and branched evolution revealed by multiregion sequencing". The New England Journal of Medicine. 366 (10): 883–92. doi:10.1056/NEJMoa1113205. PMC 4878653. PMID 22397650. 28. ^ a b López-Lázaro M (August 2015). "Stem cell division theory of cancer". Cell Cycle. 14 (16): 2547–8. doi:10.1080/15384101.2015.1062330. PMC 5242319. PMID 26090957. 29. ^ a b c López-Lázaro M (May 2015). "The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis". Oncoscience. 2 (5): 467–75. doi:10.18632/oncoscience.159. PMC 4468332. PMID 26097879. 30. ^ Tomasetti C, Vogelstein B (January 2015). "Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions". Science. 347 (6217): 78–81. doi:10.1126/science.1260825. PMC 4446723. PMID 25554788. 31. ^ Slaughter DP, Southwick HW, Smejkal W (September 1953). "Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin". Cancer. 6 (5): 963–8. doi:10.1002/1097-0142(195309)6:5<963::AID-CNCR2820060515>3.0.CO;2-Q. PMID 13094644. 32. ^ Bernstein C, Bernstein H, Payne CM, Dvorak K, Garewal H (February 2008). "Field defects in progression to gastrointestinal tract cancers". review. Cancer Letters. 260 (1–2): 1–10. doi:10.1016/j.canlet.2007.11.027. PMC 2744582. PMID 18164807. 33. ^ Nguyen H, Loustaunau C, Facista A, Ramsey L, Hassounah N, Taylor H, Krouse R, Payne CM, Tsikitis VL, Goldschmid S, Banerjee B, Perini RF, Bernstein C (2010). "Deficient Pms2, ERCC1, Ku86, CcOI in field defects during progression to colon cancer". Journal of Visualized Experiments (41): 1931. doi:10.3791/1931. PMC 3149991. PMID 20689513. 34. ^ Rubin H (March 2011). "Fields and field cancerization: the preneoplastic origins of cancer: asymptomatic hyperplastic fields are precursors of neoplasia, and their progression to tumors can be tracked by saturation density in culture". BioEssays. 33 (3): 224–31. doi:10.1002/bies.201000067. PMID 21254148. 35. ^ Tsao JL, Yatabe Y, Salovaara R, Järvinen HJ, Mecklin JP, Aaltonen LA, Tavaré S, Shibata D (February 2000). "Genetic reconstruction of individual colorectal tumor histories". Proceedings of the National Academy of Sciences of the United States of America. 97 (3): 1236–41. Bibcode:2000PNAS...97.1236T. doi:10.1073/pnas.97.3.1236. PMC 15581. PMID 10655514. 36. ^ a b c Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (March 2013). "Cancer genome landscapes". review. Science. 339 (6127): 1546–58. Bibcode:2013Sci...339.1546V. doi:10.1126/science.1235122. PMC 3749880. PMID 23539594. 37. ^ Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong J, Houlihan PS, Krouse RS, Prasad AR, Einspahr JG, Buckmeier J, Alberts DS, Hamilton SR, Issa JP (September 2005). "MGMT promoter methylation and field defect in sporadic colorectal cancer". Journal of the National Cancer Institute. 97 (18): 1330–8. doi:10.1093/jnci/dji275. PMID 16174854. 38. ^ a b Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Lee JH (October 2011). "Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence". Langenbeck's Archives of Surgery. 396 (7): 1017–26. doi:10.1007/s00423-011-0812-9. PMID 21706233. 39. ^ Svrcek M, Buhard O, Colas C, Coulet F, Dumont S, Massaoudi I, et al. (November 2010). "Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers". Gut. 59 (11): 1516–26. doi:10.1136/gut.2009.194787. PMID 20947886. 40. ^ a b c d Facista A, Nguyen H, Lewis C, Prasad AR, Ramsey L, Zaitlin B, Nfonsam V, Krouse RS, Bernstein H, Payne CM, Stern S, Oatman N, Banerjee B, Bernstein C (April 2012). "Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer". Genome Integrity. 3 (1): 3. doi:10.1186/2041-9414-3-3. PMC 3351028. PMID 22494821. 41. ^ Paluszczak J, Misiak P, Wierzbicka M, Woźniak A, Baer-Dubowska W (February 2011). "Frequent hypermethylation of DAPK, RARbeta, MGMT, RASSF1A and FHIT in laryngeal squamous cell carcinomas and adjacent normal mucosa". Oral Oncology. 47 (2): 104–7. doi:10.1016/j.oraloncology.2010.11.006. PMID 21147548. 42. ^ Zuo C, Zhang H, Spencer HJ, Vural E, Suen JY, Schichman SA, Smoller BR, Kokoska MS, Fan CY (October 2009). "Increased microsatellite instability and epigenetic inactivation of the hMLH1 gene in head and neck squamous cell carcinoma". Otolaryngology–Head and Neck Surgery. 141 (4): 484–90. doi:10.1016/j.otohns.2009.07.007. PMID 19786217. 43. ^ Tawfik HM, El-Maqsoud NM, Hak BH, El-Sherbiny YM (2011). "Head and neck squamous cell carcinoma: mismatch repair immunohistochemistry and promoter hypermethylation of hMLH1 gene". American Journal of Otolaryngology. 32 (6): 528–36. doi:10.1016/j.amjoto.2010.11.005. PMID 21353335. 44. ^ Zou XP, Zhang B, Zhang XQ, Chen M, Cao J, Liu WJ (November 2009). "Promoter hypermethylation of multiple genes in early gastric adenocarcinoma and precancerous lesions". Human Pathology. 40 (11): 1534–42. doi:10.1016/j.humpath.2009.01.029. PMID 19695681. 45. ^ Wani M, Afroze D, Makhdoomi M, Hamid I, Wani B, Bhat G, Wani R, Wani K (2012). "Promoter methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir valley" (PDF). Asian Pacific Journal of Cancer Prevention. 13 (8): 4177–81. doi:10.7314/APJCP.2012.13.8.4177. PMID 23098428. 46. ^ Agarwal A, Polineni R, Hussein Z, Vigoda I, Bhagat TD, Bhattacharyya S, Maitra A, Verma A (2012). "Role of epigenetic alterations in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma". International Journal of Clinical and Experimental Pathology. 5 (5): 382–96. PMC 3396065. PMID 22808291. Review. 47. ^ Hofstad B, Vatn MH, Andersen SN, Huitfeldt HS, Rognum T, Larsen S, Osnes M (September 1996). "Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years". Gut. 39 (3): 449–56. doi:10.1136/gut.39.3.449. PMC 1383355. PMID 8949653. 48. ^ Schmitt MW, Prindle MJ, Loeb LA (September 2012). "Implications of genetic heterogeneity in cancer". Annals of the New York Academy of Sciences. 1267 (1): 110–6. Bibcode:2012NYASA1267..110S. doi:10.1111/j.1749-6632.2012.06590.x. PMC 3674777. PMID 22954224. 49. ^ Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. (February 2001). "Initial sequencing and analysis of the human genome". Nature. 409 (6822): 860–921. Bibcode:2001Natur.409..860L. doi:10.1038/35057062. PMID 11237011. 50. ^ Yost SE, Smith EN, Schwab RB, Bao L, Jung H, Wang X, Voest E, Pierce JP, Messer K, Parker BA, Harismendy O, Frazer KA (August 2012). "Identification of high-confidence somatic mutations in whole genome sequence of formalin-fixed breast cancer specimens". Nucleic Acids Research. 40 (14): e107. doi:10.1093/nar/gks299. PMC 3413110. PMID 22492626. 51. ^ Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, et al. (May 2012). "Melanoma genome sequencing reveals frequent PREX2 mutations". Nature. 485 (7399): 502–6. Bibcode:2012Natur.485..502B. doi:10.1038/nature11071. PMC 3367798. PMID 22622578. 52. ^ Rasnick D, Duesberg PH (June 1999). "How aneuploidy affects metabolic control and causes cancer". The Biochemical Journal. 340 (3): 621–30. doi:10.1042/0264-6021:3400621. PMC 1220292. PMID 10359645. 53. ^ a b c López-Lázaro M (March 2010). "A new view of carcinogenesis and an alternative approach to cancer therapy". Molecular Medicine. 16 (3–4): 144–53. doi:10.2119/molmed.2009.00162. PMC 2802554. PMID 20062820. 54. ^ Soto AM, Sonnenschein C (October 2004). "The somatic mutation theory of cancer: growing problems with the paradigm?". BioEssays. 26 (10): 1097–107. doi:10.1002/bies.20087. PMID 15382143. 55. ^ Davies PC, Lineweaver CH (February 2011). "Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors". Physical Biology. 8 (1): 015001. Bibcode:2011PhBio...8a5001D. doi:10.1088/1478-3975/8/1/015001. PMC 3148211. PMID 21301065. 56. ^ Dean, Tim. "Cancer resembles life 1 billion years ago, say astrobiologists", Australian Life Scientist, 8 February 2011. Retrieved 15 February 2011. 57. ^ Sterrer, W (August 2016). "Cancer - Mutational Resurrection of Prokaryote Endofossils" (PDF). Cancer Hypotheses. 1 (1): 1–15. 58. ^ a b Nowell PC (October 1976). "The clonal evolution of tumor cell populations". Science. 194 (4260): 23–8. Bibcode:1976Sci...194...23N. doi:10.1126/science.959840. PMID 959840. 59. ^ a b Merlo LM, Pepper JW, Reid BJ, Maley CC (December 2006). "Cancer as an evolutionary and ecological process". Nature Reviews. Cancer. 6 (12): 924–35. doi:10.1038/nrc2013. PMID 17109012. 60. ^ Hanahan D, Weinberg RA (January 2000). "The hallmarks of cancer". Cell. 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9. PMID 10647931. 61. ^ Cho RW, Clarke MF (February 2008). "Recent advances in cancer stem cells". Current Opinion in Genetics & Development. 18 (1): 48–53. doi:10.1016/j.gde.2008.01.017. PMID 18356041. 62. ^ Taniguchi K, Wu LW, Grivennikov SI, de Jong PR, Lian I, Yu FX, Wang K, Ho SB, Boland BS, Chang JT, Sandborn WJ, Hardiman G, Raz E, Maehara Y, Yoshimura A, Zucman-Rossi J, Guan KL, Karin M (March 2015). "A gp130-Src-YAP module links inflammation to epithelial regeneration". Nature. 519 (7541): 57–62. Bibcode:2015Natur.519...57T. doi:10.1038/nature14228. PMC 4447318. PMID 25731159. 63. ^ You H, Lei P, Andreadis ST (December 2013). "JNK is a novel regulator of intercellular adhesion". Tissue Barriers. 1 (5): e26845. doi:10.4161/tisb.26845. PMC 3942331. PMID 24868495. 64. ^ Busillo JM, Azzam KM, Cidlowski JA (November 2011). "Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome". The Journal of Biological Chemistry. 286 (44): 38703–13. doi:10.1074/jbc.M111.275370. PMC 3207479. PMID 21940629. 65. ^ Wang Y, Bugatti M, Ulland TK, Vermi W, Gilfillan S, Colonna M (March 2016). "Nonredundant roles of keratinocyte-derived IL-34 and neutrophil-derived CSF1 in Langerhans cell renewal in the steady state and during inflammation". European Journal of Immunology. 46 (3): 552–9. doi:10.1002/eji.201545917. PMC 5658206. PMID 26634935. 66. ^ Siqueira Mietto B, Kroner A, Girolami EI, Santos-Nogueira E, Zhang J, David S (December 2015). "Role of IL-10 in Resolution of Inflammation and Functional Recovery after Peripheral Nerve Injury". The Journal of Neuroscience. 35 (50): 16431–42. doi:10.1523/JNEUROSCI.2119-15.2015. PMC 6605511. PMID 26674868. 67. ^ Seifert AW, Maden M (2014). "New insights into vertebrate skin regeneration". International Review of Cell and Molecular Biology. 310. pp. 129–69. doi:10.1016/B978-0-12-800180-6.00004-9. ISBN 978-0-12-800180-6. PMID 24725426. 68. ^ Kwon MJ, Shin HY, Cui Y, Kim H, Thi AH, Choi JY, Kim EY, Hwang DH, Kim BG (December 2015). "CCL2 Mediates Neuron-Macrophage Interactions to Drive Proregenerative Macrophage Activation Following Preconditioning Injury". The Journal of Neuroscience. 35 (48): 15934–47. doi:10.1523/JNEUROSCI.1924-15.2015. PMC 6605453. PMID 26631474. 69. ^ Hajishengallis G, Chavakis T (January 2013). "Endogenous modulators of inflammatory cell recruitment". Trends in Immunology. 34 (1): 1–6. doi:10.1016/j.it.2012.08.003. PMC 3703146. PMID 22951309. 70. ^ Nelson AM, Katseff AS, Ratliff TS, Garza LA (February 2016). "Interleukin 6 and STAT3 regulate p63 isoform expression in keratinocytes during regeneration". Experimental Dermatology. 25 (2): 155–7. doi:10.1111/exd.12896. PMC 4724264. PMID 26566817. 71. ^ Vidal PM, Lemmens E, Dooley D, Hendrix S (February 2013). "The role of "anti-inflammatory" cytokines in axon regeneration". Cytokine & Growth Factor Reviews. 24 (1): 1–12. doi:10.1016/j.cytogfr.2012.08.008. PMID 22985997. 72. ^ Hsueh YY, Chang YJ, Huang CW, Handayani F, Chiang YL, Fan SC, Ho CJ, Kuo YM, Yang SH, Chen YL, Lin SC, Huang CC, Wu CC (October 2015). "Synergy of endothelial and neural progenitor cells from adipose-derived stem cells to preserve neurovascular structures in rat hypoxic-ischemic brain injury". Scientific Reports. 5: 14985. Bibcode:2015NatSR...514985H. doi:10.1038/srep14985. PMC 4597209. PMID 26447335. 73. ^ Yaniv M (September 2014). "Chromatin remodeling: from transcription to cancer". Cancer Genetics. 207 (9): 352–7. doi:10.1016/j.cancergen.2014.03.006. PMID 24825771. 74. ^ Zhang X, He N, Gu D, Wickliffe J, Salazar J, Boldogh I, Xie J (October 2015). "Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development". Journal of Genetics and Genomics = Yi Chuan Xue Bao. 42 (10): 589–96. doi:10.1016/j.jgg.2015.09.006. PMC 4643398. PMID 26554912. 75. ^ Dubois-Pot-Schneider H, Fekir K, Coulouarn C, Glaise D, Aninat C, Jarnouen K, Le Guével R, Kubo T, Ishida S, Morel F, Corlu A (December 2014). "Inflammatory cytokines promote the retrodifferentiation of tumor-derived hepatocyte-like cells to progenitor cells". Hepatology. 60 (6): 2077–90. doi:10.1002/hep.27353. PMID 25098666. 76. ^ Finkin S, Yuan D, Stein I, Taniguchi K, Weber A, Unger K, et al. (December 2015). "Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma". Nature Immunology. 16 (12): 1235–44. doi:10.1038/ni.3290. PMC 4653079. PMID 26502405. 77. ^ a b Vlahopoulos SA, Cen O, Hengen N, Agan J, Moschovi M, Critselis E, Adamaki M, Bacopoulou F, Copland JA, Boldogh I, Karin M, Chrousos GP (August 2015). "Dynamic aberrant NF-κB spurs tumorigenesis: a new model encompassing the microenvironment". Cytokine & Growth Factor Reviews. 26 (4): 389–403. doi:10.1016/j.cytogfr.2015.06.001. PMC 4526340. PMID 26119834. 78. ^ Grivennikov SI, Karin M (February 2010). "Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer". Cytokine & Growth Factor Reviews. 21 (1): 11–9. doi:10.1016/j.cytogfr.2009.11.005. PMC 2834864. PMID 20018552. 79. ^ Rieger S, Zhao H, Martin P, Abe K, Lisse TS (January 2015). "The role of nuclear hormone receptors in cutaneous wound repair". Cell Biochemistry and Function. 33 (1): 1–13. doi:10.1002/cbf.3086. PMC 4357276. PMID 25529612. 80. ^ Lu X, Yarbrough WG (February 2015). "Negative regulation of RelA phosphorylation: emerging players and their roles in cancer". Cytokine & Growth Factor Reviews. 26 (1): 7–13. doi:10.1016/j.cytogfr.2014.09.003. PMID 25438737. 81. ^ Sionov RV, Fridlender ZG, Granot Z (December 2015). "The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment". Cancer Microenvironment. 8 (3): 125–58. doi:10.1007/s12307-014-0147-5. PMC 4714999. PMID 24895166. 82. ^ Venturi, Sebastiano (2011). "Evolutionary Significance of Iodine". Current Chemical Biology. 5 (3): 155–162. doi:10.2174/187231311796765012. ISSN 1872-3136. 83. ^ Venturi S (2014). "Iodine, PUFAs and Iodolipids in Health and Disease: An Evolutionary Perspective". Human Evolution. 29 (1–3): 185–205. ISSN 0393-9375. 84. ^ Walsh CJ, Luer CA, Bodine AB, Smith CA, Cox HL, Noyes DR, Maura G (December 2006). "Elasmobranch immune cells as a source of novel tumor cell inhibitors: Implications for public health". Integrative and Comparative Biology. 46 (6): 1072–1081. doi:10.1093/icb/icl041. PMC 2664222. PMID 19343108. 85. ^ Vogelstein B, Kinzler KW (August 2004). "Cancer genes and the pathways they control". Nature Medicine. 10 (8): 789–99. doi:10.1038/nm1087. PMID 15286780. 86. ^ Brand KA, Hermfisse U (April 1997). "Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species". FASEB Journal. 11 (5): 388–95. doi:10.1096/fasebj.11.5.9141507. PMID 9141507. 87. ^ Bos JL (September 1989). "ras oncogenes in human cancer: a review". Cancer Research. 49 (17): 4682–9. PMID 2547513. 88. ^ Chang EH, Furth ME, Scolnick EM, Lowy DR (June 1982). "Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus". Nature. 297 (5866): 479–83. Bibcode:1982Natur.297..479C. doi:10.1038/297479a0. PMID 6283358. 89. ^ Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V (April 2008). "The role of ATF-2 in oncogenesis". BioEssays. 30 (4): 314–27. doi:10.1002/bies.20734. PMID 18348191. 90. ^ Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (June 2006). "p53 regulates mitochondrial respiration". Science. 312 (5780): 1650–3. Bibcode:2006Sci...312.1650M. doi:10.1126/science.1126863. PMID 16728594. 91. ^ Knudson AG (April 1971). "Mutation and cancer: statistical study of retinoblastoma". Proceedings of the National Academy of Sciences of the United States of America. 68 (4): 820–3. Bibcode:1971PNAS...68..820K. doi:10.1073/pnas.68.4.820. PMC 389051. PMID 5279523. 92. ^ Fodde R, Smits R (October 2002). "Cancer biology. A matter of dosage". Science. 298 (5594): 761–3. doi:10.1126/science.1077707. PMID 12399571. 93. ^ Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. (January 2011). "Massive genomic rearrangement acquired in a single catastrophic event during cancer development". Cell. 144 (1): 27–40. doi:10.1016/j.cell.2010.11.055. PMC 3065307. PMID 21215367. Lay summary – The New York Times (10 January 2011). 94. ^ Kuipers EJ. Review article: exploring the link between Helicobacter pylori and gastric cancer. Alimentary Pharmacology & Therapeutics. Mar 1999 Supplement, Vol. 13, p3-11. 9p. DOI: 10.1046/j.1365-2036.1999.00002.x. (open access). 95. ^ Kusters JG, van Vliet AH, Kuipers EJ (July 2006). "Pathogenesis of Helicobacter pylori infection". Clin. Microbiol. Rev. 19 (3): 449–90. doi:10.1128/CMR.00054-05. PMC 1539101. PMID 16847081. 96. ^ Parkin DM (June 2006). "The global health burden of infection-associated cancers in the year 2002". Int. J. Cancer. 118 (12): 3030–44. doi:10.1002/ijc.21731. PMID 16404738. 97. ^ Wroblewski LE, Peek RM, Wilson KT (October 2010). "Helicobacter pylori and gastric cancer: factors that modulate disease risk". Clin. Microbiol. Rev. 23 (4): 713–39. doi:10.1128/CMR.00011-10. PMC 2952980. PMID 20930071. 98. ^ Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, Znaor A, Bray F (April 2019). "Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods". Int. J. Cancer. 144 (8): 1941–1953. doi:10.1002/ijc.31937. PMID 30350310. 99. ^ Meurer LN, Bower DJ (April 2002). "Management of Helicobacter pylori infection". Am Fam Physician. 65 (7): 1327–36. PMID 11996414. 100. ^ Prabhu SR, Ranganathan S, Amarapurkar DN (November 1994). "Helicobacter pylori in normal gastric mucosa". J Assoc Physicians India. 42 (11): 863–4. PMID 7868485. 101. ^ White JR, Winter JA, Robinson K (2015). "Differential inflammatory response to Helicobacter pylori infection: etiology and clinical outcomes". J Inflamm Res. 8: 137–47. doi:10.2147/JIR.S64888. PMC 4540215. PMID 26316793. 102. ^ Deng JY, Liang H (April 2014). "Clinical significance of lymph node metastasis in gastric cancer". World J. Gastroenterol. 20 (14): 3967–75. doi:10.3748/wjg.v20.i14.3967. PMC 3983452. PMID 24744586. 103. ^ a b Valenzuela MA, Canales J, Corvalán AH, Quest AF (December 2015). "Helicobacter pylori-induced inflammation and epigenetic changes during gastric carcinogenesis". World J. Gastroenterol. 21 (45): 12742–56. doi:10.3748/wjg.v21.i45.12742. PMC 4671030. PMID 26668499. 104. ^ Raza Y, Khan A, Farooqui A, Mubarak M, Facista A, Akhtar SS, Khan S, Kazi JI, Bernstein C, Kazmi SU (2014). "Oxidative DNA damage as a potential early biomarker of Helicobacter pylori associated carcinogenesis". Pathol. Oncol. Res. 20 (4): 839–46. doi:10.1007/s12253-014-9762-1. PMID 24664859. 105. ^ Koeppel M, Garcia-Alcalde F, Glowinski F, Schlaermann P, Meyer TF (June 2015). "Helicobacter pylori Infection Causes Characteristic DNA Damage Patterns in Human Cells". Cell Rep. 11 (11): 1703–13. doi:10.1016/j.celrep.2015.05.030. PMID 26074077. 106. ^ a b Muhammad JS, Eladl MA, Khoder G (February 2019). "Helicobacter pylori-induced DNA Methylation as an Epigenetic Modulator of Gastric Cancer: Recent Outcomes and Future Direction". Pathogens. 8 (1). doi:10.3390/pathogens8010023. PMC 6471032. PMID 30781778. 107. ^ a b Noto JM, Peek RM (2011). "The role of microRNAs in Helicobacter pylori pathogenesis and gastric carcinogenesis". Front Cell Infect Microbiol. 1: 21. doi:10.3389/fcimb.2011.00021. PMC 3417373. PMID 22919587. 108. ^ Santos JC, Ribeiro ML (August 2015). "Epigenetic regulation of DNA repair machinery in Helicobacter pylori-induced gastric carcinogenesis". World J. Gastroenterol. 21 (30): 9021–37. doi:10.3748/wjg.v21.i30.9021. PMC 4533035. PMID 26290630. 109. ^ a b Raza Y, Ahmed A, Khan A, Chishti AA, Akhter SS, Mubarak M, Bernstein C, Zaitlin B, Kazmi SU (February 2020). "Helicobacter pylori severely reduces expression of DNA repair proteins PMS2 and ERCC1 in gastritis and gastric cancer". DNA Repair (Amst.). 89: 102836. doi:10.1016/j.dnarep.2020.102836. PMID 32143126. 110. ^ Dore MP, Pes GM, Bassotti G, Usai-Satta P (2016). "Dyspepsia: When and How to Test for Helicobacter pylori Infection". Gastroenterol Res Pract. 2016: 8463614. doi:10.1155/2016/8463614. PMC 4864555. PMID 27239194. 111. ^ Carrillo-Infante C, Abbadessa G, Bagella L, Giordano A (June 2007). "Viral infections as a cause of cancer (review)". International Journal of Oncology. 30 (6): 1521–8. doi:10.3892/ijo.30.6.1521. PMID 17487374. 112. ^ Safdar A (2011). Management of Infections in Cancer Patients. Springer. p. 478. ISBN 978-1-60761-643-6. 113. ^ Samaras V, Rafailidis PI, Mourtzoukou EG, Peppas G, Falagas ME (June 2010). "Chronic bacterial and parasitic infections and cancer: a review". Journal of Infection in Developing Countries. 4 (5): 267–81. doi:10.3855/jidc.819. PMID 20539059. 114. ^ Daniel FI, Cherubini K, Yurgel LS, de Figueiredo MA, Salum FG (February 2011). "The role of epigenetic transcription repression and DNA methyltransferases in cancer". Cancer. 117 (4): 677–87. doi:10.1002/cncr.25482. PMID 20945317. Review. 115. ^ Kanwal R, Gupta S (April 2012). "Epigenetic modifications in cancer". Clinical Genetics. 81 (4): 303–11. doi:10.1111/j.1399-0004.2011.01809.x. PMC 3590802. PMID 22082348. 116. ^ Pattani KM, Soudry E, Glazer CA, Ochs MF, Wang H, Schussel J, Sun W, Hennessey P, Mydlarz W, Loyo M, Demokan S, Smith IM, Califano JA (2012). Tao Q (ed.). "MAGEB2 is activated by promoter demethylation in head and neck squamous cell carcinoma". PLOS One. 7 (9): e45534. Bibcode:2012PLoSO...745534P. doi:10.1371/journal.pone.0045534. PMC 3454438. PMID 23029077. 117. ^ Sampath D, Liu C, Vasan K, Sulda M, Puduvalli VK, Wierda WG, Keating MJ (February 2012). "Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia". Blood. 119 (5): 1162–72. doi:10.1182/blood-2011-05-351510. PMC 3277352. PMID 22096249. 118. ^ Hitchler MJ, Oberley LW, Domann FE (December 2008). "Epigenetic silencing of SOD2 by histone modifications in human breast cancer cells". Free Radical Biology & Medicine. 45 (11): 1573–80. doi:10.1016/j.freeradbiomed.2008.09.005. PMC 2633123. PMID 18845242. 119. ^ Baldassarre G, Battista S, Belletti B, Thakur S, Pentimalli F, Trapasso F, Fedele M, Pierantoni G, Croce CM, Fusco A (April 2003). "Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma". Molecular and Cellular Biology. 23 (7): 2225–38. doi:10.1128/MCB.23.7.2225-2238.2003. PMC 150734. PMID 12640109. 120. ^ Dalerba P, Cho RW, Clarke MF (2007). "Cancer stem cells: models and concepts". Annual Review of Medicine. 58: 267–84. doi:10.1146/annurev.med.58.062105.204854. PMID 17002552. 121. ^ Zhang W, Hanks AN, Boucher K, Florell SR, Allen SM, Alexander A, Brash DE, Grossman D (January 2005). "UVB-induced apoptosis drives clonal expansion during skin tumor development". Carcinogenesis. 26 (1): 249–57. doi:10.1093/carcin/bgh300. PMC 2292404. PMID 15498793. ## Further reading[edit] * Tokar EJ, Benbrahim-Tallaa L, Waalkes MP (2011). "Chepter 14. Metal Ions in Human Cancer Development". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel (ed.). Metal ions in toxicology: effects, interactions, interdependencies. Metal Ions in Life Sciences. 8. RSC Publishing. pp. 375–401. doi:10.1039/9781849732116-00375. ISBN 978-1-84973-091-4. * Dixon K, Kopras E (December 2004). "Genetic alterations and DNA repair in human carcinogenesis". Seminars in Cancer Biology. 14 (6): 441–8. doi:10.1016/j.semcancer.2004.06.007. PMID 15489137. * Kleinsmith LJ (2006). Principles of cancer biology. San Francisco: Pearson Benjamin Cummings. ISBN 978-0-8053-4003-7. * Sarasin A (November 2003). "An overview of the mechanisms of mutagenesis and carcinogenesis". Mutation Research. 544 (2–3): 99–106. doi:10.1016/j.mrrev.2003.06.024. PMID 14644312. * Schottenfeld D, Beebe-Dimmer JL (2005). "Advances in cancer epidemiology: understanding causal mechanisms and the evidence for implementing interventions". Annual Review of Public Health. 26: 37–60. doi:10.1146/annurev.publhealth.26.021304.144402. PMID 15760280. * Tannock I, Hill R, Bristow R, Harrington L (2005). The basic science of oncology (4th ed.). New York: McGraw-Hill. ISBN 978-0-07-138774-3. * Wicha MS, Liu S, Dontu G (February 2006). "Cancer stem cells: an old idea--a paradigm shift". Cancer Research. 66 (4): 1883–90, discussion 1895–6. doi:10.1158/0008-5472.CAN-05-3153. PMID 16488983. * v * t * e Overview of tumors, cancer and oncology Conditions Benign tumors * Hyperplasia * Cyst * Pseudocyst * Hamartoma Malignant progression * Dysplasia * Carcinoma in situ * Cancer * Metastasis * Primary tumor * Sentinel lymph node Topography * Head and neck (oral, nasopharyngeal) * Digestive system * Respiratory system * Bone * Skin * Blood * Urogenital * Nervous system * Endocrine system Histology * Carcinoma * Sarcoma * Blastoma * Papilloma * Adenoma Other * Precancerous condition * Paraneoplastic syndrome Staging/grading * TNM * Ann Arbor * Prostate cancer staging * Gleason grading system * Dukes classification Carcinogenesis * Cancer cell * Carcinogen * Tumor suppressor genes/oncogenes * Clonally transmissible cancer * Oncovirus * Carcinogenic bacteria Misc. * Research * Index of oncology articles * History * Cancer pain * Cancer and nausea * Biology portal * Medicine portal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Carcinogenesis	c0596263	6,408	wikipedia	https://en.wikipedia.org/wiki/Carcinogenesis	2021-01-18T18:52:00	{"mesh": ["D063646"], "wikidata": ["Q1637543"]}
A rare disorder of fatty acid oxidation characterized by a wide clinical spectrum ranging from severe neonatal manifestations including cardiomyopathy, hypoglycemia, metabolic acidosis, skeletal myopathy and neuropathy, liver disease and death to a mild phenotype with peripheral polyneuropathy, episodic rhabdomyolysis and pigmentary retinopathy.. ## Epidemiology TFPD has been reported in less than 100 cases in the literature. ## Clinical description The neonatal onset, severe form manifests as hepatic steatosis, cardiomyopathy, skeletal myopathy and neuropathy and is usually fatal. A moderately severe form, with onset usually from the neonatal period to 18 months of age, presents primarily with hypoketotic hypoglycemia and metabolic acidosis which is often precipitated by prolonged fasting and/or intercurrent illness. Both forms can manifest with neuropathy with or without cardiomyopathy and can be fatal. The mild form merges with the moderately severe infantile form and can present from a few months of age until adolescence as a peripheral polyneuropathy with episodic rhabdomyolysis triggered by prolonged fasting, illness, exercise or exposure to heat or cold. There is respiratory failure associated with the episodes of rhabdomyolysis. A pigmentary retinopathy may also develop over time. Very occasionally, adults presenting for the first time with a previously unrecognized disease are described. ## Etiology The TFP, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids which are the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase (LCEH), and long-chain thiolase (LCTH) steps. The HADHA gene (2p23) encodes the LCEH and LCHAD enzymes and the HADHB gene (2p23) encodes the LCTH enzyme. Two mutations in either one of these two genes causes TFPD. ## Diagnostic methods Urine organic acids may show a C6-C14 (hydroxy) dicarboxylic aciduria, and blood acylcarnitine analysis often shows increased long chain hydroxyacyl carnitine species (C14-OH, C16-OH, C18-OH, C18:1-OH). Both urine and blood markers are less reliable and more variable than those seen in LCHAD deficiency (see this term). This is because defects in LCEH may block the formation of hydroxy-metabolites. Reduced enzyme activity in at least two (usually all 3) enzymes in cultured fibroblasts is seen. Molecular analysis confirming bi-allelic non-1528C>G mutations in the HADHA gene or bi-allelic mutations in the HADHBgene confirms diagnosis. Newborn screening is available in Austria, Czech Republic, Denmark, Germany, Hungary, Iceland, Netherlands and Portugal. ## Differential diagnosis Sudden infant death syndrome and isolated LCHAD deficiency (see this term) form part of the differential diagnosis. LCHAD deficiency is clinically indistinguishable from severe TFPD. ## Antenatal diagnosis Prenatal diagnosis is possible by analyzing enzyme activity in chorionic villi samples, once a deficiency of TFP has been established in the index case/family. Molecular analysis is the preferred option when two mutations have been identified in a family. ## Genetic counseling TFPD is an autosomal recessive disorder and genetic counseling is possible. ## Management and treatment Treatment involves adherence to a low fat diet with restriction of long chain fatty acid intake and substitution with medium chain fatty acids. Fasting and exposure to environmental extremes must be strictly avoided and exercise should be limited. ## Prognosis Prognosis for the severe neonatal form of TFPD is very poor. The later onset mild form has a far more favorable prognosis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Mitochondrial trifunctional protein deficiency	c1969443	6,409	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=746	2021-01-23T17:42:21	{"gard": ["3684"], "mesh": ["C566945", "D024741"], "omim": ["609015"], "umls": ["C0342786", "C1969443"], "icd-10": ["G71.3"], "synonyms": ["TFP deficiency", "TFPD"]}
Alpha-1 antitrypsin deficiency (AATD) is an inherited disease that causes an increased risk of having chronic obstructive pulmonary disease (COPD), liver disease, skin problems (panniculitis), and inflammation of the blood vessels (vasculitis). Lung (pulmonary) problems almost always occur in adults, whereas liver and skin problems may occur in adults and children. The age symptoms begin and severity of symptoms can vary depending on how much working alpha-1 antitrypsin protein (AAT) a person has. Symptoms may include shortness of breath and wheezing, repeated infections of the lungs and liver, yellow skin, feeling overly tired (fatigue), rapid heartbeat when standing, vision problems, and weight loss. However, some people with AATD do not have any problems. AATD is caused by changes (pathogenic variants, also called mutations) in the SERPINA1 gene and it is inherited in a codominant manner. The genetic changes cause too little or no working alpha-1 antitrypsin protein (AAT) to be made. AAT is made in the liver cells and sent through the bloodstream to the lungs where it helps protect the lungs from damage. Having low levels of AAT (or no AAT) may allow the lungs to become damaged. A build-up of abnormal AAT can cause liver damage. Diagnosis may be suspected by finding low levels of AAT in the blood and confirmed by genetic testing. Treatment may include infusions of AAT. Other treatment depends on the type and severity of the person's medical problems, but may include bronchodilators to open airways, antibiotics for upper respiratory tract infections, and in severe cases, lung transplantation or liver transplantation. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Alpha-1 antitrypsin deficiency	c0221757	6,410	gard	https://rarediseases.info.nih.gov/diseases/5784/alpha-1-antitrypsin-deficiency	2021-01-18T18:02:11	{"mesh": ["D019896"], "omim": ["613490"], "umls": ["C0221757"], "orphanet": ["60"], "synonyms": ["AAT deficiency", "A1AT deficiency", "AATD", "Alpha 1 antitrypsin deficiency"]}
CLOVE syndrome is characterized by Congenital Lipomatous Overgrowth, progressive, complex and mixed truncal Vascular malformations, and Epidermal nevi. ## Clinical description Patients also present with disproportionate fat distribution. CLOVE syndrome may be associated with varying degrees of scoliosis and enlarged bony structures without progressive bony overgrowth. The presence of scoliosis/skeletal manifestations has lead to the suggestion that the acronym CLOVE should be expanded to CLOVES. In contrast to the bony distortion characteristic of Proteus syndrome (see this term), distortion in CLOVE syndrome occurs only following major surgery. Cranial asymmetry and central nervous system manifestations (generalized seizures, hemimegalencephaly, dysgenesis of the corpus callosum and neuronal migration defects) have been reported occasionally. ## Etiology The etiology is unknown. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	CLOVES syndrome	c2752042	6,411	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=140944	2021-01-23T17:30:32	{"gard": ["10939"], "mesh": ["C567863"], "omim": ["612918"], "icd-10": ["Q87.3"], "synonyms": ["Congenital lipomatous overgrowth-vascular malformation-epidermal nevi-skeletal anomaly syndrome", "Congenital lipomatous overgrowth-vascular malformation-epidermal nevi-spinal anomaly syndrome"]}
Not to be confused with Central hypoventilation syndrome. A sleep-related disorder in which the effort to breathe is diminished Central sleep apnea Other namesprimary alveolar hypoventilation, alveolar hypoventilation secondary to neurologic disease, idiopathic acquired central hypoventilation syndrome SpecialtyNeurology Central sleep apnea (CSA) or central sleep apnea syndrome (CSAS) is a sleep-related disorder in which the effort to breathe is diminished or absent, typically for 10 to 30 seconds either intermittently or in cycles, and is usually associated with a reduction in blood oxygen saturation.[1][2] CSA is usually due to an instability in the body's feedback mechanisms that control respiration.[3] Central sleep apnea can also be an indicator of Arnold–Chiari malformation.[4] ## Contents * 1 Signs and symptoms * 1.1 Secondary effects * 2 Diagnosis * 2.1 Criteria * 2.2 Differential diagnosis * 2.3 Congenital central hypoventilation syndrome * 3 Treatment * 4 References * 5 Further reading * 6 External links ## Signs and symptoms[edit] In a healthy person during sleep, breathing is regular so oxygen levels and carbon dioxide levels in the bloodstream stay fairly constant:[5] After exhalation, the blood level of oxygen decreases and that of carbon dioxide increases. Exchange of gases with a lungful of fresh air is necessary to replenish oxygen and rid the bloodstream of built-up carbon dioxide. Oxygen and carbon dioxide receptors in the body (called chemoreceptors) send nerve impulses to the brain, which then signals for reflexive opening of the larynx (enlarging the opening between the vocal cords) and movements of the rib cage muscles and diaphragm. These muscles expand the thorax (chest cavity) so that a partial vacuum is made within the lungs and air rushes in to fill it.[6] In the absence of central apnea, any sudden drop in oxygen or excess of carbon dioxide, even if small, strongly stimulates the brain's respiratory centers to breathe; the respiratory drive is so strong that even conscious efforts to hold one's breath do not overcome it.[citation needed] In pure central sleep apnea, the brain's respiratory control centers, located in the region of the human brain known as the pre-Botzinger complex,[7] are imbalanced during sleep and fail to give the signal to inhale, causing the individual to miss one or more cycles of breathing. The neurological feedback mechanism that monitors blood levels of carbon dioxide and in turn stimulates respiration fails to react quickly enough to maintain an even respiratory rate, allowing the entire respiratory system to cycle between apnea and hyperpnea, even for a brief time following an awakening during a breathing pause. The sleeper stops breathing for up to two minutes and then starts again.[8] There is no effort made to breathe during the pause in breathing: there are no chest movements and no muscular struggling, although when awakening occurs in the middle of a pause, the inability to immediately operate the breathing muscles often results in cognitive struggle accompanied by a feeling of panic exacerbated by the feeling associated with excessive blood CO2 levels. Even in severe cases of central sleep apnea, however, the effects almost always result in pauses that make breathing irregular rather than cause the total cessation of breathing over the medium term. After the episode of apnea, breathing may be faster and/or more intense (hyperpnea) for a period of time, a compensatory mechanism to blow off retained waste gases, absorb more oxygen, and, when voluntary, enable a return to normal instinctive breathing patterns by restoring oxygen to the breathing muscles themselves. ### Secondary effects[edit] The conditions of hypoxia and hypercapnia, whether caused by apnea or not, trigger additional effects on the body. The immediate effects of central sleep apnea on the body depend on how long the failure to breathe endures, how short is the interval between failures to breathe, and the presence or absence of independent conditions whose effects amplify those of an apneic episode.[citation needed] * Brain cells need constant oxygen to live, and if the level of blood oxygen remains low enough for long enough, brain damage and even death will occur. These effects, however, are rarely a result of central sleep apnea, which is a chronic condition whose effects are usually much milder. * Drops in blood oxygen levels that are severe but not severe enough to trigger brain-cell or overall death may trigger seizures even in the absence of epilepsy. * In severe cases of sleep apnea, the more translucent areas of the body will show a bluish or dusky cast from cyanosis, the change in hue ("turning blue") produced by the deoxygenation of blood in vessels near the skin. * Compounding effects of independent conditions: * In persons with epilepsy, the hypoxia caused by apnea may be powerful enough to trigger seizures even in the presence of medication that otherwise controls those seizures well. * In adults with coronary artery disease, a severe drop in blood oxygen level can cause angina, arrhythmias, or heart attacks (myocardial infarction). * Longstanding and recurrent episodes of apnea may, over months and years, have the cumulative effect of increasing blood carbon-dioxide levels to the point that enough carbon dioxide dissolves in the blood to form carbonic acid in overall proportions sufficient to cause respiratory acidosis. * In persons who have either or both forms of sleep apnea, breathing irregularities during sleep can be dangerously aggravated by taking respiration-depressing drugs, especially sedative drugs that operate by depressing the central nervous system generally; respiratory depressants include opiates, barbiturates, benzodiazepines, and, in large quantities, alcohol, the last three of which are broad-spectrum CNS depressants. Quantities that are normally considered safe may cause the person with chronic sleep apnea to stop breathing altogether. Should these individuals have general anaesthesia, for example, they require prolonged monitoring after initial recovery, as compared against a person with no history of sleep apnea, because apnea is likely to occur with even low levels of the drugs in their system. * Sudden infant death syndrome is sometimes theorized to be attributable to sleep apnea; the recommendation, prevalent since the mid-1980s, of placing infants on their backs rather than their stomachs for sleep represents an attempt to prevent those instances of breathing cessation that are attributable to compressive obstruction. * Premature infants with immature brains and reflex systems are at high risk for central sleep apnea syndrome, even if these babies are otherwise healthy. Premature babies who have the syndrome will generally outgrow it as they mature, provided that they receive careful enough monitoring and supportive care during infancy to survive. Because of premature infants' propensity toward central apnea, medications that can cause respiratory drive depression are either not given to them or administered to them only under careful monitoring, with equipment for resuscitation immediately available. Such precautions are routinely taken for premature infants after general anesthesia; administration of caffeine has been found not only to aid in maintenance of respiratory function after general anaesthesia but to reduce apnea for preterm infants regardless of context.[9] ## Diagnosis[edit] AHI Rating 5 to <15 apneas or hypopneas per hour of sleep Mild sleep apnea/hypopnea 15 to <30 apneas or hypopneas per hour of sleep Moderate sleep apnea/hypopnea A diagnosis of sleep apnea requires determination by a physician. The examination may require a study of an individual in a sleep lab, although the AAST has said a two belt IHT (In Home Test) will replace a PSG for diagnosing obstructive apnea. There, the patient will be monitored while at rest, and the periods when breathing ceases will be measured with respect to length and frequency.[6] During a PSG (polysomnography) (a sleep study), a person with sleep apnea shows breathing interruptions followed by drops/reductions in blood oxygen and increases in blood carbon dioxide level. * In adults, a pause must last 10 seconds to be scored as an apnea. However, in young children, who normally breathe at a much faster rate than adults, shorter pauses may still be considered apneas.[clarification needed] * Hypopneas in adults are defined as a 30% reduction in air flow for more than ten seconds, followed by oxygen-saturation declines of at least 3% or 4% per the AASM stndards.[clarification needed] and/or EEG arousal. The Apnea-Hypopnea Index (AHI) is expressed as the number of apneas or hypopneas per hour of sleep.[10] As noted above, in central sleep apnea, the cessation of airflow is associated with the absence of physical attempts to breathe; specifically, polysomnograms reveal correlation between absence of rib cage and abdominal movements and cessation of airflow at the nose and lips. By contrast, in obstructive sleep apnea, pauses are not correlated with the absence of attempts to breathe and may even be correlated with more effortful breathing in an instinctive attempt to overcome the pressure on the sufferer's airway. If the majority of a sleep-apnea sufferer's apneas/hypopneas are central, their condition is classified as central; likewise, if the majority are obstructive, their condition is classified as obstructive.[citation needed] ### Criteria[edit] CSA is divided in 6 categories, Primary CSA, Cheyne–Stokes respiration, High-altitude periodic breathing, CSA due to a medical condition without CSB, Central sleep apnea due to a medication or substance and Treatment Emergent Central Apnea (also called Complex Sleep Apnea).[11] The following symptoms are present in the Primary CSA: excessive daytime sleepiness, frequent arousals and awakenings during sleep or insomnia complaints, awakening short of breath, snoring, witness apneas.[12] His polysomnography shows ≥5 central apneas and/or central hypopneas per hour of sleep, representing at least 50% of total respiratory events in the apnea-hypopnea index.[12] CSA with Cheyne-Stokes breathing is characterized by at least one of the criteria of Primary CSA or the presence of atrial fibrillation/flutter, CHF, or a neurologic disorder.[12] His polysomnography looks like the Primary CSA polysomnography with the addition of a ventilatory pattern compatible with CSB.[12] High-Altitude Periodic Breathing requires that the patient has recently been at least 2500 meters.[12] In the CSA due to a medication or substance, opioid or respiratory depressants must had been taken.[12] For the CSA due to a medical condition without CSB, the criteria are the same as Primary CSA, but the symptoms are caused by a disease.[12] In the Treatment Emergent Central Apnea, there was firstly some obstructive respiratory events but after their disappearance, the CSA has appeared.[12] ### Differential diagnosis[edit] Although central and obstructive sleep apnea have some signs and symptoms in common, others are present in one but absent in another, enabling differential diagnosis as between the two types:[citation needed] Signs and symptoms of sleep apnea generally * Signs: * Observed breathing pauses during sleep * High carbon-dioxide saturation of blood, especially just before awakenings during which a sufferer experiences urgent need to breathe (see "Symptoms" below) * Low oxygen saturation of blood * Heart rate increase (response to both hypercapnia and hypoxemia/hypoxia), unless there also exist problems with the heart muscle itself or the autonomic nervous system severe enough to make this compensatory increase impossible * Symptoms: * High frequency of urgent need to breathe upon awakening (symptom created by hypercapnia), especially among subset of awakenings occurring at times other than normal for an individual's sleep schedule and circadian rhythms Signs and symptoms of central sleep apnea * Signs: * Lack of abdominal and thoracic movement for 10 seconds or longer during sleep and coincident with breathing pauses * Symptoms: * Inability, either complete or without excessive effort, to voluntarily operate diaphragm and other thoracic muscles upon awakening * The combination of this symptom with a high frequency of urgent need to breathe upon awakening is especially specific in that the co-presence of the latter symptom differentiates central sleep apnea's presentation from that of sleep paralysis generally. Signs and symptoms of and conditions associated with obstructive sleep apnea[13] * Signs: * Observably ineffective respiratory movements (observable lack of air flow despite observable muscle movements indicating efforts to breathe) * Snoring (high-sensitivity but low-specificity) * Observably dry mouth or throat (high-sensitivity but low-specificity) * Symptoms: * Sleepiness, fatigue, or tiredness, often rising to the level of excessive daytime sleepiness * Frequent feelings of choking (airway and/or lung compression), as distinguished from mere feeling of suffocation nonspecific with respect to presence/absence of pressure, upon awakening * Associated conditions: * Opioid medication use * Large neck circumference (>16" for females, > 17" for males) (frequent causal factor and possible indirect symptom; see "Obesity" below) * Obesity (frequent causal factor and possible, albeit low-specificity, sign both direct and indirect): Obesity frequently involves accumulation of fat below the chin and around the neck, depressing the trachea when one is in the supine position, and central obesity can, depending on an individual's fat distribution, lead to increased direct pressure on the thoracic cavity and/or compressive anterior (headward) displacement of the abdominal organs, in the second case reducing space for and increasing difficulty of the motion of the diaphragm. Poor breathing during sleep a] reduces oxygen available for metabolism and may therefore depress basal metabolic rate during sleep, increasing the difference between supply of food energy and demand for it during that time and thereby promoting weight gain, and b] reduces sleep quality and recovery per time unit of sleep, resulting in sleepiness and/or fatigue that may prompt sufferers to eat more in an attempt to increase short-term energy levels. * Correlation with cardiac disorders: * Atrial fibrillation (AF): A study in the medical journal Sleep found that the prevalence of atrial fibrillation among patients with idiopathic central sleep apnea was significantly higher than the prevalence among patients with obstructive sleep apnea or no sleep apnea (27%, 1.7%, and 3.3%, respectively). The study was based on 180 subjects with 60 people in each of the 3 groups. Possible explanations for the association between CSA and AF include a causal relationship in one direction or the other between the two conditions or a common cause involving an abnormality of central cardiorespiratory regulation.[14] * Adults suffering from congestive heart failure are at risk for a form of central apnea called Cheyne-Stokes respiration, which manifests itself both during sleep and during waking hours. Cheyne-Stokes respiration is characterized by periodic breathing featuring recurrent episodes of apnea alternating with episodes of rapid breathing. There is good evidence[clarification needed] that replacement of the failing heart (heart transplant) cures central apnea in these patients. Temporary measures (e.g., those taken pending the availability of an organ donor) include the administration of drugs whose effects include respiratory stimulation, although these drugs are not universally effective in reducing the severity of Cheyne-Stokes apneas. ### Congenital central hypoventilation syndrome[edit] Congenital central hypoventilation syndrome (CCHS), often referred to by its older name "Ondine's curse," is a rare and very severe inborn form of abnormal interruption and reduction in breathing during sleep. This condition involves a specific homeobox gene, PHOX2B, which guides maturation of the autonomic nervous system; certain loss-of-function mutations interfere with the brain's development of the ability to effectively control breathing. There may be a recognizable pattern of facial features among individuals affected with this syndrome.[15] Once almost uniformly fatal, CCHS is now treatable. Children who have it must have tracheotomies and access to mechanical ventilation on respirators while sleeping, but most do not need to use a respirator while awake. The use of a diaphragmatic pacemaker may offer an alternative for some patients. When pacemakers have enabled some children to sleep without the use of a mechanical respirator, reported cases still required the tracheotomy to remain in place because the vocal cords did not move apart with inhalation.[citation needed] Persons with the syndrome who survive to adulthood are strongly instructed to avoid certain condition-aggravating factors, such as alcohol use, which can easily prove lethal.[16] ## Treatment[edit] After a patient receives a diagnosis, the diagnosing physician can provide different options for treatment. If central sleep apnea is medication-induced (e.g., opioids), reducing the dose or eventual withdrawal of the offending medication often improves CSA.[citation needed] * The FDA has recently approved a pacemaker-like implantable device called the remedē System for adult patients with moderate to severe central sleep apnea. After a commonly performed procedure, the device stimulates a nerve in the chest (phrenic nerve) to send signals to the large muscle that controls breathing (the diaphragm). It monitors respiratory signals during sleep and helps restore normal breathing patterns. The device is silent, activates automatically during the night, and does not require the patient to wear a mask.[17][18] * Mechanical regulation of airflow and/or airway pressure: * Treatment for central sleep apnea differs in that the device is set not at one constant optimal pressure but rather at two different settings, one for inhalation (IPAP) and for exhalation (EPAP), maintaining normal breathing rhythm by inflating the patient's lungs at regular intervals whose specifics, such as the breathing rate and the duration of a single breath, can be programmed. Devices tailored to this purpose are known as BiPAP ("bilevel positive airway pressure") devices. * Both CPAP and BiPAP devices can be connected to a humidifier to humidify and heat the inhaled air, thus reducing unpleasant symptoms such as a sore throat or blocked nose that can result from inhaling cold, dry air. * CPAP and BiPAP devices can trigger central Apneas in those with obstructive sleep apnea requiring the use of an ASV (automatic servo ventilation) device, which is also the proper machine for those who have central sleep apnea or mixed/complex apnea. ## References[edit] 1. ^ Becker, K; Wallace JM (2010-01-22). "Central Sleep Apnea". emedicine. Medscape. Retrieved 2010-07-31. 2. ^ AASM (2001). The International Classification of Sleep Disorders, Revised (PDF). Westchester, Illinois: American Academy of Sleep Medicine. pp. 58–61. Archived from the original (PDF) on 2011-07-26. Retrieved 2010-09-11. 3. ^ Becker K, Wallace JM (2010-01-22). "Central Sleep Apnea: Follow-up". emedicine. Medscape. Retrieved 2010-09-17. 4. ^ Watson (2009-11-09). "Sleep Disordered Breathing and Sleepiness in Patients with Chiari type I Malformation". Archived from the original on 2013-05-10. Retrieved 2014-04-17. 5. ^ Whittemore, Susan. "Science Online". Facts on File, Inc. Retrieved December 6, 2012. 6. ^ a b Whittemore, Susan. "How the respiratory system adjusts to meet changing oxygen demands". Facts on File, Inc. Retrieved December 11, 2012. 7. ^ Brownlee, C. (2005-08-13). "Science News". A Slumber Not So Sweet. 168 (7): 102. Retrieved December 7, 2012. 8. ^ Gilliam, Marjie. "NewsBank". Cox Ohio Publishing. Retrieved December 6, 2012. 9. ^ Henderson-Smart DJ, Steer P (2001). Haughton D (ed.). "Prophylactic caffeine to prevent postoperative apnea following general anesthesia in preterm infants". The Cochrane Database of Systematic Reviews (4): CD000048. doi:10.1002/14651858.CD000048. PMC 7052743. PMID 11687065. 10. ^ Ruehland WR, Rochford PD, O'Donoghue FJ, Pierce RJ, Singh P, Thornton AT (February 2009). "The new AASM criteria for scoring hypopneas: impact on the apnea hypopnea index". Sleep. 32 (2): 150–7. doi:10.1093/sleep/32.2.150. PMC 2635578. PMID 19238801. 11. ^ Macrea, M., Katz, E. S., & Malhotra, A. (2017). Central Sleep Apnea. In Principles and Practice of Sleep Medicine (p. 1049-1058.e5). https://doi.org/10.1016/B978-0-323-24288-2.00109-4 12. ^ a b c d e f g h American Academy of Sleep Medicine (2014). International Classification of Sleep Disorders, 3rd edition. Darien, IL: American Academy of Sleep Medicine 13. ^ Fiely, Dennis (January 12, 2005). "BREATHING {AND SLEEPING} EASIER - Apnea considered dangerous, debilitating but treatable". The Columbus Dispatch. Retrieved December 7, 2012. 14. ^ Leung RS, Huber MA, Rogge T, Maimon N, Chiu KL, Bradley TD (December 2005). "Association between atrial fibrillation and central sleep apnea" (PDF). Sleep. 28 (12): 1543–6. doi:10.1093/sleep/28.12.1543. PMID 16408413. Archived from the original (PDF) on 2011-07-23. Retrieved 2010-07-16. 15. ^ Todd ES, Weinberg SM, Berry-Kravis EM, Silvestri JM, Kenny AS, Rand CM, Zhou L, Maher BS, Marazita ML, Weese-Mayer DE (January 2006). "Facial phenotype in children and young adults with PHOX2B-determined congenital central hypoventilation syndrome: quantitative pattern of dysmorphology". Pediatric Research. 59 (1): 39–45. doi:10.1203/01.pdr.0000191814.73340.1d. PMID 16327002. 16. ^ Chen ML, Turkel SB, Jacobson JR, Keens TG (March 2006). "Alcohol use in congenital central hypoventilation syndrome". Pediatric Pulmonology. 41 (3): 283–5. doi:10.1002/ppul.20366. PMID 16429433. S2CID 24950172. 17. ^ Health, Center for Devices and Radiological. "Recently-Approved Devices - remedē® System – P160039". www.fda.gov. Retrieved 2018-07-11. 18. ^ Costanzo MR, Khayat R, Ponikowski P, Augostini R, Stellbrink C, Mianulli M, Abraham WT (January 2015). "Mechanisms and clinical consequences of untreated central sleep apnea in heart failure". Journal of the American College of Cardiology. 65 (1): 72–84. doi:10.1016/j.jacc.2014.10.025. PMC 4391015. PMID 25572513. * Medicine portal ## Further reading[edit] * Macey PM, Macey KE, Woo MA, Keens TG, Harper RM (April 2005). "Aberrant neural responses to cold pressor challenges in congenital central hypoventilation syndrome". Pediatric Research. 57 (4): 500–9. doi:10.1203/01.PDR.0000155757.98389.53. PMID 15718375. * Bradley TD, Floras JS (April 2003). "Sleep apnea and heart failure: Part II: central sleep apnea". Circulation. 107 (13): 1822–6. doi:10.1161/01.CIR.0000061758.05044.64. PMID 12682029. * Mansfield DR, Solin P, Roebuck T, Bergin P, Kaye DM, Naughton MT (November 2003). "The effect of successful heart transplant treatment of heart failure on central sleep apnea". Chest. 124 (5): 1675–81. doi:10.1378/chest.124.5.1675. PMID 14605034. S2CID 628757. * Javaheri S (January 2006). "Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study". American Journal of Respiratory and Critical Care Medicine. 173 (2): 234–7. doi:10.1164/rccm.200507-1035OC. PMID 16239622. ## External links[edit] Classification D * ICD-10: G47.3 * ICD-9-CM: 348.8 * OMIM: 209880 * MeSH: D020182 * DiseasesDB: 32976 * SNOMED CT: 27405005 External resources * MedlinePlus: 000078 * eMedicine: article/1002927 * GeneReviews: Congenital central hypoventilation syndrome * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Central sleep apnea	c0520680	6,412	wikipedia	https://en.wikipedia.org/wiki/Central_sleep_apnea	2021-01-18T19:05:09	{"mesh": ["D020182"], "umls": ["C0520680"], "wikidata": ["Q3620651"]}
AREDYLD syndrome AREDYLD syndrome is inherited in an autosomal recessive manner AREDYLD stands for acral renal ectodermal dysplasia lipoatrophic diabetes. AREDLYD is categorized as a rare disease, meaning it affects fewer than 200,000 people in the American population at any given time. It was characterized in 1983.[1] A second case was identified in 1992.[2] ## References[edit] 1. ^ Pinheiro M, Freire-Maia N, Chautard-Freire-Maia E, Araujo L, Liberman B (1983). "AREDYLD: a syndrome combining an acrorenal field defect, ectodermal dysplasia, lipoatrophic diabetes, and other manifestations". Am J Med Genet. 16 (1): 29–33. doi:10.1002/ajmg.1320160106. PMID 6638067. 2. ^ Breslau-Siderius E, Toonstra J, Baart J, Koppeschaar H, Maassen J, Beemer F (1992). "Ectodermal dysplasia, lipoatrophy, diabetes mellitus, and amastia: a second case of the AREDYLD syndrome". Am J Med Genet. 44 (3): 374–7. doi:10.1002/ajmg.1320440321. PMID 1488989. ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 207780 * MeSH: C537427 External resources * Orphanet: 1133 This article about an endocrine, nutritional, or metabolic disease is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	AREDYLD syndrome	c0342280	6,413	wikipedia	https://en.wikipedia.org/wiki/AREDYLD_syndrome	2021-01-18T18:33:52	{"gard": ["8509"], "mesh": ["C537427"], "umls": ["C0342280"], "orphanet": ["1133"], "wikidata": ["Q4653653"]}
## Summary ### Clinical characteristics. Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The age of onset ranges from 19 to 73 years; mean age of onset is between 43 and 52 years. Initial symptoms are gait unsteadiness, stumbling, and imbalance (in ~90%) and dysarthria (in ~10%). Eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common. Visual disturbances may result from diplopia, difficulty fixating on moving objects, horizontal gaze-evoked nystagmus, and vertical nystagmus. Hyperreflexia and extensor plantar responses occur in up to 40%-50%. Basal ganglia signs, including dystonia and blepharospasm, occur in up to 25%. Mentation is generally preserved. ### Diagnosis/testing. The diagnosis of SCA6 rests on the use of molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion in CACNA1A. Affected individuals have 20 to 33 CAG repeats. ### Management. Treatment of manifestations: Acetazolamide may eliminate episodes of ataxia; canes, walking sticks, and walkers to prevent falling; home modifications for safety and convenience; weighted eating utensils and dressing hooks; physical therapy and exercises enhancing balance and core strength; vitamin supplements particularly if caloric intake is reduced; feeding recommendations as per feeding therapist / occupational therapist; weight control, as obesity exacerbates ambulation and mobility problems; vestibular symptoms may be managed with medications including diphenhydramine, baclofen, and gabapentin. 4-aminopyridine may be helpful with vestibular symptoms and to suppress nystagmus; refractive or surgical management per ophthalmologist for diplopia; speech therapy and communication devices for dysarthria; clonazepam for REM sleep disorders; continuous positive airway pressure for sleep apnea. Surveillance: Annual or semiannual evaluation by a neurologist; driving ability should be assessed by professionals periodically. Annual consultations with a physiatrist and physical and/or occupational therapist; review need for walking aid(s) and home adaptations. Nutrition evaluation, video esophagram, and feeding assessments as needed. Ophthalmology and/or optometry evaluation as needed for prisms or surgery. Agents/circumstances to avoid: Sedative hypnotics (ethanol or certain medications) that increase incoordination. ### Genetic counseling. SCA6 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting an abnormal CAG trinucleotide repeat expansion in CACNA1A. Once a CACNA1A CAG repeat expansion has been identified in an affected family member, prenatal testing and preimplantation genetic testing for SCA6 are possible. ## Diagnosis Formal diagnostic criteria for spinocerebellar ataxia type 6 (SCA6) have not been established. ### Suggestive Findings SCA6 should be suspected in individuals with the following clinical and imaging findings: * Clinical findings include adult-onset, slowly progressive cerebellar ataxia; dysarthria; and nystagmus. * Imaging findings. Atrophy of the cerebellum, most pronounced in the cerebellar vermis, is present in symptomatic individuals with SCA6 [Butteriss et al 2005, Lukas et al 2011]. ### Establishing the Diagnosis The diagnosis of SCA6 is established in a proband with a heterozygous CAG repeat expansion in CACNA1A by molecular genetic testing (see Table 1). Allele sizes * Normal alleles. ≤18 CAG repeats [Shizuka et al 1998] * Full-penetrance alleles. 20-33 CAG repeats [Jodice et al 1997, Yabe et al 1998]. Asymptomatic individuals bearing an expansion of (CAG)20 or greater are expected to develop symptoms at some time in their life. The most common pathogenic allele has 22 CAG repeats. * Alleles of questionable significance. 19 CAG repeats. The clinical significance of alleles with 19 CAG repeats is unclear because alleles of this size have been documented in the following: * Meiotic expansion of a 19-CAG repeat allele into the known pathogenic range [Mariotti et al 2001, Shimazaki et al 2001]. In this instance, the allele is considered an "intermediate allele" or a "mutable normal allele" (i.e., it is not disease causing but predisposes to expansion into the abnormal range). * Elderly asymptomatic individuals [Ishikawa et al 1997, Mariotti et al 2001] * An individual with atypical features of SCA6 [Katayama et al 2000] * An ataxic individual homozygous for the 19-CAG repeat allele [Mariotti et al 2001] Molecular genetic testing approaches can include single-gene testing or use of a multigene panel: * Single-gene testing. Targeted analysis for a heterozygous CACNA1A allele with more than 18 repeats should be performed first. * An ataxia multigene panel that includes CACNA1A CAG-repeat analysis and other genes of interest (see Differential Diagnosis) may also be considered to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. ### Table 1. Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 6 View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method CACNA1ATargeted analysis for pathogenic variants 3100% 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. PCR amplification can detect CAG trinucleotide repeat expansions up to ~100 repeats. ## Clinical Characteristics ### Clinical Description To date, fewer than 10,000 individuals with spinocerebellar ataxia type 6 (SCA6) have been identified. The following description of the phenotypic features associated with this condition is based on these reported individuals. ### Table 2. Features of Spinocerebellar Ataxia Type 6 View in own window Feature% of Persons with Feature Gait unsteadiness, upper-limb incoordination, intention tremor, & dysarthria100% Horizontal gaze-evoked nystagmus70%-100% Vertical nystagmus65%-83% Diplopia50% Hyperreflexia & extensor plantar responses40%-50% Dystonia & blepharospasm<25% SCA6 is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The range in age of onset is from 19 to 73 years. The mean age of onset is between 43 and 52 years. Age of onset and clinical picture vary even within the same family; sibs with the same size full-penetrance allele may differ in age of onset by as much as 12 years, or exhibit, at least initially, an episodic course [Gomez et al 1997, Jodice et al 1997]. Initial symptoms are gait unsteadiness, stumbling, and imbalance in approximately 90% of individuals; the remainder present with dysarthria. Symptoms progress slowly, and eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common. Diplopia occurs in approximately 50% of individuals. Others experience visual disturbances related to difficulty fixating on moving objects, as well as horizontal gaze-evoked nystagmus (70%-100%) [Moscovich et al 2015] and vertical nystagmus (65%-83%), which is observed in fewer than 10% of those with other forms of SCA [Yabe et al 2003]. Other eye movement abnormalities, including periodic alternating nystagmus and rebound nystagmus, have also been described [Hashimoto et al 2003]. Hyperreflexia and extensor plantar responses occur in up to 40%-50% of individuals with SCA6. Basal ganglia signs, such as dystonia and blepharospasm, are noted in up to 25% of individuals. Mentation is generally preserved. Formal neuropsychological testing in one series revealed no significant cognitive deficits [Globas et al 2003]. Individuals with SCA6 do not have sensory complaints, restless legs, stiffness, migraine, primary visual disturbances, or muscle atrophy. Life span is not shortened. Other. REM sleep behavior disorders are rarely reported [Boesch et al 2006, Howell et al 2006]. Pregnancy. The severity of the disease increases during pregnancy. No effect on the viability of the fetus has been reported. Neuropathology. Neuropathologic studies in individuals with SCA6 have demonstrated either selective Purkinje cell degeneration or a combined degeneration of Purkinje cells and granule cells [Gomez et al 1997, Sasaki et al 1998]. ### Genotype-Phenotype Correlations Heterozygous individuals. Although the age of onset of symptoms of SCA6 correlates inversely with the length of the expanded CAG repeat, the same broad range of onset has been noted for individuals with 22 CAG repeats, the most common disease-associated allele [Gomez et al 1997, Schöls et al 1998]. In the few individuals with (CAG)30 or (CAG)33, onset has been later than in individuals with (CAG)22 and (CAG)23 [Matsuyama et al 1997, Yabe et al 1998]. A recent retrospective study showed even closer correlation of age of onset with the sum of the two allele sizes [Takahashi et al 2004]. Homozygous individuals. Several individuals who are homozygous for an abnormal expansion in CACNA1A have been reported [Geschwind et al 1997a, Ikeuchi et al 1997, Matsuyama et al 1997]. In three individuals, the onset was earlier and symptoms appeared to be slightly more severe than in individuals who were heterozygous [Geschwind et al 1997a, Ikeuchi et al 1997]; in one study age of onset correlated with the sum of two allele sizes [Takahashi et al 2004]. ### Penetrance Penetrance is nearly 100%, although symptoms may not appear until the seventh decade. ### Anticipation Expansions of CACNA1A are not commonly observed in transmission from parent to child; thus, anticipation has not been observed in SCA6. The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be predicted by the family history or CAG repeat size. ### Nomenclature Hereditary forms of ataxia once known as Holmes type of cerebellar cortical degeneration, and later as autosomal dominant cerebellar ataxia type III (pure cerebellar ataxia), may have included SCA6. ### Prevalence The prevalence of SCA6 appears to vary by geographic area, presumably relating to founder effects. Estimated as the fraction of all kindreds with autosomal dominant spinocerebellar ataxia, rates for SCA6 are 1%-2% in Spain and France, 3% in China, 12% in the US, 13% in Germany, and 31% in Japan. The overall prevalence of autosomal dominant ataxia is estimated at 1:100,000, and the prevalence of SCA6 at 0.02:100,000 to 0.31:100,000 [Geschwind et al 1997a, Ikeuchi et al 1997, Matsumura et al 1997, Matsuyama et al 1997, Riess et al 1997, Stevanin et al 1997, Schöls et al 1998, Pujana et al 1999, Jiang et al 2005]. In the most accurate assessment to date, Craig et al [2004] used a large collection of non-selected samples of genomic DNA; they estimated the prevalence of the pathogenic CACNA1A expansion in the United Kingdom at 5:100,000. The frequency of CACNA1A expansions among individuals with ataxia and no known family history of ataxia was determined to be 5% in one study [Schöls et al 1998] and 43% in another [Geschwind et al 1997a]; however, premature death of parents may have hindered complete ascertainment (see Hereditary Ataxia Overview). ## Differential Diagnosis Individuals with spinocerebellar ataxia type 6 (SCA6) may present with unexplained ataxia that is part of the larger differential diagnosis of hereditary and acquired ataxias (see Hereditary Ataxia Overview). It is difficult and often impossible to distinguish spinocerebellar ataxia type 6 (SCA6) from the other hereditary ataxias (see Hereditary Ataxia Overview). The differential diagnosis should also include Parkinson disease and acquired causes of cerebellar ataxia. SCA6-related CACNA1A pathogenic variants should be in the differential diagnosis of adult-onset sporadic progressive ataxia, multiple system atrophy (MSA). ### Table 4. Proportion of Individuals with SCA6 Manifesting Phenotypic Features Compared with Individuals with SCA1, SCA3, and SCA2 View in own window Phenotypic FeatureSCA2SCA1SCA3SCA6 Cerebellar dysfunction100%100%100%100% Reduced saccadic velocity71%-92%50%10%0%-6% Myoclonus0%-40%0%4%0% Dystonia or chorea0%-38%20%8%0%-25% Pyramidal involvement29%-31%70%70%33%-44% Peripheral neuropathy44%-94%100%80%16%-44% Intellectual impairment31%-37%20%5%0% Percentages modified from Geschwind et al [1997a], Geschwind et al [1997b], Schöls et al [1997a], and Schöls et al [1997b] ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 6 (SCA6), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 6 View in own window System/ConcernEvaluationComment NeurologicNeurologic examinationIncl annual use of rating scale to assess progression Brain MRITo evaluate extent of atrophy of cerebellum or other structures Videofluoroscopic swallow studyTo identify safest behaviors & consistency of food least likely to trigger aspiration Physical therapy evaluationTo assess risk of falling, determine whether assisted ambulation is necessary, & advise regarding exercise OphthalmologicConsultation w/ophthalmologist OtherConsultation w/clinical geneticist &/or genetic counselor Family support/resourcesPatients & their families should be informed about natural history, treatment, mode of inheritance, genetic risks to other family members, & consumer-oriented resources. ### Treatment of Manifestations Management for individuals with SCA6 is supportive. ### Table 6. Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 6 View in own window Manifestation/ ConcernTreatmentConsiderations/Other AtaxiaAcetazolamideMay eliminate episodes of ataxia but does not delay or slow overall progression Physical medicine & rehabilitation / PT / OT * Canes, walking sticks, & walkers help prevent falling. * Modification of home w/aids incl grab bars, raised toilet seats, & ramps to accommodate motorized chairs may be necessary. * Weighted eating utensils & dressing hooks help maintain sense of independence. * Regular physical activity * PT & exercises enhancing balance & core strength However, neither exercise nor physical therapy stems progression of incoordination or muscle weakness. NutritionVitamin supplementsParticularly if caloric intake is reduced Feeding recommendations per feeding therapist / OT Weight controlObesity can exacerbate difficulties w/ambulation & mobility. Vertigo/ OsscilopsiaDiphenhydramine, baclofen, gabapentin * May reduce vertigo &/or osscilopsia * Some literature supports 4-aminopyridine for vestibular symptoms. 1 DiplopiaRefractive or surgical management per ophthalmologistSome literature supports 4-aminopyridine for suppression of nystagmus. 1 DysarthriaSpeech therapyCommunication devices such as writing pads & computer-based devices as needed REM sleep behavior disordersClonazepamUnless sedative effects increase imbalance in the morning Sleep apneaContinuous positive airway pressure OT = occupational therapist/therapy; PT = physical therapist/therapy 1\. Jayabal et al [2016] ### Surveillance ### Table 7. Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 6 View in own window System/ConcernEvaluationFrequency AtaxiaNeurologic evaluationEvery 6-12 mos Physiatrist & physical &/or occupational therapist consultationsEvery 12 mos to review need for walking aid(s) & home adaptations Nutrition * Nutrition evaluation * Video esophagram * Feeding assessment when dysphagia becomes troublesome As needed (e.g., w/any change in nutrition/feeding status) DiplopiaEvaluation w/ophthalmologist &/or optometrist for prisms or surgeryAs needed (e.g., when other interventions fail) Assessment of driving ability by professionalPeriodically ### Agents/Circumstances to Avoid Agents with sedative/hypnotic properties such as ethanol or certain medications may produce marked increases in incoordination. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Although the disease rarely manifests during years of fertility, measures to support imbalance should be enhanced in symptomatic pregnant women. ### Therapies Under Investigation Gazulla & Tintore [2007] suggested gabapentin and pregabalin as potential therapeutic agents. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. ### Other Tremor-controlling drugs are not usually effective in reducing cerebellar tremors. The growing interest in cannabidiol (CBD) requires further empiric experience or clinical trials. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Spinocerebellar Ataxia Type 6	c0752124	6,414	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1140/	2021-01-18T20:54:58	{"mesh": ["D020754"], "synonyms": ["SCA6"]}
Ictal asystole is a rare occurrence for patients that have temporal lobe epilepsy.[1] It can often be identified by loss of muscle tone or the presence of bilateral asymmetric jerky limb movements during a seizure, although ECG monitoring is necessary to provide a firm result.[2] Ictal asystole and Ictal bradycardia can cause an epileptic patient to die suddenly.[3] ## References[edit] 1. ^ Video-electrographic and clinical features in patients with ictal asystole 2. ^ Clinical cues for detecting ictal asystole 3. ^ Adam Strzelczyk, "Ictal Asystole in temporal lobe epilepsy before and after pacemaker implantation" "Epileptic Disorders", 12/2007 This neuroscience article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Ictal asystole	None	6,415	wikipedia	https://en.wikipedia.org/wiki/Ictal_asystole	2021-01-18T19:05:56	{"wikidata": ["Q5986769"]}
A rare mitochondrial disease characterized by bilateral auditory neuropathy and optic atrophy. Patients present hearing and visual impairment in the first or second decade of life, while psychomotor development is normal. Bilateral retinitis pigmentosa has been reported in association. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Auditory neuropathy-optic atrophy syndrome	c4521678	6,416	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=542585	2021-01-23T17:09:36	{"omim": ["617717"]}
Chemical eye injury Other namesChemical burns to the eye An alkali burn to the human cornea can cause ocular surface failure with neovascularisation, opacification and blindness resulting from LESC deficiency. SpecialtyOphthalmology Chemical eye injury are due to either an acidic or alkali substance getting in the eye.[1] Alkalis are typically worse than acidic burns.[2] Mild burns will produce conjunctivitis while more severe burns may cause the cornea to turn white.[2] Litmus paper is an easy way to rule out the diagnosis by verifying that the pH is within the normal range of 7.0—7.2.[1] Large volumes of irrigation is the treatment of choice and should continue until the pH is 6–8.[2] Local anesthetic eye drops can be used to decrease the pain.[2] ## Epidemiology[edit] In the United States, chemical eye injuries most commonly occur among working-age adults.[3] A 2016 analysis of emergency department visits from 2010-2013 reported over 36,000 visits annually for chemical burns to the eye, with a median age at presentation of 32 years.[4] By individual year of age, 1- and 2-year-old children have the highest incidence of these injuries, with rates approximately 50% higher than the highest-risk adult group (25 years), and 13 times higher than the rate among 7-year-olds.[4] Further research identified laundry detergent pods as a major source of injury among small children.[5] ## References[edit] 1. ^ a b Zentani A, Burslem J (December 2009). "Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 4: use of litmus paper in chemical eye injury". Emerg Med J. 26 (12): 887. doi:10.1136/emj.2009.086124. PMID 19934140. 2. ^ a b c d Hodge C, Lawless M (July 2008). "Ocular emergencies". Aust Fam Physician. 37 (7): 506–9. PMID 18592066. 3. ^ Saini JS, Sharma A (February 1993). "Ocular chemical burns-clinical and demographic profile". Burns. 19 (1): 67–69. doi:10.1016/0305-4179(93)90104-G. 4. ^ a b Haring RS, Sheffield ID, Channa R, Canner JK, Schneider EB (August 2016). "Epidemiologic Trends of Chemical Ocular Burns in the United States". JAMA Ophthalmology. 134: 1119–1124. doi:10.1001/jamaophthalmol.2016.2645. PMID 27490908. 5. ^ Haring, R. S.; Sheffield, I. D.; Frattaroli, S (2 February 2017). "Detergent Pod–Related Eye Injuries Among Preschool-Aged Children". JAMA Ophthalmology. doi:10.1001/jamaophthalmol.2016.5694. This article about the eye is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Chemical eye injury	c1096387	6,417	wikipedia	https://en.wikipedia.org/wiki/Chemical_eye_injury	2021-01-18T18:46:09	{"icd-10": ["T26.9"], "wikidata": ["Q5090456"]}
A number sign (#) is used with this entry because of evidence that glycogen storage disease XIII (GSD13) is caused by compound heterozygous mutation in the ENO3 gene (131370), which encodes beta-enolase, on chromosome 17p13. One such patient has been reported. Clinical Features Comi et al. (2001) described a 47-year-old man affected with exercise intolerance, myalgias, and increased serum creatine kinase. No rise of serum lactate was observed with the ischemic forearm exercise. Ultrastructural analysis showed focal sarcoplasmic accumulation of glycogen-beta particles. He had severe deficiency of muscle enolase activity (5% of control values). Molecular Genetics In a man with GSD13, Comi et al. (2001) identified compound heterozygosity for 2 mutations in the ENO3 gene (131370.0001 and 131370.0002). Immunohistochemistry and immunoblotting detected dramatically reduced beta-enolase protein in this patient, while alpha-enolase was normally represented. INHERITANCE \- Autosomal recessive MUSCLE, SOFT TISSUES \- Exercise intolerance \- Myalgias \- Muscle biopsy shows glycogen storage LABORATORY ABNORMALITIES \- Increased serum creatine kinase \- Decreased ENO3 activity MISCELLANEOUS \- Onset in adulthood \- Symptoms induced by strenuous exercise MOLECULAR BASIS \- Caused by mutation in the enolase 3 gene (ENO3, 131370.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	GLYCOGEN STORAGE DISEASE XIII	c2752027	6,418	omim	https://www.omim.org/entry/612932	2019-09-22T16:00:20	{"mesh": ["C567861"], "omim": ["612932"], "orphanet": ["99849"], "synonyms": ["Alternative titles", "GSD XIII", "ENOLASE 3 DEFICIENCY", "ENOLASE-BETA DEFICIENCY"]}
## Summary ### Clinical characteristics. Epimerase deficiency galactosemia (GALE deficiency galactosemia) is a continuum comprising three forms: * Generalized. Enzyme activity is profoundly decreased in all tissues tested. * Peripheral. Enzyme activity is deficient in red blood cells (RBC) and circulating white blood cells, but normal or near normal in all other tissues. * Intermediate. Enzyme activity is deficient in red blood cells and circulating white blood cells and less than 50% of normal levels in other cells tested. Infants with generalized epimerase deficiency galactosemia develop clinical findings on a regular milk diet (which contains lactose, a disaccharide of galactose and glucose); manifestations include hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria, and cataracts. Prompt removal of galactose/lactose from their diet resolves or prevents these acute symptoms. In contrast, neonates with the peripheral or intermediate form generally remain clinically well even on a regular milk diet and are usually only identified by biochemical testing, often in newborn screening programs. ### Diagnosis/testing. The diagnosis of epimerase deficiency galactosemia is established in a proband with impaired GALE activity in RBC and/or the identification of biallelic pathogenic variants in GALE on molecular genetic testing. The degree of GALE enzyme activity impairment in RBC does not distinguish between the clinically severe generalized and the milder intermediate or peripheral forms of epimerase deficiency. Further testing in other cell types such as stimulated leukocytes or EBV-transformed lymphoblasts is required to make that distinction. ### Management. Treatment of manifestations: The acute and potentially lethal symptoms of generalized epimerase deficiency galactosemia are prevented or corrected by a galactose/lactose-restricted diet. Note: Affected individuals may require trace environmental sources of galactose: infants should be fed a formula (e.g., soy formula) that contains trace levels of galactose or lactose. Continued dietary restriction of dairy products in older children is recommended. In contrast, infants with peripheral epimerase deficiency galactosemia are believed to remain asymptomatic regardless of diet; infants with intermediate epimerase deficiency galactosemia may benefit in the long term from early dietary galactose/lactose restriction, but this remains unclear. Prevention of primary manifestations: In generalized epimerase deficiency galactosemia, restriction of dietary galactose/lactose appears to correct or prevent the acute signs and symptoms of the disorder (hepatic dysfunction, renal dysfunction, and mild cataracts), but not the developmental delay or learning impairment observed in some children. Because of the difficulty in distinguishing peripheral and intermediate forms of epimerase deficiency galactosemia, dietary restriction of galactose/lactose is recommended for all infants with GALE deficiency, relaxing the restriction as warranted once a more accurate diagnosis has been confirmed. Surveillance: Hemolysate gal-1P (galactose-1-phosphate) or urinary galactitol is monitored, especially if the diet is to be normalized. Acceptable levels of RBC gal-1P are not known, but are estimated to be <3.5 mg/100 mL (normal ≤1.0 mg/100 mL) on data from classic galactosemia. Other parameters that warrant monitoring are growth and developmental milestones. Agents/circumstances to avoid: Dietary galactose/lactose in persons with generalized epimerase deficiency galactosemia, certainly as infants and perhaps for life. Evaluation of relatives at risk: Each at-risk newborn sib should be treated from birth while awaiting results of diagnostic testing for epimerase deficiency galactosemia; either molecular genetic testing (if the pathogenic variants in the family are known) or measurement of GALE enzyme activity in RBC (if the pathogenic variants in the family are not known) can be performed. ### Genetic counseling. Epimerase deficiency galactosemia is inherited in an autosomal recessive manner. At conception, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known. ## Diagnosis Epimerase deficiency galactosemia (GALE deficiency galactosemia) is a continuum comprising three forms: * Generalized. Enzyme activity is profoundly decreased in all tissues tested. * Peripheral. Enzyme activity is deficient in red blood cells (RBC) and circulating white blood cells, but normal or near normal in all other tissues. * Intermediate. Enzyme activity is deficient in RBC and circulating white blood cells and less than 50% of normal levels in other cells tested. ### Suggestive Findings Epimerase deficiency galactosemia should be suspected in individuals (on a normal milk diet) with the following newborn screening results, clinical features, and supportive laboratory findings: Newborn screening results * In states in which the newborn screening program includes measurements of both total galactose (gal+gal-1P) and GALT enzyme activity (see Galactosemia): * Total galactose (sum of galactose and galactose-1-phosphate) is elevated; and * GALT enzyme activity is normal. * In states in which total galactose is only measured if GALT enzyme activity is low, an affected infant will have a normal newborn screening result for galactosemia. Clinical features * Hypotonia * Poor feeding * Vomiting * Weight loss * Jaundice * Hepatomegaly * Liver dysfunction * Cataracts * No clinical findings (peripheral and intermediate forms) Supportive laboratory findings * Elevated RBC hemolysate gal-1P concentration (normal 0-1.0 mg/100 mL RBC): * As high as 170 mg/100 mL packed RBC in those with generalized epimerase deficiency * >30 mg/100 mL packed RBC in those with intermediate or peripheral epimerase deficiency * Urinary galactose concentrations as high as 116 mmol/L (2.09 g/100 mL, control <30 mg/100 mL) * Non-glucose reducing substance in the urine (which represents urinary galactose) * Elevated urinary galactitol concentrations (normal <94.7 mmol/mol creatinine for age <1 year, <45.3 mmol/mol creatinine for age 1-6 years, <18.4 mmol/mol creatinine for age >6 years) * Generalized aminoaciduria * Normal GALT enzyme activity ### Establishing the Diagnosis A diagnosis of epimerase deficiency galactosemia is established in a proband by one or more of the following: * 0.0-8.0 μmol/hr/g hemoglobin (Hb) GALE enzyme activity in red blood cells (RBC) (normal 17.1-40.1 μmol/hr/g Hb) as determined by the traditional spectrophotometric assay * <0.5 μmol/hr/g Hb GALE enzyme activity in RBC using liquid chromatography/tandem mass spectrometry (normal 2.3-12.7 μmol/hr/g Hb) [Chen et al 2014] * The identification of biallelic pathogenic variants in GALE on molecular genetic testing (see Table 1) Molecular testing approaches can include single-gene testing and use of a multigene panel: * Single-gene testing. Sequence analysis of GALE is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. * A multigene panel that includes GALE and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. ### Table 1. Molecular Genetic Testing Used in Epimerase Deficiency Galactosemia View in own window Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method GALESequence analysis 314/16 alleles and 13/14 alleles (~90%) 4 Gene-targeted deletion/duplication analysis 5None reported 6 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Whole-gene sequencing has revealed ostensibly causal GALE variants in most persons with biochemically confirmed GALE deficiency who have been studied (e.g., Park et al [2005], Openo et al [2006], reviewed in Fridovich-Keil & Walter [2008]); however due to the small number of alleles studied and the biochemical complexity of the diagnosis this estimate may change with time. 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. No deletions or duplications involving GALE have been reported to cause epimerase deficiency galactosemia. #### Additional Testing GALE enzyme activity can be measured in fibroblasts or lymphoblasts to help distinguish between the generalized, peripheral, and intermediate forms of epimerase deficiency galactosemia; however, to the authors’ knowledge this testing is not currently offered on a clinical basis. ## Clinical Characteristics ### Clinical Description The clinical severity of epimerase deficiency galactosemia caused by reduced activity of the enzyme GALE [Fridovich-Keil & Walter 2008] ranges from potentially lethal [Holton et al 1981, Henderson et al 1983, Walter et al 1999, Sarkar et al 2010] to apparently benign [Gitzelmann 1972]. Epimerase deficiency galactosemia can be divided by apparent enzyme activity level into the following three forms: generalized, peripheral, and intermediate (see Diagnosis) [Openo et al 2006]. Note: In all three forms GALE enzyme activity is deficient in peripheral circulating red and white blood cells. A key difference between generalized epimerase deficiency galactosemia and intermediate or peripheral epimerase deficiency galactosemia is that individuals with generalized epimerase deficiency galactosemia develop clinical findings on a normal milk diet while infants with peripheral or intermediate epimerase deficiency galactosemia remain clinically well, at least in the neonatal period. #### Generalized Epimerase Deficiency Galactosemia Infants with generalized epimerase deficiency galactosemia who are on a diet containing galactose/lactose typically present with symptoms reminiscent of classic galactosemia: hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction (e.g., markedly elevated serum transaminases), aminoaciduria, and cataracts. Prompt removal of galactose/lactose from the diet resolves or prevents these acute symptoms [Walter et al 1999, Sarkar et al 2010] (see Management). Long-term outcome information for persons with generalized epimerase deficiency galactosemia is limited: fewer than ten persons with this form have been reported [Walter et al 1999, Sarkar et al 2010]. Some have demonstrated long-term complications that became evident by early childhood (including sensorineural hearing impairment and physical and cognitive developmental delay and/or learning difficulties) while others have not. Of note, a majority of the individuals reported were born to consanguineous parents, raising the concern that homozygosity for other autosomal recessive alleles, independent of GALE, may underlie some if not most of the long-term complications reported. Those few individuals with generalized epimerase deficiency who have been followed long-term demonstrate apparently normal puberty with no apparent evidence of premature ovarian insufficiency [Walter et al 1999]. #### Peripheral Epimerase Deficiency Galactosemia Neonates with the peripheral form are usually asymptomatic even on a regular milk diet; these infants are only identified following biochemical detection of elevated total galactose on newborn screening. Children with peripheral epimerase deficiency galactosemia appear to remain asymptomatic even if maintained on a normal milk diet. #### Intermediate Epimerase Deficiency Galactosemia Neonates with the intermediate form are also usually asymptomatic even on a regular milk diet and are only identified through newborn screening. The long-term outcome remains unclear. One affected individual who was not treated with dietary restriction of galactose/lactose as an infant experienced delays in both motor and cognitive development that became evident by early childhood [Alano et al 1998, Openo et al 2006]. All other individuals known to have intermediate epimerase deficiency galactosemia have been treated by dietary galactose/lactose restriction, at least in infancy, and thus far those who have been followed appear to remain clinically well. #### Pathophysiology Galactose is metabolized in humans and other species by the three-enzyme Leloir pathway comprising the enzymes galactokinase (GALK, EC 2.7.1.6), galactose 1-P uridylyltransferase (GALT, EC 2.7.7.12), and UDP-galactose 4'-epimerase (GALE, EC 5.1.3.2). As illustrated in Figure 1, GALE catalyzes an essential step in this pathway converting UDP-galactose to UDP-glucose. GALE is a reversible enzyme that also catalyzes the synthesis of UDP-galactose from UDP-glucose when other sources of UDP-galactose are limiting. Functioning outside of the Leloir pathway, GALE also interconverts UDP-N-acetyl galactosamine and UDP-N-acetylglucosamine. All four of these UDP-sugars are essential substrates for the biosynthesis of glycoproteins and glycolipids in humans. #### Figure 1 Leloir pathway As in classic galactosemia, the cataracts associated with epimerase deficiency galactosemia are believed to be caused by galactitol accumulation in the ocular lens; it is possible, but not proven, that other acute findings may be caused by tissue accumulation of gal-1P (galactose-1-phosphate) or other metabolites. Persons with epimerase deficiency galactosemia who are exposed to galactose demonstrate abnormal accumulation of UDP-galactose (UDP-gal). However, because GALE is required in humans for the endogenous biosynthesis of UDP-gal and also UDP-N-acetylgalactosamine (UDP-galNAc), at least part of the pathophysiology of epimerase deficiency galactosemia may result from inadequate production of these compounds, especially in utero, ostensibly leading to deficient or aberrant production of glycoproteins and glycolipids including cerebrosides. ### Genotype-Phenotype Correlations Because insufficient numbers of individuals with molecularly confirmed epimerase deficiency galactosemia have been followed clinically to identify genotype/phenotype correlations, studies of transformed lymphoblasts or other "non-peripheral" cell types are the only way to distinguish biochemically between the different forms of epimerase deficiency galactosemia [Mitchell et al 1975, Openo et al 2006]. ### Nomenclature Some authors refer to the different forms of galactosemia as type I, type II, and type III galactosemia, in which: * Type I galactosemia refers to GALT deficiency * Type II galactosemia refers to GALK deficiency * Type III galactosemia refers to GALE deficiency (epimerase deficiency galactosemia) ### Prevalence True prevalence figures are unavailable at this time. Generalized epimerase deficiency galactosemia is very rare; however, epimerase deficiency galactosemia detected by newborn screening may be as frequent as about 1:6,700 among African American infants and about 1:70,000 among American infants of European ancestry [Alano et al 1997, Fridovich-Keil & Walter 2008]. ## Differential Diagnosis GALT deficiency. Galactosemia caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT) may be divided into three clinical/biochemical phenotypes: (1) classic galactosemia; (2) clinical variant galactosemia; and (3) Duarte (biochemical variant) galactosemia. This categorization is based on: residual erythrocyte GALT enzyme activity; the levels of galactose metabolites (e.g., erythrocyte galactose-1-phosphate and urine galactitol) that are observed both off and on a lactose-restricted diet; and, most importantly, the likelihood that the affected individual will develop acute and chronic long-term complications. Biallelic pathogenic variants in GALT are causative; inheritance is autosomal recessive. * Classic galactosemia can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage, bleeding, and E. coli sepsis in untreated infants. If a lactose-restricted diet is provided during the first ten days of life, the neonatal signs usually quickly resolve and the complications of liver failure, sepsis, and neonatal death are prevented; however, despite adequate treatment from an early age, children with classic galactosemia remain at increased risk for developmental delays, speech problems (termed childhood apraxia of speech and dysarthria), and abnormalities of motor function. The vast majority of women with classic galactosemia manifest premature ovarian insufficiency (POI). * Clinical variant galactosemia can result in life-threatening complications in untreated infants including feeding problems, failure to thrive, hepatocellular damage including cirrhosis, and bleeding. It can occur in individuals of any ancestry with low residual GALT enzyme activity, but is perhaps exemplified by the disease associated with the p.Ser135Leu GALT allele that occurs at high frequency in African Americans and native Africans in South Africa. Persons with clinical variant galactosemia may be missed with newborn screening (NBS) as the hypergalactosemia is not as marked as in classic galactosemia. As in classic galactosemia, if a lactose-restricted diet is provided during the first days of life, the severe acute neonatal complications are usually prevented. Long-term outcomes among treated individuals with clinical variant galactosemia may also be milder. * Duarte variant galactosemia (biochemical variant galactosemia). Persons with Duarte variant galactosemia who are fed breast milk or a lactose-containing formula are typically (though not always) asymptomatic, at least as infants. Galactokinase (GALK) deficiency (OMIM 230200) should be considered in otherwise healthy individuals with cataracts, increased plasma concentration of galactose, and increased urinary excretion of galactitol. Affected individuals have normal GALT enzyme activity and do NOT accumulate gal-1P. The cataracts are caused by accumulation of the galactose metabolite, galactitol, in the lens. Galactitol is an impermeant alcohol which results in increased intracellular osmolality and swelling with loss of plasma membrane redox potential and consequent cell death. Detection of reduced GALK enzyme activity in hemolysates is diagnostic. Biallelic pathogenic variants in GALK1 are causative [Kolosha et al 2000, Hunter et al 2001]; inheritance is autosomal recessive. The prevalence of GALK deficiency in most populations is unknown; however, a recent study from Germany reported a prevalence of about 1:40,000, which is similar to the prevalence of classic galactosemia in the same population [Hennermann et al 2011]. In other populations the prevalence may be far lower. Other. A number of other rare conditions, including the following, can also lead to elevated galactose or galactose metabolites in the blood or urine of an infant consuming milk: * Portosystemic venous shunting * Hepatic arteriovenous malformations * Fanconi-Bickel syndrome (OMIM 227810) due to biallelic pathogenic variants in SLC2A2. Individuals with this condition have hepatorenal glycogen accumulation, impaired utilization of glucose and galatose, and proximal tubular nephropathy. * Congenital disorder of glycosylation type 1T (OMIM 614921) due to biallelic pathogenic variants in PGM1 [Tegtmeyer et al 2014]. Individuals with this condition can manifest mildly increased galactose-1-phosphate levels in RBC. They may have cleft palate/bifid uvula at birth, and can develop intermittent hypoglycemia, dilated cardiomyopathy, exercise intolerance with increased serum creatine kinase, and liver disease. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with epimerase deficiency galactosemia the following evaluations are recommended: * Measurement of height, weight, and head circumference * Nutrition and feeding assessments * Neurologic examination * Developmental assessment * Liver function testing (serum AST, ALT, albumin, total protein, total and conjugated bilirubin, prothrombin time, and partial thromboplastin time) * Ophthalmology consult to evaluate for cataracts * Consultation with a clinical geneticist ### Treatment of Manifestations #### Generalized Epimerase Deficiency Galactosemia The acute and potentially lethal symptoms of generalized epimerase deficiency galactosemia are prevented or corrected by a galactose/lactose-restricted diet. This means switching infants from breast milk or a milk-based formula to a formula with only trace levels of galactose or lactose, such as soy formula. Of note, some infants with classic galactosemia are prescribed elemental formula, which has even lower galactose content than soy formula. Elemental formula should not be prescribed for infants with generalized epimerase deficiency galactosemia because the GALE enzyme is required for the endogenous biosynthesis of UDP-galactose; that is, persons with epimerase deficiency galactosemia may require trace environmental sources of galactose. However, the galactose intake needed for optimum outcome remains unknown. For older children with generalized epimerase deficiency galactosemia, dietary restriction of galactose/lactose involves continued restriction of dairy products. Note: Some, but not all, physicians recommend that individuals with classic galactosemia also abstain from non-dairy foods that contain more than trace levels of galactose/lactose (e.g., some fruits and vegetables, organ meats); this more rigorous dietary restriction may not be advisable for persons with generalized epimerase deficiency galactosemia. In generalized epimerase deficiency galactosemia restriction of dietary galactose/lactose appears to correct or prevent the acute signs and symptoms of the disorder: hepatic dysfunction, renal dysfunction, and mild cataracts. Presumably, as in classic galactosemia, dietary treatment would not correct profound tissue damage resulting from prolonged galactose exposure (e.g., hepatic cirrhosis or mature cataracts). Mature cataracts that do not resolve with dietary restriction of galactose/lactose may require surgical removal. #### Peripheral Epimerase Deficiency Galactosemia Individuals with peripheral epimerase deficiency galactosemia do not require any dietary restriction. #### Intermediate Epimerase Deficiency Galactosemia Individuals with intermediate epimerase deficiency galactosemia are typically treated with dietary galactose/lactose restriction, at least in infancy. They may be an (as-yet unknown) increased risk for long-term complications including learning impairment and/or cataracts. Continued breastfeeding or exposure to a milk-based formula containing high levels of galactose/lactose may therefore be inadvisable for these infants; however, insufficient data exist to make firm recommendations. ### Prevention of Primary Manifestations In generalized epimerase deficiency galactosemia dietary restriction of galactose/lactose prevents early feeding problems, vomiting, poor weight gain, hepatic dysfunction, and cataracts. The challenge in treating an asymptomatic newborn with epimerase deficiency galactosemia is that it may take months to obtain the results of tests used to distinguish peripheral epimerase deficiency galactosemia from intermediate epimerase deficiency galactosemia (see Establishing the Diagnosis, Additional Testing); furthermore, such tests may not be available. The most conservative approach, therefore, is to advise dietary restriction of galactose/lactose for all infants with epimerase deficiency galactosemia, relaxing the restriction as warranted once a more accurate diagnosis has been confirmed. ### Surveillance The following are appropriate: * Monitor hemolysate gal-1P or urinary galactitol, especially if the diet is to be normalized. Acceptable levels of gal-1P in GALE deficiency are not known but are estimated from experience with classic galactosemia to be <3.5 mg/100 mL in red blood cells. * Follow growth. * Monitor developmental milestones; propose supportive intervention as needed. ### Agents/Circumstances to Avoid Persons with generalized epimerase deficiency galactosemia should be on a galactose/lactose-restricted diet, certainly as infants and perhaps for life. Persons with intermediate epimerase deficiency galactosemia may be placed on a galactose/lactose-restricted diet, either transiently or long-term. Assessment of hemolysate gal-1P and/or urinary galactitol following a galactose challenge (e.g., 2 weeks on a normal diet) may help determine if an individual should remain on a galactose/lactose-restricted diet for longer periods of time. ### Evaluation of Relatives at Risk If prenatal testing has not been performed (see Genetic Counseling), each at-risk newborn sib should be treated from birth until results of diagnostic testing are available. Diagnostic evaluations can include: * Molecular genetic testing if the pathogenic variants in the family are known; * Measurement of GALE enzyme activity in red blood cells if the pathogenic variants in the family are not known. Note: If there are concerns about the reliability of the prenatal testing, soy-based formula may be given while the diagnostic testing is being performed. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Epimerase Deficiency Galactosemia	c0268151	6,419	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK51671/	2021-01-18T21:28:31	{"mesh": ["D005693"], "synonyms": ["GALE Deficiency", "Galactosemia Type III", "UDP-Galactose-4'-Epimerase Deficiency"]}
A rare, potentially lethal intoxication characterized by life-threatening arrhythmias (sinus tachycardias, premature ventricular contractions, ventricular arrhythmias), anticholinergic toxidrome (mydriasis, dry mucous membrane, tachycardia, hypertension), central nervous system toxicity (lethargy, coma, myoclonic jerks), refractory hypotension and sudden death. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Acute tricyclic antidepressant poisoning	None	6,420	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=43117	2021-01-23T18:32:41	{"icd-10": ["T43.0"]}
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-43 (SCA43) is caused by heterozygous mutation in the MME gene (120520) on chromosome 3q25. One such family has been reported. Description Spinocerebellar ataxia-43 is an autosomal dominant, slowly progressive neurologic disorder characterized by adult-onset gait and limb ataxia and often associated with peripheral neuropathy mainly affecting the motor system, although some patients may have distal sensory impairment (summary by Depondt et al., 2016). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). Clinical Features Depondt et al. (2016) reported a large 5-generation Belgian family in which 7 living members had adult-onset spinocerebellar ataxia and peripheral neuropathy. The 69-year-old proband presented around age 58 with gait and balance problems and pain in the distal lower limbs. She had pes cavus, mild distal lower limb atrophy, hyporeflexia with absent Achilles reflexes, and mild upper and lower limb ataxia. She also had mild upper limb cogwheel rigidity, positive palmomental reflex, hypometric saccades, and dysarthria. Sensory examination was normal. EMG showed a severe motor neuropathy with preserved sensory responses; nerve conduction velocities were normal. Brain imaging showed moderate cerebellar vermis atrophy. The 6 additional living affected family members had similar features, including balance problems, ataxia, unsteady gait, tremor, and hyporeflexia. More variable features included dysarthria, nystagmus, and distal sensory impairment consistent with a peripheral polyneuropathy. Two patients had an MRI that showed cerebellar atrophy, and 1 patient had a sural nerve biopsy that showed axonal neuropathy. Many of the patients also had pectus carinatum. None of the individuals reported cognitive problems. Inheritance The transmission pattern of SCA43 in the family reported by Depondt et al. (2016) was consistent with autosomal dominant inheritance. Molecular Genetics In 7 affected members of a large Belgian family with SCA43, Depondt et al. (2016) identified a heterozygous missense mutation in the MME gene (C143Y; 120520.0006). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. Sequencing of the MME gene in 96 additional patients with dominant ataxia did not identify any more mutations. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Hypometric saccades (in some patients) \- Nystagmus (in some patients) CHEST External Features \- Pectus carinatum SKELETAL Feet \- Pes cavus MUSCLE, SOFT TISSUES \- Distal amyotrophy NEUROLOGIC Central Nervous System \- Cerebellar ataxia \- Gait ataxia \- Limb ataxia \- Balance problems \- Dysarthria \- Tremor \- Upper limb involvement (in some patients) \- Rigidity (in some patients) \- Cerebellar atrophy Peripheral Nervous System \- Hyporeflexia \- Axonal motor neuropathy \- Distal sensory impairment (in some patients) \- Distal limb pain MISCELLANEOUS \- Adult onset (range 42 to 68 years) \- Slowly progressive \- One Belgian family has been reported (last curated July 2016) MOLECULAR BASIS \- Caused by mutation in the membrane metalloendopeptidase gene (MME, 120520.0006 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	SPINOCEREBELLAR ATAXIA 43	c4310763	6,421	omim	https://www.omim.org/entry/617018	2019-09-22T15:47:14	{"omim": ["617018"]}
A number sign (#) is used with this entry because osteogenesis imperfecta type VII (OI7) is caused by homozygous or compound heterozygous mutation in the CRTAP gene (605497) on chromosome 3p22. Description Osteogenesis imperfecta is a connective tissue disorder characterized by bone fragility and low bone mass. OI type VII is an autosomal recessive form of severe or lethal OI (summary by Barnes et al., 2006). Clinical Features Ward et al. (2002) reported the clinical, radiologic, and histologic features of 4 children (aged 3.9-8.6 years at last follow-up; all girls) and 4 adults (aged 28-33 years; 2 women) with a novel form of autosomal recessive OI. All of the patients were identified in 2 generations of 3 interrelated families in the small First Nations community in northern Quebec. Multiple fractures were present at birth in all children. Recurrent fractures occurred in all patients but fracture frequency appeared to decrease after puberty. Sclerae were minimally bluish. Progressive deformities led to short stature and severe ambulatory restriction in 2 of the 4 adults. None of the patients had dentinogenesis imperfecta, hearing loss, or ligamentous laxity. Striking radiographic findings included rhizomelia and coxa vara in all affected patients. Histomorphometric analyses of the iliac crest revealed findings similar to OI type I (166200): decreased cortical width and trabecular number, increased bone turnover, and preservation of the birefringent pattern of lamellar bone. Barnes et al. (2006) identified 10 children who had lethal or severe osteogenesis imperfecta without primary collagen mutations but with excess posttranslational modification of type I collagen, indicative of delayed folding of the collagen helix. Three patients had a clinical presentation similar to that of infants with autosomal dominant perinatal lethal type II osteogenesis imperfecta (OI2; 166210), but with distinctive features. In patients with CRTAP deficiency owing to recessive mutation, the head circumference is small, the eyes show proptosis because of shallow orbits, and the sclerae are white or light blue; patients with type II osteogenesis imperfecta, caused by a structural collagen defect, have relative macrocephaly and dark blue sclerae. In recessive and dominant lethal osteogenesis imperfecta the bones are severely undermineralized and have multiple fractures prenatally, resulting in an abducted positioning of the legs. On radiography, the long bones in infants with CRTAP deficiency are characterized by a lack of diaphyseal modeling (undertubulation). In both type II and type VII, respiratory insufficiency causes early death. Balasubramanian et al. (2015) described a 12-year-old girl, born to first-cousin parents of Asian Pakistani origin, who had sustained multiple fractures of her long bones immediately after birth and was diagnosed with OI type 3 (OI3; 259420). She had a history of bronchiolitis, failure to thrive, initial gross motor delay, mild thoracolumbar scoliosis, coronal and lambdoid sutural craniosynostosis, bilateral limb deformities, hypermobility in all joints, prominent eyes with a proptotic appearance, grayish-blue sclerae, and dentinogenesis imperfecta. Radiographs showed generalized osteopenia, multiple fractures of ribs, and crush fractures of her vertebrae and long bones, with progressive deformity of the spine and long bones. Balasubramanian et al. (2015) thought her features were consistent with a diagnosis of Cole-Carpenter syndrome (see 112240). Population Genetics Barnes et al. (2006) estimated that CRTAP mutations cause 2 to 3% of cases of lethal osteogenesis imperfecta. Mapping Labuda et al. (2002) performed linkage and protein studies on the family described by Ward et al. (2002). Mutation analysis of the COL1A1 (120150) and COL1A2 (120160) genes revealed no mutations, and type I collagen protein analysis was normal. Genomewide screening on pooled DNA from 7 affected patients localized the disease locus to chromosome 3p24.1-p22 between markers D3S2324 and D3S1561 (maximum multipoint lod score of 3.44). Two genes mapped to this region, transforming growth factor receptor beta receptor-2 (190182) and parathyroid hormone/parathyroid hormone-related peptide receptor (168468), were excluded as candidates for the disorder. Molecular Genetics In genomic DNA from an affected member of a large consanguineous Quebec family with OI type VII described by Ward et al. (2002), Morello et al. (2006) identified homozygosity for a mutation in the CRTAP gene (605497.0001). The CRTAP gene encodes cartilage-associated protein, which Morello et al. (2006) showed is required for prolyl 3-hydroxylation (see 610339) of fibrillar type I (see 120150) and II (see 120140) collagens. Morello et al. (2006) studied a consanguineous family in which 4 pregnancies were affected with severe OI (short limbs and multiple fractures). The diagnosis of recurrent OI type II had been made based on the clinical features and the biochemical finding of type I collagen overmodification, but mutations in COL1A1 (120150) or COL1A2 (120160) could not be identified. Sequence analysis of CRTAP coding regions from DNA of 3 affected individuals detected a homozygous mutation (605497.0002). The parents were asymptomatic but carriers of the deletion. Biochemical and MS/MS analysis of collagen from cultured fibroblasts from the proband confirmed collagen overmodification and showed that the target proline was underhydroxylated. CRTAP protein could not be identified in fibroblasts from 1 affected individual. Real-time PCR performed on RNA extracted from cultured fibroblasts showed that they contained 10% of the amount seen in the OI type VII cells and about 1% of that seen in control cells. Barnes et al. (2006) investigated the CRTAP gene in patients with osteogenesis imperfecta without a primary collagen mutation. They found homozygous or compound heterozygous mutations in the CRTAP gene in 3 of the 10 patients (605497.0003-605497.0006). The affected infants had null mutations in both CRTAP alleles, low levels of CRTAP mRNA, a lack of CRTAP protein, and minimal prolyl 3-hydroxylation of type I collagen. Type I collagen had a normal primary structure but showed excess posttranslational modification of the alpha-chain helical region. Valli et al. (2012) reported a 7-year-old Egyptian boy with nonlethal OI type VII caused by a homozygous null mutation in the CRTAP gene (605497.0007). The mutation resulted in reduction of CRTAP transcript levels to approximately 10% of normal levels and undetectable CRTAP protein in fibroblasts. The abnormal posttranslational modification of the patient's type I collagen was typical for OI type VII, with alpha-1(I)pro986 3-hydroxylation reduced to 5% of normal, and full helical overmodification indicated by 40% hydroxylysine levels. By immunofluorescence of long-term cultures, Valli et al. (2012) also identified a severe deficiency (10-15% of control) of collagen deposited in extracellular matrix, with disorganization of the minimal fibrillar network. Quantitative pulse-chase experiments corroborated deficiency of matrix deposition, rather than increased matrix turnover. Valli et al. (2012) concluded that defects of extracellular matrix, as well as intracellular defects in collagen modification, contribute to the pathology of OI type VII. In affected members of 2 Saudi families with OI type VII, Shaheen et al. (2012) identified homozygous mutations in the CRTAP gene (605497.0004 and 605497.0008, respectively). The affected individuals displayed severe prenatal onset of fractures. The proband in 1 family died during the neonatal period. The proband in the other family had blue sclerae and dentinogenesis imperfecta, with no hearing or other organ involvement; on bisphosphonate therapy, she had fewer fractures and bone density improvement. In a 12-year-old girl, born to first-cousin parents of Asian Pakistani origin, who had a skeletal phenotype diagnosed as Cole-Carpenter syndrome, Balasubramanian et al. (2015) identified a truncating mutation (E40X; 605497.0009) in the CRTAP gene. INHERITANCE \- Autosomal recessive GROWTH Height \- Normal birth length \- Short stature (adult) Weight \- Normal birth weight HEAD & NECK Head \- Large open anterior fontanelle \- Open sutures Face \- Round face \- Long philtrum Ears \- Normal hearing Eyes \- Proptosis \- Bluish sclerae Teeth \- No dentinogenesis imperfecta CARDIOVASCULAR Vascular \- Absent pulmonary artery \- Hypoplastic pulmonary veins CHEST External Features \- Narrow chest Ribs Sternum Clavicles & Scapulae \- Pectus excavatum \- Multiple rib fractures GENITOURINARY Kidneys \- Hydronephrosis SKELETAL \- Multiple fractures present at birth \- Moderate-severe bone fragility \- Osteopenia Skull \- Wormian bones \- Poorly ossified calvaria Spine \- Vertebral compression fractures \- Scoliosis Pelvis \- Coxa vara \- Protrusio acetabulae Limbs \- Rhizomelia \- Micromelia \- Externally rotated/abducted legs \- Osteopenic long bones \- Crumpled long bones \- Undertubulation (lack of diaphyseal modeling) \- Bowed lower limbs PRENATAL MANIFESTATIONS Delivery \- Term delivery \- Breech presentation MISCELLANEOUS \- Multiple fractures present at birth \- Death in infancy secondary to respiratory insufficiency/pneumonia \- Fracture frequency decreased post puberty MOLECULAR BASIS \- Caused by mutation in the cartilage-associated protein gene (CRTAP, 605497.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	OSTEOGENESIS IMPERFECTA, TYPE VII	c0268362	6,422	omim	https://www.omim.org/entry/610682	2019-09-22T16:04:13	{"doid": ["0110337"], "mesh": ["C536044"], "omim": ["610682"], "orphanet": ["216812", "216804", "216820", "666"], "synonyms": ["Alternative titles", "OI, TYPE VII", "OSTEOGENESIS IMPERFECTA, TYPE IIB, FORMERLY"]}
A number sign (#) is used with this entry because of evidence that a reduced level of plasma LDL cholesterol is caused by heterozygous mutation in the LIMA1 gene (608364) on chromosome 12q13. Description LDLCQ8 is a quantitative trait affecting LDL cholesterol levels that is effected through the LIMA1 gene, which has a key role in intestinal cholesterol absorption. Individuals with LIMA1 mutations that impair protein function have reduced plasma LDL cholesterol levels and reduced cholesterol absorption (Zhang et al., 2018). Clinical Features Zhang et al. (2018) identified a Chinese Kazakh family (Family 1) with inherited low levels of LDL cholesterol from the Cardiovascular Risk Survey in western China. Affected members carried a heterozygous frameshift mutation in the LIMA1 gene (see MOLECULAR GENETICS). The plasma total cholesterol and LDL cholesterol levels in mutation carriers were significantly lower than those of wildtype individuals; however, plasma levels of triglycerides, HDL cholesterol, and glucose were similar in both frameshift carriers and wildtype individuals. Zhang et al. (2018) found that K306fs carriers had a significantly lower plasma campesterol:lathosterol (Ca:L) ratio than wildtype family members, suggesting that K306fs carriers have reduced intestinal cholesterol absorption. Zhang et al. (2018) also identified a missense mutation in LIMA1 in members of 3 additional Chinese Kazakh families whose plasma LDL cholesterol levels were lower than in wildtype individuals but higher than those of the frameshift carriers. Molecular Genetics In affected members of a Chinese Kazakh family (Family 1) with inherited low levels of LDL cholesterol, Zhang et al. (2018) identified heterozygosity for an 8-bp deletion in exon 7 of the LIMA1 gene (K306fs; 608364.0001) that resulted in frameshift and premature termination. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing and segregated with the phenotype in the family. Targeted sequencing of LIMA1 in approximately 1,000 Chinese Kazakhs revealed a missense variant in exon 2 (L25I; 608364.0002). in 3 additional families with low LDL cholesterol levels. Animal Model Zhang et al. (2018) generated mice in which Lima1 was specifically depleted from mouse intestine, in which it is highly expressed, without affecting the level of Npc1l1 (608010), a key transmembrane protein that facilitates intestinal cholsterol uptake. Intestine-specific (I-Lima1) null mice appeared normal without obvious morphologic changes in the small intestine. There was significantly lower cholesterol uptake in I-Lima1 heterozygous mice and null mice (35.5% for heterozygotes and 28.6% for null) compared with wildtype littermates (51.6%). The plasma dual-isotope ratio method showed that cholesterol absorption was reduced by about 40% in Lima1-deficient mice. I-Lima1 null mice had lower levels of cholesterol in intestinal epithelial cells after cholesterol gavage than wildtype mice; however, I-Lima1 null mice had increased fecal cholesterol compared to wildtype mice, with similar fecal triglyceride levels, demonstrating that intestinal cholesterol absorption was reduced in I-Lima1 null mice. When fed a chow diet, all mice showed similar total cholesterol levels in plasma and liver. In comparison, mice that consumed a high cholesterol diet had 1.63-fold and 4-fold increases in plasma and liver total cholesterol levels respectively. The plasma and liver total cholesterol content of intestinal Lima1-null mice were respectively 28.8% and 58.3% lower than those of wildtype mice fed the high cholesterol diet. Whole-body Lima1 heterozygous knockout mice appeared normal and had less dietary cholesterol absorption and lower plasma total cholesterol levels compared to wildtype mice, similar to human heterozygotes for the LIMA1 K306fs (608364.0002) mutation. Homozygous knockout mice also appeared normal and displayed reduced dietary cholesterol absorption. Cholesterol absorption was ablated to a lesser degree than in Npc1l1 knockout mice. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 8	None	6,423	omim	https://www.omim.org/entry/618079	2019-09-22T15:43:49	{"omim": ["618079"]}
This article has an unclear citation style. The references used may be made clearer with a different or consistent style of citation and footnoting. (October 2017) (Learn how and when to remove this template message) Neuromuscular junction disease SpecialtyNeurology Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly. ## Contents * 1 Autoimmune * 2 Neuromuscular junction * 3 Classification * 3.1 Immune-mediated * 3.2 Toxic/metabolic * 3.3 Congenital * 3.4 Presynaptic * 3.5 Synapse * 3.6 Postsynaptic * 4 Most common diseases * 4.1 Myasthenia gravis * 4.2 Lambert-Eaton myasthenic syndrome (LEMS) * 5 Other diseases * 5.1 Neuromyotonia * 5.2 Congenital myasthenia * 5.3 Botulism * 6 Diagnosis * 6.1 Tests * 7 Treatment * 7.1 Symptomatic treatment * 7.2 Immunosuppressive treatment * 8 References * 9 External links ## Autoimmune[edit] In diseases such as myasthenia gravis, the end plate potential (EPP) fails to effectively activate the muscle fiber due to an autoimmune reaction against acetylcholine receptors, resulting in muscle weakness and fatigue.[1] Myasthenia gravis is caused most commonly by auto-antibodies against the acetylcholine receptor. It has recently been realized that a second category of gravis is due to auto-antibodies against MuSK. A different condition, Lambert–Eaton myasthenic syndrome, is usually associated with presynaptic antibodies to the voltage-dependent calcium channel. It is possible for these conditions to coexist.[2] ## Neuromuscular junction[edit] The neuromuscular junction is a specialized synapse between a neuron and the muscle it innervates. It allows efferent signals from the nervous system to contact muscle fibers causing them to contract. In vertebrates, the neuromuscular junction is always excitatory, therefore to stop contraction of the muscle, inhibition must occur at the level of the efferent motor neuron. In other words, the inhibition must occur at the level of the spinal cord. Release of acetylcholine vesicles from the presynaptic terminal occurs only after adequate depolarization of the efferent nerve. Once a motor nerve action potential reaches the presynaptic nerve terminal it causes an increase in intracellular calcium concentration by causing an increase in ion conductance through voltage gated calcium channels. This increase in calcium concentration allows the acetylcholine vesicles to fuse with the plasma membrane at the presynaptic membrane, in a process called exocytosis, thus releasing acetylcholine into the synapse. Once acetylcholine is present in the synapse it is able to bind to nicotinic acetylcholine receptors increasing conductance of certain cations, sodium and potassium in the postsynaptic membrane and producing an excitatory end т и ироооurrent. As cations flow into the postsynaptic cell, this causes a depolarization, as the membrane voltage increases above normal resting potential. If the signal is of sufficient magnitude, than an action potential will be generated post synaptically. The action potential will propagate through the sarcolemma to the interior of the muscle fibers eventually leading to an increase in intracellular calcium levels and subsequently initiating the process of Excitation–contraction coupling. Once coupling begins it allows the sarcomeres of the muscles to shorten, thus leading to the contraction of the muscle. Neuromuscular junction diseases are a result of a malfunction in one or more steps of the above pathway. As a result, normal functioning can be completely or partially inhibited, with the symptoms largely presenting themselves as problems in mobility and muscle contraction as expected from disorders in motor end plates. Neuromuscular junction diseases can also be referred to as end plate diseases or disorders. Among neuromuscular diseases some can be autoimmune disease, or hereditary disorders. They can affect either presynaptic mechanisms or postsynaptic mechanisms, preventing the junction from functioning normally. The most studied diseases affecting the human acetylcholine receptor are myasthenia gravis and some forms of congenital myasthenic syndrome. Other diseases include the Lambert–Eaton syndrome and botulism. ## Classification[edit] There are two ways to classify neuromuscular diseases. The first relies on its mechanism of action, or how the action of the diseases affects normal functioning (whether it is through mutations in genes or more direct pathways such as poisoning). This category divides neuromuscular diseases into three broad categories: immune-mediated disease, toxic/metabolic and congenital syndromes. The second classification method divides the diseases according to the location of their disruption. In the neuromuscular junction, the diseases will either act on the presynaptic membrane of the motor neuron, the synapse separating the motor neuron from the muscle fiber, or the postsynaptic membrane (the muscle fiber). ### Immune-mediated[edit] Immune-mediated diseases include a variety of diseases not only affecting the neuromuscular junction. Immune-mediated disorders range from simple and common problems such as allergies to disorders such as HIV/AIDS. Within this classification, autoimmune disorders are considered to be a subset of immune-mediated syndromes. Autoimmune diseases occur when the body's immune system begins to target its own cells, often causing harmful effects. The neuromuscular junction diseases present within this subset are myasthenia gravis, and Lambert-Eaton syndrome.(reference 26) In each of these diseases, a receptor or other protein essential to normal function of the junction is targeted by antibodies in an autoimmune attack by the body. ### Toxic/metabolic[edit] Metabolic diseases are usually a result of abnormal functioning of one of the metabolic processes required for regular production and utilization of energy in a cell. This can occur by damaging or disabling an important enzyme, or when a feedback system is abnormally functioning. Toxic diseases are a result of a form of poison that effects neuromuscular junction functioning. Most commonly animal venom or poison, or other toxic substances are the origin of the problem. Neuromuscular junction diseases in this category include snake venom poisoning, botulism, arthropod poisoning, organophosphates and hypermagnesemia.(reference 13) Organophosphates are present in many insecticides and herbicides. They are also the basis of many nerve gases.(reference 27) Hypermagnesmia is a condition where the balance of magnesium in the body is unstable and concentrations are higher than normal baseline values.(reference 28) ### Congenital[edit] Congenital syndromes affecting the neuromuscular junction are considered a very rare form of disease, occurring in 1 out of 200,000 in the United Kingdom.(reference 29) These are genetically inherited disorders. Symptoms are seen early since the affected individuals carry the mutation from birth. Congenital syndromes are usually classified by the location of the affected gene products. Congenital syndromes can have multiple targets affecting either the presynaptic, synaptic or postsynaptic parts of the neuromuscular junction.(reference 30) For example, if the malfunctioning or inactive protein is acetylcholinesterase, this would be classified as a synapse congenital syndrome.(reference 29) ### Presynaptic[edit] The diseases that act on the presynaptic membrane are autoimmune neuromyotonia, Lambert–Eaton syndrome, congenital myasthenia gravis and botulism.(reference 5) All of these disorders negatively affect the presynaptic membrane in some way. Neuromyotonia causes antibodies to damage the normal function of potassium rectifier channels, while Lambert–Eaton syndrome causes antibodies to attack presynaptic calcium channels.(reference 7) Congenital myasthenia gravis is a large group of diseases, since the genetic defects can affect any point in the chain of events leading to successful transmission across the junction. One discovered type of congenital myasthenia gravis can affect the junction presynaptically by a mutation in the gene encoding choline acetyl transferase.(reference 29) This protein is an enzyme that is responsible for catalyzing the reaction that combines acetyl-coenzyime A with choline, yielding acetylcholine.(reference 31) There are many mechanisms through which presynaptic function can be impaired. Most often this causes a decrease in the release of acetylcholine. It can also impair vesicle exocytosis by interfering with the complex guiding vesicle fusion and release of contents. Mechanism of action can also impair the calcium channels that induce exocytosis of the vesicles. Other ion channels can also be disrupted, such as the potassium channels causing inefficient repolarization at the presynaptic membrane as in neuromyotonia.(reference 5) ### Synapse[edit] At the synaptic cleft, the neurotransmitter normally diffuses across the synapse to eventually contact postsynaptic receptors. However, after exiting the presynaptic membrane, the neurotransmitters can be hindered by a subset of diseases that interfere with the transmission of the neurotransmitter across the synapse. The mechanism currently known that operates via the synaptic cleft causing impairment of normal functioning is another congenital myasthenia gravis.(reference 7) This mechanism is the only currently known disease that acts on the synapse.(reference 12) It acts by impairing the function of the enzyme that breaks down acetylcholine causing it to become very hypertonic at the synapse.(reference 12) This increase in acetylcholine in the synapse disrupts normal functioning of the junction,.(reference 32)(reference 33) ### Postsynaptic[edit] The highest number of diseases affect the neuromuscular junction postsynaptically. In other words, it is the most susceptible to negative intervention.(reference 7) The targets of these postsynaptic diseases can be multiple different proteins. Immune-mediated myasthenia gravis being the most common, effecting the acetylcholine receptors at the post synaptic membrane.(reference 35) All the diseases that affect the postsynaptic membrane are forms of myasthenia gravis.(reference 5) Here is a list of the diseases: myasthenia gravis, neonatal myasthenia gravis, drug-induced myasthenia gravis and several types of Congenital myasthenia where the product of the mutated gene is a postsynaptic protein (reference renamed from 5) ## Most common diseases[edit] ### Myasthenia gravis[edit] Myasthenia gravis is the most common neuromuscular disease affecting function of the end plate in patients. It is present in 1 people out of 10,000 in the population, and its onset is usually in either younger or older individuals. (reference 14) Acquired myasthenia gravis is the most common neuromuscular junction disease.(reference 7) Important observations were made by Patrick and Lindstrom in 1973 when they found that antibodies attacking the acetylcholine receptors were present in around 85% of cases of myasthenia gravis.(reference renamed form 13)(reference 36) The remaining diseases were also a result of antibody attacks on vital proteins, but instead of the acetylcholine receptor, the culprits were MuSK, a muscle-specific serum kinase, and lipoprotein receptor-related protein.(reference 36) So these mechanisms describe myasthenia gravis that is acquired, and not congenital, affecting these vital proteins by an immunological response against self-antigens. The cases not caused by antibodies against the acetylcholine receptors became by convention called seronegative myasthenia gravis.(reference 37) The term seronegative came about because scientists would be testing for acetylcholine receptor antibodies in patients that had myasthenia gravis resulting in negative tests in the serum. This does not imply that there are no antibodies present, but this terminology only became present because scientists were testing for the wrong antigen.(reference 36)(reference 38) Neonatal myasthenia gravis is a very rare condition in which a mother with myasthenia gravis passes down her antibodies to her infant through the placenta, causing the it to be born with antibodies that will attach self-antigens.(reference 12) Drug-induced myasthenia gravis is also a very rare condition in which pharmacological drugs cause a blockade or disruption of the NMJ machinery.(reference 12) Robert W. Barrons summarizes the possible causes of drug-induced myasthenia gravis: "Prednisone was most commonly implicated as aggravating myasthenia gravis, and D-penicillamine was most commonly associated with myasthenic syndrome. The greatest frequency of drug-induced neuromuscular blockade was seen with aminoglycoside-induced postoperative respiratory depression. However, drugs most likely to impact myasthenic patients negatively are those used in the treatment of the disease. These include overuse of anticholinesterase drugs, high-dose prednisone, and anesthesia and neuromuscular blockers for thymectomy."(reference 39) ### Lambert-Eaton myasthenic syndrome (LEMS)[edit] Lambert-Eaton myasthenic syndrome (LEMS) is similar to myasthenia gravis in that it is an immune-mediated response acting against a specific protein in the neuromuscular junction. The difference is that LEMS is a result of an autoimmune response on the voltage gated calcium channels of the presynaptic membrane.(reference 14) The antibodies attack the voltage gated calcium channels of the P/Q type.(reference 35) Abnormal activity of this ion channel, which usually initiates the process of acetylcholine vesicles from the presynaptic membrane once the membrane is sufficiently depolarized, causes less acetylcholine to be released into the synapse.(reference 12) LEMS is about 20 times more rare than myasthenia gravis.(reference 40) LEMS also differs from myasthenia gravis in that it is usually associated with small-cell lung cancer, which is present in 60% percent of patients.(reference 40) It seems that as cancer develops, the body will begin to develop antibodies against the cancer, and in some cases the antibodies can also attack the calcium channels present at the presynaptic membrane.(reference 12) In the cases where no cancer is present in the patient, there is usually an underlying different autoimmune disease which causes the immune system to become hyperactive attacking its own antigens.(reference 40) ## Other diseases[edit] ### Neuromyotonia[edit] Neuromyotonia is classified into three types.(reference 14) The most common form of this disease is acquired neuromyotonia, which is the result of an autoimmune attack on rectifier voltage-gated potassium channels.(reference 12) This causes the presynaptic membrane to remain hyperpolarized, making it difficult for adequate depolarizations to occur.(reference 5) ### Congenital myasthenia[edit] This is the most complex and diverse congenital myasthenic syndrome.(reference 29) Since this is a genetic disorder, there are infinite possibilities of genes that could be mutated in different ways that could disrupt normal functioning of the neuromuscular junction. Around 11 gene targets have been specified.(reference 3) Its prevalence in the population is very difficult to measure since it is a rare genetic disorder that presents itself as a neuromuscular junction disorder, but in the United Kingdom, estimates are 1 in 200,000 of the population.(reference 29) The major signs that indicate a congenital syndrome are symptoms present at birth, such as weakness and a depressive response to repetitive nerve stimulation.(reference 29) Since the disease is genetic in nature and is not immune-mediated, any serum test will show up negative since congenital myasthenia is not a result of antibodies attacking the vital proteins of the NMJ.(reference 7) Knowledge of this disease is very plastic as new genes that could be "effected" (affected? effective?) could be discovered as we gain more insight into the different types. ### Botulism[edit] Neurotoxin may act on the neuromuscular junction either post synaptically or presynaptically as there are several different forms of toxins that the NMJ is sensitive to.(reference 14) Common mechanisms of action include blockage of acetylcholine release at the synapse via inhibition of the SNARE protein, thus causing the NMJ to become abnormal in function.(reference 12) ## Diagnosis[edit] ### Tests[edit] * Repetitive nerve stimulation * Electromyography (EMG) * Nerve conduction studies * Exercise testing * Single-fiber EMG ## Treatment[edit] ### Symptomatic treatment[edit] Cholinesterase inhibitors at AChR ### Immunosuppressive treatment[edit] * Thymectomy * Medical therapy: corticosteroids, non-steroidal immunosuppression * Short-term treatment: plasmapherisis, IVIG ## References[edit] 1. ^ Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A (2001). "Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies". Nat Med. 7 (3): 365–8. doi:10.1038/85520. PMID 11231638. S2CID 18641849. 2. ^ Sha SJ, Layzer RB (July 2007). "Myasthenia gravis and Lambert-Eaton myasthenic syndrome in the same patient". Muscle Nerve. 36 (1): 115–7. doi:10.1002/mus.20735. PMID 17206662. S2CID 297071. ## External links[edit] Classification D * MeSH: D020511 External resources * Orphanet: 98491 * v * t * e Diseases of muscle, neuromuscular junction, and neuromuscular disease Neuromuscular- junction disease * autoimmune * Myasthenia gravis * Lambert–Eaton myasthenic syndrome * Neuromyotonia Myopathy Muscular dystrophy (DAPC) AD * Limb-girdle muscular dystrophy 1 * Oculopharyngeal * Facioscapulohumeral * Myotonic * Distal (most) AR * Calpainopathy * Limb-girdle muscular dystrophy 2 * Congenital * Fukuyama * Ullrich * Walker–Warburg XR * dystrophin * Becker's * Duchenne * Emery–Dreifuss Other structural * collagen disease * Bethlem myopathy * PTP disease * X-linked MTM * adaptor protein disease * BIN1-linked centronuclear myopathy * cytoskeleton disease * Nemaline myopathy * Zaspopathy Channelopathy Myotonia * Myotonia congenita * Thomsen disease * Neuromyotonia/Isaacs syndrome * Paramyotonia congenita Periodic paralysis * Hypokalemic * Thyrotoxic * Hyperkalemic Other * Central core disease Mitochondrial myopathy * MELAS * MERRF * KSS * PEO General * Inflammatory myopathy * Congenital myopathy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Neuromuscular junction disease	c0751950	6,424	wikipedia	https://en.wikipedia.org/wiki/Neuromuscular_junction_disease	2021-01-18T18:45:19	{"mesh": ["D020511"], "umls": ["C0751950"], "orphanet": ["98491"], "wikidata": ["Q7002430"]}
Late-onset junctional epidermolysis bullosa is a subtype of junctional epidermolysis bullosa (JEB, see this term) occurring in childhood or young adulthood. ## Epidemiology Prevalence is unknown. 22 patients in 12 families have been reported to date. ## Clinical description Blistering occurs at first around nails, accompanied by nail dystrophy and shedding, and then affects the hands and feet and, to a lesser extent, the elbows, knees, along with atrophic scarring. Other manifestations include disappearance of dermatoglyphs and palmoplantar hyperhidrosis. Extracutaneous involvement is restricted to soft tissue abnormalities of the oral cavity and enamel defects with development of caries. ## Etiology COL17A1 mutations have recently been described in a family affected with JEB of late-onset. ## Genetic counseling The condition follows an autosomal recessive pattern of inheritance. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Late-onset junctional epidermolysis bullosa	c4304724	6,425	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79406	2021-01-23T18:44:23	{"gard": ["12921"], "icd-10": ["Q81.8"], "synonyms": ["Epidermolysis bullosa progressiva", "JEB-lo", "Late-onset JEB"]}
In 4 generations of a family in Germany, Hamann et al. (1992) observed the combination of multiple exostoses of typical nature (133700) in association with spastic tetraparesis. There were no exostoses in the spine or cranium to account for the tetraspastic disorder. The pedigree pattern was consistent with autosomal dominant inheritance. In the second generation, all of 5 sibs were affected. Hamann et al. (1992) concluded that this represented a new syndrome, although the possibility of a contiguous gene syndrome was considered. Skel \- Multiple exostoses Neuro \- Spastic tetraparesis Inheritance \- Autosomal dominant \- possibly a contiguous gene syndrome ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	MULTIPLE EXOSTOSES WITH SPASTIC TETRAPARESIS	c1834724	6,426	omim	https://www.omim.org/entry/158345	2019-09-22T16:37:58	{"mesh": ["C563566"], "omim": ["158345"]}
A number sign (#) is used with this entry because of evidence that Fontaine progeroid syndrome (FPS) is caused by heterozygous mutation in the SLC25A24 gene (608744) on chromosome 1p36. Description Fontaine progeroid syndrome is characterized by prenatal and postnatal growth retardation, decreased subcutaneous fat tissue, sparse hair, triangular face, widely open anterior fontanel, convex and broad nasal ridge, micrognathia, craniosynostosis in some patients, and early death in many (summary by Writzl et al., 2017). Nomenclature Fontaine progeroid syndrome and Gorlin-Chaudhry-Moss syndrome (GCMS) were originally thought to be separate disorders. Ehmke et al. (2017) reported mutations in SLC25A24 in patients clinically diagnosed with GCMS. Because the patients originally reported by Gorlin et al. (1960) and Ippel et al. (1992) are deceased and not available for sequence analysis, GCMS is now considered a milder form of FPS (Hennekam, 2018). See HISTORY. Clinical Features Petty et al. (1990) described what they considered to be a newly recognized form of congenital progeroid syndrome in a 5-year-old girl. They suggested that the 46-year-old woman reported by Wiedemann (1979) had the same syndrome. Common manifestations included pre- and postnatal growth retardation, markedly diminished subcutaneous fat, wrinkled skin, abnormally scant hair growth, hypoplastic distal phalanges with hypoplastic nails, umbilical hernia, large open anterior fontanel, and normal cognitive and motor development. Both patients had a prematurely aged appearance since birth. Petty et al. (1990) noted that patients with Wiedemann-Rautenstrauch syndrome (WRS; 264090) show similarities to their patient, but differ by the presence of natal teeth, large hands and feet with long, tapering digits, developmental delay, and neurologic impairment. Rodriguez et al. (1999) reported a severe prenatal form of progeria. Marked intrauterine growth retardation (IUGR) and oligohydramnios had been detected at 32 weeks' gestation by ultrasonography, and the patient was born by cesarean section at 35 weeks. She died 7 hours after birth with features including premature aging, absence of subcutaneous fat, brachydactyly, absent nipples, hypoplastic external genitalia, and abnormal ear lobes. The authors designated this case as a prenatal form of Hutchinson-Gilford progeria syndrome (HGPS; 176670). However, Faivre et al. (1999) reported a similarly affected female neonate and stated that HGPS was an 'inappropriate' diagnosis for both their own patient and the patient reported by Rodriguez et al. (1999). Despite some overlap in clinical manifestations, Faivre et al. (1999) also thought it unlikely that their infant had WRS, also known as neonatal progeroid syndrome. Rodriguez and Perez-Alonso (1999) defended the 'diagnosis of progeria syndrome [as] the only one possible.' Castori et al. (2009) described a male infant born with marked IUGR and oligohydramnios, for which he was delivered by cesarean section at 32 weeks' gestation. At birth he was cyanotic and hypotonic, with severe respiratory distress, and he died at 20 hours after birth from cardiopulmonary failure. Postmortem examination showed brachycephaly, wide anterior fontanel, hypertelorism, midface hypoplasia with depressed periorbital area, short nose with broad base and anteverted nares, and low-set ears with flattened helix. There was a generalized deficiency of subcutaneous fat, and his scalp hair showed an unusual distribution, being sparse in the parietal area bilaterally. The digits of all 4 limbs were shortened and markedly tapered with nail hypoplasia/aplasia. Abdominal muscles were severely hypoplastic and the overlying skin was mildly redundant. In addition, he had micropenis, hypoplasia of the scrotum, and bilateral cryptorchidism. X-ray showed synostotic brachycephaly due to premature fusion of the coronal sutures, universal platyspondyly with superior and inferior notching of multiple vertebral bodies, and hypoplasia/aplasia of the distal phalanx of all digits. Dissection revealed pachygyria and cerebellar hypoplasia, as well as intestinal malrotation and multiple volvuli. Noting the triad of craniosynostosis, anonychia, and extensive abdominal muscle hypoplasia in this patient, the authors concluded that the disorder was consistent with what they designated 'Fontaine-Farriaux syndrome.' Adolphs et al. (2011) reported a 7-year-old Hungarian girl with GCMS who underwent frontofacial advancement by internal distraction for functional and psychosocial amelioration of her complex craniofacial malformation. In addition to brachycephaly with severe midface hypoplasia and retrusion, she had short eyebrows and palpebral fissures, hypertrichosis of the scalp and trunk with low frontal hairline, hyperopia, dental anomalies, and hypoplasia of the labia majora, and she was given a diagnosis of Gorlin-Chaudhry-Moss syndrome. Her postoperative course was complicated by a necrotizing soft tissue infection of the scalp. Ehmke et al. (2017) studied 5 unrelated girls, including the Hungarian girl previously reported by Adolphs et al. (2011) (patient 2), who all exhibited brachycephaly, broad forehead, depressed supraorbital ridge, midface hypoplasia, prognathia or tongue protrusion, low anterior and posterior hairlines, hypertrichosis, and wrinkled skin. Other features included large anterior fontanel, coarse scalp hair, short downslanting palpebral fissures, and low-set dysplastic ears. All had failure to thrive, and 4 of the 5 showed IUGR and postnatal short stature, with reduced subcutaneous fat tissue and dermal translucency. In addition, 4 exhibited coronal craniosynostosis, oligodontia and/or microdontia, and small nails; short distal phalanges and syndactyly were also present in 3, and 3 had conductive hearing impairment. Four had umbilical hernia, and 2 also had hypoplasia of the abdominal wall muscles. Four of the 5 patients were alive at ages 5, 5.5, 7, and 14 years, but a Turkish girl (patient 4) died at 20 months after a urinary tract infection. Two of the girls had initially been diagnosed with neonatal progeroid syndrome (WRS), but the authors stated that the 5 girls showed the typical hallmarks of GCMS. Writzl et al. (2017) studied 2 boys and 2 girls with a progeroid appearance. The 2 girls were previously reported by Rodriguez et al. (1999) (patient 3) and Faivre et al. (1999) (patient 2), and 1 of the boys was reported by Castori et al. (2009) (patient 4). All presented with pre- and postnatal growth retardation as well as an aged appearance characterized by decreased subcutaneous fat, wrinkled skin, and prominent veins. Other features included wide fontanels, abnormal scalp hair pattern, triangular face, midface hypoplasia, convex nasal ridge, micrognathia, low-set dysplastic ears, small distal phalanges, and small nails. Umbilical hernia was present in 2 patients, and another had abdominal muscle hypoplasia. Cryptorchidism was present in both boys, and 1 also had micropenis and hypoplastic scrotum. Two patients had craniosynostosis, with premature fusion of coronal sutures in both and parietotemporal synostosis in 1. All 4 patients died within the first year of life: patients 3 and 4 from respiratory distress, at 7 hours and 20 hours after birth, respectively; patient 1 from pulmonary hypertension at age 6 months; and patient 2 from sepsis at age 7 months. For historic reasons, the authors designated the congenital progeroid disorder in these patients as Fontaine syndrome, noting that a similarly affected patient was first described by Fontaine et al. (1977); Writzl et al. (2017) also stated that the phenotype was likely to represent the same entity as that described by Petty et al. (1990). Molecular Genetics By whole-exome or whole-genome sequencing in 4 unrelated girls with a progeroid appearance, including the Hungarian girl with GCMS reported by Adolphs et al. (2011), Ehmke et al. (2017) identified heterozygosity for 2 different de novo missense mutations in the SLC25A24 gene, both occurring at the same codon: R217H (608744.0001) in 3 patients, and R217C (608744.0002) in 1 patient. Sanger sequencing in a similarly affected fifth girl revealed heterozygosity for the R217H variant, which had also occurred de novo. Neither mutation was found in the ExAC, gnomAD, or 1000 Genomes Project databases. Noting that the patients studied by Writzl et al. (2017) showed overlapping clinical features and carried the same mutations in the SLC25A24 gene, but exhibited early demise in contrast to their patients, 4 of whom were alive and over 5 years of age, Ehmke et al. (2017) suggested that variation in the function of other genes involved in mitochondrial function, as well as other genetic, epigenetic, or environmental influences might explain the variability of the phenotype. In 2 patients with Fontaine syndrome, including a Slovenian boy (patient 1) and a French girl (patient 2) who was originally reported by Faivre et al. (1999), and their parents, Writzl et al. (2017) performed whole-exome sequencing and identified heterozygosity for the same de novo R217H mutation in the SLC25A24 gene in both patients. Whole-genome sequencing in a similarly affected Spanish girl (patient 3), originally reported by Rodriguez et al. (1999), revealed heterozygosity for a de novo R217C mutation in the SLC25A24 gene. Screening SLC25A24 by Sanger sequencing in an Italian boy with Fontaine syndrome (patient 4), previously described by Castori et al. (2009), revealed the same de novo variant as in the first 2 patients, R217H. Noting that the patients studied by Ehmke et al. (2017) carried the same SLC25A24 mutations and also resembled their patients except for some facial characteristics and early demise, Writzl et al. (2017) suggested that variations in function of other genes involved in mitochondrial functioning, other genetic and epigenetic influences, and environmental influences might play a role. History Gorlin et al. (1960) described 2 sisters with craniofacial dysostosis, patent ductus arteriosus, hypertrichosis, genital hypoplasia, and ocular, dental, and digital anomalies. The parents were not known to be related. The same sisters were reported by Feinberg (1960) as instances of the Weill-Marchesani syndrome (277600), which was clearly an incorrect diagnosis. Ippel et al. (1992) provided follow-up of the 2 sisters reported by Gorlin et al. (1960), G.G. and N.G., then aged 36 and 34, respectively. Although there had been slight coarsening of the facial features with time, the overall clinical picture had not changed. Ippel et al. (1992) reported 2 additional patients, both female, aged 4 and 33 years. All 4 patients had conductive hearing loss, hypertrichosis, coarse hair, and low frontal hairline. The 2 new patients had very short distal phalanges of fingers and toes. As in the original patients, G.G. and N.G. (as reported by Feinberg, 1960), the skeletal abnormalities included shortened metacarpals and distal phalanges. Parental consanguinity had not been established in any of these patients. Hennekam (2018) stated that the patients reported by Gorlin et al. (1960) and Ippel et al. (1992) are deceased and that their DNA is unavailable for study. Preis et al. (1995) pointed out phenotypic overlap between GCMS and the Saethre-Chotzen syndrome (101400). Aravena et al. (2011) described 2 Chilean sisters with features overlapping those of GCMS patients, including intrauterine growth retardation, short stature, brachycephaly, midface hypoplasia, small eyes, downslanting palpebral fissures, epicanthal folds, hypertrichosis, coarse hair, low frontal hairline, nail hypoplasia, patent ductus arteriosus, umbilical hernia, and hypoplastic labia majora. However, the Chilean patients did not have upper eyelid coloboma, hearing loss, or stocky body build, and the proband had cutis aplasia and an occipital mass in the same area, which on autopsy appeared to be an encephalocele. In addition, both sisters had hyperthermia, sweating, and persistent respiratory distress; both died of pneumonia, at ages 5 months and 18 months. Aravena et al. (2011) noted that the sisters' features also overlapped with those of Petty progeroid syndrome, but stated that the overall pattern was more consistent with a diagnosis of GCMS. Rosti et al. (2013) reported what they considered to be the seventh case of GCMS and reviewed the clinical presentations of previously published patients. Their proband was a Turkish girl who was born with coronal craniosynostosis, which was repaired at 18 months of age, as well as with laryngomalacia, which became asymptomatic by age 3 years. Examination at 4.5 years of age revealed stocky body build, brachy/turricephaly, generalized hypertrichosis with low anterior and posterior hairlines, midface hypoplasia, bilateral upper lid colobomas, hyperopia, small posteriorly rotated ears, and hypoplastic labia majora. Dental evaluation showed microdontia, irregularly shaped and widely spaced teeth, oligodontia, and narrow high-arched palate with medial cleft. She also had bilateral mild conductive hearing loss. Although this patient exhibited the cardinal features of GCMS, she displayed other features not previously reported, including bifid nasal tip, absent flexion crease of thumbs and bilateral single transverse palmar crease, and laryngomalacia. Rosti et al. (2013) suggested that the 7 reported GCMS patients could be divided into 2 subsets with differing facial gestalts: group 'A' included their Turkish case, the Chilean sisters described by Aravena et al. (2011), and the 4-year-old girl reported by Ippel et al. (1992), all of whom exhibited synophrys and a laterally widening and extending eyebrow pattern that forms a 'stair case' descending to the lateral orbital rim and canthus, as well as prominent columella and relatively underdeveloped ala nasi, with bifid nasal tip in some. In addition, these patients had small medial clefts of the palate and cutaneous syndactyly. In contrast, group 'B' patients displayed deeply set eyes, with eyebrows that were underdeveloped medially and showed gradual thinning laterally. Rosti et al. (2013) noted that these subsets might represent different phenotypic expressions of the same molecular entity or distinct molecular entities with significant clinical overlap. The original patients reported by Gorlin et al. (1960) were sibs born to unaffected parents, suggesting autosomal recessive inheritance. However, Rosti et al. (2013) noted that all 7 patients reported with GCMS have been female with no known parental consanguinity, suggesting a de novo X-linked dominant disorder with male lethality. In that case, the mothers of the affected sisters of Gorlin et al. (1960) and Aravena et al. (2011) might have gonadal mosaicism for the causative mutation. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature Other \- Intrauterine growth retardation \- Failure to thrive HEAD & NECK Head \- Brachycephaly \- Turricephaly \- Microcephaly (in some patients) \- Large anterior fontanel Face \- Progeroid appearance \- Broad forehead \- Triangular face \- Low anterior hairline \- Depressed supraorbital ridges \- Midface hypoplasia \- Long philtrum \- Flat philtrum \- Micrognathia \- Retrognathia \- Prognathia Ears \- Low-set ears \- Dysplastic ears \- Posteriorly rotated ears \- Hypoplastic or absent ear lobes \- Conductive hearing loss (in some patients) Eyes \- Short palpebral fissures \- Downslanting palpebral fissures \- Deeply set eyes \- Prominent eyes \- Hypertelorism \- Hyperopia \- Laterally upslanting eyebrows \- Synophrys Nose \- Depressed nasal root \- Convex nasal ridge \- Small nose Mouth \- Small mouth \- Protruding tongue \- Thin upper lip \- Protruding lower lip \- High-arched palate (in some patients) Teeth \- Oligodontia \- Microdontia Neck \- Low posterior hairline \- Hypertrichosis CARDIOVASCULAR Heart \- Patent ductus arteriosus \- Atrial septal defect \- Left ventricular hypertrophy \- Tricuspid insufficiency \- Bicuspid aortic valve Vascular \- Pulmonary artery hypertension \- Aortic ectasia RESPIRATORY Lung \- Respiratory insufficiency \- Pulmonary hypoplasia \- Reduced number of alveoli \- Recurrent aspiration pneumonia \- Pneumothorax due to bronchopleural fistula CHEST Breasts \- Widely space nipples \- Small nipples \- Absent nipples ABDOMEN External Features \- Umbilical hernia \- Abdominal muscle hypoplasia Gastrointestinal \- Gastroesophageal reflux \- Feeding problems \- Partial malrotation \- Anteriorly placed anus GENITOURINARY External Genitalia (Male) \- Micropenis \- Scrotal hypoplasia External Genitalia (Female) \- Hypoplastic labia majora Internal Genitalia (Male) \- Cryptorchidism SKELETAL \- Delayed bone age \- Deficient endochondral ossification \- Low bone density Skull \- Craniosynostosis \- Premature fusion of coronal sutures \- Premature fusion of parietotemporal sutures (uncommon) \- Widely open metopic suture (uncommon) \- Widely open sagittal sutures (uncommon) \- Poor skull ossification Spine \- Scoliosis \- Platyspondyly \- Notching of multiple vertebral bodies, superior and inferior Pelvis \- Hypoplastic or absent pubic bones Hands \- Short distal phalanges \- Absent distal phalanges \- Syndactyly Feet \- Short distal phalanges \- Absent distal phalanges \- Syndactyly SKIN, NAILS, & HAIR Skin \- Wrinkled skin \- Dermal translucency \- Reduced subcutaneous fat \- Redundant skin \- Deep palmar creases Nails \- Small nails \- Absent nails (in some patients) Hair \- Coarse scalp hair \- Sparse scalp hair (parietal area may be particularly affected) \- Abnormal scalp hair pattern \- Low anterior and posterior hairlines \- Hypertrichosis (including face, neck, trunk, and limbs) MUSCLE, SOFT TISSUES \- Muscle weakness (in some patients) NEUROLOGIC Central Nervous System \- Psychomotor delay with normal outcome \- Delayed motor development due to muscle weakness \- Hydrocephalus \- Hypotonia \- Gyral simplification \- Thin corpus callosum \- Large lateral ventricles \- Large posterior fossa \- Hypoplastic cerebellum \- Hypoplastic cerebellar vermis \- Periventricular heterotopia PRENATAL MANIFESTATIONS Movement \- Reduction of fetal movements (uncommon) Amniotic Fluid \- Oligohydramnios MISCELLANEOUS \- Early lethality in some patients \- Variable features may be present MOLECULAR BASIS \- Caused by mutation in the solute carrier family 25 (mitochondrial carrier, phosphate carrier), member 24 gene (SLC25A24, 608744.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	FONTAINE PROGEROID SYNDROME	c2931653	6,427	omim	https://www.omim.org/entry/612289	2019-09-22T16:01:53	{"mesh": ["C537886"], "omim": ["612289"], "orphanet": ["2963", "2095"], "synonyms": ["Alternative titles", "GORLIN-CHAUDHRY-MOSS SYNDROME", "PROGEROID SYNDROME, CONGENITAL, PETTY TYPE", "CRANIOFACIAL DYSOSTOSIS, HYPERTRICHOSIS, HYPOPLASIA OF LABIA MAJORA, DENTAL AND EYE ANOMALIES, PATENT DUCTUS ARTERIOSUS, AND NORMAL INTELLIGENCE"]}
Keratitis-ichthyosis-deafness (KID) syndrome is characterized by eye problems, skin abnormalities, and hearing loss. People with KID syndrome usually have keratitis, which is inflammation of the front surface of the eye (the cornea). The keratitis may cause pain, increased sensitivity to light (photophobia), abnormal blood vessel growth over the cornea (neovascularization), and scarring. Over time, affected individuals experience a loss of sharp vision (reduced visual acuity); in severe cases the keratitis can lead to blindness. Most people with KID syndrome have thick, hard skin on the palms of the hands and soles of the feet (palmoplantar keratoderma). Affected individuals also have thick, reddened patches of skin (erythrokeratoderma) that are dry and scaly (ichthyosis). These dry patches can occur anywhere on the body, although they most commonly affect the neck, groin, and armpits. Breaks in the skin often occur and may lead to infections. In severe cases these infections can be life-threatening, especially in infancy. Approximately 12 percent of people with KID syndrome develop a type of skin cancer called squamous cell carcinoma, which may also affect mucous membranes such as the lining of the mouth. Partial hair loss is a common feature of KID syndrome, and often affects the eyebrows and eyelashes. Affected individuals may also have small, abnormally formed nails. Hearing loss in this condition is usually profound, but occasionally is less severe. ## Frequency KID syndrome is a rare disorder. Its prevalence is unknown. Approximately 100 cases have been reported. ## Causes KID syndrome is caused by mutations in the GJB2 gene. This gene provides instructions for making a protein called gap junction beta 2, more commonly known as connexin 26. Connexin 26 is a member of the connexin protein family. Connexin proteins form channels called gap junctions that permit the transport of nutrients, charged atoms (ions), and signaling molecules between neighboring cells that are in contact with each other. Gap junctions made with connexin 26 transport potassium ions and certain small molecules. Connexin 26 is found in cells throughout the body, including the inner ear and the skin. In the inner ear, channels made from connexin 26 are found in a snail-shaped structure called the cochlea. These channels may help to maintain the proper level of potassium ions required for the conversion of sound waves to electrical nerve impulses. This conversion is essential for normal hearing. In addition, connexin 26 may be involved in the maturation of certain cells in the cochlea. Connexin 26 also plays a role in the growth and maturation of the outermost layer of skin (the epidermis). The GJB2 gene mutations that cause KID syndrome change single protein building blocks (amino acids) in connexin 26. The mutations are thought to result in channels that constantly leak ions, which impairs the health of the cells and increases cell death. Death of cells in the skin and the inner ear may underlie the ichthyosis and deafness that occur in KID syndrome. It is unclear how GJB2 gene mutations affect the eye. Because at least one of the GJB2 gene mutations identified in people with KID syndrome also occurs in hystrix-like ichthyosis with deafness (HID), a disorder with similar features but without keratitis, many researchers categorize KID syndrome and HID as a single disorder, which they call KID/HID. It is not known why some people with this mutation have eye problems while others do not. ### Learn more about the gene associated with Keratitis-ichthyosis-deafness syndrome * GJB2 ## Inheritance Pattern KID syndrome is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. However, most cases result from new mutations in the gene and occur in people with no history of the disorder in their family. A few families have had a condition resembling KID syndrome with an autosomal recessive pattern of inheritance. In autosomal recessive inheritance, both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Affected individuals in these families have liver disease, which is not a feature of the autosomal dominant form. The autosomal recessive condition is sometimes called Desmons syndrome. It is unknown whether it is also caused by GJB2 gene mutations. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Keratitis-ichthyosis-deafness syndrome	c0265336	6,428	medlineplus	https://medlineplus.gov/genetics/condition/keratitis-ichthyosis-deafness-syndrome/	2021-01-27T08:25:31	{"gard": ["2946", "3113"], "mesh": ["C536168"], "omim": ["148210", "242150"], "synonyms": []}
Fetal valproate syndrome (FVS) may occur if a developing baby is exposed to valproic acid during pregnancy. Valproic acid, also known as valproate, is a medication that is often used to treat epilepsy, bipolar disorder, and migraines. Many babies who are exposed to this medication during pregnancy are born healthy with normal growth and development. However, studies have found that women who take valproate during pregnancy have a greater chance of having a baby with a major birth defect or other health problem. Symptoms of FVS vary but may include characteristic facial features, spina bifida, congenital heart defects, cleft lip and/or cleft palate, genital abnormalities, skeletal abnormalities, and developmental delay. A child exposed to valproic acid may be at a higher risk for learning and behavioral problems. Although there is no cure for FVS, many of the possible signs and symptoms of FVS do have treatments or therapies available. Early intervention programs may also be helpful. The U.S. Food and Drug Administration (FDA) advises that valproate and related products should not be taken by women for the prevention of migraine headaches during pregancy. With regard to valproate use in pregnant women with epilepsy or bipolar disorder, valproate products should only be prescribed if other medications are not effective in treating the condition or are otherwise unacceptable. However, it is important to note that women who are pregnant and taking a valproate medication should not stop their medication but should talk to their doctor or other trusted medical professional immediately. Stopping valproate treatment suddenly can cause serious and life-threatening medical problems to the woman or her baby. For example, the sudden discontinuation of valproate in pregnant women with seizures can result in persistent seizures, which can cause harm, including death, to the mother and/or the unborn baby. The FDA suggests a pregnant woman taking valproate or other anti-seizure medication should talk to her doctor or other trusted medical professional about registering with the North American Antiepileptic Drug Pregnancy Registry. The purpose of this registry is to collect information about the safety of anti-seizure medications during pregnancy. A pregnant woman taking anti-seizure medication can enroll in this registry by calling 1-888-233-2334. You can read more about the registry on the North American AED (Antiepileptic Drug) Pregnancy Registry website. It is suggested that physicians refer pregnant patients who are using valproate to register for an antiepileptic drug registration program called North American Antiepileptic Drug (NAAED) Pregnancy Registry: http://www.aedpregnancyregistry.org/ [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Fetal valproate syndrome	c0236026	6,429	gard	https://rarediseases.info.nih.gov/diseases/5447/fetal-valproate-syndrome	2021-01-18T18:00:29	{"mesh": ["C536525"], "omim": ["609442"], "orphanet": ["1906"], "synonyms": ["Valproic acid embryopathy", "Susceptibility to valproate embryopathy", "FVS", "Fetal valproic acid syndrome"]}
A number sign (#) is used with this entry because of evidence that peripheral neuropathy, myopathy, hoarseness, and hearing loss (PNMHH) is caused by heterozygous mutation in the MYH14 gene (608568) on chromosome 19q13. One such family has been reported. Clinical Features Choi et al. (2011) reported a large 5-generation Korean family with a complex phenotype of progressive peripheral neuropathy and distal myopathy, with later onset of hoarseness and hearing loss. Affected individuals developed distal muscle weakness at a mean age of 10.6 years, followed by progressive atrophy of these muscles. The lower limbs were more severely affected than the upper limbs, and the muscle weakness first affected anterior leg muscles and later posterior leg muscles. Three older patients, around age 40 years, reported proximal weakness of the thigh muscles. Most patients had foot deformities and a- or hyporeflexia, although none had sensory loss. Eight (53%) of 15 patients had hoarse voice, but none had dysphagia or vocal cord paresis. Audiologic studies showed late-onset sensorineural hearing loss in 5 (45%), all of whom were older than 28 years. Serum creatine kinase was mildly increased only in a few patients. Nerve conduction studies showed mildly reduced or normal sensory values, but peroneal nerves showed severely reduced compound motor action potentials (CMAPs). MRI showed fatty replacement in affected muscles, and muscle biopsies of 2 patients showed variation of fiber size and shape and subsarcolemmal accumulation of enlarged mitochondria with variably sized rectangular or elongated rhomboidal paracrystalline inclusions. The findings were consistent with both a myopathic and a neuropathic process. Inheritance The transmission pattern of the disorder in the family reported by Choi et al. (2011) was compatible with autosomal dominant inheritance. Mapping By genomewide linkage analysis, Choi et al. (2011) found linkage of the complex phenotype of peripheral neuropathy, myopathy, hoarseness, and hearing loss in a 5-generation Korean family to chromosome 19q13.3, with a maximum multipoint lod score of 3.794 at SNP (rs1058511) under an autosomal dominant inheritance model. Fine mapping of the chromosomal linkage region revealed a 2-point maximum lod score of 6.360 at D19S246. Molecular Genetics By candidate gene sequencing in the 19q13.3 linkage region for the phenotype of peripheral neuropathy, myopathy, hoarseness, and hearing loss, Choi et al. (2011) identified a heterozygous mutation in the MYH14 gene (608568.0006). INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Deafness, sensorineural (45%) SKELETAL Feet \- Foot deformities MUSCLE, SOFT TISSUES \- Distal muscle weakness (first affects anterior leg muscles, then posterior leg muscles) \- Distal muscle atrophy (lower limbs more affected than upper limbs) \- Proximal weakness of the lower limbs with longer disease duration \- MRI shows fatty replacement \- Muscle biopsy shows small rounded fibers \- Degenerating fibers \- Endomysial fibrosis \- Variation of fiber size and shape \- Fiber-type grouping \- Subsarcolemmal accumulation of enlarged mitochondria with variably sized rectangular or elongated rhomboidal paracrystalline inclusions NEUROLOGIC Central Nervous System \- Tremor (3 patients) Peripheral Nervous System \- Areflexia \- Hyporeflexia \- Nerve conduction studies show mildly reduced or normal sensory values \- Peroneal nerves show severely reduced CMAPs VOICE \- Hoarseness (53%) LABORATORY ABNORMALITIES \- Mildly increased serum creatine kinase MISCELLANEOUS \- Mean age at onset 10.6 years \- Progressive disorder \- Hearing loss and hoarseness occur later \- One Korean family has been reported (as of November 2011) MOLECULAR BASIS \- Caused by mutation in the nonmuscle myosin heavy chain 14 gene (MYH14, 608568.0006 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	PERIPHERAL NEUROPATHY, MYOPATHY, HOARSENESS, AND HEARING LOSS	c3280556	6,430	omim	https://www.omim.org/entry/614369	2019-09-22T15:55:39	{"omim": ["614369"], "orphanet": ["397744"], "synonyms": ["Peripheral neuropathy-myopathy-hoarseness-deafness syndrome"]}
A number sign (#) is used with this entry because spastic paraplegia-2 can be caused by mutation in the myelin proteolipid protein gene (PLP1; 300401) and is therefore allelic to Pelizaeus-Merzbacher disease (PMD; 312080). Description The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of Fink et al. (1996) and Fink (1997). Some forms of SPG are considered 'uncomplicated,' i.e., progressive spasticity occurs in isolation; others are considered 'complicated,' i.e., progressive spasticity occurs with other neurologic features. X-linked, autosomal dominant (see 182600), and autosomal recessive (see 270800) forms of SPG have been described. For discussion of genetic heterogeneity of X-linked SPG, see 303350. Clinical Features Johnston and McKusick (1962) reported a kindred in which the disorder began as 'pure' spastic paraparesis, but the patients later developed nystagmus, dysarthria, sensory disturbance, and mental retardation, with half the patients having optic atrophy. Later symptoms included muscle wasting, joint contractures, and a requirement for crutches or wheelchair by early adult life. Johnston and McKusick (1962) observed early onset, slow progression, and long survival with eventual involvement of the cerebellum, cerebral cortex and optic nerves as features of the X-linked recessive form. Thurmon et al. (1971) studied 2 rather extensively affected kindreds with X-linked spastic paraplegia, one of which was previously reported by Johnston and McKusick (1962). Ginter et al. (1974) examined the central nervous system at autopsy in 1 patient from the Johnston-McKusick kindred. Degeneration of both corticospinal and spinocerebellar traits was found. Many of the affected members showed cerebellar signs. Keppen et al. (1987) studied a large family in which 12 males had X-linked recessive uncomplicated spastic paraplegia. The disorder was characterized by hyperreflexia and spastic gait. Intelligence was normal, and there were no other complicating features such as optic atrophy or spinocerebellar manifestations. Goldblatt et al. (1989) described a family with complicated X-linked spastic paraplegia with manifestations including nystagmus, optic atrophy, intellectual handicap, and mild ataxia of the arms. Bonneau et al. (1993) reported a 3-generation family in which some members had a complicated form of spastic paraplegia with mental retardation, whereas others had mild spastic paraplegia and normal intelligence. One presumably heterozygous female had spastic paraparesis. Naidu et al. (1997) presented the case of a boy first examined at the age of 3.5 years for toe walking and frequent falls that had begun when he was 2 years old. He had intact cognition, delayed walking, progressive spastic paraparesis, and congenital nystagmus. The patient was found to have the same PLP1 mutation as in the family of Johnston and McKusick (1962) (see MOLECULAR GENETICS) and genealogic connections were subsequently established. Differences from the disorder in other members of the kindred were observed. His condition began at birth, whereas in the other boys it began when they began to walk or later. Most significantly, his MRI scan demonstrated patchy leukodystrophy, but this was to a lesser degree than usually seen in connatal Pelizaeus-Merzbacher disease. Nystagmus was of earlier onset than usual. The patient also had lysinuria as did his otherwise unaffected sister and mother, with normal urinary excretions of cystine, arginine, and ornithine, and no hyperammonemia. Since these individuals were clinically asymptomatic with a normal MRI scan and wildtype PLP alleles, the lysinuria was thought to be a benign finding segregating independently of the PLP mutation in this kindred. The lysinuria was thought to be very similar to that described by Whelan and Scriver (1968); see 222690. Gorman et al. (2007) reported a boy with SPG2 due to a hemizygous mutation in the PLP1 gene (300401.0026). He presented at age 10 years with poor school performance, diplopia, and clumsiness after an upper respiratory infection. MRI showed multifocal areas of T2 white matter hyperintensities. Treatment with high-dose intravenous methylprednisolone resulted in clinical improvement. Over the next few years, he had episodes of neurologic deterioration characterized by nystagmus, dysmetria, ataxia, tremor, and progressive cognitive decline. These episodes responded temporarily to methylprednisolone treatment, suggesting an inflammatory process. The patient even fulfilled the criteria for relapsing-remitting multiple sclerosis (MS; 128200), including the presence of oligoclonal bands in the CSF. His mother, who carried the mutation, developed tremor and incoordination in her late forties, although this was complicated by alcohol abuse. A grandfather with the mutation was asymptomatic except for mild tremor. Mapping Linkage studies by Keppen et al. (1987) demonstrated location of the locus for this disorder, designated SPG2, on the middle of the long arm of the X chromosome. The markers to which this pure form of spastic paraplegia was linked (DXS17 and another marker identified by probe YNH3) are located in the Xq21-q22 region. Goldblatt et al. (1989) described a family with complicated X-linked spastic paraplegia and tight linkage to a marker located at Xq13-q21.1. By multipoint linkage analysis, Bonneau et al. (1993) located the SPG2 locus at Xq21. Bonneau et al. (1993) suggested that there is variable clinical expression of a single gene at the SPG2 locus, accounting for both complicated and uncomplicated forms of X-linked spastic paraplegia. Molecular Genetics While narrowing the genetic interval containing the SPG2 gene in the X-linked SPG family reported by Bonneau et al. (1993), Saugier-Veber et al. (1994) found that the gene for proteolipid protein was the closest marker, implicating PLP as a possible candidate gene. In an affected male, they found a his139-to-tyr mutation in exon 3B of the PLP gene (300401.0012) and showed that it segregated with the disease (maximum lod = 6.63 at theta = 0.00). The PLP gene encodes 2 myelin proteins, PLP and DM20; the his139-to-tyr mutation resulted in a mutant PLP, but a normal DM20. Saugier-Veber et al. (1994) concluded that SPG2 and Pelizaeus-Merzbacher disease are allelic disorders. Kobayashi et al. (1994) demonstrated that the family with X-linked SPG described by Johnston and McKusick (1962) showed linkage of the disease phenotype to markers in the region Xq21.3-q24 which includes the PLP locus. By SSCP and direct sequencing methods, they found a T-to-C transition in exon 4 of the PLP gene in affected males in this family, which altered isoleucine to threonine at residue 186 (300401.0013). The ile186-to-thr mutation altered both the PLP and DM20 protein products, in contrast to the his139-to-tyr X-linked SPG mutation which altered only PLP. Cailloux et al. (2000) investigated 28 SPG families without large PLP duplications or deletions by PCR amplification and sequencing of the 7 coding regions and the splice sites of the PLP gene. Abnormalities were identified in 4 (14%) of the cases. Clinical severity was found to be correlated with the nature of the mutation when compared to the more severe allelic PMD. The 4 mutations identified were either splice site mutations or changes in the PLP-specific intracytoplasmic B-C loop of the protein (exon 3B). Inoue (2005) provided a detailed review of SPG2 and the PLP1 gene. Lee et al. (2006) reported a patient with a mild form of SPG2 who also had a peripheral axonal neuropathy. Although there were no mutations, duplications, or deletions in the PLP1 gene, detailed molecular analysis detected a small duplication of less than 150 kb approximately 136 kb downstream of the PLP1 gene in the patient and his unaffected mother. Lee et al. (2006) suggested that the duplication resulted in silencing of the PLP1 gene by position effect since the patient's relatively mild phenotype resembled that seen with PLP1-null mutations. Animal Model Nixon and Conneally (1968) described hind-leg paralysis as an X-linked trait in the Syrian hamster. This may be homologous to X-linked spastic paraplegia in man. The mutation in the PLP1 gene (300401.0013) identified in affected patients with SPG2 by Kobayashi et al. (1994) is identical to the mutation identified in the 'rumpshaker' mouse model (Schneider et al., 1992). 'Rumpshaker' is an allele of the 'jimpy' locus. 'Jimpy' mice are clinically similar to PMD and show failure of development and differentiation of oligodendrocytes leading to early death. 'Rumpshaker' mice, although myelin-deficient like other jimpy mutants, have normal longevity and a full complement of morphologically normal oligodendrocytes. Affected mice show a generalized tremor at about 12 days of age, which generally becomes confined to the rear end. The differences between 'rumpshaker' and other 'jimpy' alleles suggested a dual function of PLP: it is required for early development and survival of oligodendrocytes, and also in the terminal stages of myelin compaction. History Blumel et al. (1957) reported a likely case of X-linked spastic paraplegia. From Maine, Baar and Gabriel (1966) reported a kindred with 13 affected males in 3 generations and 5 sibships. Mental retardation and death before age 1 year were features. The oldest survivor was aged 44 years. Bundey and Griffiths (1977) published an X-linked recessive pedigree of spastic athetosis that they concluded was probably the same condition as that reported by Baar and Gabriel (1966). A total of 7 males were thought to be affected. The proband developed athetosis of all 4 limbs and spasticity in the legs by 11 months. He had occasional grand mal seizures and occasional myoclonus. He was never able to stand or walk. At age 13 he was moderately retarded. Uric acid metabolism in him and other affected members of the pedigree was normal. Gutmann et al. (1990) presented extensive studies of a family in which 5 brothers in a sibship of 7 had complicated hereditary spastic paraparesis with evidence on magnetic resonance imaging of bilateral posterior periventricular white matter lesions. The findings did not appear to be consistent with any other well-described spastic paraplegia condition. Three of the 4 living brothers showed red-green color vision defects. Preliminary RFLP analysis demonstrated no linkage to St14 (DXS52). INHERITANCE \- X-linked recessive HEAD & NECK Eyes \- Nystagmus \- Optic atrophy SKELETAL Limbs \- Joint contractures Feet \- Pes cavus MUSCLE, SOFT TISSUES \- Atrophy NEUROLOGIC Central Nervous System \- Lower limb weakness \- Lower limb spasticity \- Spastic gait \- Hyperreflexia \- Extensor plantar responses \- Dysarthria \- Dysmetria \- Ataxia \- Cerebellar signs \- Mental retardation \- Upper limb involvement \- Degeneration of the lateral corticospinal tracts \- Degeneration of the spinocerebellar tracts MISCELLANEOUS \- Onset in childhood \- Highly variable phenotype \- Pelizaeus-Merzbacher disease (PMD, 312080 ) is an allelic disorder MOLECULAR BASIS \- Caused by mutation in the proteolipid protein 1 gene (PLP1, 300401.0012 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	SPASTIC PARAPLEGIA 2, X-LINKED	c1839264	6,431	omim	https://www.omim.org/entry/312920	2019-09-22T16:17:15	{"doid": ["0110773"], "mesh": ["C536857"], "omim": ["312920"], "orphanet": ["99015"], "synonyms": ["Alternative titles", "SPPX2"], "genereviews": ["NBK1182"]}
For a general discussion of susceptibility to infection by Mycobacterium tuberculosis, see 607948. Bellamy et al. (2000) conducted a 2-stage genomewide linkage study of 136 African families to search for regions of the human genome containing tuberculosis susceptibility genes. They used sib-pair families that contained 2 full sibs who had both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis susceptibility gene, affected sib-pairs inherit the same parental alleles much more than expected by chance. In the first round of the screen, 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sib-pairs from The Gambia and South Africa. In this process, they identified 7 chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis. From these regions, 22 markers were genotyped in a second set of 81 sib-pairs from the same countries. Markers on 15q11-q13 and Xq showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. An X chromosome susceptibility gene might contribute to the excess of males with tuberculosis observed in many different populations. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO, X-LINKED	c1866629	6,432	omim	https://www.omim.org/entry/300259	2019-09-22T16:20:36	{"omim": ["300259"], "synonyms": ["Alternative titles", "MTBSX"]}
The endemic nephropathy commonly called 'Balkan' is more properly called Danubian. It occurs in a relatively restricted rural area of Roumania, Bulgaria and Yugoslavia near the Danubian Iron Gates. Clinical, epidemiologic and laboratory investigations are thought to have excluded selected forms (although not necessarily all forms) of infection, parasitism, intoxication, and radiation. 'No genetic factors are evident. Of paramount importance are household factors and living conditions' (Craciun and Rosculescu, 1970). On the other hand these authors state that 'the disease in a family may disappear within two or three generations.' The histologic end stage of the kidney lesion is thought to be a form of primary amyloidosis. Nephropathia epidemica (NE) is endemic in Scandinavia, European Russia, and the Balkans (Lee and van der Groen, 1989). Mustonen et al. (1996) stated that the causative agent, Puumala virus, is a member of the hantavirus genus. Korean hemorrhagic fever is caused by one hantavirus serotype and the Balkan form by another. The natural host of hantaviruses are chronically but asymptomatically infected rodents and insectivores, which transmit the virus to humans in their excretions. Transmission from human to human has not been reported. A hantavirus pulmonary syndrome was described by Duchin et al. (1994) in U.S. patients. There is considerable variability in the clinical severity of NE. As judged from the seroprevalence in Finland (6%), many infections must be subclinical or undiagnosed. In 74 adult patients with NE, Mustonen et al. (1996) found that patients with the most severe course of the disease had a very high frequency of HLA-B8 (142830), C4AQ0 (120810), and DRB10301 (142857) alleles. HLA-B8 was found in all 7 cases (100%) with shock and in 9 of the 13 (69%) patients who required dialysis, versus only 25 of 74 (34%) in the entire population, and 14 of 93 (15%) controls. Toncheva and Dimitrov (1996) performed chromosome studies of healthy relatives of patients with Balkan endemic nephropathy who were born in nonendemic areas and found a high frequency of abnormalities at 3q25. The authors concluded that an increased frequency of nonrandom 3q25 aberrations may be involved in the development of the disease even in the absence of exposure to a 'BEN' environment. Toncheva et al. (1988) observed mosaicism for t(1;3)(q11.2;q25) in a patient with BEN. Stefanovic (1998) interpreted the accumulating evidence that BEN is an environmentally induced disease. Weathering of low-rank coals near the villages where BEN is endemic produces water-soluble polycyclic aromatic hydrocarbons and aromatic amines, similar to metabolic products of acetaminophen that cause analgesic nephropathy. Familial aggregation of BEN was first described by Danilovic et al. (1957). Stefanovic (1998) pointed out that the development of BEN in emigrants from the endemic region who resettled far away supports the role of inheritance in the disorder. An increased incidence of tumors of the renal pelvis and ureter in the population from endemic settlements has been observed. Familial clustering of urinary tract tumors was also reported from these areas. GU \- Endemic nephropathy \- Primary amyloid renal disease Inheritance \- No proved genetic factors ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	DANUBIAN ENDEMIC FAMILIAL NEPHROPATHY	c0004698	6,433	omim	https://www.omim.org/entry/124100	2019-09-22T16:42:35	{"doid": ["3052"], "mesh": ["D001449"], "omim": ["124100"], "icd-10": ["N15.0"], "synonyms": ["Alternative titles", "DEFN", "BALKAN ENDEMIC NEPHROPATHY", "NEPHROPATHIA EPIDEMICA"]}
A number sign (#) is used with this entry because of evidence that Joubert syndrome-25 (JBTS25) is caused by homozygous or compound heterozygous mutation in the CEP104 gene (616690) on chromosome 1p36. Description Joubert syndrome-25 is an autosomal recessive ciliopathy characterized by delayed psychomotor development and oculomotor apraxia associated with cerebellar hypoplasia manifest as the molar tooth sign on brain imaging. The clinical manifestations appear to be confined to the neurologic system, as patients tend not to have additional renal, liver, or limb involvement (summary by Srour et al., 2015) For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300. Clinical Features Srour et al. (2015) reported 3 unrelated children with Joubert syndrome. All had a neurologic form of the disorder characterized by significantly delayed psychomotor development, oculomotor apraxia, and the molar tooth sign on brain imaging. Two patients had hypotonia and ataxia, 1 had breathing abnormalities, and 1 had an abnormal electroretinogram. None had renal, liver, or limb abnormalities. Inheritance The transmission pattern of JBTS25 in the families reported by Srour et al. (2015) was consistent with autosomal recessive inheritance. Molecular Genetics In 3 unrelated children with Joubert syndrome-25, Srour et al. (2015) identified homozygous or compound heterozygous mutations in the CEP104 gene (616690.0001-616690.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies and studies on patient cells were not performed. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Oculomotor apraxia \- Abnormal electroretinogram (in some patients) RESPIRATORY \- Respiratory abnormalities (in some patients) MUSCLE, SOFT TISSUES \- Hypotonia (in some patients) NEUROLOGIC Central Nervous System \- Delayed psychomotor development, severe \- Ataxia (in some patients) \- Cerebellar hypoplasia \- Molar tooth sign MISCELLANEOUS \- Onset in infancy \- Three unrelated patients have been reported (last curated February 2016) MOLECULAR BASIS \- Caused by mutation in the 104-kD centrosomal protein gene (CEP104, 616690.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	JOUBERT SYNDROME 25	c4084842	6,434	omim	https://www.omim.org/entry/616781	2019-09-22T15:47:56	{"doid": ["0110994"], "omim": ["616781", "213300"], "orphanet": ["475"], "synonyms": ["CPD IV", "Cerebelloparenchymal disorder IV", "Classic Joubert syndrome", "Joubert syndrome type A", "Joubert-Boltshauser syndrome", "Pure Joubert syndrome"], "genereviews": ["NBK1325"]}
A rare glial tumor originating from pituicytes, the specialized glial cells of the neurohypophysis, characterized by a sellar or suprasellar mass manifesting with clinical signs secondary to mass effect. Typical manifestations are visual disturbances, headaches, and hypopituitarism. Pituicytomas are low-grade tumors, and prognosis is good after total resection. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Pituicytoma	c2986550	6,435	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251623	2021-01-23T17:07:41	{"umls": ["C2986550"], "icd-10": ["C71.9"]}
A number sign (#) is used with this entry because autosomal recessive nonsyndromic mental retardation-3 can be caused by homozygous mutation in the CC2D1A gene (610055). Clinical Features Basel-Vanagaite et al. (2003) studied nonsyndromic mental retardation in 4 consanguineous families of Israeli-Arab origin with 10 affected and 24 unaffected members. All families originated from the same small village and had the same family name. Basel-Vanagaite et al. (2006) reported 5 additional families with nonsyndromic mental retardation from the same village with the same family name, for a total of 16 affected individuals. The initial clinical presentation in all affected family members was psychomotor developmental delay in early childhood. All had no or only single words and were severely mentally retarded; none had autistic features or seizures, and there were no dysmorphic features. Mapping In 4 consanguineous, interrelated Israeli-Arab families with nonsyndromic mental retardation from the same village, Basel-Vanagaite et al. (2003) established linkage with marker D19S840 at 19p13.2-p13.12 (maximum lod = 7.06 at theta = 0.00). All affected individuals were found to be homozygous for a common haplotype within a 2.4-Mb critical region between the markers D19S547 proximally and D19S1165 distally. In 4 consanguineous Israeli-Arab families originally reported by Basel-Vanagaite et al. (2003) and 5 additional families with nonsyndromic mental retardation from the same village and with the same family name, Basel-Vanagaite et al. (2006) identified a common homozygous disease-bearing haplotype for the polymorphic markers RFX1 and D19S840 that defined a critical 0.9-Mb region between D19S564 and D19S547 on chromosome 19p13.12. Basel-Vanagaite et al. (2006) suggested that the disease was caused by a single mutation derived from a single ancestral founder in all the families. Molecular Genetics In 9 consanguineous Israeli-Arab families with nonsyndromic mental retardation from the same village and with the same family name, Basel-Vanagaite et al. (2006) analyzed 14 candidate genes located in a haplotype-defined critical region on chromosome 19p13.12. Homozygosity for a protein-truncating mutation in the CC2D1A gene (610055.0001) was identified in all affected family members; parents were heterozygous for the mutation. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Dull facial expression NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation, severe \- Limited verbal comprehension \- Speech limited to single word or no words \- Incomprehensible speech Behavioral Psychiatric Manifestations \- Dull facial expression \- Hyperactivity \- Easily frustrated \- Short attention span MISCELLANEOUS \- Onset in early childhood MOLECULAR BASIS \- Caused by mutation in the coiled-coil and C2 domain-containing 1A gene (CC2D1A, 610055.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	MENTAL RETARDATION, AUTOSOMAL RECESSIVE 3	c1838023	6,436	omim	https://www.omim.org/entry/608443	2019-09-22T16:07:51	{"doid": ["0060308"], "mesh": ["C563929"], "omim": ["608443"], "orphanet": ["88616"], "synonyms": ["AR-NSID", "NS-ARID"]}
## Summary ### Clinical characteristics. KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes caused by a heterozygous pathogenic variant in KCNQ2. The clinical features of KCNQ2-related disorders range from KCNQ2-related benign familial neonatal epilepsy (KCNQ2-BFNE) at the mild end to KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE) at the severe end. * KCNQ2-BFNE is characterized by a wide spectrum of seizure types (tonic or apneic episodes, focal clonic activity, or autonomic changes) that start in otherwise healthy infants between the second and eighth day of life and spontaneously disappear between the first and the sixth to 12th month of life. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are generally brief, lasting one to two minutes. Rarely, KCNQ2-BFNE may evolve into status epilepticus. About 10%-15% of individuals with BFNE develop epileptic seizures later in life. * KCNQ2-NEE is characterized by multiple daily seizures beginning in the first week of life that are mostly tonic, with associated focal motor and autonomic features. Seizures generally cease between ages nine months and four years. At onset, EEG shows a burst-suppression pattern or multifocal epileptiform activity; early brain MRI can show basal ganglia and thalamic hyperintensities that later resolve. Moderate to severe developmental impairment is present. ### Diagnosis/testing. The diagnosis relies on the presence of characteristic clinical findings and heterozygous pathogenic variants in KCNQ2 (also known as Kv7.2), which codes for voltage-gated potassium channel subunits. ### Management. Treatment of manifestations: * KCNQ2-BFNE. The majority of children can be kept seizure-free by using phenobarbital (20 mg/kg as loading dose and 5 mg/kg/day as maintenance dose). In some affected individuals, seizures require other antiepileptic drugs (AEDs). * KCNQ2-NEE. Children have multiple daily seizures resistant at onset to phenobarbital and other common old- and new-generation AEDs, alone or in combination. Sodium channel blockers like phenytoin (PHT) or carbamazepine (CBZ) were shown to control seizures in several patients and should be considered first-line treatment. Surveillance: * KCNQ2-BFNE. EEG at age three, 12, and 24 months is appropriate. At 24 months EEG should be normal. * KCNQ2-NEE. EEG monitoring is highly recommended, although specific guidelines are not available. ### Genetic counseling. KCNQ2-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with KCNQ2-BFNE have an affected parent; however, a proband may have KCNQ2-BFNE as the result of a de novo pathogenic variant. Almost all individuals with KCNQ2-NEE have a de novo pathogenic variant. Each child of an individual with a KCNQ2-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known. ## Diagnosis KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes ranging from KCNQ2-related benign familial neonatal epilepsy (BFNE) at the mild end to KCNQ2-related neonatal epileptic encephalopathy (NEE) at the severe end. ### Testing In KCNQ2-BFNE, all laboratory tests are normal, including brain CT and MRI. In KCNQ2-NEE, brain MRI frequently shows bilateral or asymmetric hyperintensities in the basal ganglia, and sometimes in the thalamus; these may resolve over time. Other common findings are small frontal lobes with increased adjacent extra-axial spaces, thin corpus callosum, and decreased posterior white matter volume. ### Establishing the Diagnosis The diagnosis of a KCNQ2-related disorder is established in a proband with a characteristic history and examination when a heterozygous pathogenic variant is identified in KCNQ2 by molecular genetic testing (see Table 1). Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing: * Single-gene testing. Sequence analysis of KCNQ2 is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. * A multigene panel that includes KCNQ2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes KCNQ2) fails to confirm a diagnosis in an individual with features of a KCNQ2-related disorder. Such testing may provide an unexpected or previously unconsidered diagnosis, such as mutation in another gene that causes a similar clinical presentation. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in KCNQ2-Related Disorders View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method KCNQ2Sequence analysis 3 * 60%-80% in familial KCNQ2-BFNE 4 * Nearly 100% of the KCNQ2 variants responsible for NEE are missense detectable by direct sequence analysis. Gene-targeted deletion/duplication analysis5 * 20%-40% of KCNQ2-BFNE 6 * No deletions/duplications described in individuals with KCNQ2-NEE 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. In 60% and 80% of probands with BFNE, a likely-pathogenic variant in KCNQ2 can be found (17/30 [Singh et al 2003]; 27/33 [Grinton et al 2015]). In 10/80 [Weckhuysen et al 2012] or 11/84 [Weckhuysen et al 2013] of individuals with unexplained neonatal or early-infantile seizures and psychomotor retardation with a negative family history, a pathogenic de novo KCNQ2 variant can be detected (~10% overall). This figure is higher if probands with neonatal-onset EE only are included (3/12 [Saitsu et al 2012]) or if individuals with epilepsy onset in the first three months are included (16/71 [Milh et al 2013]). It is lower (5%) if individuals with later-onset infantile seizures (West syndrome) are also included (12/239 [Kato et al 2013]). 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. In BFNE, one large duplication and several large deletions involving KCNQ2, some also involving contiguous genes, have been reported [Singh et al 1998, Heron et al 2007, Kurahashi et al 2009, Soldovieri et al 2014, Grinton et al 2015]. Deletions or duplications of KCNQ2 were found in 4/21 individuals with BFNE, benign familial neonatal-infantile seizures (BFNIS), or simplex neonatal seizures (i.e., a single occurrence in a family) in whom no coding or splice site pathogenic variants had been identified in either KCNQ2 or KCNQ3. Among families with BFNE, the detection rate was 4/9 cases [Heron et al 2007]. In the RIKEE database (www.rikee.org), which contains information about KCNQ2 variants that have been published in the medical literature through December 2015, nine submicrosopic deletions are reported among 119 reported unrelated BFNE cases/pedigrees (7.6%). For information about KCNQ3 see Differential Diagnosis. ### Suggestive Findings KCNQ2-related disorders should be suspected in individuals with the following two presentations. KCNQ2-related benign familial neonatal epilepsy (KCNQ2-BFNE) [Berg et al 2010] is characterized by the following general features: * Seizures starting between two and eight days after term birth and spontaneously disappearing between the first and the sixth to the 12th month of life in an otherwise healthy infant * Normal physical examination and laboratory tests prior to, between, and after seizures * No specific EEG criteria Seizure features include the following [International League Against Epilepsy 1989, Ronen et al 1993, Engel 2001]: * A wide spectrum of seizure types is seen, encompassing tonic (often focal) or apneic episodes, focal clonic activity, or autonomic changes. * Ictal motor activity may be confined to one limb, migrate to other body regions, or generalize. * Seizures are generally brief, lasting one to two minutes. However, they may be very frequent and cause considerable concern, especially if the proband is the first family member being affected. * Infants are well between seizures, feed normally, and show normal social and motor developmental progression. * Rarely, seizures occur in a crescendo of activity, with a possible evolution into status epilepticus. * Interictal EEG may be normal, rarely showing a pattern of "theta pointu alternant." * Ictal EEG shows focal discharges with possible secondary generalization. KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE) is characterized by the following: * Seizure onset occurs in the first week of life. * Seizures are mostly tonic, with associated focal motor and autonomic features (similar to KCNQ2-BFNE). * Multiple daily seizures occur at onset, with frequent seizures in the first few months to the first year of life. * Cessation of seizures generally occurs between age nine months and four years. * Encephalopathy is present from birth and persists during and after the period when seizures are uncontrolled. Subsequently, developmental impairment is moderate in about one third of individuals, and severe to profound in the remaining two thirds. * EEGs in the first week of life show a burst suppression pattern or multifocal epileptiform activity. * Over time, seizure frequency diminishes, and interictal epileptiform discharges become less frequent. EEGs after seizure freedom is achieved are normal or show mild slow background activity. ### Contiguous Gene Rearrangements In two individuals with BFNE in whom exon deletions in KCNQ2 were identified, concomitant deletions of the adjacent gene CHRNA4, encoding the cholinergic receptor, nicotinic alpha 4 subunit, have been described [Kurahashi et al 2009]. The clinical course in these individuals was that of typical BFNE, and neither had the phenotype of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), another focal epilepsy caused by pathogenic missense (but not deletion) variants in CHRNA4. Individuals with chromosomal microdeletions at 20q13.33 were shown to have epileptic seizures mostly beginning within the neonatal period and disappearing by age four months, similar to epilepsy phenotypes of BFNE; developmental outcome was good in patients with deletion restricted to CHRNA4, KCNQ2, and COL20A1, whereas delay in developmental milestones and behavioral problems such as autistic spectrum disorder was observed in patients with a wider range of deletion [Traylor et al 2010, Pascual et al 2013, Okumura et al 2015]. ## Clinical Characteristics ### Clinical Description KCNQ2-related disorders include a continuum of overlapping neonatal-onset epileptic phenotypes ranging from benign familial neonatal epilepsy at the mild end to epileptic encephalopathy at the severe end. #### KCNQ2-Related Benign Familial Neonatal Epilepsy (KCNQ2-BFNE) Seizures in neonates with KCNQ2-BFNE start between age two and eight days of life and spontaneously disappear between the first and the sixth to 12th month of life in otherwise healthy infants, in a context of normal neuropsychological development and EEG recordings. Historically, the percentage of children with KCNQ2-BFNE who experience subsequent (i.e., post-infantile) focal or generalized seizures has been thought to be in the 10%-15% range [Ronen et al 1993, Plouin & Neubauer 2012]. However, in a recent comprehensive follow-up study in which 140 individuals (27 families) were followed for up to 25 years, post-infantile seizures recurred in 40 (31%). Although the characteristics of such recurrences were varied, three common patterns emerged: simple febrile seizures (n=18; 13%), seizures in childhood (n=14; 10%), and seizures primarily in adolescence or adulthood (n=19; 14%). A few children with KCNQ2-BFNE have been noted to develop an EEG trait characterized by centrotemporal spikes (CTS) and sharp waves or benign epilepsy with centrotemporal spikes (BECT) [Coppola et al 2003, Ishii et al 2012]. #### KCNQ2-Related Neonatal Epileptic Encephalopathy (KCNQ2-NEE) In rare instances, KCNQ2 pathogenic variants have been observed in families with KCNQ2-BFNE including one or more individuals who developed a therapy-resistant epileptic encephalopathy shortly after birth and a variable degree of intellectual disability by age four to five years [Alfonso et al 1997, Dedek et al 2003, Borgatti et al 2004]. In all these cases, the poor developmental outcome was not associated with neuroradiologic abnormalities suggestive of prenatal or perinatal damage. In light of more recent findings (see following), the BFNE phenotype of some family members could be explained by genetic mosaicism. More recently, a distinct neonatal epileptic encephalopathy linked to KCNQ2 pathogenic variants has been reported in eight of 80 probands with neonatal epileptic encephalopathy, early-onset refractory seizures, and intellectual disability of unknown origin [Weckhuysen et al 2012]. In most of these affected individuals, developmental delay was associated with axial hypotonia and/or spastic quadriplegia. Most patients are severely delayed in reaching developmental milestones, are nonverbal, or only use a few words or short sentences. Some are unable to sit independently, have poor eye contact, and show little interest in their surroundings. Seizures as well as early MRI brain abnormalities (mainly occurring in the basal ganglia and thalamus) generally resolved by age three years. After this first report, additional studies have identified novel KCNQ2 variants in individuals with neonatal epileptic encephalopathy [Allen et al 2013, Carvill et al 2013, Milh et al 2013, Weckhuysen et al 2013, Allen et al 2014, Dalen Meurs-van der Schoor et al 2014, Milh et al 2015, Pisano et al 2015]. At the most severe end of the spectrum, some affected individuals have symptoms that fall within the clinical description of Ohtahara syndrome [Saitsu et al 2012, Kato et al 2013, Martin et al 2014], an early-onset age-related epileptic encephalopathy characterized by typical suppression-burst EEG pattern within the first months of life and poor outcome in terms of psychomotor development and seizure control (see Differential Diagnosis). #### Other Rarer Phenotypes Myokymia. In two families with a KCNQ2 pathogenic variant (p.Arg207Trp) neonatal seizures were later followed by peripheral nerve hyperexcitability (myokymia) [Dedek et al 2001] or myoclonus-like dyskinesia [Blumkin et al 2012]. Myokymia in the absence of neonatal seizures was described in one individual with a KCNQ2 pathogenic variant who represented a simplex case (i.e., a single occurrence in a family) [Wuttke et al 2007]. Benign familial infantile seizures (BFIS) is characterized by later onset of seizures (age ~6 months). A KCNQ2 pathogenic variant has been detected in a Chinese family with BFIS [Zhou et al 2006]. In this case, the proband also developed paroxysmal myokymic episodes. Infantile spasms. Three children with a de novo KCNQ2 pathogenic variant who did not have neonatal seizures but onset of infantile spasms at a few months of age have been reported [Allen et al 2013, Carvill et al 2013, Weckhuysen et al 2013]. They all had concomitant intellectual disability. ### Genotype-Phenotype Correlations Given the rarity of KCNQ2-related disorders and the inter- and intrafamilial phenotypic variability, genotype-phenotype correlations are difficult to establish. Nonetheless, attempts are under way to correlate the KCNQ2 variant type with the clinical course and severity of the disease. In general, haploinsufficiency caused by the loss of function of a single KCNQ2 allele (nonsense, splice, or frameshift variant) is the most common cause of familial KCNQ2-BFNE. Pathogenic variants so far identified in KCNQ2-NEE are all de novo missense variants, and are thought to exert more severe functional defects on potassium current function [Miceli et al 2013, Orhan et al 2014]. Individuals harboring identical recurring pathogenic variants so far appear to have broadly similar seizure and developmental outcomes, although some cases in which clinical heterogeneity appears to be associated with the same variant are also present in the literature. For example, the p.Arg213Trp KCNQ2 pathogenic variant has been reported in a severely affected individual and in a family with BFNS [Sadewa et al 2008, Milh et al 2015]. Moreover, although neurodevelopmental outcome was overall poor among individuals with KCNQ2-NEE caused by the recurrent p.Ala294Val variant, and all infants had burst-suppression on EEG, one child appeared less impaired (i.e., sat up and spoke 3 words at age 2 years). Genetic background and environmental factors such as treatment and seizure duration may further influence the phenotypic expression of the variants. A few children with KCNQ2-NEE were born from mosaic parents (the pathogenic allele detected in blood, skin, and hair root samples ranging from 5% to 30% of cells). The neurologic development of the mosaic parents was normal, although several had neonatal seizures [Weckhuysen et al 2012, Milh et al 2015]; these ﬁndings suggest that in order to cause a persistent neurologic disease, KCNQ2 pathogenic variants with a more severe functional effect must be present in a sufﬁcient proportion of cells. ### Penetrance For KCNQ2-BFNE, penetrance is incomplete, with about 77%-85% of individuals heterozygous for a pathogenic variant in KCNQ2 showing neonatal or early-infantile seizures [Plouin & Neubauer 2012, Grinton et al 2015]. Penetrance is complete for germline variants leading to KCNQ2-NEE. No age- or sex-related differences have been reported. ### Nomenclature The familial occurrence of neonatal seizures was first reported by Rett & Teubel [1964], who described an epileptic syndrome in which children in three generations had neonatal seizures that mostly disappeared in girls after six to eight weeks but persisted in boys throughout adolescence. The neonatal seizures were not associated with perinatal complications, such as intracranial bleeding. The term "benign" was added to the designation "familial neonatal convulsions" by Bjerre & Corelius [1968], who described a five-generation family with neonatal convulsions but normal motor and mental development, highlighting the mostly favorable outcome of the syndrome. Subsequently it was noted that in rare instances, KCNQ2 pathogenic variants can be observed in children who develop a therapy-resistant epileptic encephalopathy shortly after birth and a variable degree of intellectual disability by age four to five years [Alfonso et al 1997, Dedek et al 2003, Borgatti et al 2004, Schmitt et al 2005]. Thus, the favorable outcome of this disorder implied by the name "benign" was questioned [Steinlein et al 2007]. More recent reports of certain KCNQ2 pathogenic variants leading to a neonatal epileptic encephalopathy with early-onset refractory seizures and intellectual disability of unknown origin have led to proposal of the name "KCNQ2 encephalopathy" [Weckhuysen et al 2012]. Because of the variable clinical phenotypes associated to pathogenic variants in KCNQ2, the authors refer to a spectrum of KCNQ2-related diseases ranging from self-limiting KCNQ2-BFNE to severe KCNQ2-NEE. ### Prevalence KCNQ2-related disorders comprise a large spectrum of phenotypes. Both KCNQ2-related classic BFNE and the recently described KCNQ2-NEE are rare. To date, about 100 families with KCNQ2-BFNE and about 100 individuals with KCNQ2-NEE from many different nationalities have been described in the literature. It is likely that many cases of KCNQ2-BFNE go untested and/or are not reported owing to the brief duration of symptoms and good outcome. KCNQ2-NEE is a very recently described syndrome. Therefore, at present, it is difficult to determine overall prevalence or ethnicity-dependent variability. ## Differential Diagnosis ### Other Causes of Benign Familial Neonatal Epilepsy (BFNE) KCNQ3, a close homolog of KCNQ2, encodes a voltage-gated potassium channel subunit that co-assembles with the KCNQ2 protein product [Wang et al 1998, Cooper et al 2000]. KCNQ3 is a minor locus for BFNE [Charlier et al 1998]. The clinical characteristics of BFNE caused by pathogenic variants in KCNQ2 or in KCNQ3 appear indistinguishable; thus, molecular genetic testing of both genes is commonly performed when BFNE is suspected. See KCNQ3-Related Disorders. Other genetic loci. The existence of other loci associated with BFNE cannot be excluded. Concolino et al [2002] reported a family in whom a pericentric inversion of chromosome 5 segregates with BFNE; no linkage to KCNQ2 or KCNQ3 was found in this family. Among 36 families with familial neonatal-onset seizures, three did not have pathogenic variants identified in KCNQ2 or KCNQ3, as well as in other genes associated with early-onset epilepsies (SCN2A or PRRT2); in these families, no linkage was found to any other chromosomal region [Grinton et al 2015]. ### Other Causes of Neonatal Epilepsy The diagnosis of BFNE is based on the absence of any other explanation for the seizures. The reason for ordering laboratory tests is, therefore, to exclude other possible causes of the seizures. Late hypocalcemia, vitamin B6 deficiency, hyperthyroidism, and benign sleep myoclonus should be excluded. It is also important not to miss a diagnosis of a treatable meningoencephalitis in the early stage or an intracranial hemorrhage. Both of these conditions in neonates lack the typical findings observed in older infants and children, and seizures may be the only early symptom. The following laboratory, imaging, and instrumental studies may be helpful for the differential diagnosis: * Chemistries * Basic metabolic panel plus serum concentration of calcium, magnesium, phosphorus * Evaluation of alpha-AASA levels in serum and urine as a biomarker of pyridoxine (vitamin B6)-dependent seizures, a rare genetic disorder of vitamin B6 metabolism caused by pathogenic variants in ALDH7A1 and characterized by neonatal-onset seizures that are resistant to common anticonvulsants, but controlled by daily treatment with vitamin B6 In this context it should be noted that in a recent study, a de novo KCNQ2 pathogenic variant (c.629G>A; p.Arg210His) was identified in a patient age seven years whose neonatal seizures showed a response to pyridoxine and who had a high plasma-to-CSF pyridoxal 5'-phosphate ratio but no further proof of an inborn error of vitamin B6 metabolism [Reid et al 2016]. * Thyroid function tests, as neonatal hyperthyroid state and thyrotoxicosis may be associated with excessive tremor and jitteriness, clinical conditions that should be differentiated from seizures * Basic hematologic labs. CBC, prothrombin time, activated partial thromboplastin time * Lumbar puncture. Cerebrospinal fluid examination to exclude neonatal meningoencephalitis or occult blood * MRI and/or CT scan of the brain. Indicated for any individual with neonatal seizures to exclude structural lesions and intracranial hemorrhage * Electroencephalography. No specific EEG trait characterizes BFNE during neonatal seizures; the interictal EEG is most commonly normal (50%-70% of infants). #### Later-Onset Benign Familial Seizures Two genetic conditions that can closely resemble BFNE in rare instances are benign familial infantile seizures (BFIS), in which seizure onset is around age six months, and benign familial neonatal-infantile seizures (BFNIS), in which seizures display an intermediate age of onset between the neonatal and infantile period [Berkovic et al 2004]. Only a few KCNQ2 pathogenic variants have been detected in families with BFIS or BFNIS [Zhou et al 2006, Zara et al 2013]. * BFIS is genetically distinct from BFNE, with at least three loci being involved. * In the largest percentage of affected families, pathogenic variants in PRRT2 can be identified (see PRRT2-Associated Paroxysmal Movement Disorders). PRRT2 encodes the proline-rich transmembrane protein 2 (PRRT2), a membrane protein that interacts with the presynaptic protein SNAP-25 [Heron et al 2012, Zara et al 2013]. * Additional families show linkage to chromosome locus 19q12-q13.1 [Guipponi et al 1997] (unknown gene; OMIM 601764) and 2q24, the latter involving SCN2A, encoding one of the main pore-forming subunits of neuronal voltage-gated sodium channels [Striano et al 2006] (OMIM 607745). * BFNIS is mainly caused by pathogenic variants in SCN2A [Heron et al 2002, Berkovic et al 2004] , and less frequently in KCNQ2 [Zara et al 2013]. #### Early-Infantile Epileptic Encephalopathies (EIEEs) KCNQ2-related neonatal epileptic encephalopathy (NEE) (recently classified as early-infantile epileptic encephalopathy type 7, or EIEE 7) should be distinguished from other early-onset epileptic encephalopathies, also characterized by recurrent seizures, prominent interictal epileptiform discharges, and poor neurocognitive development. Although epileptic encephalopathies are often associated with structural brain defects or inherited metabolic disorders, pathogenic variants may also be involved in the development of epileptic encephalopathies even when no clear genetic inheritance patterns or consanguinity exist [Gürsoy & Erçal 2016]. The EIEEs are genetically very heterogeneous. Based on the genes in which pathogenic variants have been found, current classification of EIEE is as follows: ### Table 2. Genetic Heterogeneity of Early-Infantile Epileptic Encephalopathies (EIEEs) View in own window Disease Name (OMIM/GeneReview)GeneMOI EIEE1 (308350)ARXXL EIEE2 (300672)CDKL5XL EIEE3 (609304)SLC25A22AR EIEE4 (STXBP1 Encephalopathy with Epilepsy)STXBP1AD EIEE5 (613477)SPTAN1AD EIEE6 (SCN1A-Related Seizure Disorders)SCN1AAD EIEE7 (613720)KCNQ2AD EIEE8 (300607)ARHGEF9XL EIEE9 (300088)PCDH19XL EIEE10 (613402)PNKPAR EIEE11 (613721)SCN2AAD EIEE12 (613722)PLCB1AR EIEE13 (SCN8A-Related Epilepsy with Encephalopathy)SCN8AAD EIEE14 (KCNT1-Related Epilepsy)KCNT1AD EIEE15 (615006)ST3GAL3AR EIEE16 (TBC1D24-Related Disorders)TBC1D24AR EIEE17 (615473)GNAO1AD EIEE18 (615476)SZT2AR EIEE19 (615744)GABRA1AD EIEE20 (300868)PIGAXL EIEE21 (615833)NECAP1AR EIEE22 (300896)SLC35A2XL EIEE23 (615859)DOCK7AR EIEE24 (615871)HCN1AD EIEE25 (615905)SLC13A5AR EIEE26 (615056)KCNB1AD EIEE27 (GRIN2B-Related Neurodevelopmental Disorder)GRIN2BAD EIEE28 (616211)WWOXAR EIEE29 (616339)AARS1AR EIEE30 (616341)SIK1AD EIEE31 (616346)DNM1AD EIEE32 (616366)KCNA2AD EIEE33 (616409)EEF1A2AD EIEE34 (SLC12A5-Related Epilepsy of Infancy with Migrating Focal Seizures)SLC12A5AR EIEE35 (616647)ITPAAR AD = autodomal dominant; AR = autosomal recessive; EIEE = early-infantile epileptic encephalopathy; MOI = mode of inheritance; XL = X-linked Several of these EIEEs can have neonatal onset of seizures, including those associated with pathogenic variants in ARX, SLC25A22, CDKL5, STXBP1, PLCB1, SCN2A, KCNT1, and SLC13A5. Some specific clinical features can point toward a certain gene other than KCNQ2, such as the presence of prominent movement disorders in ARX- and SCN2A-related EIEE [Howell et al 2015], a hypermotor-tonic-spasm seizure phenotype in girls with pathogenic CDKL5 variants [Klein et al 2011], or convulsive seizures and hypodontia in SLC13A5-related EIEE [Hardies et al 2015]. Also, unlike many EIEEs, those caused by KCNQ2 pathogenic variants are characterized by decreasing frequency of seizures over the first few months or years of life. Ohtahara syndrome is the most severe and the earliest developing age-related epileptic encephalopathy, characterized by tonic seizures occurring within the first three months of life, often within the first two weeks. Seizures that can be either generalized or lateralized may occur singly or in clusters, and are independent of the sleep cycle. The EEG in individuals with Ohtahara syndrome typically shows bursts of high-amplitude spikes and polyspikes that alternate at a regular rate with periods of electric suppression (suppression-burst EEG pattern). Psychomotor development and prognosis are generally very poor. Clinical features of Ohtahara syndrome can be caused by pathogenic variants in several genes, including ARX (EIEE1), CDKL5 (EIEE2), SLC25A22 (EIEE3), STXBP1 (EIEE4), and SCN2A (EIEE11) [Mastrangelo & Leuzzi 2012, Pavone et al 2012, Mastrangelo 2015]. Since its description, several individuals diagnosed with Ohtahara syndrome have been found to carry pathogenic variants in KCNQ2 (EIEE7). Mosaic chromosome 20 ring [r(20)] is a chromosomal disorder that has been associated with a rare syndrome, consisting of refractory epilepsy with non-convulsive status epilepticus (NCSE) and cognitive problems [Inoue et al 1997]. FISH analyses have not shown deletions of the telomeric and subtelomeric chromosome 20 regions and, more particularly, no deletion of CHRNA4 or KCNQ2 [Zou et al 2006, Elghezal et al 2007]. Although differential diagnosis is rather straightforward because of the later (non-neonatal) onset of seizures in r(20), the direct physical link between distal 20p and 20q segments in the ring structure may disturb the correct expression or the regulation of genes located near the telomeric regions, including subtelomeric CHRNA4 and KCNQ2 [Giardino et al 2010]. ## Management ### Evaluations Following Initial Diagnosis KCNQ2-related disorders represent a broad prognostic spectrum, and evaluation following a positive KCNQ2 genetic test differs depending on severity of the phenotype. Individuals with benign familial neonatal epilepsy (BFNE) * In-depth neurologic examination * Developmental evaluation Individuals with neonatal epileptic encephalopathy (NEE) * Video EEG monitoring including sleep phase to obtain information on presence of seizures. A burst suppression EEG pattern might only be seen during sleep. * Cognitive and behavioral neuropsychological testing * Assessment of digestive and other non-neurologic comorbidities All individuals with a KCNQ2-related disorder. Consultation with a clinical geneticist and/or genetic counselor is also recommended. ### Treatment of Manifestations KCNQ2-BFNE. Seizures in individuals with BFNE are generally controlled with conventional antiepileptic treatment. Phenobarbital and phenytoin (loading doses of 15-20 mg/kg; maintenance doses of 3-4 mg/kg for both agents) [Painter et al 1981] are the antiepileptic drugs (AEDs) most commonly used to treat neonatal seizures. Because of concerns over the suboptimal effectiveness and safety of phenytoin and phenobarbital, other anticonvulsants, such as levetiracetam and topiramate, are often used (off-label and despite limited data) in neonates with refractory seizures [Tulloch et al 2012]. Refractory seizures are uncommon in KCNQ2-related BFNE. KCNQ2-NEE. Children with KCNQ2-related neonatal epileptic encephalopathy generally present with tonic seizures accompanied by motor and autonomic features, similar to seizures in KCNQ2-BFNE. However, individuals with KCNQ2-NEE clearly differ from those with KCNQ2-BFNE as to seizure response. Although seizure response to any of the AEDs has been described in isolated patients, many patients at onset show multiple daily seizures resistant to multiple common old- and new-generation AEDs, alone or in combination. Seizures then tend to gradually decrease by age nine months to four years [Weckhuysen et al 2012]. A favorable response to drugs acting on voltage-gated sodium channels has been suggested in several studies [Kato et al 2013, Weckhuysen et al 2013, Numis et al 2014, Pisano et al 2015]. It has been suggested that early effective treatment reduces cognitive disability [Pisano et al 2015]; however, it remains a matter of debate whether early control of seizures translates to better neuropsychological outcome. VGB or ACTH therapy can be tried for treatment of infantile spasms that can occur during the course of the disease [Dedek et al 2003, Borgatti et al 2004, Serino et al 2013]. Management should further focus on the optimization of the patient's functional and communication skills. A multidisciplinary team approach including physiotherapists, speech therapists, and behavioral therapists is best suited to addressing the individual's needs. Augmentative communication techniques can be valuable for many patients. ### Prevention of Secondary Complications As seizure frequency tends to decrease with age, the option to taper and eventually stop AED after a sufficient seizure-free period should be considered in order to prevent complications of long-term AED use. Some children may require lifelong antiepileptic treatment. ### Surveillance KCNQ2-BFNE. EEG at age three, 12, and 24 months is appropriate. The EEG at 24 months should be normal. KCNQ2-NEE. Video-EEG monitoring is appropriate when new or different seizure types are suspected. Serial neuropsychological evaluation of neurologic, cognitive, and behavioral problems is advised. Regular follow up by a multidisciplinary team with particular attention to nutritional intake, gastrointestinal function, mobility, and communication skills is recommended. ### Agents/Circumstances to Avoid In patients with known gain-of-function pathogenic variants in KCNQ2, the use of the potassium channel opener retigabine/ezogabine may be contraindicated. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management The pregnancy management of a woman with a KCNQ2 pathogenic variant and epilepsy does not differ from that of any other pregnant woman with a seizure disorder. A fetus with a KCNQ2 pathogenic variant may have neonatal seizures in the first few days of life. Therefore, a woman who is carrying a fetus at risk of inheriting a KCNQ2-related disorder should consider delivering in a hospital with a neonatal intensive care unit. ### Therapies Under Investigation A recent report described a positive effect of vitamin B6 on seizures in a few patients with KCNQ2-NEE [Reid et al 2016], but further studies are needed to confirm the antiepileptic effect of pyridoxine in the absence of an inherited disorder of vitamin B6 metabolism. The selective neuronal KCNQ potassium channel opener retigabine/ezogabine, an AED introduced in 2013 as adjunctive treatment of partial epilepsy in adults [Porter et al 2012], may represent a targeted therapy for KCNQ2-NEE. However, the discovery of additional side effects in the early post-marketing (blue discoloration of skin and retina) raise concerns about its use in children. Although a good effect on seizures was described in one patient [Weckhuysen et al 2013], additional experience has not yet been reported. Furthermore, given existing in vitro evidence that some variants may lead to a gain of function, the use of retigabine/ezogabine may theoretically even be contraindicated in some patients. Further studies are needed to address whether early use of the drug in specific patient groups is effective. Search Clinical Trials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	KCNQ2-Related Disorders	None	6,437	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK32534/	2021-01-18T21:16:41	{"synonyms": []}
A number sign (#) is used with this entry because immunodeficiency-31A (IMD31A) is caused by heterozygous mutation in the STAT1 gene (600555) on chromosome 2q32. Immunodeficiency-31B (IMD31B; 613796), an autosomal recessive disorder, and immunodeficiency-31C (IMD31C; 614162), an autosomal dominant disorder, are allelic. Description IMD31A results from autosomal dominant (AD) STAT1 deficiency. STAT1 is crucial for cellular responses to IFNA (147660)/IFNB (147640) (type I interferon) and IFNG (147570) (type III interferon). AD STAT1 deficiency selectively affects the IFNG pathway, but not the IFNA/IFNB pathway, and confers a predisposition to mycobacterial infections. Pathogens reported in IMD31A patients include bacillus Calmette-Guerin (BCG) and Mycobacterium avium complex, as well as Mycobacterium tuberculosis. IMD31A has low penetrance and a mild clinical phenotype with good prognosis for recovery (review by Al-Muhsen and Casanova, 2008). Two patients with heterozygous STAT1 mutations have been reported with increased susceptibility to adult-onset herpes simplex encephalitis (HSE) without a history of other significant infections (Mork et al., 2015). Molecular Genetics In cells from a French patient with a history of disseminated BCG infection with no mutations in the IL12 (see 161561), IL12RB (601604), or IFNGR (see 107470) genes, Dupuis et al. (2001) observed severely impaired nuclear protein binding to IFNG-activating sequences when the cells were stimulated with IFNG or IFNA. Sequence analysis identified a mutation in the STAT1 gene (600555.0001). The patient's daughter, who was not vaccinated with BCG, had a similar cellular phenotype in vitro and carried the same mutation. An unrelated American patient with a history of M. avium infection was heterozygous for the same mutation. The mutation was not detected in healthy cohorts. In 2 unrelated patients from Japan and Saudi Arabia with autosomal dominant STAT1 deficiency, Tsumura et al. (2012) identified heterozygous missense mutations affecting the SH2 domain of STAT1. One mutation, lys673 to arg (K673R; 600555.0023), was hypomorphic and impaired STAT1 tyrosine phosphorylation. The other mutation, lys637 to glu (K637E; 600555.0024), was null and affected both STAT1 phosphorylation and DNA-binding activity. Both alleles were dominant-negative and impaired STAT1-mediated cellular responses to IFNG and IL27 (608273), whereas responses to IFNA and IFN-lambda (see 607403) were preserved at normal levels. Tsumura et al. (2012) concluded that the STAT1 SH2 domain is important for tyrosine phosphorylation and DNA binding, as well as antimycobacterial immunity. In 2 unrelated Danish men (P7 and P8), with IMD31A manifest as adult-onset herpes simplex encephalitis (HSE) after age 60, Mork et al. (2015) identified a heterozygous missense mutation in the STAT1 gene (V266I; 600555.0028). The mutation was found by whole-exome sequencing of a cohort of 16 patients with adult-onset HSE and confirmed by Sanger sequencing. Patient peripheral blood mononuclear cells showed significantly lower beta-interferon (IFNB1; 147640), CXCL10 (147310), and TNFA (191160) responses to HSV-1 infection compared to controls, suggesting defective antiviral response and a loss of function. Patient cells did not have impaired responses to the TLR3 (603029) agonist poly(I;C). The findings suggested that STAT1 variants may contribute to HSE susceptibility in adults. INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Herpes simplex encephalitis IMMUNOLOGY \- Increased susceptibility to disseminated mycobacterial infections \- Increased susceptibility to herpes simplex encephalitis LABORATORY ABNORMALITIES \- Poor immunologic response to gamma-interferon MISCELLANEOUS \- Onset in early childhood \- Infections may be triggered by BCG vaccination \- Incomplete penetrance MOLECULAR BASIS \- Caused by mutation in the signal transducer and activator of transcription 1 gene (STAT1, 600555.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	IMMUNODEFICIENCY 31A	c4013950	6,438	omim	https://www.omim.org/entry/614892	2019-09-22T15:53:48	{"omim": ["614892"], "orphanet": ["319595"], "synonyms": ["MSMD due to partial STAT1 deficiency", "Mendelian susceptibility to mycobacterial diseases due to partial signal transducer and activator of transcription 1 deficiency", "IMMUNODEFICIENCY 31A, MYCOBACTERIOSIS, AUTOSOMAL DOMINANT", "Alternative titles", "MSMD due to partial signal transducer and activator of transcription 1 deficiency", "STAT1 DEFICIENCY, AUTOSOMAL DOMINANT"]}
A number sign (#) is used with this entry because, as reviewed in 168600, parkinsonism is a conspicuous and even predominant feature of some of the various neurologic disorders and, as reviewed here, mitochondrial mutations may be involved. The electron transport chain (ETC) of mitochondria is the last step in cellular respiration. The ETC composes the primary mechanism by which electrons are conferred to oxygen for the production of adenosine triphosphate (ATP), a major energy supplying molecule in all cells. The ETC is composed of five transmembrane (spanning the inner mitochondrial membrane) complexes, 4 of which have subunits coded for by mitochondrial and nuclear DNA, 1 of which has subunits coded for by nuclear DNA only. Complexes I, II, III, and IV transport electrons to oxygen and pump protons into the space between the two mitochondrial membranes. Complex V uses the proton gradient to generate ATP. Reactive oxygen species (ROS), molecules that cause damage to existing cellular structures as well as DNA, are created by the activities of the ETC. As a result, abnormal complex activity can lead to an excess of ROS and potential mitochondrial damage. As reviewed by Di Monte (1991), the first suggestion that a mitochondrial defect may be involved in the neuronal death observed in Parkinson disease stems from studies on the mechanism of neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Death of dopaminergic neurons of the substantia nigra after exposure to MPTP is due to the fact that this neurotoxicant is oxidized in the CNS by monoamine oxidase (MAO) type B, generating a metabolite that is the ultimate mediator of MPTP toxicity. Pretreatment of animals with MAO inhibitors protected against the neurotoxic effects of MPTP. In some studies a reduction of complex I activity was found in autopsy specimens of the substantia nigra of patients affected by Parkinson disease. The low concordance of the disease among twins and the reports that prevalence is similar in identical and fraternal twins (Duvoisin, 1986; Marttila et al., 1988) could be explained by mitochondrial inheritance; different mitochondrial phenotypes in monozygotic twins can occur because of random segregation of heteroplasmic mitochondrial DNA from the ovum. To test the mitochondrial hypothesis, Zweig et al. (1992) questioned the occurrence of Parkinson disease in the parents of 252 patients. It was found that 11 fathers and 5 mothers had had this disease. These data failed to provide support for the hypothesis of maternal inheritance. In a review of similar studies in the literature and an additional unpublished study, Zweig et al. (1992) found 922 patients with this disease among whose parents 37 fathers and 19 mothers were reportedly affected. Parker et al. (1989), using platelet mitochondria from 10 patients with idiopathic Parkinson disease (PD), evaluated catalytic activities for complex I (NADH:ubiquinone oxidoreductase) and complex IV (succinate:cytochrome c oxidoreductase) activity. They found in all ten patients significant reduction of complex I activity and nonsignificant reduction of complex IV activity, suggesting that defects in complex I may explain the pathogenesis of PD. Mizuno et al. (1989), using mitochondria from striata of patients who died of PD, performed immunoblotting studies to assess the amount present of each subunit of complexes I, III, and IV. They found that 3 of 7 subunits of complex I coded for by the mitochondrial genome were present in lower amounts than those of control mitochondria. Shoffner et al. (1991), using skeletal muscle mitochondria from six patients with PD, performed functional assays for all five ETC complexes and looked for mutations in the mitochondrial DNA. The advantage to muscle mitochondria for these studies was the low complex I activity in platelets, the loss of neurons in the substantia nigra of patients with PD, and the more extensive experience with oxidative phosphorylation enzymology in skeletal muscle compared to platelets or neurons. In 4 patients, a decrease in complex I activity was observed. In 1 patient, a decrease in complex IV activity was found. In one patient, no decreases in activity of any complex were found. No known pathological mitochondrial DNA insertion-deletions or point mutations were found. Ikebe et al. (1995) examined mitochondrial DNA from five patients with PD to locate possible mutations. While no recognized point mutations were found, each patient had multiple point mutations that would cause significant changes to products of genes. Each patient had at least one significant point mutation in genes encoding subunits of complex I. The authors suggested that these changes may lead to the increase of or increased susceptibility to damage from oxygen radicals. Swerdlow et al. (1996) used a cybrid cell fusion to repopulate human neuroblastoma cells that had had their mitochondria inactivated with platelet derived mitochondria of patients with idiopathic PD. The cells were assessed for ETC activities, production of ROS, and sensitivity to apoptotic cell death as induced by 1-methyl-4-phenylpyridinium (MPP+), a known inhibitor of complex I. The cybrid technique removes the possibility that ETC assays for activity may not be assessing flaws inherent to ETC complexes rather but toxins or medicines present in the cells of patients with PD. A 20% decrease in complex I activity was seen in the neuroblastoma cell cultures after 5 to 6 weeks of cell division. No significant decrease in complex IV activity was seen. An increase in the production of ROS was seen. Increased susceptibility to MPP+-induced apoptosis was seen. The authors concluded that the complex I defect in PD appeared to arise genetically from mitochondrial DNA, a significant conclusion towards the etiology and pathology of PD. The possibility of mitochondrial dysfunction as the basis of idiopathic Parkinson disease has been particularly attractive since Vyas et al. (1986) recognized that the parkinsonism-inducing compound N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a mitochondrial toxin. Parker and Swerdlow (1998) pointed out that the unique genetic properties of mitochondria also make them worthy of consideration for a pathogenic role in PD. Although affected persons occasionally provide family histories that suggest mendelian inheritance and mutations in the gene encoding alpha-synuclein, SNCA (163890), have been described in autosomal dominant Parkinson disease, most cases are sporadic. Because of unique features such as heteroplasmy, replicative segregation, and threshold effects, mitochondrial inheritance can allow for the apparent sporadic nature of these diseases. To test the hypothesis that mitochondrial variation contributes to expression, van der Walt et al. (2003) genotyped 10 single-nucleotide polymorphisms that define the European mitochondrial DNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio = 0.55; 95% CI 0.91; P = 0.02) or K (odds ratio = 0.52; 95% CI 0.30-0.90; P = 0.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup H. Furthermore, a specific SNP that defines these 2 haplogroups, 10398G, is strongly associated with this protective effect (odds ratio = 0.53; 95% CI 0.39-0.73; P = 0.0001). The 10398G SNP causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3; 516002) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men. In addition, the 9055A SNP of ATP6 (516060) demonstrated a protective effect for women. Van der Walt et al. (2003) concluded that ND3 may be an important factor in PD susceptibility among white individuals and could help explain the role of complex I in Parkinson disease expression. By haplotype analysis of 455 patients with PD, 185 patients with Alzheimer disease (AD; 104300), and 447 controls, Pyle et al. (2005) found that the UKJT haplotype cluster (Torroni et al., 1996) was associated with a 22% reduction in risk for development of PD. There was no association between any haplotypes and AD, indicating that the association was specific for Parkinson disease. Reanalysis of the data reported by van der Walt et al. (2003) showed similar results for the pooled data of haplotypes U, K, J, and T. Pyle et al. (2005) noted that the 10398A-G polymorphism has been described on several other haplotypes (see Herrnstadt et al., 2002), indicating that the 10398A-G polymorphism does not 'define' haplotypes J and K, as asserted by van der Walt et al. (2003). Horvath et al. (2007) reported a 66-year-old German man with parkinsonism due to an 8344A-G mutation in the MTTK gene (590060.0001). Symptoms included bradykinesia, resting tremor, and asymmetric rigidity. He also had proximal muscle weakness, hyporeflexia, decreased distal sensation, and bilateral hearing loss. Serum creatine kinase was elevated. He showed good response to levodopa. Skeletal muscle biopsy showed ragged-red fibers, fiber size variability, centrally placed nuclei, and atrophic and necrotic fibers. There was a mild decrease in some respiratory chain enzymes. The 8344A-G mutation was homoplasmic in muscle and 80% in leukocytes. A brother with progressive hearing loss since age 10 had 70% heteroplasmy in blood. In a patient with early-onset Parkinson disease (PARK6; 605909) due to homozygous mutation in the PINK1 gene (608309.0002), Piccoli et al. (2008) identified homoplasmic mutations in the MTND5 (516005.0010) and MTND6 genes (516006.0008), respectively. The patient had onset at age 22 years. His mother, who was heterozygous for the PINK1 mutation, was also homoplasmic for both mitochondrial mutations and showed disease onset at age 53. The father was heterozygous for the PINK1 mutation only and was unaffected at age 79. Biochemical studies of the proband's fibroblasts showed mitochondrial dysfunction, with decreased amounts of cytochrome c oxidase, impaired complex I activity, and increased hydrogen peroxide generation. Piccoli et al. (2008) concluded that the presence of the mitochondrial mutations in combination with the PINK1 mutation may have accelerated the onset of the disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	PARKINSON DISEASE, MITOCHONDRIAL	c1838867	6,439	omim	https://www.omim.org/entry/556500	2019-09-22T16:16:46	{"mesh": ["C564015"], "omim": ["556500"]}
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Myoclonic astatic epilepsy" – news · newspapers · books · scholar · JSTOR (March 2018) (Learn how and when to remove this template message) Myoclonic astatic epilepsy Other namesMyoclonic-astatic epilepsy, myoclonic atonic epilepsy, Doose syndrome, epilepsy with myoclonic-atonic seizures, myoclonic-astatic epilepsy in early childhood Myoclonic astatic epilepsy (MAE), also known as myoclonic atonic epilepsy or Doose syndrome, is a generalized idiopathic epilepsy. It is characterized by the development of myoclonic seizures and/or myoclonic astatic seizures. ## Contents * 1 Signs and symptoms * 1.1 Onset * 2 Diagnosis * 3 Treatments * 3.1 Medication * 3.2 Diet * 4 Prognosis * 5 History * 6 References * 7 External links ## Signs and symptoms[edit] * Tonic-clonic seizures: seizures with repetitive sequences of stiffening and jerking of the extremities. * Myoclonic seizures: seizures with rapid, brief contractions of muscles. * Atonic seizures: seizures with a sudden loss of muscle tone, often resulting in sudden collapse. These are also called drop seizures. * Absence seizures: a generalized seizure characterized by staring off and occasionally some orofacial automatisms. * Myoclonic astatic seizures: seizures that involve a myoclonic seizure followed immediately by an atonic seizure. This type of seizure is exclusive to MAE and is one of the defining characteristics of this syndrome. * Tonic seizures: muscle stiffening or rigidity. This seizure is rare in this syndrome. ### Onset[edit] The onset of seizures is between the ages of 2 and 5 years of age. EEG shows regular and irregular bilaterally synchronous 2- to 3-Hz spike-waves and polyspike patterns with a 4- to 7-Hz background. 84% of affected children show normal development prior to seizures; the remainder show moderate psychomotor retardation mainly affecting speech. Boys (74%) are more often affected than girls (Doose and Baier 1987a).[1] ## Diagnosis[edit] This section is empty. You can help by adding to it. (October 2017) ## Treatments[edit] The treatment for seizures may include antiepileptic medications, diet and vagus nerve stimulator. ### Medication[edit] Any number of medications may be used to both prevent and treat seizures. Generally after three medications are tried, different treatment should be considered. Some medications are harmful to those with this syndrome and can increase seizures. ### Diet[edit] The ketogenic diet mimics some of the effects of starvation, in which the body first uses up glucose and glycogen before burning stored body fat. In the absence of glucose, the body produces ketones, a chemical by-product of fat metabolism that has been known to inhibit seizures. A modified version of a popular low-carbohydrate, high-fat diet which is less restrictive than the ketogenic diet. The low glycemic index treatment (LGIT) is a new dietary therapy currently being studied to treat epilepsy. LGIT attempts to reproduce the positive effects of the ketogenic diet. The treatment allows a more generous intake of carbohydrates than the ketogenic diet, but is restricted to foods that have a low glycemic index, meaning foods that have a relatively low impact on blood-glucose levels. These foods include meats, cheeses, and most vegetables because these foods have a relatively low glycemic index. Foods do not have to be weighed, but instead careful attention must be paid to portion size and balancing the intake of carbohydrates throughout the day with adequate amounts of fats and proteins.[2] ## Prognosis[edit] Epilepsy with myoclonic-astatic seizures has a variable course and outcome. Spontaneous remission with normal development has been observed in a few untreated cases. Complete seizure control can be achieved in about half of the cases with antiepileptic drug treatment (Doose and Baier 1987b; Dulac et al. 1990). In the remainder of cases, the level of intelligence deteriorates and the children become severely intellectually disabled.[citation needed] Other neurologic abnormalities such as ataxia, poor motor function, dysarthria, and poor language development may emerge (Doose 1992b). However, this proportion may not be representative because in this series the data were collected in an institution for children with severe epilepsy. The outcome is unfavorable if generalized tonic-clonic, tonic, or clonic seizures appear at the onset or occur frequently during the course. Generalized tonic-clonic seizures usually occur during the daytime in this disorder, at least in the early stages. Nocturnal generalized tonic-clonic seizures, which may develop later, are another unfavorable sign.[citation needed] If tonic seizures appear, prognosis is poor. Status epilepticus with myoclonic, astatic, myoclonic-astatic, or absence seizures is another ominous sign, especially when prolonged or appearing early. Failure to suppress the EEG abnormalities (4- to 7-Hz rhythms and spike-wave discharges) during therapy and absence of occipital alpha-rhythm with therapy also suggest a poor prognosis (Doose 1992a).[3] ## History[edit] Myoclonic-astatic epilepsy was first described and identified in 1970 by Herman Doose as an epilepsy syndrome, hence its original label, Doose syndrome.[4][5] 1989, it was classified as a symptomatic generalized epilepsy by the International League Against Epilepsy (ILAE).[4] ## References[edit] 1. ^ http://www.ilae-epilepsy.org/ctf/myoclonic_astatic_child.html 2. ^ http://www.med.nyu.edu/cec/treatment/diet/glycemic.html 3. ^ http://www.ilae-epilepsy.org/ctf/myoclonic_astatic_child.html 4. ^ a b Kelley, Sarah A; Kossof, Eric H (November 2010). "Doose syndrome (myoclonic-astatic epilepsy): 40 years of progress". Developmental Medicine & Child Neurology. 52 (11): 988–993. doi:10.1111/j.1469-8749.2010.03744.x. PMID 20722665. S2CID 15674178. 5. ^ Delgado-Escueta, Antonio V. (2005). Myoclonic Epilepsies. Lippincott Williams & Wilkins. p. 147. ISBN 9780781752480. ## External links[edit] * Myoclonic astatic epilepsy at Curlie Classification D * ICD-10: G40.4 External resources * Orphanet: 1942 * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis * v * t * e Seizures and epilepsy Basics * Seizure types * Aura (warning sign) * Postictal state * Epileptogenesis * Neonatal seizure * Epilepsy in children Management * Anticonvulsants * Investigations * Electroencephalography * Epileptologist Personal issues * Epilepsy and driving * Epilepsy and employment Seizure types Focal Seizures Simple partial Complex partial Gelastic seizure Epilepsy Temporal lobe epilepsy Frontal lobe epilepsy Rolandic epilepsy Nocturnal epilepsy Panayiotopoulos syndrome Vertiginous epilepsy Generalised * Tonic–clonic * Absence seizure * Atonic seizure * Automatism * Benign familial neonatal seizures * Lennox–Gastaut syndrome * Myoclonic astatic epilepsy * Epileptic spasms Status epilepticus * Epilepsia partialis continua * Complex partial status epilepticus Myoclonic epilepsy * Progressive myoclonus epilepsy * Dentatorubral–pallidoluysian atrophy * Unverricht–Lundborg disease * MERRF syndrome * Lafora disease * Juvenile myoclonic epilepsy Non-epileptic seizure * Febrile seizure * Psychogenic non-epileptic seizure Related disorders * Sudden unexpected death in epilepsy * Todd's paresis * Landau–Kleffner syndrome * Epilepsy in animals Organizations * Citizens United for Research in Epilepsy (US) * Epilepsy Action (UK) * Epilepsy Action Australia * Epilepsy Foundation (US) * Epilepsy Outlook (UK) * Epilepsy Research UK * Epilepsy Society (UK) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Myoclonic astatic epilepsy	c4085238	6,440	wikipedia	https://en.wikipedia.org/wiki/Myoclonic_astatic_epilepsy	2021-01-18T19:05:34	{"gard": ["2169"], "umls": ["C4085238"], "orphanet": ["1942"], "wikidata": ["Q6947909"]}
A rare congenital anomaly of the inferior vena cava characterized by complete interruption of the vessel in which no direct continuity exists between the inferior vena cava and the azygos/hemiazygos system. Clinical manifestations depend on the variant drainage patterns or collaterals and include lower extremity deep vein thrombosis, thromboembolic attacks, leg swelling and pain, lower extremity varices, abdominal pain, intraabdominal varices, and hematochezia, among others. Additional venous abnormalities or cardiac malformations are frequently present. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Inferior vena cava interruption without azygos continuation	None	6,441	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99123	2021-01-23T17:45:48	{"icd-10": ["Q26.8"], "synonyms": ["IVC interruption", "Inferior caval vein interruption"]}
Serine-deficiency syndrome is a very rare infantile-onset potentially treatable neurometabolic disorder characterized clinically by microcephaly, neurodevelopmental disorders and seizures. Three serine-deficiency syndromes have been described: 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, 3-phosphoserine phosphatase (3-PSP) deficiency, and phosphoserine aminotransferase deficiency (see these terms). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Neurometabolic disorder due to serine deficiency	None	6,442	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=35705	2021-01-23T18:02:25	{"icd-10": ["E72.8"], "synonyms": ["Serine deficiency"]}
## Description The CYP1A2 gene encodes a P450 enzyme involved in O-deethylation of phenacetin. It is 1 of several forms of cytochrome P-450 that have been purified to electrophoretic homogeneity from human liver microsomes (Guengerich et al., 1986). P1-450 (CYP1A1; 108330) and P3-450 are 2 members of the dioxin-inducible P450 gene family. Cloning and Expression Jaiswal et al. (1987) isolated a cDNA corresponding to the CYP1A2 gene. The deduced 515-residue protein has a molecular mass of 583 kD. Phenacetin O-deethylase differs from another cytochrome P-450 enzyme that shows genetic polymorphism, debrisoquine 4-hydroxylase (124030), in molecular mass, amino acid composition, catalytic activity, and immunochemical properties. Butler et al. (1989) reviewed the evidence that phenacetin O-deethylase, otherwise known as P450(PA), is the product of the CYP1A2 gene. Gene Structure Ikeya et al. (1989) found that the human CYP1A2 gene spans almost 7.8 kb and contains 7 exons. The first exon is noncoding exon. Between CYP1A2 and CYP1A1, exons 2, 4, 6, and especially 5 are strikingly conserved in both nucleotides and total number of bases. The regulatory elements of the 2 genes, however, appeared to differ in location. Mapping By somatic cell hybrid analysis, Jaiswal et al. (1987) determined that both the P3-450 and the P1-450 loci reside on human chromosome 15. In the mouse and hamster, the 2 genes are located near the equivalent of the mannosephosphate isomerase (MPI) locus (154550). The same may be true in man; MPI is located in the region 15q22-qter. The 2 CYP1 genes are within 25 kb of each other and probably are not separated by other genes (Nebert, 1988). Gene Function More than 20 clinically used drugs are partly or predominantly metabolized by CYP1A2 including caffeine, theophylline, imipramine, clozapine, and propranolol. CYP1A2 accounts for nearly 15% of the cytochrome P450 in the human liver (Shimada et al., 1994). CYP1A2 displays higher activity in men than in women, and is inhibited by oral contraceptives. Inducers of CYP1A2 include cruciferous vegetables (Vistisen et al., 1992). Cigarette smoking has also been shown to increase CYP1A2 activity (Sesardic et al., 1988). Butler et al. (1989) reported that human hepatic microsomal caffeine 3-demethylation, the initial major step in caffeine biotransformation in humans, is selectively catalyzed by CYP1A2. The authors suggested that variation in caffeine 3-demethylation activity in humans could be used to characterize arylamine N-oxidation phenotypes, which may play a role in interindividual susceptibility to arylamine-induced cancers. For example, smokers have been demonstrated to have increased rates of caffeine disposition, with plasma half lives one-half that of nonsmokers. Furthermore, rates of caffeine metabolism vary between individuals, as caffeine half-life values ranging from 1.5 to 9.5 hours have been reported. Molecular Genetics Shahidi (1967) described the familial occurrence of acetophenetidin susceptibility, suggesting genetic factors in the effects of CYP1A2. Devonshire et al. (1983) demonstrated a genetic polymorphism for phenacetin O-deethylation, with 5 to 10% of the population deficient in this activity. In human liver samples, Ikeya et al. (1989) found more than 15-fold differences in levels of CYP1A2 mRNA, and Schweikl et al. (1993) observed more than 40-fold differences. These findings indicated a genetically-determined difference in constitutive and/or inducible CYP1A2 gene expression. Nakajima et al. (1999) and Sachse et al. (1999) reported single nucleotide polymorphisms (SNPs) in the CYP1A2 gene causing high inducibility. Among 786 Caucasian individuals tested for caffeine clearance derived from saliva concentrations, Tantcheva-Poor et al. (1999) found that CYP1A2 activity was influenced by the amount of coffee drunk daily, smoking, and country of residence, activities being lower in Bulgaria and Slovakia than in Germany. These and other covariates studied explained 37% of overall variation. No relative polymorphism was found for CYP1A2 activity when adjusted for covariate effects. Rasmussen et al. (2002) determined the caffeine ratio in a 6-hour urine sample from 378 Danish twin pairs following oral intake of a single dose of 200 mg of caffeine. The mean caffeine ratio was 5.9 +/- 3.4. The caffeine ratio was statistically significantly higher in men compared to women, in smoking men and women compared to nonsmoking persons of the same gender, and in women not taking oral contraceptives compared with women on oral contraceptives. In a study of heritability, Rasmussen et al. (2002) investigated 49 monozygotic twin pairs and 34 same gender dizygotic twin pairs concordant for nonsmoking and non-use of oral contraceptives. A biometrical model for the caffeine ratio including only additive genetic factors and unique environmental factors was the overall best-fitting model. The heritability estimate based on this model was 0.725; unique environmental effects seemed to account for the remaining 0.275. Individuals with the most common form of porphyria, porphyria cutanea tarda (PCT; 176100), are believed to be genetically predisposed to development of clinically overt disease through mutations and polymorphisms in genes associated with known precipitating factors. Christiansen et al. (2000) examined a group of Danish patients with PCT for the presence of a C/A polymorphism in intron 1 of CYP1A2. The results demonstrated that the frequency of the highly inducible A/A genotype is increased in both familial and sporadic PCT. The authors suggested that the A/A genotype is a susceptibility factor for PCT. Wooding et al. (2002) studied SNPs in the CYP1A2 gene in 113 individuals from 3 major continental regions of the Old World (Africa, Asia, and Europe), in comparison with the sequences in the 90-member National Institutes of Health DNA Polymorphism Discovery Resource. The African population had the highest level of nucleotide diversity, the lowest level of linkage disequilibrium, and 2 distinct haplotype clusters with broadly overlapping geographic distributions. Haplotypes found outside of Africa were mostly a subset of those found within Africa. These patterns were all consistent with the African origin of modern humans. Browning et al. (2010) sequenced the CYP1A2 gene from buccal swab DNA samples from 381 adults nearly equally divided between 5 Ethiopian ethnic groups representing an approximate northeast-to-southwest transect across the country. They identified 49 different variable sites, including 9 nonsynonymous changes, 7 of which were novel, and 1 synonymous change, and 55 different haplotypes, 52 of which were novel. None of the variant sites occurred near intron/exon boundaries, and all reported catalytic residues (i.e., asp320 and thr321 in exon 4 and phe451 and cys458 in exon 7) were monomorphic. Most individuals had at least 1 copy of the ancestral haplotype. However, Ethiopian groups displayed twice the variation seen in all other population groups combined. Browning et al. (2010) concluded that, consistent with the hypothesis of Africa, in general, and Ethiopia, in particular, being the birthplace of mankind, genetic diversity is greater in this population and that this diversity has significant implications for health care interventions in terms of increased risk of adverse drug reactions. Animal Model In mice, Buters et al. (1996) showed that the clearance of caffeine is determined primarily by Cyp1a2. CYP1A2 substrates include aflatoxin B1, acetaminophen, and a variety of environmental arylamines. To define better the developmental and metabolic functions of this enzyme, Liang et al. (1996) developed a CYP1A2-deficient mouse line by homologous recombination in embryonic stem cells. Mice homozygous for the targeted Cyp1a2 gene were completely viable and fertile; histologic examination of 15-day embryos, newborn pups, and 3-week-old mice revealed no abnormalities. No CYP1A2 mRNA was detected by Northern blot analysis. Moreover, mRNA levels of Cyp1a1, the other gene in the same subfamily, appeared unaffected by loss of the Cyp1a2 gene. Because the muscle relaxant zoxazolamine is a known substrate for CYP1A2, they studied the knockout animals by using the zoxazolamine test. The knockout mice exhibited dramatically lengthened paralysis times relative to wildtype mice and the heterozygotes showed an intermediate effect. Paolini et al. (1999) found significant increases in the carcinogen-metabolizing enzymes CYP1A1, CYP1A2, CYP3A (124010), CYP2B (123930), and CYP2A (see 122720) in the lungs of rats supplemented with high doses of beta-carotene. The authors suggested that correspondingly high levels of CYPs in humans would predispose an individual to cancer risk from the widely bioactivated tobacco-smoke procarcinogens, thus explaining the cocarcinogenic effect of beta-carotene in smokers. Lab \- Dioxin-inducible P3-P450 \- Phenacetin O-deethylase defect \- Caffeine 3-demethylation activity Inheritance \- Autosomal dominant (15q22-qter) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	CYTOCHROME P450, SUBFAMILY I, POLYPEPTIDE 2	c1852336	6,443	omim	https://www.omim.org/entry/124060	2019-09-22T16:42:36	{"omim": ["124060"], "synonyms": ["Alternative titles", "CYTOCHROME P-450, AROMATIC COMPOUND-INDUCIBLE", "DIOXIN-INDUCIBLE P3-450"]}
Not to be confused with Carney's triad. Carney complex Other namesLAMB syndrome SpecialtyOncology, cardiology Carney complex and its subsets LAMB syndrome[1] and NAME syndrome[1] are autosomal dominant conditions comprising myxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), and endocrine overactivity.[2][3] It is distinct from Carney's triad. Approximately 7% of all cardiac myxomas are associated with Carney complex.[4] ## Contents * 1 Presentation * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 History * 6 See also * 7 References * 8 External links ## Presentation[edit] The spotty skin pigmentation and lentigines occur most commonly on the face, especially on the lips, eyelids, conjunctiva and oral mucosa.[3] Cardiac myxomas may lead to embolic strokes and heart failure[4] and may present with fever, joint pain, shortness of breath, diastolic rumble and tumor plop. Myxomas may also occur outside the heart, usually in the skin and breast. Endocrine tumors may manifest as disorders such as Cushing syndrome. The most common endocrine gland manifestation is an ACTH-independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). The LAMB acronym refers to lentigines, atrial myxomas, and blue nevi.[1] NAME refers to nevi, atrial myxoma, myxoid neurofibromas, and ephelides.[1] Testicular cancer, particularly Sertoli cell type, is associated with Carney syndrome.[5] Thyroid and pancreas cancer may also occur.[6][7] Although J Aidan Carney also described Carney's triad it is entirely different.[8] ## Pathophysiology[edit] Carney complex is most commonly caused by mutations in the PRKAR1A gene on chromosome 17 (17q23-q24)[9] which may function as a tumor-suppressor gene. The encoded protein is a type 1A regulatory subunit of protein kinase A. Inactivating germline mutations of this gene are found in 70% of people with Carney complex. Less commonly, the molecular pathogenesis of Carney complex is a variety of genetic changes at chromosome 2 (2p16).[10][11] Both types of Carney complex are autosomal dominant. Despite dissimilar genetics, there appears to be no phenotypic difference between PRKAR1A and chromosome 2p16 mutations.[10] ## Diagnosis[edit] This section is empty. You can help by adding to it. (July 2018) ## Treatment[edit] Cardiac myxomas can be difficult to manage surgically because of recurrence within the heart, often far away from the site of the initial tumor.[3][4] ## History[edit] In 1914 an American neurosurgeon, Harvey Cushing, reported on a patient with a pituitary tumour on whom he had operated.[12] The post mortem findings as reported were consistent with Carney complex, though at the time this condition had yet to be described. In 2017 archived tissue from the operation in Cushing's report was subjected to DNA sequencing, revealing an Arg74His (arginine to histidine: guanine (G)-> adenosine (A) transition in the second codon position of the 74th codon in the protein) mutation in the PRKAR1A gene, confirming a diagnosis of Carney complex. Therefore, Cushing's paper appears to be the first report of this complex. ## See also[edit] * Epithelioid blue nevus * List of cutaneous neoplasms associated with systemic syndromes ## References[edit] 1. ^ a b c d Carney Syndrome at eMedicine 2. ^ Carney, J.; Gordon, H.; Carpenter, P.; Shenoy, B.; Go, V. (1985). "The complex of myxomas, spotty pigmentation, and endocrine overactivity". Medicine. 64 (4): 270–283. doi:10.1097/00005792-198507000-00007. PMID 4010501. 3. ^ a b c McCarthy, P.; Piehler, J.; Schaff, H.; Pluth, J.; Orszulak, T.; Vidaillet Jr, H.; Carney, J. (1986). "The significance of multiple, recurrent, and "complex" cardiac myxomas". The Journal of Thoracic and Cardiovascular Surgery. 91 (3): 389–396. doi:10.1016/s0022-5223(19)36054-4. PMID 3951243. 4. ^ a b c Reynen, K. (1995). "Cardiac Myxomas". New England Journal of Medicine. 333 (24): 1610–1617. doi:10.1056/NEJM199512143332407. PMID 7477198. 5. ^ Campbell Walsh urology, 10th edition, page 1693 6. ^ Gaujoux S, Tissier F, Ragazzon B, Rebours V, Saloustros E, Perlemoine K, Vincent-Dejean C, Meurette G, Cassagnau E, Dousset B, Bertagna X, Horvath A, Terris B, Carney JA, Stratakis CA, Bertherat J (2011). "Pancreatic ductal and acinar cell neoplasms in Carney complex: a possible new association". J Clin Endocrinol Metab. 96 (11): E1888–95. doi:10.1210/jc.2011-1433. PMC 3205895. PMID 21900385. 7. ^ Bano G, Hodgson S (2016). "Diagnosis and Management of Hereditary Thyroid Cancer". Recent Results Cancer Res. 205: 29–44. doi:10.1007/978-3-319-29998-3_3. PMID 27075347. 8. ^ Gaissmaier C (December 1999). "Carney complex" (letter and response). Circulation. 100 (25): e150. doi:10.1161/01.cir.100.25.e150. PMID 10604916. 9. ^ Online Mendelian Inheritance in Man (OMIM): Carney Complex, type 1; CNC1 - 160980 10. ^ a b Stratakis, C. A.; Kirschner, L. S.; Carney, J. A. (2001). "Clinical and Molecular Features of the Carney Complex: Diagnostic Criteria and Recommendations for Patient Evaluation". Journal of Clinical Endocrinology & Metabolism. 86 (9): 4041–4046. doi:10.1210/jc.86.9.4041. 11. ^ Online Mendelian Inheritance in Man (OMIM): Carney Complex, type 2; CNC2 - 605244 12. ^ Tsay CJ, Stratakis CA, Faucz FR, London E, Stathopoulou C, Allgauer M, Quezado M, Dagradi T, Spencer DD, Lodish M (2017) Harvey Cushing treated the first known patient with Carney complex. J Endocr Soc 1(10):1312-1321. doi: 10.1210/js.2017-00283 ## External links[edit] Classification D * OMIM: 160980 605244 * MeSH: D056733 External resources * eMedicine: med/2941 * Orphanet: 1359 * GeneReview/UW/NIH entry on Carney complex * v * t * e Deficiencies of intracellular signaling peptides and proteins GTP-binding protein regulators GTPase-activating protein * Neurofibromatosis type I * Watson syndrome * Tuberous sclerosis Guanine nucleotide exchange factor * Marinesco–Sjögren syndrome * Aarskog–Scott syndrome * Juvenile primary lateral sclerosis * X-Linked mental retardation 1 G protein Heterotrimeic * cAMP/GNAS1: Pseudopseudohypoparathyroidism * Progressive osseous heteroplasia * Pseudohypoparathyroidism * Albright's hereditary osteodystrophy * McCune–Albright syndrome * CGL 2 Monomeric * RAS: HRAS * Costello syndrome * KRAS * Noonan syndrome 3 * KRAS Cardiofaciocutaneous syndrome * RAB: RAB7 * Charcot–Marie–Tooth disease * RAB23 * Carpenter syndrome * RAB27 * Griscelli syndrome type 2 * RHO: RAC2 * Neutrophil immunodeficiency syndrome * ARF: SAR1B * Chylomicron retention disease * ARL13B * Joubert syndrome 8 * ARL6 * Bardet–Biedl syndrome 3 MAP kinase * Cardiofaciocutaneous syndrome Other kinase/phosphatase Tyrosine kinase * BTK * X-linked agammaglobulinemia * ZAP70 * ZAP70 deficiency Serine/threonine kinase * RPS6KA3 * Coffin-Lowry syndrome * CHEK2 * Li-Fraumeni syndrome 2 * IKBKG * Incontinentia pigmenti * STK11 * Peutz–Jeghers syndrome * DMPK * Myotonic dystrophy 1 * ATR * Seckel syndrome 1 * GRK1 * Oguchi disease 2 * WNK4/WNK1 * Pseudohypoaldosteronism 2 Tyrosine phosphatase * PTEN * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease * Cowden syndrome * Proteus-like syndrome * MTM1 * X-linked myotubular myopathy * PTPN11 * Noonan syndrome 1 * LEOPARD syndrome * Metachondromatosis Signal transducing adaptor proteins * EDARADD * EDARADD Hypohidrotic ectodermal dysplasia * SH3BP2 * Cherubism * LDB3 * Zaspopathy Other * NF2 * Neurofibromatosis type II * NOTCH3 * CADASIL * PRKAR1A * Carney complex * PRKAG2 * Wolff–Parkinson–White syndrome * PRKCSH * PRKCSH Polycystic liver disease * XIAP * XIAP2 See also intracellular signaling peptides and proteins [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Carney complex	c2607929	6,444	wikipedia	https://en.wikipedia.org/wiki/Carney_complex	2021-01-18T18:52:57	{"gard": ["1119"], "mesh": ["D056733"], "umls": ["C2607929"], "orphanet": ["1359"], "wikidata": ["Q1044007"]}
A number sign (#) is used with this entry because Ehlers-Danlos syndrome kyphoscoliotic type 1 (EDSKSCL1), previously designated EDS6, is caused by homozygous or compound heterozygous mutation in the gene encoding lysyl hydroxylase (PLOD1; 153454) on chromosome 1p36. Description The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The major characteristics of kyphoscoliotic-type EDS are severe muscle hypotonia at birth, generalized joint laxity, scoliosis at birth, and scleral fragility and rupture of the ocular globe (Beighton et al., 1998). Nevo syndrome, previously thought to be a distinct entity, is identical to EDS type VI (Voermans et al., 2009). ### Genetic Heterogeneity of Ehlers-Danlos Syndrome, Kyphoscoliotic Type See EDSSKCL2 (614557), caused by mutation in the FKBP14 gene (614505). ### Classification of Ehlers-Danlos Syndromes The current classification of Ehlers-Danlos syndromes is based on a 2017 international classification described by Malfait et al. (2017), which recognizes 13 EDS subtypes. This classification revised the 'Villefranche classification' reported by Beighton et al. (1998). Beighton et al. (1998) reported on a revised nosology of the Ehlers-Danlos syndromes, designated the Villefranche classification. Major and minor diagnostic criteria were defined for each type and complemented whenever possible with laboratory findings. Six main descriptive types were substituted for earlier types numbered with Roman numerals: classic type (EDS I and II), hypermobility type (EDS III), vascular type (EDS IV), kyphoscoliosis type (EDS VI), arthrochalasia type (EDS VIIA and VIIB), and dermatosparaxis type (EDS VIIC). Six other forms were listed, including a category of 'unspecified forms.' Clinical Features In 2 sisters with features somewhat suggestive of the Ehlers-Danlos syndrome, Pinnell et al. (1972) found deficiency of hydroxylysine in collagen with stoichiometric replacement by lysine, and Krane et al. (1972) found deficiency of collagen lysyl hydroxylase. Hydroxylysine is important to cross-linking of collagen. Skin collagen was abnormally soluble. Clinical features included severe scoliosis from an early age, recurrent joint dislocations, stretchable skin, premature rupture of fetal membranes, and floppiness in early life, leading to the diagnosis of amyotonia congenita in one. The same patient, aged 9 years, had had one eye enucleated after an automobile accident. McKusick (1966) had a patient who appeared to have the same defect; the distinctive clinical features suggested the mnemonic designation ocular-scoliotic form of EDS. This patient was reported earlier in the ophthalmologic literature (Durham, 1953), and was later studied enzymatically by Sussman et al. (1974). On the basis of this patient, Beighton (1970) raised the possibility of an autosomal recessive form of the Ehlers-Danlos syndrome in which skin and joint changes like those of the dominant form occur but in which serious ocular complications, particularly retinal detachment, are a conspicuous feature. He described an affected brother and normal parents. The brother had 4 unaffected children. The affected female died at the age of 50 years with symptoms typical of acute dissecting aneurysm of the aorta (autopsy was not performed). Studying collagen in a clinically unspecified case of Ehlers-Danlos syndrome, Mechanic (1972) found a deficiency of hydroxylysinonorleucine and other crosslinks and suggested a cross-linkage defect in this disease. The patient studied by Miller et al. (1978) had microcornea but no scoliosis. Vitamin C, 4 g per day (plasma level 0.5-2.0 microg/dL), increased muscle strength, corneal size, and rate of wound healing. Elsas et al. (1978) described a patient with apparent benefit from ascorbic acid. Krieg et al. (1979) studied the affected son of third-cousin parents, both of whom had half-normal amounts of hydroxylysine in dermal collagen. The fetal membrane broke 34 hours before birth. He was limp with flexible kyphosis, very loose joints, and hematomas of the conjunctivae, eyelids, and ears. The diagnosis of EDS and studies of skin biopsy material were made when he was 3 months old. Farag and Schimke (1989) described an Arab brother and sister with the phenotype of EDS VI who also had peripheral polyneuropathy. Both had aortic regurgitation and mitral valve prolapse. The parents were consanguineous. Although Farag and Schimke (1989) suggested that this might be a new form of the Ehlers-Danlos syndrome, they recognized the obvious possibility that these were 2 independent recessive traits in this inbred kindred. Wenstrup et al. (1989) reviewed the clinical features of 10 patients with lysyl hydroxylase deficiency. The distinctive feature common to all was muscle hypotonia with joint laxity in the newborn period and moderate to severe kyphoscoliosis. They concluded that these patients are at risk for catastrophic arterial rupture. One patient had an intracranial hemorrhage in the perinatal period without evident traumatic delivery or ventilator-dependent respiratory distress syndrome. Another patient had a rupture of a vertebral artery, and 1 had multiple ruptures of the femoral artery and 2 episodes of spontaneous intrathoracic arterial rupture. Remarkably, ocular features were relatively insignificant in the 10 patients reviewed by Wenstrup et al. (1989). One patient was said to have no abnormality, not even myopia; 2 patients had severe myopia, and 7 others had mild to moderate myopia. Three patients, including the 2 patients with severe myopia had corneal diameters measured; all were mildly decreased. One patient had bilateral glaucoma; another had unilateral retinal detachment. Yeowell and Walker (1997) reported a male patient with EDS VI who was born in 1989 to healthy nonconsanguineous parents and was delivered at 38 weeks by cesarean section after a failed eversion to correct the breech position and with known oligohydramnios. He was hypotonic at birth, with multiple contractures of the arms and legs that were considered to be positional. Although he was alert and socially interactive, his general and gross motor development progressed slowly. Kyphoscoliosis was noted early and progressed rapidly. At 9 months, an L5-S1-level spina bifida occulta was identified together with progressive leftward thoracic kyphoscoliosis. Bilateral inguinal hernias were repaired at 3 months; congenital esotropia was corrected at 7 months of age. Since infancy he was observed to have extreme joint hypermobility, soft velvety skin, easy bruisability, and the tendency to develop keloids in response to minor trauma. A highly arched palate was noted as well as increased vertex height of the skull without abnormality of the sutural plates. His academic and personal-social skills were precocious. Heim et al. (1998) described an Iranian patient, the son of consanguineous parents, who developed kyphoscoliosis at the age of approximately 3 years and glaucoma at the age of 10 years. At the age of 13 years he had a marfanoid habitus. He was able to walk only with the upper part of his body bent forward and preferred sitting in a wheelchair. He had microcornea, myopia, brownish sclerae, and tortuous retinal arteries. Salavoura et al. (2006) reported a 4-year-old girl with EDS VI. At birth, she showed neonatal hypotonia, torticollis, dislocation of the shoulders and hips, joint laxity, scoliosis, and talipes equinovarus. At age 4 years, she had severe scoliosis, clumsy and unsteady gait, heart murmur, and thin, hyperelastic skin with easy bruisability. Ocular examination was normal. Biochemical analysis showed an increased urinary lysyl pyridoline/hydroxylysyl ratio. Treatment with high doses of ascorbic acid resulted in improved healing and muscle strength. Nevo et al. (1974) described an inbred Israeli family in which 2 sibs and their cousin had increased growth, kyphosis, prominent forehead, volar edema, spindle-shaped fingers, wrist drop, talipes, hyperbilirubinemia, and generalized hypotonia. Although the authors considered their cases to be an autosomal recessive variant of Sotos syndrome (117550), Cohen (1989) proposed that these patients had a separate entity, which they called the Nevo syndrome. A similar case was reported by Hilderink and Brunner (1995). Their patient, a boy born to consanguineous parents, had neither lens luxation nor aortic dilatation. Al-Gazali et al. (1997) described 2 male patients from unrelated Arab families with features similar to those described by Nevo et al. (1974) but without hyperbilirubinemia. Both had delayed motor development. Cognitive function was normal in one at 2 years 10 months of age. While the other was too young to assess, social responses appeared normal. MRI studies in the older child revealed extreme hyperlordosis of the cervical spine and a wide spinal canal suggestive of dural ectasia. Because the clinical features in patients reported with Nevo syndrome were similar to those of EDS VIA, Giunta et al. (2005) studied 7 patients diagnosed with Nevo syndrome, 2 of whom had been reported by Al-Gazali et al. (1997) and 1 by Hilderink and Brunner (1995), and identified homozygous mutations in the PLOD1 gene in all (see 153454.0001 and 153454.0006). In the 5 patients from whom urine was available, the ratio of total urinary lysyl pyridinoline to hydroxylysyl pyridinoline was elevated compared with that in controls and similar to that observed in patients with EDS VIA. Giunta et al. (2005) concluded that Nevo syndrome is allelic to and clinically indistinguishable from EDS VIA and presented evidence that increased length at birth and wrist drop, in addition to muscular hypotonia and kyphoscoliosis, should prompt the physician to consider EDS VIA earlier than had previously been the case. Voermans et al. (2009) reexamined a male patient, born of first-cousin parents from the Netherlands, who was originally reported by Hilderink and Brunner (1995) and in whom Giunta et al. (2005) identified homozygosity for a deletion in the PLOD1 gene (153454.0006). At the age of 16 years, generalized muscle weakness and mild muscle hypotonia were still present, and the patient had reduced muscle mass. Deep tendon reflexes were symmetrically depressed, vibration sense was reduced in hands and feet bilaterally, and tandem gait was mildly impaired, but position sense of fingers and toes and coordination tests of arms was normal. In addition, he had hyperextensible skin with atrophic scars, contracture of the right elbow, and hypermobility of distal joints. Nerve conduction studies were compatible with a mild sensorimotor axonal polyneuropathy, and electromyography reflected a myopathy. MRI revealed myopathic changes in increase of fat tissue and atrophy of muscles. Needle biopsy of the right quadriceps muscle at 16 years of age showed fibrous and fatty tissue with very few remaining muscle fibers, in contrast to an earlier biopsy at 2 months of age which showed no abnormalities. Voermans et al. (2009) suggested that myopathy or peripheral nerve dysfunction might contribute to the functional decline in adolescence that is observed in patients with EDS VIA, with loss of ambulation in the second or third decade. Diagnosis Traditionally, the clinical diagnosis of EDS VI is confirmed by an insufficiency of hydroxylysine on analysis of hydrolyzed dermis and/or reduced enzyme activity in cultured skin fibroblasts (for review, see Steinmann et al., 1993) but can also be confirmed by the altered urinary ratio of lysyl pyridinoline:hydroxylysyl pyridinoline which is characteristic for EDS VI (Steinmann et al., 1995). Dembure et al. (1984) demonstrated the feasibility of prenatal diagnosis and carrier detection. Molecular Genetics In cells from 2 sisters with type VI Ehlers-Danlos syndrome in whom Pinnell et al. (1972) first demonstrated reduced lysyl hydroxylase activity, Hautala et al. (1993) demonstrated homozygosity for a large duplication in the PLOD1 gene, corresponding to 7 exons (153454.0002), caused by an Alu-Alu recombination. The same mutation was found by Pousi et al. (1994) in the patient reported by McKusick (1966) and Sussman et al. (1974). Giunta et al. (2005) studied 7 patients diagnosed with Nevo syndrome, 2 of whom had been reported by Hilderink and Brunner (1995) and 1 by Al-Gazali et al. (1997), and found homozygous mutations in the PLOD1 gene in all (see 153454.0001 and 153454.0006). In a child with EDS VI, Salavoura et al. (2006) identified a homozygous deletion in the PLOD1 gene. Nomenclature The kyphoscoliotic type of Ehlers-Danlos syndrome was at one time separated into EDS VIA (with lysyl hydroxylase deficiency) and EDS VIB (with normal lysyl hydroxylase activity). The designation EDS VIB was also thought to include the brittle cornea syndrome (229200), which was subsequently found to be a distinct disorder caused by mutation in the ZNF469 gene (612078). EDS VIB is now known as the musculocontractural type of EDS (601776), caused by mutation in the CHST14 gene (608429). History Ihme et al. (1983) described 3 variants of EDS VI: a severe form with skeletal, dermal and ocular manifestations with no hydroxylysine in skin collagen and low lysyl hydroxylase activity in cultured fibroblasts; a clinically similar form with nearly normal hydroxylysine content of skin but low enzyme activity in cultured fibroblasts; and a predominantly ocular form with no biochemical abnormality of skin or cultured fibroblasts. Sigurdson et al. (1985) reported as a case of type IV EDS a 33-year-old man with colonic perforation. He 'was born with multiple congenital defects, including severe kyphoscoliosis, keratoconus, micrognathia, mild mental retardation, and joint laxity.' He had had bilateral inguinal herniorrhaphies and a corneal transplant for keratoconus. Colonoscopy showed wide-mouthed diverticula throughout the entire transverse and descending colon. Might this be the ocular-scoliotic form of EDS VI, rather than type IV? Dumic et al. (1998) reported a patient with Nevo syndrome who manifested intrauterine and postpartum overgrowth, accelerated osseous maturation, dolichocephaly, highly arched palate, large and low-set ears, cryptorchidism, delayed neuropsychologic development, hypotonia, edema and contractures of the hands and feet, a single transverse palmar crease, and tapering digits. After meningococcal sepsis at age 6 months, he remained decerebrate. Thereafter, overgrowth and especially weight gain were markedly accelerated until his death at age 18 months, at which time his height was 103 cm and his weight was 23 kg. In addition to low plasma concentrations of growth hormone and insulin-like growth factor, severe insulin resistance was observed. Dumic et al. (1998) presumed that a selective defect in insulin-stimulated glucose uptake, with preservation of anabolic effect, was one of the causes of his 'overgrowth without growth hormone,' at least in the last 12 months of life after severe brain damage. INHERITANCE \- Autosomal recessive GROWTH Height \- Normal to tall stature Other \- Marfanoid habitus HEAD & NECK Eyes \- Keratoconus \- Microcornea \- Myopia \- Retinal detachment \- Ocular rupture \- Blue sclerae \- Epicanthal folds \- Glaucoma \- Blindness Nose \- Depressed nasal bridge Teeth \- Tooth crowding CARDIOVASCULAR Heart \- Cardiac failure (secondary to chest deformity) Vascular \- Arterial rupture RESPIRATORY \- Decreased pulmonary function (secondary to chest deformity) \- Respiratory insufficiency (secondary to chest deformity) Lung \- Recurrent episodes of pneumonia ABDOMEN Gastrointestinal \- Gastrointestinal hemorrhage GENITOURINARY External Genitalia (Male) \- Inguinal hernia Bladder \- Bladder diverticula SKELETAL \- Joint laxity \- Osteoporosis \- Recurrent joint dislocations Spine \- Congenital scoliosis, progressive \- Kyphosis Hands \- Arachnodactyly Feet \- Pes planus \- Talipes equinovarus SKIN, NAILS, & HAIR Skin \- Soft thin skin \- Hyperextensible skin \- Moderate scarring \- Easy bruisability \- Molluscoid pseudotumors \- Excessive wrinkled skin (palms and soles) MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed motor development PRENATAL MANIFESTATIONS Movement \- Decreased fetal movement Delivery \- Premature rupture of membranes LABORATORY ABNORMALITIES \- Lysyl hydroxylase deficiency \- Decreased dermal hydroxylysine content MOLECULAR BASIS \- Caused by mutation in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase gene (PLOD, 153454.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	EHLERS-DANLOS SYNDROME, KYPHOSCOLIOTIC TYPE, 1	c0268342	6,445	omim	https://www.omim.org/entry/225400	2019-09-22T16:28:23	{"mesh": ["C536198"], "omim": ["225400"], "orphanet": ["1900"], "synonyms": ["Alternative titles", "EHLERS-DANLOS SYNDROME, TYPE VI", "EDS VI", "EHLERS-DANLOS SYNDROME, OCULAR-SCOLIOTIC TYPE", "NEVO SYNDROME", "EHLERS-DANLOS SYNDROME, TYPE VIA, FORMERLY"], "genereviews": ["NBK1462"]}
This article includes a list of references, related reading or external links, but its sources remain unclear because it lacks inline citations. Please help to improve this article by introducing more precise citations. (May 2018) (Learn how and when to remove this template message) Rose spots on the chest of a patient with typhoid fever Rose spots are red macules 2-4 millimeters in diameter occurring in patients with enteric fever (which includes typhoid and paratyphoid). These fevers occur following infection by Salmonella typhi and Salmonella paratyphi respectively. Rose spots may also occur following invasive non-typhoid salmonellosis. Rose spots are bacterial emboli to the skin and occur in approximately 1/3 of cases of typhoid fever. They are one of the classic signs of untreated disease, but can also be seen in other illnesses as well including shigellosis and nontyphoidal salmonellosis. They appear as a rash between the seventh and twelfth day from the onset of symptoms. They occur in groups of five to ten lesions on the lower chest and upper abdomen, and they are more numerous following paratyphoid infection. Rose spots typically last three to four days. ## References[edit] * Gale's Encyclopedia of Medicine, published by Thomas Gale in 1999, ISBN 978-0-7876-1868-1 * "www.healthatoz.com". Typhoid fever article which includes information on rose spots. Archived from the original on 21 February 2006. Retrieved 17 February 2006. ## External links[edit] * "Organizational home". Centers for Disease Control. Retrieved 17 February 2006. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Rose spots	c1274375	6,446	wikipedia	https://en.wikipedia.org/wiki/Rose_spots	2021-01-18T19:01:29	{"umls": ["C1274375"], "wikidata": ["Q3941500"]}
Sohval and Soffer (1953) described 2 brothers who were identically affected with mental retardation, multiple skeletal anomalies, and hypogonadism. The testicular histopathology was distinctive. All the seminiferous tubules were involved by one of two distinct processes: true germinal aplasia or complete fibrosis, with no gradations between them. Both brothers had fasting hyperglycemia and glucose intolerance. Skeletal anomalies were restricted to the cervical spine and superior ribs. GU \- Primary hypogonadism Neuro \- Mental retardation Inheritance \- X-linked Metabolic \- Hyperglycemia \- Glucose intolerance Lab \- Testicular biopsy shows true germinal aplasia or complete seminiferous tubular fibrosis Skel \- Skeletal dysplasia \- Abnormal cervical spine \- Superior rib anomalies ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	HYPOGONADISM, MALE, WITH MENTAL RETARDATION AND SKELETAL ANOMALIES	c2931285	6,447	omim	https://www.omim.org/entry/307500	2019-09-22T16:18:10	{"mesh": ["C536679"], "omim": ["307500"], "orphanet": ["2234"]}
A number sign (#) is used with this entry because the lethal neonatal form of carnitine palmitoyltransferase II (CPT2) deficiency is caused by homozygous or compound heterozygous mutation in the CPT2 gene (600650) on chromosome 1p32. Description Carnitine palmitoyltransferase II deficiency is an inherited disorder of mitochondrial long-chain fatty acid oxidation. The neonatal form presents shortly after birth with respiratory distress, seizures, altered mental status, hepatomegaly, cardiomegaly, cardiac arrhythmia, and, in many cases, dysmorphic features, renal dysgenesis, and migration defects. This form is rapidly fatal (summary by Longo et al., 2006). See also the infantile (600649) and adult-onset (255110) forms of the disorder, which are also caused by mutation in the CPT2 gene. Clinical Features The lethal neonatal form was recognized by Hug et al. (1989, 1991) and Zinn et al. (1991), who described infants who died in the first days of life. The patient reported by Hug et al. (1989, 1991), who presented on day 2 of life with hypothermia and lethargy, was found to have hepatomegaly, cardiomegaly, and hypoglycemia. Neurologic signs developed, including seizures, hypotonia, and hyperreflexia, as did cardiac arrhythmias. The patient died suddenly at age 5 days. Laboratory analysis showed decreased serum and tissue total and free carnitine and increased serum and tissue long-chain acylcarnitines. CPT II activity was severely decreased (less than 10%) in multiple tissues and in cultured fibroblasts. Taroni et al. (1994) reported a premature Haitian infant who presented at birth with respiratory distress, cardiac arrhythmia, and heart failure, and died on day 4 of life. Postmortem examination showed a hypertrophied, dilated heart and lipid accumulation in liver, heart, and kidney. The brain showed polymicrogyria in the occipital lobe and evidence of intracerebral hemorrhage. CPT II residual activity was measured at less than 15% of normal control values. North et al. (1995) reported a similar patient who died at day 10 of life. Associated dysmorphic features were noted, including microcephaly, a high sloping forehead, overfolded helices, long and tapered fingers and toes, contractures, and hypoplastic toenails. Postmortem examination showed lipid accumulation in multiple tissues, including liver, kidney, and skeletal muscle. In the brain, the cingulate gyrus was abnormal and several cysts were identified. The kidneys were markedly enlarged with multiple cysts and dysplastic parenchyma. There was an increase in long-chain fatty acids in the serum and urine, and an increase in long-chain acylcarnitines in all tissues examined. The patient also showed hyperammonemia. A profound decrease in CPT II activity (average less than 10% of normal) was detected in several tissues. Land et al. (1995) described a female infant with CPT II deficiency who developed respiratory difficulty at 1 hour of age and died at 34 days of age. The child had a normal fasting ketotic response, and liver mitochondria contained appreciable amounts of total CPT activity, a substantial portion of which was insensitive to the addition of malonyl-CoA, and thus likely to be CPT2. Although there was negligible CPT2 activity in skeletal muscle, the amount detected by immunoblot from the skeletal muscle was considerable. The authors suggested that this reflected a lethal functional but conservative structural mutation of the enzyme protein. Pierce et al. (1999) reported an infant with neonatal lethal CPT II deficiency. He presented on the first day of life with nonketotic hypoglycemia, seizures, hepatomegaly, cardiomegaly with biventricular hypertrophy, and ventricular arrhythmias. Cranial ultrasound showed cystic dysplasia with several foci of hyperechogenicity within the right basal ganglia. Free carnitine was markedly decreased in the urine and plasma with a pronounced elevation of plasma long-chain acylcarnitines. Fibroblast CPT II activity was reduced to 26% and 38% in the father and mother, respectively. The infant died on day 5 from malignant ventricular tachyarrhythmias. Postmortem examination showed diffuse lipid accumulation in the liver, heart, kidney, adrenal cortex, skeletal muscle, and lungs. Elpeleg et al. (2001) reported 2 Ashkenazi Jewish sibs with the antenatal form of CPT II deficiency. The first sib was a male in whom fetal screening at 23 weeks revealed absence of the corpus callosum, ventriculomegaly, intracerebral periventricular calcifications, markedly enlarged polycystic kidneys, and cardiomegaly with a thickened myocardium. At birth, he showed a high-arched narrow palate, mild generalized hypotonia, and decreased responsiveness. He developed renal insufficiency, hepatomegaly with diffuse macrovesicular steatosis, feeding difficulties, metabolic acidosis, increased serum creatine kinase, and decreased serum carnitine. Urinary organic acid analysis showed severe nonketotic dicarboxylic aciduria. He died at age 43 days. Activity of CPT II in lymphocytes was undetectable. A younger affected sib was identified by fetal ultrasound screening. Sharma et al. (2003) reported a term male newborn who developed hypothermia, cardiac dysarrhythmia, and hyperkalemia within 24 hours of birth. Cystic renal dysplasia had been identified prenatally. Other features included hypotonia, poor feeding, renal insufficiency, and respiratory failure. Death occurred on day 12 of life, and postmortem examination confirmed lethal neonatal CPT II deficiency. Isackson et al. (2008) reported an African American patient with lethal neonatal CPT II deficiency. The infant appeared normal at birth but developed hypoglycemia and hyperammonemia in the nursery. She also had heart block, polycystic kidneys, and seizures, and she died at age 14 days. Laboratory studies showed significantly increased plasma carnitine species. Genetic analysis revealed a homozygous mutation in the CPT2 gene (P227L; 600650.0013). Diagnosis ### Prenatal Diagnosis Witt et al. (1991) performed prenatal diagnosis using fetal ultrasound, which detected polycystic kidneys, and oxidation studies on amniocytes, which showed less that 5% CPT II activity. In addition, long-chain acylcarnitine levels in fetal tissues were elevated. Elpeleg et al. (2001) achieved successful prenatal diagnosis of antenatal CPT II deficiency by ultrasound in an Ashkenazi Jewish fetus. Albers et al. (2001) reported an infant with lethal neonatal CPT II deficiency who was detected by newborn screening with tandem mass spectrometry. Vekemans et al. (2003) developed a CPT2 activity assay using 10 mg chorionic villus sampling. Combined with haplotype analysis using markers linked to the CPT2 gene, they carried out prenatal diagnosis of CPT II deficiency in 2 unrelated families at the eleventh week of gestation. Molecular Genetics In 2 sibs with lethal neonatal CPT II deficiency originally reported by Witt et al. (1991), Gellera et al. (1992) identified a heterozygous 11-bp duplication in the CPT2 gene (600650.0012). The asymptomatic mother was heterozygous for the mutation, but the father had only wildtype alleles, and Gellera et al. (1992) concluded that an additional unidentified CPT2 mutation was present in the affected sibs. In 2 Ashkenazi Jewish sibs with antenatal CPT II deficiency, Elpeleg et al. (2001) identified homozygosity for 2 mutations in exon 4 of the CPT2 gene, a 2-bp deletion and a missense mutation (see 600650.0009). Since compound heterozygosity for the same allele carrying both of these mutations was identified in several Ashkenazi patients with the adult form of CPT II deficiency (Taggart et al., 1999), Elpeleg et al. (2001) suggested that genotype determination be performed in all Ashkenazi patients with CPT II deficiency regardless of disease severity. Vladutiu et al. (2002) described a male infant of Ashkenazi Jewish descent with the lethal neonatal form of CPT II who had 2 truncating mutations in the CPT2 gene (600650.0009; 600650.0014). The infant died on the third day of life; CPT II activity was 6% and 18% of normal in fibroblasts and skeletal muscle, respectively. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly Face \- High, sloping forehead \- Prominent forehead Ears \- Overfolded helices \- Low-set ears \- Posteriorly-rotated ears Eyes \- Cataracts Nose \- Bulbous nose Mouth \- High-arched palate \- Narrow palate CARDIOVASCULAR Heart \- Cardiomegaly \- Dilated cardiomyopathy \- Thickened myocardium \- Arrhythmias \- Lipid accumulation in heart RESPIRATORY \- Respiratory distress \- Apnea \- Respiratory failure CHEST Breasts \- Widely spaced nipples ABDOMEN Liver \- Hepatomegaly \- Macrovesicular steatosis \- Lipid accumulation in hepatocytes \- Liver calcifications Gastrointestinal \- Poor feeding GENITOURINARY Kidneys \- Enlarged polycystic kidneys (detectable prenatally) \- Dysplastic renal parenchyma \- Hydronephrosis \- Lipid accumulation in kidney, especially in proximal convoluted tubules \- Renal insufficiency Ureters \- Double ureters SKELETAL Limbs \- Contractures of knees \- Contractures of elbows Hands \- Long, tapering fingers \- Extra digital creases in digits 2-4 Feet \- Long, tapering toes SKIN, NAILS, & HAIR Nails \- Hypoplastic toenails MUSCLE, SOFT TISSUES \- Lipid accumulation in skeletal muscle NEUROLOGIC Central Nervous System \- Neonatal hypotonia \- Lethargy \- Seizures \- Ventriculomegaly \- Intracerebral periventricular calcifications \- Antenatal intracerebral hemorrhage \- Dysplastic or absent corpus callosum \- Polymicrogyria \- Neuronal migration disorder \- Paraventricular cysts \- Basal ganglia cysts METABOLIC FEATURES \- Nonketotic hypoglycemia PRENATAL MANIFESTATIONS Amniotic Fluid \- Oligohydramnios in some cases LABORATORY ABNORMALITIES \- Increased liver function tests \- Increased plasma long-chain acylcarnitines \- Increased tissue long-chain acylcarnitines \- Decreased plasma total and free carnitine \- Decreased tissue total and free carnitine \- Increased serum long-chain fatty acids \- Increased tissue long-chain fatty acids \- Long-chain dicarboxylic aciduria \- Hyperammonemia \- Increased total bilirubin \- Increased tissue levels of triglycerides \- Increased tissue levels of free fatty acids \- Severely decreased palmitate oxidation \- Severely decreased carnitine palmitoyltransferase II (CPT II) activity (less than 10% of normal) in multiple tissues \- Absence of CPT II protein MISCELLANEOUS \- Sudden death within first days of life \- See also infantile ( 600649 ) and late-onset ( 255110 ) CPT II deficiency MOLECULAR BASIS \- Caused by mutation in the carnitine palmitoyltransferase II gene (CPT2, 600650.0009 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LETHAL NEONATAL	c0342790	6,448	omim	https://www.omim.org/entry/608836	2019-09-22T16:07:06	{"doid": ["0060235"], "mesh": ["C535589"], "omim": ["608836"], "orphanet": ["157", "228308"], "synonyms": ["Alternative titles", "CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, NEONATAL", "CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, ANTENATAL", "CPT II DEFICIENCY, LETHAL NEONATAL", "CPT2 DEFICIENCY, LETHAL NEONATAL"], "genereviews": ["NBK1253"]}
Not to be confused with Dysphasia. Dysphagia SpecialtyGastroenterology CausesEsophageal cancer Esophagitis Stomach cancer Dysphagia is difficulty in swallowing.[1][2] Although classified under "symptoms and signs" in ICD-10,[3] in some contexts it is classified as a condition in its own right.[4][5][6] It may be a sensation that suggests difficulty in the passage of solids or liquids from the mouth to the stomach,[7] a lack of pharyngeal sensation or various other inadequacies of the swallowing mechanism. Dysphagia is distinguished from other symptoms including odynophagia, which is defined as painful swallowing,[8] and globus, which is the sensation of a lump in the throat. A person can have dysphagia without odynophagia (dysfunction without pain), odynophagia without dysphagia (pain without dysfunction) or both together. A psychogenic dysphagia is known as phagophobia. ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Classification and cause * 3 Diagnostic approach * 3.1 Differential diagnosis * 4 Treatments * 4.1 Treatment strategies * 4.1.1 Oral vs. nonoral feeding * 4.1.2 Treatment procedures * 5 Epidemiology * 6 Etymology * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Some patients have limited awareness of their dysphagia,[9] so lack of the symptom does not exclude an underlying disease.[10] When dysphagia goes undiagnosed or untreated, patients are at a high risk of pulmonary aspiration and subsequent aspiration pneumonia secondary to food or liquids going the wrong way into the lungs. Some people present with "silent aspiration" and do not cough or show outward signs of aspiration. Undiagnosed dysphagia can also result in dehydration, malnutrition, and kidney failure. Some signs and symptoms of oropharyngeal dysphagia include difficulty controlling food in the mouth, inability to control food or saliva in the mouth, difficulty initiating a swallow, coughing, choking, frequent pneumonia, unexplained weight loss, gurgly or wet voice after swallowing, nasal regurgitation, and dysphagia (patient complaint of swallowing difficulty).[10] When asked where the food is getting stuck, patients will often point to the cervical (neck) region as the site of the obstruction. The actual site of obstruction is always at or below the level at which the level of obstruction is perceived. The most common symptom of esophageal dysphagia is the inability to swallow solid food, which the patient will describe as 'becoming stuck' or 'held up' before it either passes into the stomach or is regurgitated. Pain on swallowing or odynophagia is a distinctive symptom that can be highly indicative of carcinoma, although it also has numerous other causes that are not related to cancer.Achalasia is a major exception to usual pattern of dysphagia in that swallowing of fluid tends to cause more difficulty than swallowing solids. In achalasia, there is idiopathic destruction of parasympathetic ganglia of the Auerbach's (Myenteric) plexus of the entire esophagus, which results in functional narrowing of the lower esophagus, and peristaltic failure throughout its length.[citation needed] ### Complications[edit] Complications of dysphagia may include aspiration, pneumonia, dehydration, and weight loss. ## Classification and cause[edit] Dysphagia is classified into the following major types:[11] 1. Oropharyngeal dysphagia 2. Esophageal and obstructive dysphagia 3. Neuromuscular symptom complexes 4. Functional dysphagia is defined in some patients as having no organic cause for dysphagia that can be found. Following table enumerates possible causes of dysphagia: Location Cause Oral dysphagia * Inlammation/Infection * Tonsillitis * Peritonsillar abscess * Stomatitis * Tongue cancer * Neurological * Paralysis of soft palate, usually due to diphtheria in children and bulbar palsy in adults * Bell's palsy * Xerostomia/dry mouth - e.g. Sjogren's syndrome Pharyngeal dysphagia * Lumen: * Impacted foreign body * Wall: * Pharyngitis * Paterson-Kelly syndrome * Pharyngeal spasms * Malignant neoplasm * Outside the wall: * Retropharyngeal abscess * Lymphadenopathy of cervical lymph nodes * Thyroid malignancy * Eagle syndrome Esophageal dysphagia * Lumen * Impacted foreign body * Wall: * Esophageal atresia * Benign strictures, due to reflux esophagitis, swallowed corrosives, tuberculosis, and radiotherapy, scleroderma/systemic sclerosis * Spasms, due to achalasia, Paterson-Kelly syndrome, esophageal webs, and esophageal rings * Neoplasms, such as esophageal cancer, esophageal leiomyoma * Nervous disorders, such as bulbar palsy, pseudobulbar palsy, post-vagotomy, myasthenia gravis * Crohn's disease * Candida esophagitis * Eosinophilic esophagitis * Outside the wall: * Retrosternal goitre * Malignancy * Zenker's diverticulum * Aortic aneurysm * Mediastinal growth * Dysphagia lusoria * Periesophagitis * Hiatus hernia * Tight hiatus repairs/laparoscopic fundoplication; gastric banding Difficulty with or inability to swallow may be caused or exacerbated by usage of opiate and/or opioid drugs.[12] ## Diagnostic approach[edit] * Esophagoscopy and laryngoscopy can give direct view of lumens. * Esophageal motility study is useful in cases of esophageal achalasia and diffuse esophageal spasms. * Exfoliative cytology can be performed on esophageal lavage obtained by esophagoscopy. It can detect malignant cells in early stage. * Ultrasonography and CT scan are not very useful in finding cause of dysphagia; but can detect masses in mediastinum and aortic aneurysms. * FEES (Fibreoptic endoscopic evaluation of swallowing), sometimes with sensory evaluation, is done usually by a Medical Speech Pathologist or Deglutologist. This procedure involves the patient eating different consistencies as above. * Swallowing sounds and vibrations could be potentially used for dysphagia screening, but these approaches are in the early research stages.[13] ### Differential diagnosis[edit] All causes of dysphagia are considered as differential diagnoses. Some common ones are:[citation needed] * Esophageal atresia * Paterson-Kelly syndrome * Zenker's diverticulum * Esophageal varices * Benign strictures * Achalasia * Esophageal diverticula * Scleroderma * Diffuse esophageal spasm * Polymyositis * Webs and rings * Esophageal cancer * Eosinophilic esophagitis * Hiatus hernia, especially paraesophageal type * Dysphagia lusoria * Stroke * Fahr's disease * Wernicke encephalopathy * Charcot–Marie–Tooth disease * Parkinson's disease * Multiple sclerosis * Amyotrophic lateral sclerosis * Cervical Spondylosis[14] Esophageal[15] dysphagia is almost always caused by disease in or adjacent to the esophagus but occasionally the lesion is in the pharynx or stomach. In many of the pathological conditions causing dysphagia, the lumen becomes progressively narrowed and indistensible. Initially only fibrous solids cause difficulty but later the problem can extend to all solids and later even to liquids. Patients with difficulty swallowing may benefit from thickened fluids if the person is more comfortable with those liquids, although, so far, there are no scientific study that proves that those thickened liquids are beneficial. Dysphagia may manifest as the result of autonomic nervous system pathologies including stroke[16] and ALS,[17] or due to rapid iatrogenic correction of an electrolyte imbalance.[18] ## Treatments[edit] There are many ways to treat dysphagia, such as swallowing therapy, dietary changes, feeding tubes, certain medications, and surgery. Treatment for dysphagia is managed by a group of specialists known as a multidisciplinary team. Members of the multidisciplinary team include: a speech language pathologist specializing in swallowing disorders (swallowing therapist), primary physician, gastroenterologist, nursing staff, respiratory therapist, dietitian, occupational therapist, physical therapist, pharmacist, and radiologist.[10] The role of the members of the multidisciplinary team will differ depending on the type of swallowing disorder present. For example, the swallowing therapist will be directly involved in the treatment of a patient with oropharyngeal dysphagia, while a gastroenterologist will be directly involved in the treatment of an esophageal disorder. ### Treatment strategies[edit] The implementation of a treatment strategy should be based on a thorough evaluation by the multidisciplinary team. Treatment strategies will differ on a patient to patient basis and should be structured to meet the specific needs of each individual patient. Treatment strategies are chosen based on a number of different factors including diagnosis, prognosis, reaction to compensatory strategies, severity of dysphagia, cognitive status, respiratory function, caregiver support, and patient motivation and interest.[10] #### Oral vs. nonoral feeding[edit] Adequate nutrition and hydration must be preserved at all times during dysphagia treatment. The overall goal of dysphagia therapy is to maintain, or return the patient to, oral feeding. However, this must be done while ensuring adequate nutrition and hydration and a safe swallow (no aspiration of food into the lungs).[10] If oral feeding results in increased mealtimes and increased effort during the swallow, resulting in not enough food being ingested to maintain weight, a supplementary nonoral feeding method of nutrition may be needed. In addition, if the patient aspirates food or liquid into the lungs despite the use of compensatory strategies, and is therefore unsafe for oral feeding, nonoral feeding may be needed. Nonoral feeding includes receiving nutrition through a method that bypasses the oropharyngeal swallowing mechanism including a nasogastric tube, gastrostomy, or jejunostomy.[10] #### Treatment procedures[edit] Compensatory Treatment Procedures are designed to change the flow of the food/liquids and eliminate symptoms, but do not directly change the physiology of the swallow.[10] * Postural Techniques * Food Consistency (Diet) Changes * Modifying Volume and Speed of Food Presentation * Technique to Improve Oral Sensory Awareness * Intraoral Prosthetics Therapeutic Treatment Procedures - designed to change and/or improve the physiology of the swallow.[10][19] * Oral and Pharyngeal Range-of-Motion Exercises * Resistance Exercises * Bolus Control Exercises * Swallowing Maneuvers * Supraglottic swallow * Super-supraglottic swallow * Effortful swallow * Mendelsohn maneuver Patients may need a combination of treatment procedures to maintain a safe and nutritionally adequate swallow. For example, postural strategies may be combined with swallowing maneuvers to allow the patient to swallow in a safe and efficient manner. The most common interventions used for those with oropharyngeal dysphagia by speech language pathologists are texture modification of foods, thickening fluids and positioning changes during swallowing.[20] The effectiveness of modifying food and fluid in preventing aspiration pneumonia has been questioned and these can be associated with poorer nutrition, hydration and quality of life.[21] Also, there has been considerable variability in national approaches to describing different degrees of thickened fluids and food textures. However, in 2015, the International Dysphagia Diet Standardisation Initiative (IDDSI) group produced an agreed IDDSI framework consisting of a continuum of 8 levels (0-7), where drinks are measured from Levels 0 – 4, while foods are measured from Levels 3 – 7.[22] It is likely that this initiative, which has widespread support among dysphagia practitioners, will improve communication with carers and will lead to greater standardisation of modified diets ## Epidemiology[edit] Swallowing disorders can occur in all age groups, resulting from congenital abnormalities, structural damage, and/or medical conditions.[10] Swallowing problems are a common complaint among older individuals, and the incidence of dysphagia is higher in the elderly,[23][24] and in patients who have had strokes.[25] Dysphagia affects about 3% of the population.[26] ## Etymology[edit] The word "dysphagia" is derived from the Greek dys meaning bad or disordered, and the root phag- meaning "eat". ## See also[edit] * MEGF10 * Pseudodysphagia, an irrational fear of swallowing or choking * Aphagia ## References[edit] 1. ^ Smithard DG, Smeeton NC, Wolfe CD (January 2007). "Long-term outcome after stroke: does dysphagia matter?". Age and Ageing. 36 (1): 90–94. doi:10.1093/ageing/afl149. PMID 17172601. 2. ^ Brady A (January 2008). "Managing the patient with dysphagia". Home Healthcare Nurse. 26 (1): 41–46, quiz 47–48. doi:10.1097/01.NHH.0000305554.40220.6d. PMID 18158492. S2CID 11420756. 3. ^ "ICD-10". Retrieved 2008-02-23. 4. ^ Boczko F (November 2006). "Patients' awareness of symptoms of dysphagia". Journal of the American Medical Directors Association. 7 (9): 587–90. doi:10.1016/j.jamda.2006.08.002. PMID 17095424. 5. ^ "Dysphagia". University of Virginia. Archived from the original on 2004-07-09. Retrieved 2008-02-24. 6. ^ "Swallowing Disorders - Symptoms of Dysphagia". New York University School of Medicine. Archived from the original on 2007-11-14. Retrieved 2008-02-24. 7. ^ Sleisenger MH, Feldman M, Friedman LM (2002). Sleisenger & Fordtran's Gastrointestinal & Liver Disease, 7th edition. Philadelphia, PA: W.B. Saunders Company. pp. Chapter 6, p. 63. ISBN 978-0-7216-0010-9. 8. ^ "Dysphagia". University of Texas Medical Branch. Archived from the original on 2008-03-06. Retrieved 2008-02-23. 9. ^ Voice of Cancer Patients an online cancer patients community 10. ^ a b c d e f g h i Logemann, Jeri A. (1998). Evaluation and treatment of swallowing disorders. Austin, Tex: Pro-Ed. ISBN 978-0-89079-728-0. 11. ^ Spieker MR (June 2000). "Evaluating dysphagia". American Family Physician. 61 (12): 3639–48. PMID 10892635. 12. ^ "Opioid Effects on Swallowing and Esophageal Sphincter Pressure". clinicaltrials.gov. US National Library of Medicine. Retrieved 23 March 2018. 13. ^ Dudik JM, Coyle JL, Sejdić E (August 2015). "Dysphagia Screening: Contributions of Cervical Auscultation Signals and Modern Signal-Processing Techniques". IEEE Transactions on Human-Machine Systems. 45 (4): 465–477. doi:10.1109/thms.2015.2408615. PMC 4511276. PMID 26213659. 14. ^ Chu EC, Shum JS, Lin AF (2019). "Unusual Cause of Dysphagia in a Patient With Cervical Spondylosis". Clinical Medicine Insights. Case Reports. 12: 1179547619882707. doi:10.1177/1179547619882707. PMC 6937524. PMID 31908560. 15. ^ Voice of Cancer Patients an online cancer patients community 16. ^ Edmiaston J, Connor LT, Loehr L, Nassief A (July 2010). "Validation of a dysphagia screening tool in acute stroke patients". American Journal of Critical Care. 19 (4): 357–64. doi:10.4037/ajcc2009961. PMC 2896456. PMID 19875722. 17. ^ Noh EJ, Park MI, Park SJ, Moon W, Jung HJ (July 2010). "A case of amyotrophic lateral sclerosis presented as oropharyngeal Dysphagia". Journal of Neurogastroenterology and Motility. 16 (3): 319–22. doi:10.5056/jnm.2010.16.3.319. PMC 2912126. PMID 20680172. 18. ^ Martin RJ (September 2004). "Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes". Journal of Neurology, Neurosurgery, and Psychiatry. 75 Suppl 3: iii22–28. doi:10.1136/jnnp.2004.045906. PMC 1765665. PMID 15316041. 19. ^ Perry A, Lee SH, Cotton S, Kennedy C, et al. (Cochrane ENT Group) (August 2016). "Therapeutic exercises for affecting post-treatment swallowing in people treated for advanced-stage head and neck cancers". The Cochrane Database of Systematic Reviews (8): CD011112. doi:10.1002/14651858.CD011112.pub2. hdl:10059/1671. PMC 7104309. PMID 27562477. 20. ^ McCurtin A, Healy C (February 2017). "Why do clinicians choose the therapies and techniques they do? Exploring clinical decision-making via treatment selections in dysphagia practice". International Journal of Speech-Language Pathology. 19 (1): 69–76. doi:10.3109/17549507.2016.1159333. PMID 27063701. S2CID 31193444. 21. ^ O'Keeffe ST (July 2018). "Use of modified diets to prevent aspiration in oropharyngeal dysphagia: is current practice justified?". BMC Geriatrics. 18 (1): 167. doi:10.1186/s12877-018-0839-7. PMC 6053717. PMID 30029632. 22. ^ Cichero JA, Lam P, Steele CM, Hanson B, Chen J, Dantas RO, Duivestein J, Kayashita J, Lecko C, Murray J, Pillay M, Riquelme L, Stanschus S (April 2017). "Development of International Terminology and Definitions for Texture-Modified Foods and Thickened Fluids Used in Dysphagia Management: The IDDSI Framework". Dysphagia. 32 (2): 293–314. doi:10.1007/s00455-016-9758-y. PMC 5380696. PMID 27913916. 23. ^ Shamburek RD, Farrar JT (February 1990). "Disorders of the digestive system in the elderly". The New England Journal of Medicine. 322 (7): 438–43. doi:10.1056/NEJM199002153220705. PMID 2405269. 24. ^ Span P (April 21, 2010). "When the Meal Won't Go Down". New York Times. Retrieved July 27, 2014. 25. ^ Martino R, Foley N, Bhogal S, Diamant N, Speechley M, Teasell R (December 2005). "Dysphagia after stroke: incidence, diagnosis, and pulmonary complications". Stroke. 36 (12): 2756–63. doi:10.1161/01.STR.0000190056.76543.eb. PMID 16269630. 26. ^ Kim JP, Kahrilas PJ (January 2019). "How I Approach Dysphagia". Curr Gastroenterol Rep. 21 (10): 49. doi:10.1007/s11894-019-0718-1. PMID 31432250. S2CID 201064709.CS1 maint: uses authors parameter (link) ## External links[edit] * Dysphagia at Curlie Classification D * ICD-10: R13 * ICD-9-CM: 438.82, 787.2 * MeSH: D003680 * DiseasesDB: 17942 External resources * MedlinePlus: 003115 * eMedicine: pmr/194 * Patient UK: Dysphagia * v * t * e Symptoms and signs relating to the human digestive system or abdomen Gastrointestinal tract * Nausea * Vomiting * Heartburn * Aerophagia * Pagophagia * Dysphagia * oropharyngeal * esophageal * Odynophagia * Bad breath * Xerostomia * Hypersalivation * Burping * Wet burp * Goodsall's rule * Chilaiditi syndrome * Dance's sign * Aaron's sign * Arapov's sign * Markle sign * McBurney's point * Sherren's triangle * Radiologic signs: Hampton's line * Klemm's sign Accessory * liver: Councilman body * Mallory body * biliary: Boas' sign * Courvoisier's law * Charcot's cholangitis triad/Reynolds' pentad * cholecystitis (Murphy's sign * Lépine's sign * Mirizzi's syndrome) * Nardi test Defecation * Flatulence * Fecal incontinence * Encopresis * Fecal occult blood * Rectal tenesmus * Constipation * Obstructed defecation * Diarrhea * Rectal discharge * Psoas sign * Obturator sign * Rovsing's sign * Hamburger sign * Heel tap sign * Aure-Rozanova's sign * Dunphy sign * Alder's sign * Lockwood's sign * Rosenstein's sign Abdomen Pain * Abdominal pain * Acute abdomen * Colic * Baby colic * Abdominal guarding * Blumberg sign Distension * Abdominal distension * Bloating * Ascites * Tympanites * Shifting dullness * Ascites * Fluid wave test Masses * Abdominal mass * Hepatosplenomegaly * Hepatomegaly * Splenomegaly Other * Jaundice * Mallet-Guy sign * Puddle sign * Ballance's sign * Aortic insufficiency * Castell's sign * Kehr's sign * Cullen's sign * Grey Turner's sign Hernia * Howship–Romberg sign * Hannington-Kiff sign Other * Cupola sign * Fothergill's sign * Carnett's sign * Sister Mary Joseph nodule Authority control * GND: 4125110-6 * NDL: 00576682 * NSK: 002104703 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Dysphagia	c0011168	6,449	wikipedia	https://en.wikipedia.org/wiki/Dysphagia	2021-01-18T18:52:13	{"mesh": ["D003680"], "icd-9": ["787.2", "438.82"], "icd-10": ["R13"], "wikidata": ["Q623289"]}
Congenital nephrotic syndrome is a kidney condition that begins in infancy and typically leads to irreversible kidney failure (end-stage renal disease) by early childhood. Children with congenital nephrotic syndrome begin to have symptoms of the condition between birth and 3 months. The features of congenital nephrotic syndrome are caused by failure of the kidneys to filter waste products from the blood and remove them in urine. Signs and symptoms of this condition are excessive protein in the urine (proteinuria), increased cholesterol in the blood (hypercholesterolemia), an abnormal buildup of fluid in the abdominal cavity (ascites), and swelling (edema). Affected individuals may also have blood in the urine (hematuria), which can lead to a reduced number of red blood cells (anemia) in the body, abnormal blood clotting, or reduced amounts of certain white blood cells. Low white blood cell counts can lead to a weakened immune system and frequent infections in people with congenital nephrotic syndrome. Children with congenital nephrotic syndrome typically develop end-stage renal disease between ages 2 and 8, although with treatment, some may not have kidney failure until adolescence or early adulthood. ## Frequency Congenital nephrotic syndrome affects 1 to 3 per 100,000 children worldwide. In Finland, where this condition is particularly common, congenital nephrotic syndrome is estimated to affect 1 in 10,000 children. ## Causes Mutations in the NPHS1 or NPHS2 gene cause most cases of congenital nephrotic syndrome. These genes provide instructions for making proteins that are found in the kidneys. Specifically, the proteins produced from the NPHS1 and NPHS2 genes are found in cells called podocytes, which are located in specialized kidney structures, called glomeruli, that filter the blood. The proteins are found at the podocyte cell surface in the area between two podocytes called the slit diaphragm. The slit diaphragm is known as a filtration barrier because it captures proteins from blood so that they remain in the body while allowing other molecules like sugars and salts to be excreted in urine. The proteins produced from the NPHS1 and NPHS2 genes also help relay cell signals. Mutations in the NPHS1 or NPHS2 gene result in a decrease or absence of functional protein, which impairs the formation of normal slit diaphragms. Without a functional slit diaphragm, more molecules pass through the kidneys abnormally and get excreted in urine, including proteins and blood cells. The filtering ability of the kidneys worsens from birth, eventually leading to end-stage renal disease. NPHS1 gene mutations cause all cases of congenital nephrotic syndrome of the Finnish type. This form of the condition is found in people of Finnish ancestry. NPHS1 gene mutations can cause congenital nephrotic syndrome in non-Finnish individuals, but they are a less common cause than NPHS2 gene mutations, which appear to be the most frequent cause of all cases. Mutations in other genes cause a small number of cases of congenital nephrotic syndrome. Fifteen to 20 percent of individuals with congenital nephrotic syndrome do not have an identified mutation in one of the genes associated with this condition. In these cases, the cause of the condition may be environmental, including infections such as congenital syphilis or toxoplasmosis, or it may be caused by mutations in unidentified genes. ### Learn more about the genes associated with Congenital nephrotic syndrome * NPHS1 * NPHS2 * WT1 Additional Information from NCBI Gene: * LAMB2 * PLCE1 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Congenital nephrotic syndrome	c0403399	6,450	medlineplus	https://medlineplus.gov/genetics/condition/congenital-nephrotic-syndrome/	2021-01-27T08:25:04	{"gard": ["1500"], "mesh": ["C535761"], "omim": ["256300", "600995"], "synonyms": []}
Hidrotic ectodermal dysplasia, Halal type is a form of ectodermal dysplasia syndrome (see this term) characterized by trichodysplasia, with absent eyebrows and eyelashes, onychodysplasia, mild retrognathia, abnormal dermatoglyphics (excess of whorls on fingertips, radial loop on finger, hypothenar pattern), intellectual disability and normal teeth and sweating. Additional variable manifestations include high implanted or prominent ears, mild hearing loss, supernumerary nipple, café-au-lait spots, keratosis pilaris, and irregular menses. To date, four individuals from 2 generations of a consanguineous family of Portuguese descent have been described in the literature. Males and females were equally affected. Hidrotic ectodermal dysplasia, Halal type is inherited in an autosomal recessive manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Hidrotic ectodermal dysplasia, Halal type	c2930953	6,451	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1809	2021-01-23T18:35:02	{"gard": ["280"], "mesh": ["C535621"], "umls": ["C2930953"], "icd-10": ["Q82.8"], "synonyms": ["Halal-Setton-Wang syndrome", "Trichodysplasia-abnormal dermatoglyphics-intellectual disability syndrome"]}
Maternal uniparental disomy of chromosome 6 is an uniparental disomy of maternal origin characterized by intrauterine growth retardation. Homozygosity for a recessive disease mutation for which only a mother is a carrier may lead to other phenotypes. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Maternal uniparental disomy of chromosome 6	c4707720	6,452	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96181	2021-01-23T18:01:39	{"icd-10": ["Q99.8"], "synonyms": ["UPD(6)mat"]}
Infestation of parasitic maggots Myiasis Other namesFlystrike, blowfly strike, fly-blown Cutaneous myiasis in the shoulder of a human Pronunciation * /ˈmaɪ.əsɪs/ or /maɪˈaɪ.əsɪs/ SpecialtyInfectious disease Myiasis is the parasitic infestation of the body of a live animal by fly larvae (maggots) which grow inside the host while feeding on its tissue. Although flies are most commonly attracted to open wounds and urine\- or feces-soaked fur, some species (including the most common myiatic flies—the botfly, blowfly, and screwfly) can create an infestation even on unbroken skin and have been known to use moist soil and non-myiatic flies (such as the common housefly) as vector agents for their parasitic larvae. Because some animals (particularly non-native domestic animals) cannot react as effectively as humans to the causes and effects of myiasis, such infestations present a severe and continuing problem for livestock industries worldwide, causing severe economic losses where they are not mitigated by human action.[1] Although typically a far greater issue for animals, myiasis is also a relatively frequent affliction of humans in rural tropical regions where myiatic flies thrive, and often may require medical attention to surgically remove the parasites.[2] Myiasis varies widely in the forms it takes and its effects on the victims. Such variations depend largely on the fly species and where the larvae are located. Some flies lay eggs in open wounds, other larvae may invade unbroken skin or enter the body through the nose or ears, and still others may be swallowed if the eggs are deposited on the lips or on food.[2] There can also be accidental myiasis which E. tenax can cause in humans via water containing the larvae or in contaminated uncooked food. The name of the condition derives from ancient Greek μυῖα (myia), meaning "fly".[3] ## Contents * 1 Signs and symptoms * 1.1 Wound * 1.2 Eye * 2 Cause * 2.1 Life cycle * 2.2 Human vectors * 2.2.1 Specific myiasis * 2.2.2 Semispecific myiasis * 2.2.3 Accidental myiasis * 3 Diagnosis * 3.1 Classifications * 4 Prevention * 5 Treatment * 6 Epidemiology * 7 History * 8 Maggot therapy * 8.1 History * 9 References * 10 External links ## Signs and symptoms[edit] How myiasis affects the human body depends on where the larvae are located. Larvae may infect dead, necrotic (prematurely dying) or living tissue in various sites: the skin, eyes, ears, stomach and intestinal tract, or in genitourinary sites.[4] They may invade open wounds and lesions or unbroken skin. Some enter the body through the nose or ears. Larvae or eggs can reach the stomach or intestines if they are swallowed with food and cause gastric or intestinal myiasis.[2] Several different presentations of myiasis and their symptoms:[2] Syndrome Symptoms Cutaneous myiasis Painful, slow-developing ulcers or furuncle- (boil-) like sores that can last for a prolonged period Nasal myiasis Obstruction of nasal passages and severe irritation. In some cases facial edema and fever can develop. Death is not uncommon. Aural myiasis Crawling sensations and buzzing noises. Smelly discharge is sometimes present. If located in the middle ear, larvae may get to the brain. Ophthalmomyiasis Severe irritation, edema, and pain. Fairly common. ### Wound[edit] Wound myiasis occurs when fly larvae infest open wounds. It has been a serious complication of war wounds in tropical areas, and is sometimes seen in neglected wounds in most parts of the world. Predisposing factors include poor socioeconomic conditions, extremes of age, neglect, mental disability, psychiatric illness, alcoholism, diabetes, and vascular occlusive disease.[5][6][7][8][9] ### Eye[edit] Myiasis of the human eye or ophthalmomyiasis can be caused by Hypoderma tarandi, a parasitic botfly of caribou. It is known to lead to uveitis, glaucoma, and retinal detachment.[10] Human ophthalmomyiasis, both external and internal, has been caused by the larvae of the botfly.[10] ## Cause[edit] ### Life cycle[edit] The life cycle in sheep is typical of the disease. The female flies lay their eggs on the sheep in damp, protected areas of the body that are soaked with urine and feces, mainly the sheep's breech (buttocks). It takes approximately eight hours to a day for the eggs to hatch, depending on the conditions. Once hatched, the larvae then lacerate the skin with their mouthparts, causing open sores. Once the skin has been breached, the larvae then tunnel through the sores into the host's subcutaneous tissue, causing deep and irritating lesions highly subject to infection. After about the second day, bacterial infection is likely and, if left untreated, causes bacterial bloodstream infections or sepsis. This leads to anorexia and weakness and is generally fatal if untreated.[citation needed] ### Human vectors[edit] There are three main fly families causing economically important myiasis in livestock and also, occasionally, in humans:[citation needed] * Calliphoridae (blowflies) * Some examples include Calliphora vomitoria and Calliphora vicina * Oestridae (botflies) * Sarcophagidae (fleshflies) Sarcophaga barbata are usually found in dead and rotting meat and animal excrement, which are prime environments for them. This is because their larvae are facultative parasites, as they feed on organic tissue and use the hosts' oxygen reserve. Other families occasionally involved are: * Anisopodidae * Piophilidae * Stratiomyidae * Syrphidae #### Specific myiasis[edit] Caused by flies that need a host for larval development[citation needed] * Dermatobia hominis (human botfly) * Cordylobia anthropophaga (tumbu fly) * Oestrus ovis (sheep botfly) * Hypoderma spp. (cattle botflies or ox warbles) * Gasterophilus spp. (horse botfly) * Cochliomyia hominivorax (new world screwworm fly) * Chrysomya bezziana (old world screwworm fly) * Auchmeromyia senegalensis (Congo floor maggot) * Cuterebra spp. (rodent and rabbit botfly) #### Semispecific myiasis[edit] Caused by flies that usually lay their eggs in decaying animal or vegetable matter, but that can develop in a host if open wounds or sores are present[citation needed] * Lucilia spp. (green-bottle fly) * Cochliomyia spp. (screw-worm fly) * Phormia spp. (black-bottle fly) * Calliphora spp. (blue-bottle fly) * Sarcophaga spp. (flesh fly or sarcophagids) Flesh flies, or sarcophagids, members of the family Sarcophagidae, can cause intestinal myiasis in humans if the females lay their eggs on meat or fruit.[citation needed] #### Accidental myiasis[edit] Also called pseudomyiasis. Caused by flies that have no preference or need to develop in a host but that will do so on rare occasions. Transmission occurs through accidental deposit of eggs on oral or genitourinary openings, or by swallowing eggs or larvae that are on food.[citation needed] The cheese fly (Piophila casei) sometimes causes myiasis through intentional consumption of its maggots (which are contained in the traditional Sardinian delicacy casu marzu).[11][12] Other flies that can accidentally cause myiasis are: * Musca domestica (housefly) * Fannia spp. (latrine flies) * Eristalis tenax (rat-tailed maggots) * Muscina spp. The adult flies are not parasitic, but when they lay their eggs in open wounds and these hatch into their larval stage (also known as maggots or grubs), the larvae feed on live and/or necrotic tissue, causing myiasis to develop. They may also be ingested or enter through other body apertures.[citation needed] ## Diagnosis[edit] Myiasis is often misdiagnosed in the United States because it is rare and its symptoms are not specific. Intestinal myiasis and urinary myiasis are especially difficult to diagnose.[2] Clues that myiasis may be present include recent travel to an endemic area, one or more non-healing lesions on the skin, itchiness, movement under the skin or pain, discharge from a central punctum (tiny hole), or a small, white structure protruding from the lesion.[13] Serologic testing has also been used to diagnose the presence of botfly larvae in human ophthalmomyiasis.[10] * Play media Ultrasound showing maggot infestation[14] * Play media Ultrasound showing maggot infestation[14] * Ultrasound showing maggot infestation[14] ### Classifications[edit] German entomologist Fritz Zumpt describes myiasis as "the infestation of live human and vertebrate animals with dipterous larvae, which at least for a period, feed on the host's dead or living tissue, liquid body substances, or ingested food". For modern purposes however, this is too vague. For example, feeding on dead or necrotic tissue is not generally a problem except when larvae such as those of flies in the family Piophilidae attack stored food such as cheese or preserved meats; such activity suggests saprophagy rather than parasitism; it even may be medically beneficial in maggot debridement therapy (MDT).[citation needed] Currently myiasis commonly is classified according to aspects relevant to the case in question: * The classical description of myiasis is according to the part of the host that is infected. This is the classification used by ICD-10. For example:[15] * dermal * sub-dermal * cutaneous (B87.0) * creeping, where larvae burrow through or under the skin * furuncular, where a larva remains in one spot, causing a boil-like lesion * nasopharyngeal, in the nose, sinuses or pharynx (B87.3) * ophthalmic or ocular, in or about the eye (B87.2) * auricular, in or about the ear * gastric, rectal, or intestinal/enteric for the appropriate part of the digestive system (B87.8) * urogenital (B87.8) * Another aspect is the relationship between the host and the parasite and provides insight into the biology of the fly species causing the myiasis and its likely effect. Thus the myiasis is described as either:[15] * obligatory, where the parasite cannot complete its life cycle without its parasitic phase, which may be specific, semispecific, or opportunistic * facultative, incidental, or accidental, where it is not essential to the life cycle of the parasite; perhaps a normally free-living larva accidentally gained entrance to the host[2] Accidental myiasis commonly is enteric, resulting from swallowing eggs or larvae with one's food. The effect is called pseudomyiasis.[16] One traditional cause of pseudomyiasis was the eating of maggots of cheese flies in cheeses such as Stilton. Depending on the species present in the gut, pseudomyiasis may cause significant medical symptoms, but it is likely that most cases pass unnoticed.[citation needed] ## Prevention[edit] The first control method is preventive and aims to eradicate the adult flies before they can cause any damage and is called vector control. The second control method is the treatment once the infestation is present, and concerns the infected animals (including humans).[citation needed] The principal control method of adult populations of myiasis inducing flies involves insecticide applications in the environment where the target livestock is kept. Organophosphorus or organochlorine compounds may be used, usually in a spraying formulation. One alternative prevention method is the sterile insect technique (SIT) where a significant number of artificially reared sterilized (usually through irradiation) male flies are introduced. The male flies compete with wild breed males for females in order to copulate and thus cause females to lay batches of unfertilized eggs which cannot develop into the larval stage.[citation needed] One prevention method involves removing the environment most favourable to the flies, such as by removal of the tail. Another example is the crutching of sheep, which involves the removal of wool from around the tail and between the rear legs, which is a favourable environment for the larvae. Another, more permanent, practice which is used in some countries is mulesing, where skin is removed from young animals to tighten remaining skin – leaving it less prone to fly attack.[17] To prevent myiasis in humans, there is a need for general improvement of sanitation, personal hygiene, and extermination of the flies by insecticides. Clothes should be washed thoroughly, preferably in hot water, dried away from flies, and ironed thoroughly. The heat of the iron kills the eggs of myiasis-causing flies.[13] ## Treatment[edit] This applies once an infestation is established. In many circles the first response to cutaneous myiasis once the breathing hole has formed, is to cover the air hole thickly with petroleum jelly. Lack of oxygen then forces the larva to the surface, where it can more easily be dealt with. In a clinical or veterinary setting there may not be time for such tentative approaches, and the treatment of choice might be more direct, with or without an incision. First the larva must be eliminated through pressure around the lesion and the use of forceps. Secondly the wound must be cleaned and disinfected. Further control is necessary to avoid further reinfestation.[citation needed] Livestock may be treated prophylactically with slow release boluses containing ivermectin which can provide long-term protection against the development of the larvae.Sheep also may be dipped, a process which involves drenching the animals in persistent insecticide to poison the larvae before they develop into a problem. ## Epidemiology[edit] The most common infected animal worldwide is the domestic sheep, for more information see fly strike in sheep. This condition is caused by the blowfly (particularly Lucilia sericata and its sister species L. cuprina), especially where the weather is often hot and wet.[18] Blowfly strike accounts for over A$170 million a year in losses in the Australian sheep industry, the largest such losses in the world. Given the seriousness of the risk, Australian sheep farmers commonly perform preventive measures such as mulesing designed to remove the most common targets for the flies. The docking of lambs' tails (another frequently-soiled area that flies target) is also commonly practiced by sheep farmers worldwide. Maggots also occasionally[citation needed] infest the vulvar area, causing the condition called vulvar myiasis. Such problems are not peculiar to Australia and New Zealand; they occur worldwide, especially in countries where livestock, particularly sheep, are kept under hot, wet, conditions, including most of Africa and the Americas, ranging from the cold temperate regions in the north, to corresponding latitudes in the south. Myiasis is also not restricted to sheep; screwworm flies (Cochliomyia hominivorax in particular) regularly cause upwards of US$100 million in annual damages to domestic cows and goats,[19] though the impact has been heavily mitigated in recent years by the sterile insect technique.[citation needed] ## History[edit] Myiasis in a cat's flesh Frederick William Hope coined the term myiasis in 1840 to refer to diseases resulting from dipterous larvae as opposed to those caused by other insect larvae (the term for this was scholechiasis). Hope described several cases of myiasis from Jamaica caused by unknown larvae, one of which resulted in death.[20] Even though the term myiasis was first used in 1840, such conditions have been known since ancient times. Ambroise Paré, the chief surgeon to King Charles IX and King Henry III, observed that maggots often infested open wounds.[21] ## Maggot therapy[edit] Main article: Maggot therapy Throughout recorded history, maggots have been used therapeutically to clean out necrotic wounds, an application known as maggot therapy.[citation needed] Fly larvae that feed on dead tissue can clean wounds and may reduce bacterial activity and the chance of a secondary infection. They dissolve dead tissue by secreting digestive enzymes onto the wound as well as actively eating the dead tissue with mouth hooks, two hard, probing appendages protruding on either side of the "mouth".[22] Maggot therapy – also known as maggot debridement therapy (MDT), larval therapy, larva therapy, or larvae therapy – is the intentional introduction by a health care practitioner of live, disinfected green bottle fly maggots into the non-healing skin and soft tissue wounds of a human or other animal for the purpose of selectively cleaning out only the necrotic tissue within a wound in order to promote healing.[citation needed] Although maggot therapy has been used in the US for the past 80 years, it was approved by the FDA as a medical device only in 2004 (along with leeches).[23] Maggots were the first live organism to be marketed in the US according to FDA regulations, and are approved for treating neuropathic (diabetic) foot ulcers, pressure ulcers, venous stasis ulcers, and traumatic and post-surgical wounds that are unresponsive to conventional therapies. Maggots were used in medicine before this time, but were not federally regulated. In 1990, California internist Ronald Sherman began treating patients with maggots produced at his lab at the UC Irvine School of Medicine.[23] Sherman went on to co-found Monarch Labs in 2005, which UC Irvine contracted to produce maggots for Sherman's own continuing clinical research on myiasis at the university. Monarch Labs also sells maggots to hospitals and other medical practices, the first US commercial supplier to do so since the last one closed in 1935.[24] In the US, demand for these fly larvae doubled after the FDA ruling. Maggot therapy is now used in more than 300 sites across the country.[22] The American Medical Association and Centers for Medicare and Medicaid Services recently clarified the reimbursement guidelines to the wound care community for medicinal maggots, and this therapy may soon be covered by insurance.[25] The larvae of the green bottle fly (a type of blow-fly) are now used exclusively for this purpose, since they preferentially devour only necrotic tissue, leaving healthy tissue intact. This is an important distinction, as most other major varieties of myiasitic fly larvae attack both live and dead wound tissue indiscriminately, effectively negating their benefit in non-harmful wound debridement. Medicinal maggots are placed on the wound and covered with a sterile dressing of gauze and nylon mesh. However, too many larvae placed on the wound could result in healthy tissue being eaten, efficiently creating a new wound, rendering it as a type of myiasis.[21] ### History[edit] Maggot therapy has a long history and prehistory. The indigenous people of Australia used maggot therapy, and so do the Hill Peoples of Northern Burma, and possibly the Mayans of Central America.[2] Surgeons in Napoleon's armies recognized that wounded soldiers with myiasis were more likely to survive than those without the infestation. In the American Civil War, army surgeons treated wounds by allowing blowfly maggots to clean away the decayed tissue.[citation needed] William Baer, an orthopedic surgeon at Johns Hopkins during the late 1920s, used maggot therapy to treat a series of patients with osteomyelitis, an infection of bone or bone marrow. The idea was based on an experience in World War I in which two soldiers presented to him with broken femurs after having lain on the ground for seven days without food and water. Baer could not figure out why neither man had a fever or signs of sepsis. He observed: "On removing the clothing from the wounded part, much was my surprise to see the wound filled with thousands and thousands of maggots, apparently those of the blow fly. The sight was very disgusting and measures were taken hurriedly to wash out these abominable looking creatures." However, he then saw that the wounds were filled with "beautiful pink granulation tissue" and were healing well.[26] Maggot therapy was common in the United States during the 1930s. However, during the second half of the twentieth century, after the introduction of antibiotics, maggot therapy was used only as a last resort for very serious wounds.[2] Lately maggots have been making a comeback due to the increased resistance of bacteria to antibiotics. ## References[edit] 1. ^ Otranto, Domenico (2001). "The immunology of myiasis: parasite survival and host defense strategies". Trends in Parasitology. 17 (4): 176–182. doi:10.1016/S1471-4922(00)01943-7. PMID 11282507. 2. ^ a b c d e f g h John, David; Petri, William, eds. (2006). Markell and Voge's Medical Parasitology (9th ed.). Missouri: Saunders Elsevier. pp. 328–334. ISBN 978-0-7216-4793-7. 3. ^ μυῖα. Liddell, Henry George; Scott, Robert; A Greek–English Lexicon at the Perseus Project. 4. ^ Ockenhouse, Christian F.; Samlaska, Curt P.; Benson, Paul M.; Roberts, Lyman W.; Eliasson, Arn; Malane, Susan; Menich, Mark D. (1990). "Cutaneous myiasis caused by the African tumbu fly (Cordylobia anthropophaga)". Archives of Dermatology. 126 (2): 199–202. doi:10.1001/archderm.1990.01670260069013. PMID 2301958. 5. ^ Namazi MR, Fallahzadeh MK (November 2009). "Wound myiasis in a patient with squamous cell carcinoma". ScientificWorldJournal. 9: 1192–3. doi:10.1100/tsw.2009.138. PMC 5823144. PMID 19882087. 6. ^ "Screwworm flies as agents of wound myiasis". Fao.org. Retrieved 2013-11-05. 7. ^ El-Azazy, O.M.E. (1989). "Wound myiasis caused by Cochliomyia hominivorax in Libya". Vet. Rec. 124 (4): 103. doi:10.1136/vr.124.4.103-a. PMID 2929078. S2CID 26982759. 8. ^ Huntington, T. E.; Voigt, David W.; Higley, L. G. (January 2008). "Not the Usual Suspects: Human Wound Myiasis by Phorids". Journal of Medical Entomology. 45 (1): 157–159. doi:10.1603/0022-2585(2008)45[157:NTUSHW]2.0.CO;2. PMID 18283957. 9. ^ Cleveland Clinic (13 August 2010). Current Clinical Medicine: Expert Consult - Online. Elsevier Health Sciences. pp. 1396–. ISBN 978-1-4377-3571-0. Retrieved 22 April 2013. 10. ^ a b c Lagacé-Wiens, P. R.; et al. (January 2008). "Human ophthalmomyiasis interna caused by Hypoderma tarandi, Northern Canada". Emerging Infectious Diseases. 14 (1): 64–66. doi:10.3201/eid1401.070163. PMC 2600172. PMID 18258079. 11. ^ Peckenscneider, L.E., Polorny, C. and Hellwig, C.A., 1952 Intestinal infestation with maggots of the cheese fly (Piophila casei). J Am Med Assoc. 1952 May 17;149 (3):262-3. 12. ^ "Gastrointestinal Myiasis – Report of a case, Alonzo F. Brand, M.D., Arch Intern Med (Chic). 1931;47(1):149–154. doi:10.1001/archinte.1931.00140190160017". doi:10.1001/archinte.1931.00140190160017. Archived from the original on 9 January 2018. Retrieved 17 February 2018. Cite journal requires `\|journal=` (help) 13. ^ a b Adisa, Charles Adeyinka; Mbanaso, Augustus (2004). "Furuncular myiasis of the breast caused by the larvae of the Tumbu fly (Cordylobia anthropophaga)". BMC Surgery. 4: 5. doi:10.1186/1471-2482-4-5. PMC 394335. PMID 15113429. 14. ^ a b c "UOTW #22 - Ultrasound of the Week". Ultrasound of the Week. 14 October 2014. Retrieved 27 May 2017. 15. ^ a b Janovy, John; Schmidt, Gerald D.; Roberts, Larry S. (1996). Gerald D. Schmidt & Larry S. Roberts' Foundations of parasitology. Dubuque, Iowa: Wm. C. Brown. ISBN 0-697-26071-2. 16. ^ Zumpt, Fritz Konrad Ernst (1965). Myiasis in man and animals in the old world. Butterworth. 17. ^ "Standard Operating Procedures - sheep Mulesing". teacher's notes. New South Wales Department of Primary Industries. March 8, 2004. Retrieved 2007-01-09. 18. ^ "Royal (Dick) School of Veterinary Studies". Veterinary Record. 160 (19): 669. 2007-05-12. doi:10.1136/vr.160.19.669-b. ISSN 0042-4900. S2CID 219190547. 19. ^ Hill, Dennis S. (1997). The economic importance of insects. Springer. p. 102. ISBN 0-412-49800-6. 20. ^ "Introduction to myiasis \| Natural History Museum". Nhm.ac.uk. Retrieved 2013-11-05. 21. ^ a b Sherman, RA, Hall, MJR, Thomas, S (2000). "Medicinal Maggots: An ancient remedy for some contemporary afflictions". Annual Review of Entomology. 45: 55–81. doi:10.1146/annurev.ento.45.1.55. PMID 10761570. 22. ^ a b Greer, Kathleen A. (January–February 2005). "Age-old therapy gets new approval". Advances in Skin & Wound Care. 18 (1): 12–5. doi:10.1097/00129334-200501000-00003. PMID 15716781. 23. ^ a b Rubin, Rita (2004-07-07). "Maggots and leeches: Good medicine". Usatoday.Com. Retrieved 2013-11-05. 24. ^ Carlson, Bob (February 2006). "Crawling Through the Millennia: Maggots and Leeches Come Full Circle". Biotechnology Healthcare. 3 (1): 14–17. PMC 3571037. PMID 23424330. 25. ^ "Insurance may soon cover maggot therapy - Health - Health care \| NBC News". NBC News. 2008-11-19. Retrieved 2013-11-05. 26. ^ Baer, William S. (1931). "The treatment of chronic osteomyelitis with the maggot (larva of the blow fly)". Journal of Bone and Joint Surgery. 13 (3): 438–475. ## External links[edit] * Myiasis, reviewed and published by WikiVet * Exotic Myiasis, University of Sydney Department of Medical Entomology * Identification key to species of myiasis-causing fly larvae, Natural History Museum (London) * Parasitic Insects, Mites and Ticks: Genera of Medical and Veterinary Importance: Botflies Classification D * ICD-10: B87 * ICD-9-CM: 134.0 * MeSH: D009198 * DiseasesDB: 29588 External resources * Orphanet: 75110 * v * t * e Arthropods and ectoparasite-borne diseases and infestations Insecta Louse * Body louse (pediculosis corporis) / Head louse (head lice infestation) * Crab louse (phthiriasis) Hemiptera * Bed bug (cimicosis) Fly * Dermatobia hominis / Cordylobia anthropophaga / Cochliomyia hominivorax (myiasis) * Mosquito (mosquito-borne disease) Flea * Tunga penetrans (tungiasis) Crustacea Pentastomida * Linguatula serrata (linguatulosis) * Porocephalus crotali / Armillifer armillatus (porocephaliasis) * For ticks and mites, see Template:Tick and mite-borne diseases and infestations [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Myiasis	c0027030	6,453	wikipedia	https://en.wikipedia.org/wiki/Myiasis	2021-01-18T18:58:30	{"mesh": ["D009198"], "umls": ["C0027030"], "orphanet": ["75110"], "wikidata": ["Q304601"]}
A number sign (#) is used with this entry because generalized glucocorticoid resistance (GCCR) is caused by heterozygous mutation in the glucocorticoid receptor gene (NR3C1, GCCR; 138040) on chromosome 5q31. Description Generalized glucocorticoid resistance is an autosomal dominant disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of clinical stigmata of Cushing syndrome. The clinical expression of the disease is variable. Common features include hypoglycemia, hypertension, and metabolic alkalosis. In females, overproduction of adrenal androgens has been associated with infertility, male-pattern baldness, hirsutism, and menstrual irregularities. Other features include chronic fatigue and profound anxiety (summary by Chrousos et al., 1983; Donner et al., 2013). Clinical Features Vingerhoeds et al. (1976) reported a case of cortisol resistance. High levels of cortisol (without stigmata of Cushing syndrome), resistance of the hypothalamic-pituitary-adrenal axis to dexamethasone, and an affinity defect of the glucocorticoid receptor characterized the disorder. Chrousos et al. (1982) restudied the family reported by Vingerhoeds et al. (1976). A man who was presumably homozygous had mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis. One of his brothers, who had severe hypertension and died of a cerebrovascular accident at age 54, may also have been homozygous. Another brother and his son were apparently heterozygous; they showed slightly elevated 24-hour mean plasma cortisol levels and increased urinary free cortisol. Lipsett et al. (1986) provided further follow-up on the 4-generation family originally reported by Vingerhoeds et al. (1976). Autosomal dominant inheritance of glucocorticoid resistance was clearly demonstrated. Lipsett et al. (1986) believed that a mutation in the glucocorticoid receptor was responsible, although other explanations could be invoked. The single homozygote in the family was the proband; the other persons with elevated plasma cortisol levels and increased urinary free cortisol represented heterozygotes. The parents of the proband descended from families with consanguinity that occurred before the 16th century. The 2 parental families had lived in close proximity for many generations. This cortisol resistance is probably the rarest cause of treatable hypertension yet described. Affected mother and son with primary cortisol resistance and a reduction in glucocorticoid receptors were reported by Iida et al. (1985). Bronnegard et al. (1986) described a woman with receptor-mediated resistance to cortisol as indicated by elevated 24-hour mean plasma cortisol levels and increased free urinary cortisol. Plasma ACTH concentrations were normal but she was resistant to adrenal suppression by dexamethasone. No stigmata of Cushing syndrome were present. The patient had symptoms of pronounced fatigue. Menopause had occurred at age 43. The patient's only child, a son, aged 29 years, had periods of inexplicable fatigue that had made him stay home from school and work. Because of the extreme fatigue that led to the mother's working only half-time, Addison's disease was suspected, but rather than hypocortisolism, elevation of urinary cortisol values was found. Bronnegard et al. (1986) found that the end-organ insensitivity to cortisol was not due to decreased concentration or ligand affinity of the receptor. The woman and her son instead showed an increased thermolability of the cortisol receptor, a phenomenon also observed with the androgen receptor in patients with the testicular feminization syndrome (300068). Lamberts et al. (1986) described cortisol resistance in a 26-year-old woman with hirsutism, mild virilization, and menstrual difficulties. They thought that the abnormality was autosomal dominant because her father and 2 brothers had increased plasma cortisol concentrations that did not suppress normally in response to dexamethasone. No hypertension or hypokalemic alkalosis was present. The proband had male-pattern scalp baldness. Nawata et al. (1987) studied a 27-year-old woman with glucocorticoid resistance. She was initially thought to have Cushing disease, based on high plasma ACTH and serum cortisol levels, increased urinary cortisol secretion, resistance to adrenal suppression with dexamethasone, and bilateral adrenal hyperplasia by computed tomography and scintigraphy; however, she had no clinical signs or symptoms of Cushing syndrome. Laboratory studies indicated that the patient's glucocorticoid resistance was due to a decrease in the affinity of the receptor for glucocorticoids and a decrease in the binding of the GCCR complex to DNA. Charmandari et al. (2008) reviewed the clinical aspects, molecular mechanisms, and implications of primary generalized glucocorticoid resistance. They noted that the clinical spectrum is broad, ranging from asymptomatic to severe cases of hyperandrogenism, fatigue, and/or mineralocorticoid excess. Mutations in the GCCR gene resulting in the disorder impair glucocorticoid signal transduction and reduce tissue sensitivity to glucocorticoids. A consequent increase in the activity of the hypothalamic-pituitary-adrenal axis compensates for the reduced sensitivity of peripheral tissues to glucocorticoids at the expense of ACTH hypersecretion-related pathology. The study of functional defects of GCCR mutants highlighted the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology. Molecular Genetics In affected members of the kindred originally reported by Vingerhoeds et al. (1976) with generalized glucocorticoid deficiency, Hurley et al. (1991) identified a heterozygous missense mutation in the GCR gene (D641V; 138040.0001). In all 3 affected members of a Dutch kindred with glucocorticoid resistance, Karl et al. (1993) identified heterozygosity for a 4-bp deletion in the GCR gene (138040.0002). Bray and Cotton (2003) stated that a total of 15 missense, 3 nonsense, 3 frameshift, 1 splice site, and 2 alternatively spliced mutations had been reported in the NR3C1 gene to be associated with glucocorticoid resistance. Sixteen polymorphisms in the gene had also been reported. Heterogeneity Huizenga et al. (2000) described 5 patients with biochemical and clinical cortisol resistance. They found alterations in receptor number or ligand affinity and/or the ability of dexamethasone to inhibit mitogen-induced cell proliferation. To investigate the molecular defects leading to the clinical and biochemical pictures in these patients, they screened the GCCR gene using PCR-SSCP sequence analysis. No GCCR gene alterations were found in these patients. The authors concluded that alterations somewhere in the cascade of events starting with ligand binding to the GCCR protein, and finally resulting in the regulation of the expression of glucocorticoid-responsive genes, or postreceptor defects or interactions with other nuclear factors, form the pathophysiologic basis of cortisol resistance in these patients. Pathogenesis Generalized glucocorticoid resistance is caused by impaired cortisol signaling. This defect results in compensatory activation of the hypothalamic-pituitary adrenal axis, which leads to increased secretion of hypothalamic corticotropin-releasing hormone (CRH) and elevated secretion of the circulating ACTH from the pituitary gland. The excess ACTH secretion, in turn, results in increased secretion of cortisol, the adrenal mineralocorticoids deoxycorticosterone and corticosterone, and adrenal steroids with androgenic activity (summary by Donner et al., 2013). Evolution Two New World primates, the squirrel monkey and the marmoset, have markedly elevated plasma cortisol levels without physiologic evidence of glucocorticoid hormone excess. Chrousos et al. (1982) showed that their hypothalamic-pituitary-adrenal axis is resistant to suppression by dexamethasone. They studied glucocorticoid receptors in circulating monocytes and cultured skin fibroblasts of New and Old World monkeys and found that, although the receptor content was the same in all species, the 2 New World species had markedly decreased binding affinity for dexamethasone. The presumed mutation must have occurred after bifurcation of the Old and New World primates (about 60 Myr ago) and before diversion of the 2 New World species (about 15 Myr ago). A difference between the disorder in man with an affinity defect of the glucocorticoid receptor and the state in New World monkeys is that in the severe form of the human disease, sodium-retaining corticoids (corticosterone and deoxycorticosterone) are elevated many-fold, producing hypertension and hypokalemic alkalosis. The mineralocorticoid overproduction, which does not occur in the New World monkeys, is probably due to corticotropin hyperstimulation of the adrenal cortex. Animal Model Examples of resistance to cortisol are known; the guinea pig is a 'corticoresistant' species (Vingerhoeds et al., 1976). INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Hypertension GENITOURINARY Internal Genitalia (Female) \- Infertility (in some patients) \- Menstrual irregularities (in some patients) SKIN, NAILS, & HAIR Hair \- Male-pattern baldness (in some females) \- Hirsutism (in some females) NEUROLOGIC Behavioral Psychiatric Manifestations \- Anxiety (in some patients) METABOLIC FEATURES \- Metabolic alkalosis ENDOCRINE FEATURES \- Hypoglycemia \- Fatigue LABORATORY ABNORMALITIES \- Hypoglycemia \- Slightly elevated 24-hour mean plasma cortisol \- Increased urinary free cortisol MOLECULAR BASIS \- Caused by mutation in the nuclear receptor subfamily 3, group C, member 1 gene (NR3C1, 138040.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	GLUCOCORTICOID RESISTANCE, GENERALIZED	c1841972	6,454	omim	https://www.omim.org/entry/615962	2019-09-22T15:50:32	{"mesh": ["C564221"], "omim": ["615962"], "orphanet": ["786"], "synonyms": ["Alternative titles", "GLUCOCORTICOID RECEPTOR DEFICIENCY", "GCCR DEFICIENCY", "GCR DEFICIENCY", "GRL DEFICIENCY", "CORTISOL RESISTANCE FROM GLUCOCORTICOID RECEPTOR DEFECT"]}
Neurodegenerative disease This article is about the neurodegenerative disease. For other uses, see ALS (disambiguation). Amyotrophic lateral sclerosis (ALS) Other namesLou Gehrig's disease; Charcot's disease; motor neurone disease (MND)[1] An MRI of the brain with increased T2 signal in the posterior part of the internal capsule that can be tracked to the motor cortex, consistent with the diagnosis of ALS SpecialtyNeurology SymptomsEarly: Stiff muscles, muscle twitches, gradual increasing weakness[2] Later: Difficulty in speaking, swallowing, and breathing; respiratory failure[2] Usual onset50s–60s[3] CausesUnknown (most), inherited (few) Diagnostic methodSuspected as based on symptoms and supported by MRI[2] TreatmentNon-invasive ventilation[4] MedicationRiluzole, edaravone[5][6] PrognosisLife expectancy 2–4 years[4] Frequency2.6/100,000 per year (Europe)[7] Amyotrophic lateral sclerosis (ALS): also known as Lou Gehrig's disease in Canada and the United States, as motor neurone disease (MND) in Australia, Ireland, New Zealand, South Africa, and the United Kingdom, and Charcot disease in francophone countries; is a neurodegenerative neuromuscular disease that results in the progressive loss of motor neurons that control voluntary muscles.[2][8][9] ALS is the most common type of motor neuron disease.[10][11] Early symptoms of ALS include stiff muscles, muscle twitches, and gradual increasing weakness and muscle wasting.[2] It may begin with weakness in the arms or legs, when it is known as limb-onset, or with difficulty in speaking or swallowing, when it is known as bulbar-onset.[2][12] About half of the people affected develop at least mild difficulties with thinking and behavior and most people experience pain.[13][14] The affected muscles are responsible for chewing food, speaking, and walking.[2] Motor neuron loss continues until the ability to eat, speak, move, and finally breathe is lost.[2] ALS eventually causes paralysis and early death, usually from respiratory failure.[15] Most cases of ALS (about 90% to 95%) have no known cause, and are known as sporadic ALS.[2][16] However both genetic and environmental factors are believed to be involved.[17] The remaining 5% to 10% of cases have a genetic cause linked to a history of the disease in the family, and these are known as familial ALS.[16][3] About half of these genetic cases are due to one of two specific genes.[2] The underlying mechanism involves damage to both upper and lower motor neurons.[2] The diagnosis is based on a person's signs and symptoms, with testing done to rule out other potential causes.[2] There is no cure for ALS, and treatment is targeted at improving the symptoms.[8] A medication called riluzole may extend life by about two to three months.[5] Non-invasive ventilation may result in both improved quality and length of life.[4] Mechanical ventilation can prolong survival but does not stop disease progression.[18] A feeding tube may help.[19] The disease can affect people of any age, but usually starts around the age of 60 and in inherited cases around the age of 50.[3] The average survival from onset to death is two to four years, though this can vary, and about 10% survive longer than 10 years,[4][20][2] and death is usually due to respiratory failure.[3] In Europe, the disease affects about two to three people per 100,000 per year.[7] Rates in much of the world are unclear.[21] In the United States, it is more common in white people than black people.[22] Descriptions of the disease date back to at least 1824 by Charles Bell.[23] In 1869, the connection between the symptoms and the underlying neurological problems was first described by Jean-Martin Charcot, who in 1874 began using the term amyotrophic lateral sclerosis.[23] It became well known in the United States in the 20th century when in 1939 it affected baseball player Lou Gehrig and later worldwide following the 1963 diagnosis of cosmologist Stephen Hawking.[24][25] The first ALS gene was discovered in 1993 while the first animal model was developed in 1994.[26][27] In 2014, videos of the Ice Bucket Challenge went viral on the Internet and increased public awareness of the condition.[28] ## Contents * 1 Classification * 1.1 Classical ALS, PLS, and PMA * 1.2 Regional variants * 1.3 Age of onset * 2 Signs and symptoms * 2.1 Initial symptoms * 2.2 Progression * 2.3 Late stages * 3 Cause * 3.1 Genetics * 3.2 Environmental factors * 3.2.1 Head injury * 3.2.2 Physical activity * 3.2.3 Sports * 3.2.4 Smoking * 4 Pathophysiology * 4.1 Neuropathology * 4.2 Biochemistry * 5 Diagnosis * 5.1 Diagnostic criteria * 5.2 Differential diagnosis * 6 Management * 6.1 Medications * 6.2 Breathing support * 6.2.1 Non-invasive ventilation * 6.2.2 Invasive ventilation * 6.3 Therapy * 6.4 Nutrition * 6.5 End-of-life care * 7 Epidemiology * 8 History * 8.1 Diagnostic criteria * 8.2 Name * 9 Society and culture * 10 Research * 10.1 Model organisms * 10.2 Treatments * 10.3 Cause * 11 See also * 12 Notes * 13 References * 14 External links ## Classification[edit] ALS is a motor neuron disease, also spelled "motor neurone disease", which is a group of neurological disorders that selectively affect motor neurons, the cells that control voluntary muscles of the body.[2] Other motor neuron diseases include primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), progressive bulbar palsy, pseudobulbar palsy, and monomelic amyotrophy (MMA).[29] ALS itself can be classified in a few different ways: by how fast the disease progresses which is related to the age of onset; by whether it is familial or sporadic, and by the region first affected.[2] In about 25% of cases, muscles in the face, mouth, and throat are affected first because motor neurons in the part of the brainstem called the medulla oblongata (formerly called the "bulb") start to die first along with lower motor neurons. This form is called "bulbar-onset ALS". In about 5% of cases, muscles in the trunk of the body are affected first.[3] In most cases the disease spreads and affects other spinal cord regions. A few people with ALS have symptoms that are limited to one spinal cord region for at least 12 to 24 months before spreading to a second region; these regional variants of ALS are associated with a better prognosis.[30] ### Classical ALS, PLS, and PMA[edit] Typical or "classical" ALS involves neurons in the brain (upper motor neurons) and in the spinal cord (lower motor neurons).[31] ALS can be classified by the types of motor neurons that are affected. Typical or "classical" ALS involves upper motor neurons in the brain, and lower motor neurons in the spinal cord.[31] Primary lateral sclerosis (PLS) involves only upper motor neurons, and progressive muscular atrophy (PMA) involves only lower motor neurons. There is debate over whether PLS and PMA are separate diseases or simply variants of ALS.[13] Classic ALS accounts for about 70% of all cases of ALS and can be subdivided into limb-onset ALS (also known as spinal-onset) and bulbar-onset ALS.[13] Limb-onset ALS, begins with weakness in the arms and legs[12] and accounts for about two-thirds of all classic ALS cases.[13] Bulbar-onset ALS begins with weakness in the muscles of speech, chewing, and swallowing[31] and accounts for the other one-third of cases.[13] Bulbar onset is associated with a worse prognosis than limb-onset ALS; a population-based study found that bulbar-onset ALS has a median survival of 2.0 years and a 10-year survival rate of 3%, while limb-onset ALS has a median survival of 2.6 years and a 10-year survival rate of 13%.[32] A rare variant is respiratory-onset ALS that accounts for about 3% of all cases of ALS,[13] in which the initial symptoms are difficulty breathing (dyspnea) with exertion, at rest, or while lying down (orthopnea).[33] Spinal and bulbar symptoms tend to be mild or absent at the beginning. It is more common in males.[20] Respiratory-onset ALS has the worst prognosis of any ALS variant; in a population-based study, those with respiratory-onset had a median survival of 1.4 years and 0% survival at 10 years.[32] Primary lateral sclerosis (PLS) accounts for about 5% of all cases of ALS and affects upper motor neurons in the arms and legs.[20] However, more than 75% of people with apparent PLS develop lower motor neuron signs within four years of symptom onset, meaning that a definite diagnosis of PLS cannot be made until then.[34] PLS has a better prognosis than classic ALS, as it progresses slower, results in less functional decline, does not affect the ability to breathe, and causes less severe weight loss.[20] Progressive muscular atrophy (PMA) accounts for about 5% of all cases of ALS and affects lower motor neurons in the arms and legs.[20] While PMA is associated with longer survival on average than classic ALS, it still progresses to other spinal cord regions over time, eventually leading to respiratory failure and death.[13] Upper motor neuron signs can develop late in the course of PMA, in which case the diagnosis might be changed to classic ALS.[34] ### Regional variants[edit] Regional variants of ALS have symptoms that are limited to a single spinal cord region for at least a year; they progress more slowly than classic ALS and are associated with longer survival. Examples include flail arm syndrome, flail leg syndrome, and isolated bulbar ALS. Flail arm syndrome and flail leg syndrome are often considered to be regional variants of PMA because they only involve lower motor neurons. Isolated bulbar ALS can involve upper or lower motor neurons. These regional variants of ALS cannot be diagnosed at the onset of symptoms; a failure of the disease to spread to other spinal cord regions for an extended period of time (at least 12 months) must be observed.[30] Flail arm syndrome, also called brachial amyotrophic diplegia,[a] is characterized by lower motor neuron damage in the cervical spinal cord only, leading to gradual onset of weakness in the proximal arm muscles and decreased or absent reflexes. Flail leg syndrome, also called leg amyotrophic diplegia,[b] is characterized by lower motor neuron damage in the lumbosacral spinal cord only, leading to gradual onset of weakness in the legs and decreased or absent reflexes. Isolated bulbar ALS is characterized by upper or lower motor neuron damage in the bulbar region only, leading to gradual onset of difficulty with speech (dysarthria) and swallowing (dysphagia); breathing (respiration) is generally preserved, at least initially. Two small studies have shown that people with isolated bulbar ALS may live longer than people with bulbar-onset ALS.[30] ### Age of onset[edit] ALS can also be classified based on the age of onset. While the peak age of onset is 58 to 63 for sporadic ALS and 47 to 52 for familial ALS,[3] about 10% of all cases of ALS begin before age 45 ("young-onset" ALS), and about 1% of all cases begin before age 25 (juvenile ALS).[31] People who develop young-onset ALS are more likely to be male, less likely to have bulbar onset of symptoms, and more likely to have a slower progression of disease.[34] Juvenile ALS is more likely to be familial than adult-onset ALS; genes known to be associated with juvenile ALS include ALS2, SETX, SPG11, FUS, and SIGMAR1. Although most people with juvenile ALS live longer than those with adult-onset ALS, some of them have specific mutations in FUS and SOD1 that are associated with a poor prognosis.[35] Late onset (after age 65) is associated with a more rapid functional decline and shorter survival.[36] ## Signs and symptoms[edit] The disorder causes muscle weakness, atrophy, and muscle spasms throughout the body due to the degeneration of the upper motor and lower motor neurons. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement,[4] although bladder and bowel function and the extraocular muscles (the muscles responsible for eye movement) are usually spared[37][c] until the final stages of the disease.[39] Cognitive or behavioral dysfunction is present in 30–50% of individuals with ALS.[40] Around half of people with ALS will experience mild changes in cognition and behavior, and 10–15% will show signs of frontotemporal dementia.[4] Repeating phrases or gestures, apathy, and loss of inhibition are frequently reported behavioral features of ALS.[41] Language dysfunction, executive dysfunction, and troubles with social cognition and verbal memory are the most commonly reported cognitive symptoms in ALS; a meta-analysis found no relationship between dysfunction and disease severity.[42] However, cognitive and behavioral dysfunctions have been found to correlate with reduced survival in people with ALS and increased caregiver burden; this may be due in part to deficits in social cognition.[42] About half the people who have ALS experience emotional lability, in which they cry or laugh for no reason; it is more common in those with bulbar-onset ALS.[4] Pain is a symptom experienced by most people with ALS and can take the form of neuropathic pain (pain caused by nerve damage), spasticity, muscle cramps, and nociceptive pain caused by reduced mobility and muscle weakness; examples of nociceptive pain in ALS include contractures (permanent shortening of a muscle or joint), neck pain, back pain, shoulder pain, and pressure ulcers.[14] Sensory nerves and the autonomic nervous system are generally unaffected, meaning the majority of people with ALS maintain hearing, sight, touch, smell, and taste.[2] ### Initial symptoms[edit] The start of ALS may be so subtle that the symptoms are overlooked.[2] The earliest symptoms of ALS are muscle weakness or muscle atrophy. Other presenting symptoms include trouble swallowing or breathing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; or slurred and nasal speech. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first.[8] In limb-onset ALS, the first symptoms are in arms or the legs. If the legs are affected first, people may experience awkwardness, tripping, or stumbling when walking or running; this is often marked by walking with a "dropped foot" that drags gently on the ground. If the arms are affected first, they may experience difficulty with tasks requiring manual dexterity, such as buttoning a shirt, writing, or turning a key in a lock.[8] In bulbar-onset ALS, the first symptoms are difficulty speaking or swallowing. Speech may become slurred, nasal in character, or quieter. There may be difficulty with swallowing and loss of tongue mobility. A smaller proportion of people experience "respiratory-onset" ALS, where the intercostal muscles that support breathing are affected first.[3] Over time, people experience increasing difficulty moving, swallowing (dysphagia), and speaking or forming words (dysarthria). Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia), including an overactive gag reflex. An abnormal reflex commonly called Babinski's sign also indicates upper motor neuron damage. Symptoms of lower motor neuron degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen under the skin (fasciculations). However, twitching is more of a side effect than a diagnostic symptom; it either occurs after or accompanies weakness and atrophy.[2] ### Progression[edit] Although the initial symptoms and rate of progression vary from person to person, the disease eventually spreads to unaffected regions and the affected regions become more affected. Most people eventually are not able to walk or use their hands and arms, lose the ability to speak and swallow food and their own saliva, and begin to lose the ability to cough and to breathe on their own.[4] The rate of progression can be measured using the ALS Functional Rating Scale - Revised (ALSFRS-R), a 12-item instrument survey administered as a clinical interview or self-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability);[43] it is the most commonly used outcome measure in clinical trials and is used by doctors to track disease progression.[44] Though the degree of variability is high and a small percentage of people have a much slower disorder, on average, people with ALS lose about 0.9 FRS points per month. A survey-based study among clinicians showed that they rated a 20% change in the slope of the ALSFRS-R as being clinically meaningful.[45] Disease progression tends to be slower in people who are younger than 40 at onset,[46] are mildly obese,[47] have symptoms restricted primarily to one limb, and those with primarily upper motor neuron symptoms.[32] Conversely, progression is faster and prognosis poorer in people with bulbar-onset ALS, respiratory-onset ALS and frontotemporal dementia.[32] ### Late stages[edit] Difficulties with chewing and swallowing make eating very difficult and increase the risk of choking or of aspirating food into the lungs. In later stages of the disorder, aspiration pneumonia can develop, and maintaining a healthy weight can become a significant problem that may require the insertion of a feeding tube. As the diaphragm and intercostal muscles of the rib cage that support breathing weaken, measures of lung function such as vital capacity and inspiratory pressure diminish. In respiratory-onset ALS, this may occur before significant limb weakness is apparent. The most common cause of death among people with ALS are respiratory failure or pneumonia[3] and most people with ALS die in their own home from the former cause, with their breath stopping while they sleep.[8] Although respiratory support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Most people with ALS die between two and four years after the diagnosis.[4] Around half of people with ALS die within 30 months of their symptoms beginning, and about 20% of people with ALS live between five and 10 years after symptoms begin.[3] Guitarist Jason Becker has lived since 1989 with the disorder, while cosmologist Stephen Hawking lived for 55 more years following his diagnosis, but they are considered unusual cases.[48] ## Cause[edit] Though the exact cause of ALS is unknown, genetic and environmental factors are thought to be of roughly equal importance.[17] The genetic factors are better understood than the environmental factors; no specific environmental factor has been definitively shown to cause ALS. A liability threshold model for ALS proposes that cellular damage accumulates over time due to genetic factors present at birth and exposure to environmental risks throughout life.[21] ### Genetics[edit] Main article: Genetics of amyotrophic lateral sclerosis ALS can be classified as familial or sporadic, depending on whether or not there is a family history of the disease.[20][49] There is no consensus among neurologists on the exact definition of familial ALS. The strictest definition is that a person with ALS must have two or more first-degree relatives (children, siblings, or parents) who also have ALS. A less strict definition is that a person with ALS must have at least one first-degree or second-degree relative (grandparents, grandchildren, aunts, uncles, nephews, nieces or half-siblings) who also has ALS.[50] Familial ALS is usually said to account for 10% of all cases of ALS, though estimates range from 5%[51] to 20%.[52] Higher estimates use a broader definition of familial ALS and examine the family history of people with ALS more thoroughly.[50] In sporadic ALS, there is no family history of the disease.[39] Sporadic ALS and familial ALS appear identical clinically and pathologically and are similar genetically;[52] about 10% of people with sporadic ALS have mutations in genes that are known to cause familial ALS.[13] In light of these parallels, the term "sporadic ALS" has been criticized as misleading because it implies that cases of sporadic ALS are only caused by environmental factors; the term "isolated ALS" has been suggested as a more accurate alternative.[52] More than 20 genes have been associated with familial ALS, of which four account for the majority of familial cases:[53] C9orf72 (40%), SOD1 (20%), FUS (1–5%), and TARDBP (1–5%).[13] The genetics of familial ALS are better understood than the genetics of sporadic ALS;[13] as of 2016[update], the known ALS genes explained about 70% of familial ALS and about 15% of sporadic ALS.[54][55] Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS.[17][56] ALS has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease.[26] ALS and frontotemporal dementia (FTD) are now considered to be part of a common disease spectrum (FTD–ALS) because of genetic, clinical, and pathological similarities.[57] Genetically, C9orf72 repeat expansions account for about 40% of familial ALS and 25% of familial FTD.[26] Clinically, 50% of people with ALS have some cognitive or behavioral impairments and 5–15% have FTD, while 40% of people with FTD have some motor neuron symptoms and 12.5% have ALS.[13] Pathologically, abnormal aggregations of TDP-43 protein are seen in up to 97% of ALS patients and up to 50% of FTD patients.[58] Other genes known to cause FTD-ALS include CHCHD10, SQSTM1, and TBK1.[53] ### Environmental factors[edit] Where no family history of the disease is present — around 90% of cases — no cause is known. Possible associations for which evidence is inconclusive include military service and smoking.[40] Although studies on military history and ALS frequency are inconsistent, there is weak evidence for a positive correlation.[59] Various proposed factors include exposure to environmental toxins (inferred from geographical deployment studies), as well as alcohol and tobacco use during military service.[59] A 2016 review of 16 meta-analyses concluded that there was convincing evidence for an association with chronic occupational exposure to lead; suggestive evidence for farming, exposure to heavy metals other than lead, beta-carotene intake, and head injury; and weak evidence for omega-three fatty acid intake, exposure to extremely low frequency electromagnetic fields, pesticides, and serum uric acid.[60] In a 2017 study by the United States Centers for Disease Control and Prevention analyzing U.S. deaths from 1985 to 2011, occupations correlated with ALS deaths were white collar, such as in management, financial, architectural, computing, legal, and education jobs.[61] Other potential risk factors remain unconfirmed, including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock.[62][63] There is a tentative association with exposure to various pesticides, including the organochlorine insecticides aldrin, dieldrin, DDT, and toxaphene.[64][65][66] #### Head injury[edit] A 2015 review found that moderate to severe traumatic brain injury is a risk factor for ALS, but whether mild traumatic brain injury increases rates was unclear.[67] A 2017 meta-analysis found an association between head injuries and ALS; however, this association disappeared when the authors considered the possibility of reverse causation, which is the idea that head injuries are an early symptom of undiagnosed ALS, rather than the cause of ALS.[68] #### Physical activity[edit] A number of reviews have found no relationship between the amount of physical activity and the risk of developing ALS.[69][70][71] A 2009 review found that the evidence for physical activity as a risk factor for ALS was limited, conflicting, and of insufficient quality to come to a firm conclusion.[72] A 2014 review concluded that physical activity in general is not a risk factor for ALS, that soccer and American football are possibly associated with ALS, and that there was not enough evidence to say whether or not physically demanding occupations are associated with ALS.[73] A 2016 review found the evidence inconclusive and noted that differences in study design make it difficult to compare studies, as they do not use the same measures of physical activity or the same diagnostic criteria for ALS.[74] #### Sports[edit] Both soccer and American football have been identified as risk factors for ALS in several studies, although this association is based on small numbers of ALS cases.[75] A 2012 retrospective cohort study of 3,439 former NFL players found that their risk of dying from neurodegenerative causes was three times higher than the general US population, and their risk of dying from ALS or Alzheimer's disease was four times higher.[76] However, this increased risk was calculated on the basis of two deaths from Alzheimer's disease and six deaths from ALS out of 334 deaths total in this cohort, meaning that this study does not definitively prove that playing American football is a risk factor for ALS.[77] Some NFL players thought to have died from ALS may have actually had chronic traumatic encephalopathy (CTE), a neurodegenerative disorder associated with multiple head injuries that can present with symptoms that are very similar to ALS.[67][d] Soccer was identified as a possible risk factor for ALS in a retrospective cohort study of 24,000 Italian soccer players who played between 1960 and 1996. There were 375 deaths in this group, including eight from ALS. Based on this information and the incidence of ALS, it was calculated that the soccer players were 11 times more likely to die from ALS than the general Italian population.[21] However, this calculation has been criticized for relying on an inappropriately low number of expected cases of ALS in the cohort.[72] When the lifetime risk of developing ALS was used to predict the number of expected cases, soccer players were no more likely to die of ALS than the general population.[21] #### Smoking[edit] Smoking is possibly associated with ALS. A 2009 review concluded that smoking was an established risk factor for ALS.[80] A 2010 systematic review and meta-analysis concluded that there was not a strong association between smoking and ALS, but that smoking might be associated with a higher risk of ALS in women.[81] A 2011 meta-analysis concluded that smoking increases the risk of ALS versus never smoking. Among smokers, the younger they started smoking, the more likely they were to get ALS; however, neither the number of years smoked nor the number of cigarettes smoked per day affected their risk of developing ALS.[82] ## Pathophysiology[edit] ### Neuropathology[edit] The defining feature of ALS is the death of both upper motor neurons (located in the motor cortex of the brain) and lower motor neurons (located in the brainstem and spinal cord).[83] In ALS with frontotemporal dementia, neurons throughout the frontal and temporal lobes of the brain die as well.[39] The pathological hallmark of ALS is the presence of inclusion bodies (abnormal aggregations of protein) known as Bunina bodies in the cytoplasm of motor neurons. In about 97% of people with ALS, the main component of the inclusion bodies is TDP-43 protein;[12] however, in those with SOD1 or FUS mutations, the main component of the inclusion bodies[84][85] is SOD1 protein or FUS protein, respectively.[31] The gross pathology of ALS, which are features of the disease that can be seen with the naked eye, include skeletal muscle atrophy, motor cortex atrophy, sclerosis of the corticospinal and corticobulbar tracts, thinning of the hypoglossal nerves (which control the tongue), and thinning of the anterior roots of the spinal cord.[12] Aside from the death of motor neurons, two other characteristics common to most ALS variants are focal initial pathology, meaning that symptoms start in a single spinal cord region, and progressive continuous spread, meaning that symptoms spread to additional regions over time. Prion-like propagation of misfolded proteins from cell to cell may explain why ALS starts in one area and spreads to others.[31] The glymphatic system may also be involved in the pathogenesis of ALS.[86] ### Biochemistry[edit] This figure shows ten proposed disease mechanisms for ALS and the genes associated with them.[87] It is still not fully understood why neurons die in ALS, but this neurodegeneration is thought to involve many different cellular and molecular processes.[13] The genes known to be involved in ALS can be grouped into three general categories based on their normal function: protein degradation, the cytoskeleton, and RNA processing. Mutant SOD1 protein forms intracellular aggregations that inhibit protein degradation. Cytoplasmic aggregations of wild-type (normal) SOD1 protein are common in sporadic ALS.[39] It is thought that misfolded mutant SOD1 can cause misfolding and aggregation of wild-type SOD1 in neighboring neurons in a prion-like manner.[12] Other protein degradation genes that can cause ALS when mutated include VCP, OPTN, TBK1, and SQSTM1. Three genes implicated in ALS that are important for maintaining the cytoskeleton[39] and for axonal transport[12] include DCTN1, PFN1, and TUBA4A.[39] There are a number of ALS genes that encode for RNA-binding proteins. The first to be discovered was TDP-43 protein,[39] a nuclear protein that aggregates in the cytoplasm of motor neurons in almost all cases of ALS; however, mutations in TARDBP, the gene that codes for TDP-43, are a rare cause of ALS.[12] FUS codes for FUS, another RNA-binding protein with a similar function to TDP-43, which can cause ALS when mutated.[26] It is thought that mutations in TARDBP and FUS increase the binding affinity of the low-complexity domain, causing their respective proteins to aggregate in the cytoplasm. Once these mutant RNA-binding proteins are misfolded and aggregated, they may be able to misfold normal protein both within and between cells in a prion-like manner.[39] This also leads to decreased levels of RNA-binding protein in the nucleus, which may mean that their target RNA transcripts do not undergo the normal processing. Other RNA metabolism genes associated with ALS include ANG, SETX, and MATR3.[12] C9orf72 is the most commonly mutated gene in ALS and causes motor neuron death through a number of mechanisms.[39] The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over);[58] people with 30 repeats are normal, while people with hundreds or thousands of repeats can have familial ALS, frontotemporal dementia, or sometimes sporadic ALS. The three mechanisms of disease associated with these C9orf72 repeats are deposition of RNA transcripts in the nucleus, translation of the RNA into toxic dipeptide repeat proteins in the cytoplasm, and decreased levels of the normal C9orf72 protein.[39] Mitochondrial bioenergetic dysfunction leading to dysfunctional motor neuron axonal homeostasis (reduced axonal length and fast axonal transport of mitochondrial cargo) has been shown to occur in C9orf72-ALS using human induced pluripotent stem cell (iPSC) technologies coupled with CRSIPR/Cas9 gene-editing, and human post-mortem spinal cord tissue examination.[88] Excitotoxicity, or nerve cell death caused by high levels of intracellular calcium due to excessive stimulation by the excitatory neurotransmitter glutamate, is a mechanism thought to be common to all forms of ALS. Motor neurons are more sensitive to excitotoxicity than other types of neurons because they have a lower calcium-buffering capacity and a type of glutamate receptor (the AMPA receptor) that is more permeable to calcium. In ALS, there are decreased levels of excitatory amino acid transporter 2 (EAAT2), which is the main transporter that removes glutamate from the synapse; this leads to increased synaptic glutamate levels and excitotoxicity. Riluzole, a drug that modestly prolongs survival in ALS, inhibits glutamate release from pre-synaptic neurons; however, it is unclear if this mechanism is responsible for its therapeutic effect.[12] ## Diagnosis[edit] MRI (axial FLAIR) demonstrates increased T2 signal within the posterior part of the internal capsule, consistent with the diagnosis of ALS. No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive.[2] Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the person and a series of tests to rule out other diseases.[2] Physicians obtain the person's full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are worsening.[2] A number of biomarkers are being studied for the condition, but so far are not in general medical use.[89][90] ### Diagnostic criteria[edit] The diagnosis of ALS is based on the El Escorial Revised criteria and the Awaji criteria.[12] The original El Escorial criteria had four levels of diagnostic certainty, based on how many of the four spinal cord regions were involved: bulbar, cervical, thoracic, and lumbar. Definite ALS was defined as upper motor neuron (UMN) and lower motor neuron (LMN) signs in three spinal cord regions, probable ALS as UMN and LMN signs in two regions, possible ALS as UMN and LMN signs in only one region, and suspected ALS as LMN signs only. The El Escorial Revised criteria, also known as the Airlie House criteria, dropped the "suspected ALS" category and added a "laboratory-supported probable ALS" category. The Awaji criteria give abnormal EMG tests the same weight as clinical signs of LMN dysfunction in making the diagnosis of ALS,[34] thus making the "laboratory-supported probable ALS" category unnecessary. The only three categories in the Awaji criteria are definite ALS, probable ALS, and possible ALS.[91] The El Escorial Revised criteria are specific for ALS, which means that someone who meets the criteria is very likely to have ALS; however, they are not especially sensitive for ALS, which means that someone who does not meet the criteria can still have ALS. Their sensitivity is particularly poor in the early stages of ALS. The Awaji criteria have better sensitivity than the El Escorial Revised criteria, especially for bulbar-onset ALS.[34] A 2012 meta-analysis found that the El Escorial Revised criteria had a sensitivity of 62.2%, while the Awaji criteria had a sensitivity of 81.1%; both sets of criteria had a specificity of about 98%.[92] The El Escorial criteria were designed to standardize patient groups for clinical trials[93] but are not as useful in clinical practice; possible ALS as described by the El Escorial criteria is almost always clinically ALS.[12] ### Differential diagnosis[edit] Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions. One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles. Certain EMG findings can support the diagnosis of ALS. Another common test measures nerve conduction velocity (NCV).Specific abnormalities in the NCV results may suggest, for example, that the person has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS. While a magnetic resonance imaging (MRI) is often normal in people with early stage ALS, it can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis, a herniated disc in the neck, syringomyelia, or cervical spondylosis.[2] Based on the person's symptoms and findings from the examination and from these tests, the physician may order tests on blood and urine samples to eliminate the possibility of other diseases, as well as routine laboratory tests. In some cases, for example, if a physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed.[2] A number of infectious diseases can sometimes cause ALS-like symptoms,[2] including human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), Lyme disease, and syphilis.[13] Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, CIDP, spinal muscular atrophy, and spinal and bulbar muscular atrophy can also mimic certain aspects of the disease and should be considered.[2] ALS must be differentiated from the "ALS mimic syndromes", which are unrelated disorders that may have a similar presentation and clinical features to ALS or its variants.[94] Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, people with ALS symptoms should always obtain a specialist neurological opinion in order to rule out alternative diagnoses. Myasthenic syndrome, also known as Lambert–Eaton syndrome, can mimic ALS, and its initial presentation can be similar to that of myasthenia gravis (MG), a treatable autoimmune disease sometimes mistaken for ALS.[95][96] Benign fasciculation syndrome and Cramp fasciculation syndrome are other conditions that mimic some of the early symptoms of ALS, but are accompanied by normal EMG readings and no major disablement.[97] Most cases of ALS, however, are correctly diagnosed, with the error rate of diagnosis in large ALS clinics being less than 10%.[98][99] One study examined 190 people who met the MND/ALS diagnostic criteria, complemented with laboratory research in compliance with both research protocols and regular monitoring. Thirty of these people (16%) had their diagnosis completely changed during the clinical observation development period.[100] In the same study, three people had a false negative diagnosis of MG, which can mimic ALS and other neurological disorders, leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not.[101] ## Management[edit] There is no cure for ALS. Management focuses on treating symptoms and providing supportive care, with the goal of improving quality of life and prolonging survival.[13] This care is best provided by multidisciplinary teams of healthcare professionals; attending a multidisciplinary ALS clinic is associated with longer survival, fewer hospitalizations, and improved quality of life.[4] Riluzole prolongs survival by about 2–3 months.[5] Edaravone slows functional decline slightly in a small number of people with ALS;[102] it is expensive and must be administered by daily IV infusions that may decrease quality of life.[103] Other medications may be used to manage other symptoms.[104] Non-invasive ventilation (NIV) is the main treatment for respiratory failure in ALS.[12] In people with normal bulbar function, it prolongs survival by about seven months and improves quality of life. One study found that NIV is ineffective for people with poor bulbar function[105] while another suggested that it may provide a modest survival benefit.[13] Many people with ALS have difficulty tolerating NIV.[106] Invasive ventilation is an option for people with advanced ALS when NIV is not enough to manage their symptoms.[4] While invasive ventilation prolongs survival, disease progression and functional decline continue.[18] It may decrease the quality of life of people with ALS or their caregivers.[19][18] Invasive ventilation is more commonly used in Japan than North America or Europe.[107] Physical therapy can promote functional independence[108][109] through aerobic, range of motion, and stretching exercises.[104] Occupational therapy can assist with activities of daily living through adaptive equipment.[110] Speech therapy can assist people with ALS who have difficulty speaking.[109] Preventing weight loss and malnutrition in people with ALS improves both survival and quality of life.[13] Initially, difficulty swallowing (dysphagia) can be managed by dietary changes and swallowing techniques. A feeding tube should be considered if someone with ALS loses 5% or more of their body weight or if they cannot safely swallow food and water.[12] The feeding tube is usually inserted by percutaneous endoscopic gastrostomy (PEG). There is weak evidence that PEG tubes improve survival.[111] PEG insertion is usually performed with the intent of improving quality of life.[19] Palliative care should begin shortly after someone is diagnosed with ALS.[112] Discussion of end-of-life issues gives people with ALS time to reflect on their preferences for end-of-life care and can help avoid unwanted interventions or procedures. Hospice care can improve symptom management at the end of life and increases the likelihood of a peaceful death.[19] In the final days of life, opioids can be used to treat pain and dyspnea, while benzodiazepines can be used to treat anxiety.[18] ### Medications[edit] Chemical structure of riluzole, a medication that prolongs survival by 2–3 months[5] Riluzole has been found to modestly prolong survival by about 2–3 months.[113][5] It may have a greater survival benefit for those with bulbar-onset ALS.[5] It may work by decreasing release of the excitatory neurotransmitter glutamate from pre-synaptic neurons.[12] The most common side effects are nausea and a lack of energy (asthenia).[5] People with ALS should begin treatment with riluzole as soon as possible following their diagnosis.[112] Edaravone has been shown to modestly slow the decline in function in a small group of people with early-stage ALS.[e][f][102][115] It may work by protecting motor neurons from oxidative stress.[116] The most common side effects are bruising and gait disturbance.[115] Treatment with edaravone is expensive and requires daily hour-long IV infusions for 10 days in a two-week period.[103] Other medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and phlegm.[104] Gabapentin, pregabalin, and tricyclic antidepressants (e.g., amitriptyline) can be used for neuropathic pain, while nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and opioids can be used for nociceptive pain.[14] Depression can be treated with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants,[12] while benzodiazepines can be used for anxiety.[4] There are no medications to treat cognitive impairment/frontotemporal dementia (FTD); however, SSRIs and antipsychotics can help treat some of the symptoms of FTD.[12] Baclofen and tizanidine are the most commonly used oral drugs for treating spasticity; an intrathecal baclofen pump can be used for severe spasticity.[12] Atropine, scopolamine, amitriptyline or glycopyrrolate may be prescribed when people with ALS begin having trouble swallowing their saliva (sialorrhea).[12] A 2017 review concluded that mexiletine was safe and effective for treating cramps in ALS based on a randomized controlled trial from 2016.[115] In a study from 2020, AMX0035, a combination of sodium phenylbutyrate and taurursodiol, was shown to prolong the survival of patients by several months.[117][118] ### Breathing support[edit] #### Non-invasive ventilation[edit] Non-invasive ventilation supports breathing with a face or nasal mask connected to a ventilator. Non-invasive ventilation (NIV) is the primary treatment for respiratory failure in ALS[12] and was the first treatment shown to improve both survival and quality of life.[4] NIV uses a face or nasal mask connected to a ventilator that provides intermittent positive pressure to support breathing. Continuous positive pressure is not recommended for people with ALS because it makes breathing more difficult.[18] Initially, NIV is used only at night[4] because the first sign of respiratory failure is decreased gas exchange (hypoventilation) during sleep; symptoms associated with this nocturnal hypoventilation include interrupted sleep, anxiety, morning headaches, and daytime fatigue. As the disease progresses, people with ALS develop shortness of breath when lying down, during physical activity or talking, and eventually at rest.[119] Other symptoms include poor concentration, poor memory, confusion, respiratory tract infections, and a weak cough. Respiratory failure is the most common cause of death in ALS.[4] It is important to monitor the respiratory function of people with ALS every three months, because beginning NIV soon after the start of respiratory symptoms is associated with increased survival. This involves asking the person with ALS if they have any respiratory symptoms and measuring their respiratory function.[4] The most commonly used measurement is upright forced vital capacity (FVC), but it is a poor detector of early respiratory failure and is not a good choice for those with bulbar symptoms, as they have difficulty maintaining a tight seal around the mouthpiece. Measuring FVC while the person is lying on their back (supine FVC) is a more accurate measure of diaphragm weakness than upright FVC.[106] Sniff nasal inspiratory pressure (SNIP) is a rapid, convenient test of diaphragm strength that is not affected by bulbar muscle weakness.[18] If someone with ALS has signs and symptoms of respiratory failure, they should undergo daytime blood gas analysis[4] to look for hypoxemia (low oxygen in the blood) and hypercapnia (too much carbon dioxide in the blood).[18] If their daytime blood gas analysis is normal, they should then have nocturnal pulse oximetry to look for hypoxemia during sleep.[4] Non-invasive ventilation prolongs survival longer than riluzole. A 2006 randomized controlled trial found that NIV prolongs survival by about 48 days and improves quality of life; however, it also found that some people with ALS benefit more from this intervention than others. For those with normal or only moderately impaired bulbar function, NIV prolongs survival by about seven months and significantly improves quality of life. For those with poor bulbar function, NIV neither prolongs survival nor improves quality of life, though it does improve some sleep-related symptoms.[105] Despite the clear benefits of NIV, about 25–30% of all people with ALS are unable to tolerate it, especially those with cognitive impairment or bulbar dysfunction.[106] Results from a large 2015 cohort study suggest that NIV may prolong survival in those with bulbar weakness, and so NIV should be offered to all people with ALS, even if it is likely that they will have difficulty tolerating it.[13] #### Invasive ventilation[edit] Invasive ventilation bypasses the nose and mouth (the upper airways) by making a cut in the trachea (tracheostomy) and inserting a tube connected to a ventilator.[18] It is an option for people with advanced ALS whose respiratory symptoms are poorly managed despite continuous NIV use.[4] While invasive ventilation prolongs survival, especially for those younger than 60, it does not treat the underlying neurodegenerative process. The person with ALS will continue to lose motor function, making communication increasingly difficult and sometimes leading to locked-in syndrome, in which they are completely paralyzed except for their eye muscles.[18] About half of the people with ALS who choose to undergo invasive ventilation report a decrease in their quality of life[19] but most still consider it to be satisfactory. However, invasive ventilation imposes a heavy burden on caregivers and may decrease their quality of life.[18] Attitudes toward invasive ventilation vary from country to country; about 30% of people with ALS in Japan choose invasive ventilation, versus less than 5% in North America and Europe.[107] ### Therapy[edit] A man with ALS communicates by pointing to letters and words using a head-mounted laser pointer. Physical therapy plays a large role in rehabilitation for individuals with ALS. Specifically, physical, occupational, and speech therapists can set goals and promote benefits for individuals with ALS by delaying loss of strength, maintaining endurance, limiting pain, improving speech and swallowing, preventing complications, and promoting functional independence.[108][109] Occupational therapy and special equipment such as assistive technology can also enhance people's independence and safety throughout the course of ALS.[110] Gentle, low-impact aerobic exercise such as performing activities of daily living, walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular health, and help people fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles. Physical and occupational therapists can recommend exercises that provide these benefits without overworking muscles, because muscle exhaustion can lead to worsening of symptoms associated with ALS, rather than providing help to people with ALS.[104] They can suggest devices such as ramps, braces, walkers, bathroom equipment (shower chairs, toilet risers, etc.), and wheelchairs that help people remain mobile. Occupational therapists can provide or recommend equipment and adaptations to enable ALS people to retain as much safety and independence in activities of daily living as possible.[110] People with ALS who have difficulty speaking or swallowing may benefit from working with a speech-language pathologist.[109] These health professionals can teach people adaptive strategies such as techniques to help them speak louder and more clearly. As ALS progresses, speech-language pathologists can recommend the use of augmentative and alternative communication such as voice amplifiers, speech-generating devices (or voice output communication devices) or low-tech communication techniques such as head mounted laser pointers, alphabet boards or yes/no signals.[109] Speech-language pathologists may also help people diagnosed with ALS with their swallowing impairment (dysphagia) which may include modified diet, swallowing exercises, compensatory strategies. People with ALS might require tracheostomy placement, which SLPs will help to manage.[citation needed] ### Nutrition[edit] A gastrostomy tube is placed through the wall of the abdomen into the stomach. Preventing weight loss and malnutrition in people with ALS improves both survival and quality of life.[13] Weight loss in ALS is caused by muscle wasting due to motor neuron death, increased resting energy expenditure, and decreased food intake. Difficulty swallowing (dysphagia) develops in about 85% of people with ALS at some point over the course of their disease and is a major cause of decreased food intake, leading to malnutrition and weight loss.[18] It is important to regularly assess the weight and swallowing ability of people with ALS.[4] Initially, dysphagia may be managed by dietary changes and modified swallowing techniques.[12] Difficulty swallowing liquids usually develops first and can be managed by switching to thicker liquids like fruit nectar or smoothies, or by adding fluid thickeners to thin fluids like water and coffee. People with ALS should eat soft, moist foods, which tend to be easier to swallow than dry, crumbly, or chewy foods.[119] They should also be instructed on proper head posture during swallowing, which can make swallowing easier.[12] There is tentative evidence that high-calorie diets may prevent further weight loss and improve survival.[115] Patients will receive speech therapy to address their dysphagia and to continuously assess for the most least restrictive, and safe diet consistency. A feeding tube should be considered if someone with ALS loses 5% or more of their body weight or if they cannot safely swallow food and water.[12] This can take the form of a gastrostomy tube, in which a tube is placed through the wall of the abdomen into the stomach, or a nasogastric tube, in which a tube is placed through the nose and down the esophagus into the stomach.[18] A gastrostomy tube is more appropriate for long-term use[4] than a nasogastric tube, which is uncomfortable and can cause esophageal ulcers.[18] The feeding tube is usually inserted by percutaneous endoscopic gastrostomy (PEG). There is some evidence that a PEG tube should be inserted before vital capacity drops below 50% of expected, as a low vital capacity may be associated with a higher risk of complications. However, a large 2015 study showed that PEG insertion is safe in people with advanced ALS and low vital capacities, as long as they are on NIV during the procedure.[115] There is weak evidence that PEG tubes improve survival.[111] PEG insertion is usually performed with the intent of improving quality of life[19] by sustaining nutrition and medication intake.[4] This reduces the risk of weight loss and dehydration, and can decrease anxiety from extended mealtimes[19] and decreased oral food intake.[4] ### End-of-life care[edit] Palliative care, which relieves symptoms and improves quality of life without treating the underlying disease, should begin shortly after someone is diagnosed with ALS.[112] Early discussion of end-of-life issues gives people with ALS time to reflect on their preferences for end-of-life care and can help avoid unwanted interventions or procedures.[19] Once they have been fully informed about all aspects of various life-prolonging measures, they can fill out advanced directives indicating their attitude toward noninvasive ventilation, invasive ventilation, and feeding tubes.[115] Late in the disease course, difficulty speaking due to muscle weakness (dysarthria) and cognitive dysfunction may impair their ability to communicate their wishes regarding care.[12] Continued failure to solicit the preferences of the person with ALS may lead to unplanned and potentially unwanted emergency interventions, such as invasive ventilation. If people with ALS or their family members are reluctant to discuss end-of-life issues, it may be useful to use the introduction of gastrostomy or noninvasive ventilation as an opportunity to bring up the subject.[19] Hospice care, or palliative care at the end of life, is especially important in ALS because it helps to optimize the management of symptoms and increases the likelihood of a peaceful death.[19] It is unclear exactly when the end-of-life phase begins in ALS, but it is associated with significant difficulty moving, communicating, and, in some cases, thinking.[12] Although many people with ALS fear choking to death (suffocating),[19] they can be reassured that this occurs rarely, about 0–3% of the time. About 90% of people with ALS die peacefully.[120] In the final days of life, opioids can be used to treat pain and dyspnea, while benzodiazepines can be used to treat anxiety.[18] ## Epidemiology[edit] ALS is the most common motor neuron disease in adults and the third most common neurodegenerative disease[26] after Alzheimer's disease and Parkinson's disease.[121] Worldwide the number of people who develop ALS yearly is estimated to be 1.9 people per 100,000 per year, while the number of people who have ALS at any given time is estimated to be about 4.5 people per 100,000.[122] In Europe, the number of new cases a year is about 2.6 people per 100,000, while the number affected is 7–9 people per 100,000.[7] The lifetime risk of developing ALS is 1:350 for European men and 1:400 for European women. Men have a higher risk mainly because spinal-onset ALS is more common in men than women.[21] The number of those with ALS in the United States in 2015 was 5.2 people per 100,000, and was higher in whites, males, and people over 60 years old.[22] The number of new cases is about 0.8 people per 100,000 per year in east Asia and about 0.7 people per 100,000 per year in south Asia. About 80% of ALS epidemiology studies have been conducted in Europe and the United States, mostly in people of northern European descent.[12] There is not enough information to determine the rates of ALS in much of the world, including Africa, parts of Asia, India, Russia, and South America.[21] There are several geographic clusters in the Western Pacific where the prevalence of ALS was reported to be 50–100 times higher than the rest of the world, including Guam, the Kii Peninsula of Japan, and Western New Guinea. The incidence in these areas has decreased since the 1960s;[1] the cause remains unknown.[21] People of all races and ethnic backgrounds may be affected by ALS,[22] but it is more common in whites than in Africans, Asians, or Hispanics.[123] In the United States in 2015, the prevalence of ALS in whites was 5.4 people per 100,000, while the prevalence in blacks was 2.3 people per 100,000. The Midwest had the highest prevalence of the four US Census regions with 5.5 people per 100,000, followed by the Northeast (5.1), the South (4.7), and the West (4.4). The Midwest and Northeast likely had a higher prevalence of ALS because they have a higher proportion of whites than the South and West.[22] Ethnically mixed populations may be at a lower risk of developing ALS; a study in Cuba found that people of mixed ancestry were less likely to die from ALS than whites or blacks.[124] There are also differences in the genetics of ALS between different ethnic groups; the most common ALS gene in Europe is C9orf72, followed by SOD1, TARDBP, and FUS, while the most common ALS gene in Asia is SOD1, followed by FUS, C9orf72, and TARDBP.[125] Estimated prevalence of ALS in the United States by age group, 2012–2015[22] ALS can affect people at any age,[40] but the peak incidence is between 50 and 75 years[13] and decreases dramatically after 80 years.[3] The reason for the decreased incidence in the elderly is unclear. One thought is that people who survive into their 80s may not be genetically susceptible to developing ALS; alternatively, ALS in the elderly might go undiagnosed because of comorbidities (other diseases they have), difficulty seeing a neurologist, or dying quickly from an aggressive form of ALS.[124] In the United States in 2015, the lowest prevalence was in the 18–39 age group, while the highest prevalence was in the 70–79 age group.[22] Sporadic ALS usually starts around the ages of 58 to 63 years, while familial ALS starts earlier, usually around 47 to 52 years.[3] The number of ALS cases worldwide is projected to increase from 222,801 in 2015 to 376,674 in 2040, an increase of 69%. This will largely be due to the aging of the world's population, especially in developing countries.[123] ## History[edit] The French neurologist Jean-Martin Charcot coined the term amyotrophic lateral sclerosis in 1874.[23] Descriptions of the disease date back to at least 1824 by Charles Bell.[23] In 1850, François-Amilcar Aran was the first to describe a disorder he named "progressive muscular atrophy", a form of ALS in which only the lower motor neurons are affected.[126] In 1869, the connection between the symptoms and the underlying neurological problems were first described by Jean-Martin Charcot, who initially introduced the term amyotrophic lateral sclerosis in his 1874 paper.[23] Flail arm syndrome, a regional variant of ALS, was first described by Alfred Vulpian in 1886. Flail leg syndrome, another regional variant of ALS, was first described by Pierre Marie and his student Patrikios in 1918.[127] In 1945, American naval doctors reported that ALS was 100 times more prevalent among the Chamorro people of Guam than in the rest of the world. In 1956 the variant of ALS endemic to Guam was named "amyotrophic lateral sclerosis/parkinsonism dementia complex" (ALS/PDC), as it had the typical symptoms of ALS accompanied by parkinsonism-like symptoms; the name in the local language is lytico-bodig disease. Despite a number of genetic and environmental studies, the cause of ALS/PDC remains unknown. Rates peaked in the early 1950s and steadily declined thereafter, and by 1985 the incidence of ALS/PDC in Guam was about the same as the rest of the world.[128] The first gene to be associated with ALS was SOD1, which was identified in 1993.[26] This led to the development of the first animal model of ALS, the transgenic SOD1 mouse, in 1994.[27] In December 1995, riluzole became the first FDA-approved drug for ALS. It was then approved in Europe in 1996 and in Japan in 1998.[103] In 1996, the ALS Functional Rating Scale (ALSFRS) was first published; it was a 10-item questionnaire that measured the ability of people with ALS to perform activities of daily living.[129] In 1999, the scale was changed to give more weight to respiratory symptoms. The resulting ALS Functional Rating Scale - Revised (ALSFRS-R) is a 12-item questionnaire that replaces the single question about breathing with a question each about dyspnea, orthopnea, and respiratory insufficiency.[130] In 2006, it was discovered that the protein TDP-43 is a major component of the inclusion bodies seen in both ALS and frontotemporal dementia (FTD), which provided evidence that ALS and FTD are part of a common disease spectrum. This led to the discovery in 2008 that mutations in TARDBP, the gene that codes for TDP-43, are a cause of familial ALS.[26] In 2011, noncoding repeat expansions in C9orf72 were found to be a major cause of ALS and FTD.[12] Edaravone was approved to treat ALS in Japan and South Korea in 2015 and in the United States in 2017.[116] As of 2017[update], it has not been approved to treat ALS in Europe.[115] ### Diagnostic criteria[edit] In the 1950s, electrodiagnostic testing (EMG and NCV) began to be used to evaluate clinically suspected ALS. In 1969 Edward H. Lambert published the first EMG/NCS diagnostic criteria for ALS, consisting of four findings he considered to strongly support the diagnosis.[131] In 1990, the World Federation of Neurology (WFN) held a meeting at El Escorial, Spain, to come up with precise diagnostic criteria for ALS to help standardize clinical trials; the resulting "El Escorial" criteria were published in 1994.[132] In 1998, the WFN held another meeting to revise the criteria at Airlie House in Warrenton, Virginia; the resulting "Airlie House" or "El Escorial Revised" criteria were published in 2000.[133] In 2006, a meeting was held on Awaji Island in Japan to discuss how to use EMG and NCV tests to help diagnose ALS earlier; the resulting "Awaji" criteria were published in 2008.[91] ### Name[edit] In some countries, especially the United States, ALS is called "Lou Gehrig's disease".[134] Other names for ALS include Charcot's disease, Lou Gehrig's disease, and motor neurone disease.[1] Amyotrophic comes from the Greek word amyotrophia: a- means "no", myo refers to "muscle", and trophia means "nourishment". Therefore, amyotrophia means "no muscle nourishment,"[135] which describes the loss of signals motor neurons usually send to muscle cells;[136] this leads to the characteristic muscle atrophy seen in people with ALS. Lateral identifies the areas in a person's spinal cord where the affected motor neurons that control muscle are located. Sclerosis means "scarring" or "hardening" and refers to the death of the motor neurons in the spinal cord.[135] ALS is sometimes referred to as "Charcot's disease" because Jean-Martin Charcot was the first to connect the clinical symptoms with the pathology seen at autopsy. The term is ambiguous and can also refer to Charcot–Marie–Tooth disease and Charcot joint disease.[137] The British neurologist Russell Brain coined the term "motor neurone disease" in 1933 to reflect his belief that ALS, progressive bulbar palsy, and progressive muscular atrophy were all different forms of the same disease,[138] although "neurone" should be spelt "neuron".[139] In some countries, especially the United States, ALS is called "Lou Gehrig's disease",[134] after American baseball player Lou Gehrig, who developed ALS in 1938, had to stop playing baseball in 1939, and died from it in 1941.[140] In the United States and continental Europe, the terms "ALS" or "Lou Gehrig's disease" refer to all forms of the disease, including classical ALS, progressive bulbar palsy, progressive muscular atrophy, and primary lateral sclerosis.[141][36] In the United Kingdom and Australia, the term "motor neurone disease" is the name used for ALS; and other diseases that affect the motor neurons are separately treated motor neuron diseases.[142][141] ## Society and culture[edit] See also: List of people with amyotrophic lateral sclerosis Play media A student demonstrating the ice bucket challenge In August 2014, a challenge went viral online, commonly known as the "ALS Ice Bucket Challenge".[143] Contestants fill a bucket full of ice and water, then state who nominated them to do the challenge, and nominate three other individuals of their choice to take part in it. The contestants then dump the buckets of ice and water onto themselves. However, it can be done in a different order. The contestants then donate at least US$10 (or a similar amount in their local currency) to ALS research at the ALS Association, the ALS Therapy Development Institute, ALS Society of Canada or Motor Neurone Disease Association in the UK. Any contestants who refuse to have the ice and water dumped on them are expected to donate at least US$100 to ALS research. As of July 2015[update], the Ice Bucket Challenge had raised $115 million for the ALS Association.[144] Many celebrities have taken part in the challenge.[145] The Ice Bucket Challenge was credited with helping to raise funds that contributed to the discovery that the gene NEK1 may potentially contribute to the development for ALS.[146][147] ## Research[edit] Main article: Amyotrophic lateral sclerosis research ### Model organisms[edit] Some of the most common models used to study ALS. Many different organisms are used as models for studying ALS, including Saccharomyces cerevisiae (a species of yeast),[87] Caenorhabditis elegans (a roundworm), Drosophila melanogaster (the common fruit fly), Danio rerio (the zebrafish), Mus musculus (the house mouse), and Rattus norvegicus (the common rat).[13] None of these models perfectly represents ALS in humans, partly because most animal models are based on gene overexpression, meaning that multiple copies of the mutant human gene are inserted into the transgenic model, and partly because the human nervous system is very different from that of other animals.[12] The first animal model for ALS was the SOD1G93A transgenic mouse,[g] which was developed in 1994. It expresses about 20–24 copies of the mutant human SOD1 gene[148] and reproduces most of the clinical and pathological findings seen in ALS.[149] Although there are now over 20 different SOD1 mouse models, the SOD1G93A model remains both the most widely used SOD1 mouse model[148] and the most widely used ALS mouse model overall.[27] Much of the present understanding of ALS pathophysiology came from studying mouse models that overexpress mutant SOD1,[148] especially SOD1G93A mice.[27] However, many drug targets that were shown to be effective in the SOD1G93A transgenic mouse failed in clinical trials in humans; other SOD1 models have had similar problems.[148] Most of these drugs were identified as potentially effective based on a single study in a rodent SOD1 model and then failed in clinical trials in patients who primarily had sporadic ALS.[87] It is thought that these clinical trials failed because SOD1 mutations account for only 2% of all ALS cases[148] and because the pathology of SOD1 ALS is thought to be distinct from all other types of ALS; it lacks the abnormal aggregations of TDP-43 protein or FUS protein seen in nearly all other cases of ALS.[26] As of 2018, there are about 20 TARDBP mouse models, a dozen FUS mouse models, and a number of C9orf72, PFN1, and UBQLN2 mouse models. There are also new methods of developing animal models, including viral transgenesis, in which viruses are used to deliver mutant genes to an animal model, and CRISPR/Cas9, which can be used to give an animal model multiple mutated genes. Both of these methods are faster and cheaper than traditional methods of genetically engineering mice; they also allow scientists to study the effects of a mutation in mice of different genetic backgrounds, which better represents the genetic diversity seen in humans.[27] Cellular models used to study ALS include the yeast Saccharomyces cerevisiae and rat or mouse motor neurons in culture. Small-animal models include the fruit fly, the roundworm C. elegans, and the zebrafish. Of the three, the fruit fly is the most widely used; it has a rapid life-cycle, short lifespan, a sophisticated nervous system, and many genetic tools available. C. elegans has a short life-cycle, is easy to manipulate genetically, and has a simple but well-understood nervous system. The zebrafish has transparent embryos that can be injected with DNA or RNA and has a lifespan of up to two years.[87] Induced pluripotent stem cells (iPSCs) can be used to convert skin fibroblasts into motor neurons.[13] It is now possible to generate iPSCs from people with ALS, which can then be converted into spinal motor neurons, which are useful for studying disease mechanisms and for testing potential drugs for ALS.[150] iPSCs allow sporadic ALS to be modelled, which cannot be done with animal models.[87] ### Treatments[edit] From the 1960s until 2014, about 50 drugs for ALS were tested in randomized controlled trials (RCTs);[h] of these, riluzole was the only one that showed a slight benefit in improving survival. Drugs tested and not shown to be effective in clinical trials in humans include antiviral drugs, anti-excitotoxic drugs, growth factors, neurotrophic factors, anti-inflammatory drugs, antioxidants, anti-apoptotic drugs, and drugs to improve mitochondria function.[151] An analysis of 23 large phase II and phase III RCTs that failed between 2004 and 2014 concluded that there were many potential reasons for their lack of success. These trials in humans went ahead on the basis of positive results in SOD1 transgenic mice, which are not a good animal model for sporadic ALS. Additionally, in most preclinical studies the SOD1 mice were given the drug during the presymptomatic stage; this makes the results less likely to apply to people with ALS, who begin treatment well after their symptoms begin. Positive results in small phase II studies in humans could also be misleading and lead to failure in phase III trials. Other potential issues included the drug not reaching its intended site of action in the central nervous system and drug interactions between the study drug and riluzole.[151] Repetitive transcranial magnetic stimulation had been studied in ALS in small and poorly designed clinical trials; as of 2013[update], evidence was insufficient to know whether rTMS is safe or effective for ALS.[152] One 2016 review of stem-cell therapy trials found tentative evidence that intraspinal stem cell implantation was relatively safe and possibly effective.[153] A 2019 Cochrane review of cell-based therapies found that there was insufficient evidence to speculate about efficacy.[154] Masitinib has been approved as an orphan drug in Europe and the United States, with studies ongoing as of 2016[update].[155] Beta-adrenergic agonist drugs have been proposed as a treatment for their effects on muscle growth and neuroprotection, but research in humans is insufficient to determine their efficacy.[156] ### Cause[edit] With the discovery that TDP-43, FUS, and C9orf72 can cause ALS as well as related forms of frontotemporal dementia (FTD/ALS)[157][158] there has been intense effort to understand how these mutations cause disease, and whether other protein dysfunction may be important. As of 2013[update] it appeared that differences in the methylation of arginine residues in FUS protein may be relevant, and methylation status may be a way to distinguish some forms of FTD from ALS.[159] ## See also[edit] * Transportin 1 ## Notes[edit] 1. ^ Additional names for flail arm syndrome include the scapulohumeral form of ALS, Vulpian–Bernart syndrome, hanging arm syndrome, and neurogenic man-in-a-barrel syndrome.[20] 2. ^ Additional names for flail leg syndrome that involves both lower legs (bilateral distal involvement) include pseudopolyneuritic ALS, Patrikios syndrome, Marie-Patrikios ALS, and the peroneal form of ALS.[20] 3. ^ According to one cohort study, 11.5% of people with ALS have extraocular muscle dysfunction.[38] 4. ^ In 2013, the NFL reached a $765 million agreement to compensate more than five thousand former NFL players for concussion-related injuries and illnesses.[78] Some NFL players involved in the legal settlement complained that the NFL was not doing enough to help players. The judge in the case concurred, and in 2015 the NFL agreed to pay an unlimited amount of damages for players found to have ALS, Parkinson's disease, Alzheimer's disease, or dementia.[79] 5. ^ The criteria are "scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less."[102] 6. ^ Based on population-based ALS registries, it is estimated that less than 7% of people with ALS meet these criteria.[114] 7. ^ "G93A" means that the 93rd amino acid residue in the SOD1 protein has been changed from glycine to alanine. 8. ^ For the complete list, see Amyotrophic lateral sclerosis research#Past clinical trials. ## References[edit] 1. ^ a b c Wijesekera LC, Leigh PN (February 2009). "Amyotrophic lateral sclerosis". Orphanet Journal of Rare Diseases. 3 (4): 3. doi:10.1186/1750-1172-4-3. PMC 2656493. PMID 19192301. 2. ^ a b c d e f g h i j k l m n o p q r s t u v w x y "Amyotrophic Lateral Sclerosis (ALS) Fact Sheet \| National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 22 October 2020. 3. ^ a b c d e f g h i j k Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC (March 2011). "Amyotrophic lateral sclerosis". Lancet. 377 (9769): 942–55. doi:10.1016/s0140-6736(10)61156-7. PMID 21296405. 4. ^ a b c d e f g h i j k l m n o p q r s t u v w Hobson EV, McDermott CJ (September 2016). "Supportive and symptomatic management of amyotrophic lateral sclerosis" (PDF). Nature Reviews. Neurology. 12 (9): 526–38. doi:10.1038/nrneurol.2016.111. PMID 27514291. S2CID 8547381. 5. ^ a b c d e f g Miller RG, Mitchell JD, Moore DH (March 2012). "Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)". The Cochrane Database of Systematic Reviews. 3 (3): CD001447. doi:10.1002/14651858.CD001447.pub3. PMC 7055506. PMID 22419278. 6. ^ "FDA approves drug to treat ALS". U.S. Food and Drug Administration. 5 May 2017. Archived from the original on 8 May 2017. 7. ^ a b c Hardiman O, Al-Chalabi A, Brayne C, Beghi E, van den Berg LH, Chio A, Martin S, Logroscino G, Rooney J (July 2017). "The changing picture of amyotrophic lateral sclerosis: lessons from European registers". Journal of Neurology, Neurosurgery, and Psychiatry. 88 (7): 557–63. doi:10.1136/jnnp-2016-314495. PMID 28285264. S2CID 52871105. 8. ^ a b c d e "Motor neurone disease – NHS". nhs.uk. 15 January 2018. Retrieved 24 October 2020. 9. ^ Australia, Healthdirect (17 April 2020). "Motor neurone disease (MND)". www.healthdirect.gov.au. Retrieved 24 October 2020. 10. ^ Zucchi E, Bonetto V, Sorarù G, et al. (15 October 2020). "Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers". Molecular Neurodegeneration. 15 (1): 58. doi:10.1186/s13024-020-00406-3. PMID 33059698. S2CID 222385359. 11. ^ "Motor Neuron Diseases Fact Sheet \| National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 27 October 2020. 12. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, Shaw PJ, Simmons Z, van den Berg LH (October 2017). "Amyotrophic lateral sclerosis" (PDF). Nature Reviews. Disease Primers. 3 (17071): 17071. doi:10.1038/nrdp.2017.71. PMID 28980624. S2CID 1002680. 13. ^ a b c d e f g h i j k l m n o p q r s t u van Es MA, Hardiman O, Chio A, Al-Chalabi A, Pasterkamp RJ, Veldink JH, van den Berg LH (November 2017). "Amyotrophic lateral sclerosis". Lancet. 390 (10107): 2084–2098. doi:10.1016/S0140-6736(17)31287-4. PMID 28552366. S2CID 24483077. 14. ^ a b c Chiò A, Mora G, Lauria G (February 2017). "Pain in amyotrophic lateral sclerosis". The Lancet. Neurology. 16 (2): 144–57. arXiv:1607.02870. doi:10.1016/S1474-4422(16)30358-1. PMID 27964824. S2CID 38905437. 15. ^ Hilton JB, White AR, Crouch PJ (May 2015). "Metal-deficient SOD1 in amyotrophic lateral sclerosis". Journal of Molecular Medicine (Berlin, Germany). 93 (5): 481–7. doi:10.1007/s00109-015-1273-3. PMID 25754173. S2CID 12043749. 16. ^ a b "Understanding ALS". The ALS Association. 17. ^ a b c Wingo TS, Cutler DJ, Yarab N, Kelly CM, Glass JD (2011). "The heritability of amyotrophic lateral sclerosis in a clinically ascertained United States research registry". PLOS ONE. 6 (11): e27985. Bibcode:2011PLoSO...627985W. doi:10.1371/journal.pone.0027985. PMC 3222666. PMID 22132186. 18. ^ a b c d e f g h i j k l m n Soriani M, Desnuelle C (May 2017). "Care management in amyotrophic lateral sclerosis". Revue Neurologique. 173 (5): 288–89. doi:10.1016/j.neurol.2017.03.031. PMID 28461024. 19. ^ a b c d e f g h i j k Connolly S, Galvin M, Hardiman O (April 2015). "End-of-life management in patients with amyotrophic lateral sclerosis". The Lancet. Neurology. 14 (4): 435–42. doi:10.1016/S1474-4422(14)70221-2. PMID 25728958. S2CID 34109901. 20. ^ a b c d e f g h Swinnen B, Robberecht W (November 2014). "The phenotypic variability of amyotrophic lateral sclerosis". Nature Reviews. Neurology. 10 (11): 661–70. doi:10.1038/nrneurol.2014.184. PMID 25311585. S2CID 205516010. 21. ^ a b c d e f g Al-Chalabi A, Hardiman O (November 2013). "The epidemiology of ALS: a conspiracy of genes, environment and time". Nature Reviews. Neurology. 9 (11): 617–28. doi:10.1038/nrneurol.2013.203. PMID 24126629. S2CID 25040863. 22. ^ a b c d e f Mehta P, Kaye W, Raymond J, Punjabi R, Larson T, Cohen J, Muravov O, Horton K (November 2018). "Prevalence of Amyotrophic Lateral Sclerosis – United States, 2015". Morbidity and Mortality Weekly Report. 67 (46): 1285–1289. doi:10.15585/mmwr.mm6746a1. PMC 5858037. PMID 30462626. 23. ^ a b c d e Rowland LP (March 2001). "How amyotrophic lateral sclerosis got its name: the clinical-pathologic genius of Jean-Martin Charcot". Archives of Neurology. 58 (3): 512–15. doi:10.1001/archneur.58.3.512. PMID 11255459. 24. ^ Kelly, Evelyn B. (2013). Encyclopedia of human genetics and disease. Santa Barbara, CA: Greenwood. pp. 79–80. ISBN 978-0-313-38713-5. Archived from the original on 8 September 2017. 25. ^ Youngson, David B. Jacoby, Robert M. (2004). Encyclopedia of family health (3rd ed.). Tarrytown, NY: Marshall Cavendish. p. 1256. ISBN 978-0-7614-7486-9. Archived from the original on 8 September 2017. 26. ^ a b c d e f g h Renton AE, Chiò A, Traynor BJ (January 2014). "State of play in amyotrophic lateral sclerosis genetics". Nature Neuroscience. 17 (1): 17–23. doi:10.1038/nn.3584. hdl:2318/156177. PMC 4544832. PMID 24369373. 27. ^ a b c d e Lutz C (August 2018). "Mouse models of ALS: Past, present and future". Brain Research. 1693 (Part A): 1–10. doi:10.1016/j.brainres.2018.03.024. PMID 29577886. S2CID 4641251. 28. ^ Song P (August 2014). "The Ice Bucket Challenge: The public sector should get ready to promptly promote the sustained development of a system of medical care for and research into rare diseases". Intractable & Rare Diseases Research. 3 (3): 94–96. doi:10.5582/irdr.2014.01015. PMC 4214244. PMID 25364651. 29. ^ "8B60 Motor neuron disease". ICD-11 for Mortality and Morbidity Statistics. World Health Organization. Retrieved 24 January 2019. 30. ^ a b c Jawdat O, Statland JM, Barohn RJ, Katz JS, Dimachkie MM (November 2015). "Amyotrophic Lateral Sclerosis Regional Variants (Brachial Amyotrophic Diplegia, Leg Amyotrophic Diplegia, and Isolated Bulbar Amyotrophic Lateral Sclerosis)". Neurologic Clinics. 33 (4): 775–85. doi:10.1016/j.ncl.2015.07.003. PMC 4629514. PMID 26515621. 31. ^ a b c d e f Grad LI, Rouleau GA, Ravits J, Cashman NR (August 2017). "Clinical Spectrum of Amyotrophic Lateral Sclerosis (ALS)". Cold Spring Harbor Perspectives in Medicine. 7 (8): a024117. doi:10.1101/cshperspect.a024117. PMC 5538408. PMID 28003278. 32. ^ a b c d Chiò A, Calvo A, Moglia C, Mazzini L, Mora G (July 2011). "Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study". Journal of Neurology, Neurosurgery, and Psychiatry. 82 (7): 740–46. doi:10.1136/jnnp.2010.235952. PMID 21402743. S2CID 13416164. 33. ^ Gautier G, Verschueren A, Monnier A, Attarian S, Salort-Campana E, Pouget J (August 2010). "ALS with respiratory onset: Clinical features and effects of non-invasive ventilation on the prognosis". Amyotrophic Lateral Sclerosis. 11 (4): 379–82. doi:10.3109/17482960903426543. PMID 20001486. S2CID 27672209. 34. ^ a b c d e Al-Chalabi A, Hardiman O, Kiernan MC, Chiò A, Rix-Brooks B, van den Berg LH (October 2016). "Amyotrophic lateral sclerosis: moving towards a new classification system". The Lancet. Neurology. 15 (11): 1182–94. doi:10.1016/S1474-4422(16)30199-5. hdl:2318/1636249. PMID 27647646. S2CID 45285510. 35. ^ Teoh HL, Carey K, Sampaio H, Mowat D, Roscioli T, Farrar M (2017). "Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy". Neural Plasticity. 2017: 6509493. doi:10.1155/2017/6509493. PMC 5467325. PMID 28634552. 36. ^ a b Tard C, Defebvre L, Moreau C, Devos D, Danel-Brunaud V (May 2017). "Clinical features of amyotrophic lateral sclerosis and their prognostic value". Revue Neurologique. 173 (5): 263–72. doi:10.1016/j.neurol.2017.03.029. PMID 28477850. 37. ^ Lui AJ, Byl NN (June 2009). "A Systematic Review of the Effect of Moderate Intensity Exercise on Function and Disease Progression in Amyotrophic Lateral Sclerosis". Journal of Neurologic Physical Therapy. 33 (2): 68–87. doi:10.1097/NPT.0b013e31819912d0. PMID 19556916. S2CID 7650356. 38. ^ McCluskey L, Vandriel S, Elman L, Van Deerlin VM, Powers J, Boller A, et al. (15 October 2014). "ALS-Plus syndrome: Non-pyramidal features in a large ALS cohort". Journal of the Neurological Sciences. 345 (1–2): 118–24. doi:10.1016/j.jns.2014.07.022. PMC 4177937. PMID 25086858. 39. ^ a b c d e f g h i j Brown RH, Al-Chalabi A (13 July 2017). "Amyotrophic Lateral Sclerosis". The New England Journal of Medicine. 377 (2): 162–172. doi:10.1056/NEJMra1603471. PMID 28700839. 40. ^ a b c Martin S, Al Khleifat A, Al-Chalabi A (2017). "What causes amyotrophic lateral sclerosis?". F1000Research. 6: 371. doi:10.12688/f1000research.10476.1. PMC 5373425. PMID 28408982. 41. ^ Raaphorst J, Beeldman E, De Visser M, De Haan RJ, Schmand B (October 2012). "A systematic review of behavioural changes in motor neuron disease". Amyotrophic Lateral Sclerosis. 13 (6): 493–501. doi:10.3109/17482968.2012.656652. PMID 22424127. S2CID 22224140. 42. ^ a b Beeldman E, Raaphorst J, Klein Twennaar M, de Visser M, Schmand BA, de Haan RJ (June 2016). "The cognitive profile of ALS: a systematic review and meta-analysis update". Journal of Neurology, Neurosurgery, and Psychiatry. 87 (6): 611–19. doi:10.1136/jnnp-2015-310734. PMID 26283685. S2CID 22082109. 43. ^ Gordon PH, Miller RG, Moore DH (September 2004). "ALSFRS-R". Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders. 5 Suppl 1: 90–93. doi:10.1080/17434470410019906. PMID 15512883. S2CID 218987659. 44. ^ Creemers H, Grupstra H, Nollet F, van den Berg LH, Beelen A (June 2015). "Prognostic factors for the course of functional status of patients with ALS: a systematic review". Journal of Neurology. 262 (6): 1407–23. doi:10.1007/s00415-014-7564-8. PMID 25385051. S2CID 31734765. 45. ^ Castrillo-Viguera C, Grasso DL, Simpson E, Shefner J, Cudkowicz ME (2010). "Clinical significance in the change of decline in ALSFRS-R". Amyotrophic Lateral Sclerosis (Journal Article). 11 (1–2): 178–80. doi:10.3109/17482960903093710. PMID 19634063. S2CID 207619689. 46. ^ Sabatelli M, Madia F, Conte A, Luigetti M, Zollino M, Mancuso I, Lo Monaco M, Lippi G, Tonali P (September 2008). "Natural history of young-adult amyotrophic lateral sclerosis". Neurology. 71 (12): 876–81. doi:10.1212/01.wnl.0000312378.94737.45. PMID 18596241. S2CID 10848454. 47. ^ Paganoni S, Deng J, Jaffa M, Cudkowicz ME, Wills AM (July 2011). "Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis". Muscle & Nerve. 44 (1): 20–24. doi:10.1002/mus.22114. PMC 4441750. PMID 21607987. Lay summary – Massachusetts General Hospital (11 May 2011). 48. ^ "Stephen Hawking serves as role model for ALS patients". CNN. 20 April 2009. Archived from the original on 15 August 2016. 49. ^ "About Familial ALS – ALS Research Collaboration". Retrieved 27 October 2020. 50. ^ a b Vajda A, McLaughlin RL, Heverin M, Thorpe O, Abrahams S, Al-Chalabi A, Hardiman O (March 2017). "Genetic testing in ALS: A survey of current practices". Neurology. 88 (10): 991–999. doi:10.1212/WNL.0000000000003686. PMC 5333513. PMID 28159885. 51. ^ Byrne S, Walsh C, Lynch C, Bede P, Elamin M, Kenna K, McLaughlin R, Hardiman O (June 2011). "Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis". Journal of Neurology, Neurosurgery, and Psychiatry. 82 (6): 623–7. doi:10.1136/jnnp.2010.224501. hdl:2262/53330. PMID 21047878. S2CID 6254190. 52. ^ a b c He J, Mangelsdorf M, Fan D, Bartlett P, Brown MA (December 2015). "Amyotrophic Lateral Sclerosis Genetic Studies: From Genome-wide Association Mapping to Genome Sequencing" (PDF). The Neuroscientist. 21 (6): 599–615. doi:10.1177/1073858414555404. PMID 25378359. S2CID 3437565. 53. ^ a b Corcia P, Couratier P, Blasco H, Andres CR, Beltran S, Meininger V, Vourc'h P (May 2017). "Genetics of amyotrophic lateral sclerosis". Revue Neurologique. 173 (5): 254–262. doi:10.1016/j.neurol.2017.03.030. PMID 28449881. 54. ^ Chia R, Chiò A, Traynor BJ (January 2018). "Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications". The Lancet. Neurology. 17 (1): 94–102. doi:10.1016/S1474-4422(17)30401-5. PMC 5901717. PMID 29154141. 55. ^ Zou ZY, Liu CY, Che CH, Huang HP (January 2016). "Toward precision medicine in amyotrophic lateral sclerosis". Annals of Translational Medicine. 4 (2): 27. doi:10.3978/j.issn.2305-5839.2016.01.16. PMC 4731596. PMID 26889480. 56. ^ Sontheimer, Harald (2015). Diseases of the Nervous System. Academic Press. p. 170. ISBN 978-0-12-800403-6. Archived from the original on 8 September 2017. Retrieved 2 May 2015. 57. ^ Couratier P, Corcia P, Lautrette G, Nicol M, Marin B (May 2017). "ALS and frontotemporal dementia belong to a common disease spectrum". Revue Neurologique. 173 (5): 273–279. doi:10.1016/j.neurol.2017.04.001. PMID 28449882. 58. ^ a b Nguyen HP, Van Broeckhoven C, van der Zee J (June 2018). "ALS Genes in the Genomic Era and their Implications for FTD". Trends in Genetics. 34 (6): 404–423. doi:10.1016/j.tig.2018.03.001. PMID 29605155. 59. ^ a b Beard JD, Kamel F (1 January 2015). "Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology and survival". Epidemiologic Reviews. 37 (1): 55–70. doi:10.1093/epirev/mxu001. PMC 4325667. PMID 25365170. 60. ^ Belbasis L, Bellou V, Evangelou E (March 2016). "Environmental Risk Factors and Amyotrophic Lateral Sclerosis: An Umbrella Review and Critical Assessment of Current Evidence from Systematic Reviews and Meta-Analyses of Observational Studies". Neuroepidemiology. 46 (2): 96–105. doi:10.1159/000443146. PMID 26731747. S2CID 13163292. 61. ^ Beard JD, Steege AL, Ju J, Lu J, Luckhaupt SE, Schubauer-Berigan MK (July 2017). "Mortality from Amyotrophic Lateral Sclerosis and Parkinson's Disease Among Different Occupation Groups - United States, 1985-2011". MMWR. Morbidity and Mortality Weekly Report. 66 (27): 718–722. doi:10.15585/mmwr.mm6627a2. PMC 5687590. PMID 28704346. 62. ^ Sutedja NA, Fischer K, Veldink JH, van der Heijden GJ, Kromhout H, Heederik D, Huisman MH, Wokke JJ, van den Berg LH (2009). "What we truly know about occupation as a risk factor for ALS: a critical and systematic review". Amyotrophic Lateral Sclerosis. 10 (5–6): 295–301. doi:10.3109/17482960802430799. PMID 19922116. S2CID 25772664. 63. ^ Ingre C, Roos PM, Piehl F, Kamel F, Fang F (2015). "Risk factors for amyotrophic lateral sclerosis". Clinical Epidemiology. 7: 181–93. doi:10.2147/CLEP.S37505. PMC 4334292. PMID 25709501. 64. ^ Kamel F, Umbach DM, Bedlack RS, Richards M, Watson M, Alavanja MC, Blair A, Hoppin JA, Schmidt S, Sandler DP (June 2012). "Pesticide exposure and amyotrophic lateral sclerosis". Neurotoxicology. 33 (3): 457–62. doi:10.1016/j.neuro.2012.04.001. PMC 3358481. PMID 22521219. 65. ^ Bozzoni V, Pansarasa O, Diamanti L, Nosari G, Cereda C, Ceroni M (2016). "Amyotrophic lateral sclerosis and environmental factors". Functional Neurology. 31 (1): 7–19. PMC 4819821. PMID 27027889. 66. ^ Malek AM, Barchowsky A, Bowser R, Youk A, Talbott EO (August 2012). "Pesticide exposure as a risk factor for amyotrophic lateral sclerosis: a meta-analysis of epidemiological studies: pesticide exposure as a risk factor for ALS". Environmental Research. 117: 112–9. Bibcode:2012ER....117..112M. doi:10.1016/j.envres.2012.06.007. PMID 22819005. 67. ^ a b Gardner RC, Yaffe K (May 2015). "Epidemiology of mild traumatic brain injury and neurodegenerative disease". Molecular and Cellular Neurosciences. 66 (Pt B): 75–80. doi:10.1016/j.mcn.2015.03.001. PMC 4461453. PMID 25748121. 68. ^ Watanabe Y, Watanabe T (October 2017). "Meta-analytic evaluation of the association between head injury and risk of amyotrophic lateral sclerosis". European Journal of Epidemiology. 32 (10): 867–879. doi:10.1007/s10654-017-0327-y. PMID 29080013. S2CID 449855. 69. ^ Luna, J.; Logroscino, G.; Couratier, P.; Marin, B. (May 2017). "Current issues in ALS epidemiology: Variation of ALS occurrence between populations and physical activity as a risk factor". Revue Neurologique. 173 (5): 244–253. doi:10.1016/j.neurol.2017.03.035. ISSN 0035-3787. PMID 28477849. 70. ^ Veldink JH, Kalmijn S, Groeneveld GJ, Titulaer MJ, Wokke JH, van den Berg LH (January 2005). "Physical activity and the association with sporadic ALS". Neurology. 64 (2): 241–5. doi:10.1212/01.WNL.0000149513.82332.5C. PMID 15668420. S2CID 36449771. 71. ^ Armon C (November 2007). "Sports and trauma in amyotrophic lateral sclerosis revisited". Journal of the Neurological Sciences. 262 (1–2): 45–53. doi:10.1016/j.jns.2007.06.021. PMID 17681549. S2CID 20733887. 72. ^ a b Harwood CA, McDermott CJ, Shaw PJ (August 2009). "Physical activity as an exogenous risk factor in motor neuron disease (MND): a review of the evidence". Amyotrophic Lateral Sclerosis. 10 (4): 191–204. doi:10.1080/17482960802549739. PMID 19263258. S2CID 14749160. 73. ^ Hamidou B, Couratier P, Besançon C, Nicol M, Preux PM, Marin B (July 2014). "Epidemiological evidence that physical activity is not a risk factor for ALS". European Journal of Epidemiology. 29 (7): 459–75. doi:10.1007/s10654-014-9923-2. PMID 24986107. S2CID 20563636. 74. ^ Lacorte E, Ferrigno L, Leoncini E, Corbo M, Boccia S, Vanacore N (July 2016). "Physical activity, and physical activity related to sports, leisure and occupational activity as risk factors for ALS: A systematic review". Neuroscience and Biobehavioral Reviews. 66: 61–79. doi:10.1016/j.neubiorev.2016.04.007. PMID 27108217. S2CID 24844638. 75. ^ Couratier P, Corcia P, Lautrette G, Nicol M, Preux P, Marin B (January 2016). "Epidemiology of amyotrophic lateral sclerosis: A review of literature". Neuroepidemiology. 172 (1): 37–45. doi:10.1016/j.neurol.2015.11.002. PMID 26727307. 76. ^ Tharmaratnam T, Iskandar M, Tabobondung T, Tobbia I, Gopee-Ramanan P, Tabobondung T (19 June 2018). "Chronic Traumatic Encephalopathy in Professional American Football Players: Where Are We Now?". Frontiers in Neurology. 19 (9): 445. doi:10.3389/fneur.2018.00445. PMC 6018081. PMID 29971037. 77. ^ Gardner A, Iverson G, McCrory P (January 2014). "Chronic traumatic encephalopathy in sport: a systematic review". British Journal of Sports Medicine. 48 (2): 84–90. doi:10.1136/bjsports-2013-092646. PMID 23803602. S2CID 7182895. 78. ^ Belson, Ken (22 April 2015). "Judge Approves Deal in N.F.L. Concussion Suit". The New York Times. Retrieved 10 August 2018. 79. ^ "Kevin Turner, N.F.L. Player Who Later Fought the League, Dies at 46". The New York Times. 24 March 2016. Archived from the original on 28 March 2016. Retrieved 27 March 2016. 80. ^ Armon C (November 2009). "Smoking may be considered an established risk factor for sporadic ALS". Neurology. 73 (20): 1693–8. doi:10.1212/WNL.0b013e3181c1df48. PMC 2788806. PMID 19917993. 81. ^ Alonso A, Logroscino G, Hernán MA (November 2010). "Smoking and the risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis". Journal of Neurology, Neurosurgery, and Psychiatry. 81 (11): 1249–52. doi:10.1136/jnnp.2009.180232. PMID 20639382. S2CID 2079442. 82. ^ Wang H, O'Reilly ÉJ, Weisskopf MG, Logroscino G, McCullough ML, Thun MJ, Schatzkin A, Kolonel LN, Ascherio A (February 2011). "Smoking and risk of amyotrophic lateral sclerosis: a pooled analysis of 5 prospective cohorts". Archives of Neurology. 68 (2): 207–13. doi:10.1001/archneurol.2010.367. PMC 3319086. PMID 21320987. 83. ^ Robberecht W, Philips T (April 2013). "The changing scene of amyotrophic lateral sclerosis". Nature Reviews. Neuroscience. 14 (4): 248–64. doi:10.1038/nrn3430. PMID 23463272. S2CID 208941. 84. ^ Okamoto K, Mizuno Y (April 2008). "Bunina bodies in amyotrophic lateral sclerosis". Neuropathology. 28 (2): 109–15. doi:10.1111/j.1440-1789.2007.00873.x. PMID 18069968. S2CID 34398467. 85. ^ White JA, Banerjee R, Gunawardena S (19 May 2016). "Axonal Transport and Neurodegeneration: How Marine Drugs Can Be Used for the Development of Therapeutics". Marine Drugs. 14 (5): 102. doi:10.3390/md14050102. PMC 4882576. PMID 27213408. 86. ^ Ng Kee Kwong, Koy Chong; Mehta, Arpan R.; Nedergaard, Maiken; Chandran, Siddharthan (20 August 2020). "Defining novel functions for cerebrospinal fluid in ALS pathophysiology". Acta Neuropathologica Communications. 8 (1): 140. doi:10.1186/s40478-020-01018-0. ISSN 2051-5960. PMC 7439665. PMID 32819425. 87. ^ a b c d e Philip Van Damme P, Robberecht W, Van Den Bosch L (May 2017). "Modelling amyotrophic lateral sclerosis: progress and possibilities". Disease Models and Mechanisms. 10 (5): 537–49. doi:10.1242/dmm.029058. PMC 5451175. PMID 28468939. 88. ^ Mehta, Arpan R.; Gregory, Jenna M.; Dando, Owen; Carter, Roderick N.; Burr, Karen; Nanda, Jyoti; Story, David; McDade, Karina; Smith, Colin; Morton, Nicholas M.; Mahad, Don J. (4 January 2021). "Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis". Acta Neuropathologica. doi:10.1007/s00401-020-02252-5. ISSN 0001-6322. 89. ^ Xu Z, Henderson RD, David M, McCombe PA (2016). "Neurofilaments as Biomarkers for Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis". PLOS ONE. 11 (10): e0164625. Bibcode:2016PLoSO..1164625X. doi:10.1371/journal.pone.0164625. PMC 5061412. PMID 27732645. 90. ^ Vu LT, Bowser R (January 2017). "Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis". Neurotherapeutics. 14 (1): 119–134. doi:10.1007/s13311-016-0503-x. PMC 5233638. PMID 27933485. 91. ^ a b de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, et al. (March 2008). "Electrodiagnostic criteria for diagnosis of ALS". Clinical Neurophysiology. 119 (3): 497–503. doi:10.1016/j.clinph.2007.09.143. PMID 18164242. S2CID 14851649. 92. ^ Costa J, Swash M, de Carvalho M (November 2012). "Awaji Criteria for the Diagnosis of Amyotrophic Lateral Sclerosis: A Systematic Review". Archives of Neurology. 69 (11): 1410–1416. doi:10.1001/archneurol.2012.254. PMID 22892641. 93. ^ Belsh JM (March 2000). "ALS diagnostic criteria of El Escorial Revisited: do they meet the needs of clinicians as well as researchers?". Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders. 1 (Supplement 1): S57–S60. doi:10.1080/14660820052415925. PMID 11464928. S2CID 6828235. 94. ^ Silani V, Messina S, Poletti B, Morelli C, Doretti A, Ticozzi N, Maderna L (March 2011). "The diagnosis of Amyotrophic lateral sclerosis in 2010". Archives Italiennes de Biologie. 149 (1): 5–27. doi:10.4449/aib.v149i1.1260. PMID 21412713. 95. ^ "Lambert-Eaton Myasthenic Syndrome (LEMS)". Misc.medscape.com. Archived from the original on 14 May 2013. Retrieved 18 April 2013. 96. ^ "LEMS.com, Lambert-Eaton Myasthenic Syndrome: About". Lems.com. Archived from the original on 20 January 2013. Retrieved 18 April 2013. 97. ^ Mills KR (November 2010). "Characteristics of fasciculations in amyotrophic lateral sclerosis and the benign fasciculation syndrome". Brain. 133 (11): 3458–69. doi:10.1093/brain/awq290. PMID 20959307. 98. ^ Eisen A (2002). "Amyotrophic lateral sclerosis: A review". BCMJ. 44 (7): 362–366. Archived from the original on 21 June 2013. Retrieved 21 August 2014. 99. ^ Davenport RJ, Swingler RJ, Chancellor AM, Warlow CP (February 1996). "Avoiding false positive diagnoses of motor neuron disease: lessons from the Scottish Motor Neuron Disease Register". Journal of Neurology, Neurosurgery, and Psychiatry. 60 (2): 147–51. doi:10.1136/jnnp.60.2.147. PMC 1073793. PMID 8708642. 100. ^ Chieia MA, Oliveira AS, Silva HC, Gabbai AA (December 2010). "Amyotrophic lateral sclerosis: considerations on diagnostic criteria". Arquivos de Neuro-Psiquiatria. 68 (6): 837–42. doi:10.1590/S0004-282X2010000600002. PMID 21243238. 101. ^ Al-Asmi A, Nandhagopal R, Jacob PC, Gujjar A (February 2012). "Misdiagnosis of Myasthenia Gravis and Subsequent Clinical Implication: A case report and review of literature". Sultan Qaboos University Medical Journal. 12 (1): 103–8. doi:10.12816/0003095. PMC 3286704. PMID 22375266. 102. ^ a b c Abe K, Masashi A, Tsuji S, Itoyama Y, Sobue G, Togo M, et al. (July 2017). "Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial". The Lancet. Neurology. 16 (7): 505–12. doi:10.1016/S1474-4422(17)30115-1. PMID 28522181. 103. ^ a b c Yeo CJ, Simmons Z (May 2018). "Discussing edaravone with the ALS patient: an ethical framework from a U.S. perspective". Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 19 (3–4): 167–72. doi:10.1080/21678421.2018.1425455. PMID 29334251. S2CID 4627647. 104. ^ a b c d Orrell RW (2010). "Motor neuron disease: systematic reviews of treatment for ALS and SMA". British Medical Bulletin. 93: 145–59. doi:10.1093/bmb/ldp049. PMID 20015852. 105. ^ a b Radunovic A, Annane D, Rafiq M, Brassington R, Mustfa N (6 October 2017). "Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease". The Cochrane Database of Systematic Reviews. 10 (10): CD004427. doi:10.1002/14651858.CD004427.pub4. PMC 6485636. PMID 28982219. 106. ^ a b c Ahmed R, Newcombe R, Piper A, Lewis S, Yee B, Kiernan M, Grunstein R (April 2016). "Sleep disorders and respiratory function in amyotrophic lateral sclerosis". Sleep Medicine Reviews. 26: 33–42. doi:10.1016/j.smrv.2015.05.007. PMID 26166297. 107. ^ a b Eisen A, Krieger C (November 2013). "Ethical considerations in the management of amyotrophic lateral sclerosis". Progress in Neurobiology. 110: 45–53. doi:10.1016/j.pneurobio.2013.05.001. PMID 23735671. S2CID 26282198. 108. ^ a b Lewis M, Rushanan S (2007). "The role of physical therapy and occupational therapy in the treatment of amyotrophic lateral sclerosis". NeuroRehabilitation. 22 (6): 451–61. doi:10.3233/NRE-2007-22608. PMID 18198431. 109. ^ a b c d e "Amyotrophic Lateral Sclerosis (ALS)". American Speech-Language-Hearing Association, Rockville, MD. Archived from the original on 2 August 2012. Retrieved 30 November 2016. 110. ^ a b c Arbesman M, Sheard K (2014). "Systematic review of the effectiveness of occupational therapy-related interventions for people with amyotrophic lateral sclerosis". The American Journal of Occupational Therapy. 68 (1): 20–26. doi:10.5014/ajot.2014.008649. PMID 24367951. 111. ^ a b Katzberg HD, Benatar M (January 2011). "Enteral tube feeding for amyotrophic lateral sclerosis/motor neuron disease". The Cochrane Database of Systematic Reviews (1): CD004030. doi:10.1002/14651858.CD004030.pub3. PMC 7163276. PMID 21249659. 112. ^ a b c Andersen PM, Abrahams S, Borasio GD, de Carvalho M, Chio A, Van Damme P, et al. (March 2012). "EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS) – revised report of an EFNS task force". European Journal of Neurology. 19 (3): 360–75. doi:10.1111/j.1468-1331.2011.03501.x. PMID 21914052. S2CID 5746940. 113. ^ Carlesi C, Pasquali L, Piazza S, Lo Gerfo A, Caldarazzo Ienco E, Alessi R, Fornai F, Siciliano G (March 2011). "Strategies for clinical approach to neurodegeneration in Amyotrophic lateral sclerosis". Archives Italiennes de Biologie. 149 (1): 151–67. doi:10.4449/aib.v149i1.1267. PMID 21412722. 114. ^ Hardiman O, van den Berg LH (July 2017). "Edaravone: a new treatment for ALS on the horizon?". The Lancet. Neurology. 16 (7): 490–91. doi:10.1016/S1474-4422(17)30163-1. PMID 28522180. S2CID 7609862. 115. ^ a b c d e f g Dorst J, Ludolph A, Huebers A (2018). "Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis". Therapeutic Advances in Neurological Disorders. 11: 1756285617734734. doi:10.1177/1756285617734734. PMC 5784546. PMID 29399045. 116. ^ a b Takei K, Watanabe K, Yuki S, Akimoto M, Sakata T, Palumbo J (October 2017). "Edaravone and its clinical development for amyotrophic lateral sclerosis". Amyotrophic Lateral Sclerosis. 18 (sup 1): 5–10. doi:10.1080/21678421.2017.1353101. PMID 28872907. 117. ^ Paganoni, Sabrina; Hendrix, Suzanne; Dickson, Samuel P.; Knowlton, Newman; Macklin, Eric A.; Berry, James D.; Elliott, Michael A.; Maiser, Samuel; Karam, Chafic; Caress, James B.; Owegi, Margaret Ayo (2020). "Long-Term Survival of Participants in the CENTAUR Trial of Sodium Phenylbutyrate-Taurursodiol in ALS". Muscle & Nerve. n/a (n/a). doi:10.1002/mus.27091. ISSN 1097-4598. PMID 33063909. 118. ^ Belluck, Pam. "Drug may extend ALS patients' lives by several months, study finds". chicagotribune.com. Retrieved 23 October 2020. 119. ^ a b Paganoni S, Karam C, Joyce N, Bedlack R, Carter G (2015). "Comprehensive rehabilitative care across the spectrum of amyotrophic lateral sclerosis". NeuroRehabilitation. 37 (1): 53–68. doi:10.3233/NRE-151240. PMC 5223769. PMID 26409693. 120. ^ Danel-Brunaud V, Touzet L, Chevalier L, Moreau C, Devos D, Vandoolaeghe S, Lefebvre L (May 2017). "Ethical considerations and palliative care in patients with amyotrophic lateral sclerosis: A review". Revue Neurologique. 173 (5): 300–07. doi:10.1016/j.neurol.2017.03.032. PMID 28479121. 121. ^ Checkoway H, Lundin JI, Kelada SN (2011). "Chapter 22: Neurodegenerative diseases". In Rothman N, Hainaut P, Schulte P, Smith M, Boffetta P, Perera F (eds.). Molecular Epidemiology: Principles and Practices. International Agency for Research on Cancer. pp. 408–409. ISBN 978-9283221630. 122. ^ Chiò A, Logroscino G, Traynor BJ, Collins J, Simeone JC, Goldstein LA, White LA (2013). "Global Epidemiology of Amyotrophic Lateral Sclerosis: A Systematic Review of the Published Literature". Neuroepidemiology. 41 (2): 118–30. doi:10.1159/000351153. PMC 4049265. PMID 23860588. 123. ^ a b Arthur KC, Calvo A, Price TR, Geiger JT, Chiò A, Traynor BJ (11 August 2016). "Projected increase in amyotrophic lateral sclerosis from 2015 to 2040". Nature Communications. 7 (12408): 12408. Bibcode:2016NatCo...712408A. doi:10.1038/ncomms12408. PMC 4987527. PMID 27510634. 124. ^ a b Luna J, Logroscino G, Couratier P, Marin B (May 2017). "Current issues in ALS epidemiology: Variation of ALS occurrence between populations and physical activity as a risk factor". Revue Neurologique. 173 (5): 244–53. doi:10.1016/j.neurol.2017.03.035. PMID 28477849. 125. ^ Zou ZY, Zhou ZR, Che CH, Liu CY, He RL, Huang HP (July 2017). "Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis". Journal of Neurology, Neurosurgery, and Psychiatry. 88 (77): 540–49. doi:10.1136/jnnp-2016-315018. PMID 28057713. S2CID 41974606. 126. ^ Visser J, de Jong JM, de Visser M (February 2008). "The history of progressive muscular atrophy: syndrome or disease?". Neurology. 70 (9): 723–27. doi:10.1212/01.wnl.0000302187.20239.93. PMID 18299524. S2CID 22629725. 127. ^ Wijesekera LC, Mathers S, Talman P, Galtrey C, Parkinson MH, Ganesalingam J, Willey E, Ampong MA, Ellis CM, Shaw CE, Al-Chalabi A, Leigh PN (March 2009). "Natural history and clinical features of the flail arm and flail leg ALS variants". Neurology. 72 (12): 1087–94. doi:10.1212/01.wnl.0000345041.83406.a2. PMC 2821838. PMID 19307543. 128. ^ Lee SE (December 2011). "Guam dementia syndrome revisited in 2011". Current Opinion in Neurology. 24 (6): 517–24. doi:10.1097/WCO.0b013e32834cd50a. PMID 21986681. 129. ^ Brooks BR, Sanjak M, Ringel S, England J, Brinkmann J, Pestronk A, et al. (February 1996). "The Amyotrophic Lateral Sclerosis Functional Rating Scale: Assessment of Activities of Daily Living in Patients with Amyotrophic Lateral Sclerosis". Archives of Neurology. 53 (2): 141–7. doi:10.1001/archneur.1996.00550020045014. PMID 8639063. 130. ^ Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A (October 1999). "The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function". Journal of the Neurological Sciences. 162 (1–2): 13–21. doi:10.1016/s0022-510x(99)00210-5. PMID 10540002. S2CID 7057926. 131. ^ Wilbourn AJ (October 1998). "Clinical neurophysiology in the diagnosis of amyotrophic lateral sclerosis: The Lambert and the El Escorial criteria". Journal of the Neurological Sciences. 160 (Supplement 1): S25–29. doi:10.1016/s0022-510x(98)00194-4. PMID 9851644. S2CID 32884687. 132. ^ Brooks BR (July 1994). "El Escorial World Federation of Neurology Criteria for the Diagnosis of Amyotrophic Lateral Sclerosis". Journal of the Neurological Sciences. 124 (Supplement): 96–107. doi:10.1016/0022-510x(94)90191-0. PMID 7807156. S2CID 32678612. 133. ^ Brooks BR, Miller RG, Swash M, Munsat TL (December 2000). "El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis". Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders. 1 (5): 293–9. doi:10.1080/146608200300079536. PMID 11464847. S2CID 22725949. 134. ^ a b Teive HA, Lima PM, Germiniani FM, Munhoz RP (May 2016). "What's in a name? Problems, facts and controversies regarding neurological eponyms". Arquivos de Neuro-Psiquiatria. 74 (5): 423–25. doi:10.1590/0004-282X20160040. PMID 27191240. 135. ^ a b "What is ALS?". The ALS Association. Archived from the original on 21 December 2018. Retrieved 23 December 2018. 136. ^ "ALS: Amyotrophic Lateral Sclerosis". Muscular Dystrophy Association. 18 December 2015. Archived from the original on 6 August 2018. Retrieved 23 December 2018. 137. ^ Goetz CG (March 2000). "Amyotrophic lateral sclerosis: early contributions of Jean-Martin Charcot". Muscle & Nerve. 23 (3): 336–43. doi:10.1002/(SICI)1097-4598(200003)23:3<336::AID-MUS4>3.0.CO;2-L. PMID 10679709. 138. ^ Gordon PH (2006). "Chapter 1: History of ALS". In Mitsumoto H, Przedborski S, Gordon PH (eds.). Amyotrophic Lateral Sclerosis. CRC Press. p. 9. ISBN 978-0824729240. 139. ^ Mehta AR, Mehta PR, Anderson SP, MacKinnon BL, Compston A (January 2020). "Grey Matter Etymology and the neuron(e)". Brain. 143 (1): 374–379. doi:10.1093/brain/awz367. PMC 6935745. PMID 31844876. 140. ^ Gordon PH (October 2013). "Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials". Aging and Disease. 4 (5): 295–310. doi:10.14336/AD.2013.0400295. PMC 3794725. PMID 24124634. 141. ^ a b Huynh W, Simon NG, Grosskreutz J, Turner MR, Vucic S, Kiernan MC (July 2016). "Assessment of the upper motor neuron in amyotrophic lateral sclerosis". Clinical Neurophysiology. 127 (7): 2643–2660. doi:10.1016/j.clinph.2016.04.025. PMID 27291884. S2CID 3757685. 142. ^ "Motor Neuron Diseases". www.uclh.nhs.uk. Retrieved 26 October 2020. 143. ^ "George Bush delivers possibly the best ALS ice bucket challenge yet". The Independent. Archived from the original on 21 August 2014. Retrieved 20 August 2014. 144. ^ "Ice Bucket Challenge funds gene discovery in ALS (MND) research". BBC News. 27 July 2016. Archived from the original on 28 July 2016. Retrieved 27 July 2016. 145. ^ Alexander, Ella. "Ice Bucket Challenge: Lady Gaga, Justin Bieber, G-Dragon and Oprah – the most entertaining reactions so far". 146. ^ "Ice Bucket Challenge funds discovery of gene linked to ALS". Archived from the original on 27 July 2016. Retrieved 27 July 2016. 147. ^ Kenna KP, van Doormaal PT, Dekker AM, et al. (September 2016). "NEK1 variants confer susceptibility to amyotrophic lateral sclerosis". Nature Genetics. 48 (9): 1037–42. doi:10.1038/ng.3626. PMC 5560030. PMID 27455347. 148. ^ a b c d e Moujalled D, White AR (March 2016). "Advances in the Development of Disease-Modifying Treatments for Amyotrophic Lateral Sclerosis". CNS Drugs. 30 (3): 227–43. doi:10.1007/s40263-016-0317-8. hdl:11343/216653. PMID 26895253. S2CID 13487502. 149. ^ Picher-Martel V, Valdmanis PN, Gould PV, Julien JP, Dupré N (July 2016). "From animal models to human disease: a genetic approach for personalized medicine in ALS". Acta Neuropathologica Communications. 11 (4): 70. doi:10.1186/s40478-016-0340-5. PMC 4940869. PMID 27400686. 150. ^ Mehta, Arpan R.; Gregory, Jenna M.; Dando, Owen; Carter, Roderick N.; Burr, Karen; Nanda, Jyoti; Story, David; McDade, Karina; Smith, Colin; Morton, Nicholas M.; Mahad, Don J. (4 January 2021). "Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis". Acta Neuropathologica. doi:10.1007/s00401-020-02252-5. ISSN 0001-6322. 151. ^ a b Mitsumoto H, Brooks BR, Silani V (November 2014). "Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved?". The Lancet. Neurology. 13 (11): 1127–38. doi:10.1016/S1474-4422(14)70129-2. PMID 25316019. S2CID 28510979. 152. ^ Fang J, Zhou M, Yang M, Zhu C, He L (May 2013). "Repetitive transcranial magnetic stimulation for the treatment of amyotrophic lateral sclerosis or motor neuron disease". The Cochrane Database of Systematic Reviews (5): CD008554. doi:10.1002/14651858.CD008554.pub3. PMC 7173713. PMID 23728676. 153. ^ Chen KS, Sakowski SA, Feldman EL (March 2016). "Intraspinal stem cell transplantation for amyotrophic lateral sclerosis". Annals of Neurology. 79 (3): 342–53. doi:10.1002/ana.24584. PMC 4789073. PMID 26696091. 154. ^ Abdul Wahid, S. Fadilah; Law, Zhe Kang; Ismail, Nor Azimah; Lai, Nai Ming (19 December 2019). "Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease". The Cochrane Database of Systematic Reviews. 12: CD011742. doi:10.1002/14651858.CD011742.pub3. ISSN 1469-493X. PMC 6920743. PMID 31853962. 155. ^ "Public summary of opinion on orphan designation Masitinib mesilate for treatment of amyotrophic lateral sclerosis" (PDF). EMA. European Medicines Agency, Committee for Orphan Medicinal Products. 22 September 2016. Archived (PDF) from the original on 6 November 2016. Retrieved 6 November 2016. 156. ^ Bartus RT, Bétourné A, Basile A, Peterson BL, Glass J, Boulis NM (January 2016). "β2-Adrenoceptor agonists as novel, safe and potentially effective therapies for Amyotrophic lateral sclerosis (ALS)". Neurobiology of Disease. 85: 11–24. doi:10.1016/j.nbd.2015.10.006. PMID 26459114. S2CID 536279. 157. ^ Bräuer S, Zimyanin V, Hermann A (April 2018). "Prion-like properties of disease-relevant proteins in amyotrophic lateral sclerosis". Journal of Neural Transmission. 125 (4): 591–613. doi:10.1007/s00702-018-1851-y. PMID 29417336. S2CID 3895544. 158. ^ Lau DH, Hartopp N, Welsh NJ, Mueller S, Glennon EB, Mórotz GM, Annibali A, Gomez-Suaga P, Stoica R, Paillusson S, Miller CC (February 2018). "Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis". Cell Death & Disease. 9 (3): 327. doi:10.1038/s41419-017-0022-7. PMC 5832427. PMID 29491392. 159. ^ Neumann M (October 2013). "Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: molecular similarities and differences". Revue Neurologique. 169 (10): 793–98. doi:10.1016/j.neurol.2013.07.019. PMID 24011641. ## External links[edit] Wikimedia Commons has media related to Amyotrophic lateral sclerosis. * Amyotrophic lateral sclerosis at Curlie Classification D * ICD-10: G12.2 * ICD-10-CM: G12.21 * ICD-9-CM: 335.20 * OMIM: 105400 * MeSH: D000690 * DiseasesDB: 29148 External resources * MedlinePlus: 000688 * eMedicine: neuro/14 emerg/24 pmr/10 * Patient UK: Amyotrophic lateral sclerosis * GeneReviews: Amyotrophic lateral sclerosis * Orphanet: 803 * Scholia: Q206901 * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis * v * t * e Amyotrophic lateral sclerosis General * Genetics of ALS * ALS research Organizations in the United States * ALS Association * ALS Therapy Development Institute * Les Turner ALS Foundation * Muscular Dystrophy Association * Project ALS * Prize4Life International organizations * ALS Society of Canada * Motor Neurone Disease Association Events * ALS Awareness Month * Ice Bucket Challenge * Annual ALS Awareness Game People * O.J. Brigance * Paul Cellucci * Dwight Clark * Jay Fishman * Pete Frates * Lou Gehrig * Richard Glatzer * Steve Gleason * Stephen Hawking * Stephen Heywood * Stephen Hillenburg * Jacob Javits * Jason Becker * Augie Nieto * Jon Stone * Kevin Turner * Henry Wallace * Mickey Marvin Related * List of people with ALS * Lou Gehrig Memorial Award * Ice Bucket Challenge: Pete Frates and the Fight Against ALS Authority control * BNF: cb12110754p (data) * LCCN: sh85004728 * NDL: 01127913 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Amyotrophic lateral sclerosis	c0002736	6,455	wikipedia	https://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis	2021-01-18T18:58:10	{"gard": ["5786"], "mesh": ["D000690"], "umls": ["C0002736"], "orphanet": ["803"], "wikidata": ["Q206901"]}
Amblyaudia (amblyos- blunt; audia-hearing) is a term coined by Dr. Deborah Moncrieff to characterize a specific pattern of performance from dichotic listening tests. Dichotic listening tests are widely used to assess individuals for binaural integration, a type of auditory processing skill. During the tests, individuals are asked to identify different words presented simultaneously to the two ears. Normal listeners can identify the words fairly well and show a small difference between the two ears with one ear slightly dominant over the other. For the majority of listeners, this small difference is referred to as a "right-ear advantage" because their right ear performs slightly better than their left ear. But some normal individuals produce a "left-ear advantage" during dichotic tests and others perform at equal levels in the two ears. Amblyaudia is diagnosed when the scores from the two ears are significantly different with the individual's dominant ear score much higher than the score in the non-dominant ear [1] Researchers interested in understanding the neurophysiological underpinnings of amblyaudia consider it to be a brain based hearing disorder that may be inherited or that may result from auditory deprivation during critical periods of brain development.[2] Individuals with amblyaudia have normal hearing sensitivity (in other words they hear soft sounds) but have difficulty hearing in noisy environments like restaurants or classrooms. Even in quiet environments, individuals with amblyaudia may fail to understand what they are hearing, especially if the information is new or complicated. Amblyaudia can be conceptualized as the auditory analog of the better known central visual disorder amblyopia. The term “lazy ear” has been used to describe amblyaudia although it is currently not known whether it stems from deficits in the auditory periphery (middle ear or cochlea) or from other parts of the auditory system in the brain, or both. A characteristic of amblyaudia is suppression of activity in the non-dominant auditory pathway by activity in the dominant pathway which may be genetically determined[3] and which could also be exacerbated by conditions throughout early development. ## Contents * 1 Symptoms * 2 Risk Factors * 3 Physiology * 4 Diagnosis * 5 Treatments * 6 See also * 7 References * 8 External links ## Symptoms[edit] Children with amblyaudia experience difficulties in speech perception,[4] particularly in noisy environments, sound localization,[5] and binaural unmasking[6][7][8][9][10] (using interaural cues to hear better in noise) despite having normal hearing sensitivity (as indexed through pure tone audiometry). These symptoms may lead to difficulty attending to auditory information causing many to speculate that language acquisition and academic achievement may be deleteriously affected in children with amblyaudia. A significant deficit in a child's ability to use and comprehend expressive language may be seen in children who lacked auditory stimulation throughout the critical periods of auditory system development. A child suffering from amblyaudia may have trouble in appropriate vocabulary comprehension and production and the use of past, present and future tenses. Amblyaudia has been diagnosed in many children with reported difficulties understanding and learning from listening[11][12][13] and adjudicated adolescents are at a significantly high risk for amblyaudia (Moncrieff, et al., 2013, Seminars in Hearing). ## Risk Factors[edit] Families report the presence of amblyaudia in several individuals, suggesting that it may be genetic in nature. It is possible that abnormal auditory input during the first two years of life may increase a child’s risk for amblyaudia, although the precise relationship between deprivation timing and development of amblyaudia is still unclear. Recurrent ear infections (otitis media) are the leading cause of temporary auditory deprivation in young children.[14][15][16] During ear infection bouts, the quality of the signal that reaches the auditory regions of the brains of a subset of children with OM is degraded in both timing and magnitude.[17][18] When this degradation is asymmetric (worse in one ear than the other) the binaural cues associated with sound localization can also be degraded. Aural atresia (a closed external auditory canal) also causes temporary auditory deprivation in young children. Hearing can be restored to children with ear infections and aural atresia through surgical intervention (although ear infections will also resolve spontaneously). Nevertheless, children with histories of auditory deprivation secondary to these diseases can experience amblyaudia for years after their hearing has been restored.[6][19] ## Physiology[edit] Amblyaudia is a deficit in binaural integration of environmental information entering the auditory system. It is a disorder related to brain organization and function rather than what is typically considered a “hearing loss” (damage to the cochlea). It may be genetic or developmentally acquired or both. When animals are temporarily deprived of hearing from an early age, profound changes occur in the brain. Specifically, cell sizes in brainstem nuclei are reduced,[20][21][22][23] the configuration of brainstem dendrites are altered[24][25][26] and neurons respond in different ways to sounds presented to both the deprived and non-deprived ears[27][28][29][30] (in cases of asymmetric deprivation). This last point is particularly important for listening tasks that require inputs from two ears to perform well. There are multiple auditory functions that rely on the computation of well calibrated inputs from the two ears. Chief among these is the ability to localize sound sources and separate what we want to hear from a background of noise. In the brainstem, the auditory system compares the timing and levels of sounds between the two ears to encode the location of sound sources (sounds that originate from our right as opposed to left side are louder and arrive earlier in our right ear).[citation needed] An electrophysiologic study demonstrated that children with amblyaudia (referred to then as a "left-ear deficit") were less able to process information from their non-dominant ears when competing information is arriving at their dominant ears. The N400-P800 complex[31] showed a strong and highly correlated response from the dominant and non-dominant ears among normal children while the response from children with amblyaudia was uncorrelated and indicated an inability to separate information arriving at the non-dominant ear from the information arriving at the dominant ear. The same children also produced weaker fMRI responses from their non-dominant left ears[32] when processing dichotic material in the scanner. ## Diagnosis[edit] A clinical diagnosis of amblyaudia is made following dichotic listening testing as part of an auditory processing evaluation. Clinicians are advised to use newly developed dichotic listening tests that provide normative cut-off scores for the listener's dominant and non-dominant ears. These are the Randomized Dichotic Digits Test [33] and the Dichotic Words Test.[34] Older dichotic listening tests that provide normative information for the right and left ears can be used to supplement these two tests for support of the diagnosis ([35]). If performance across two or more dichotic listening tests is normal in the dominant ear and significantly below normal in the non-dominant ear, a diagnosis of amblyaudia can be made.[36] The diagnosis can also be made if performance in both ears is below normal but performance in the non-dominant ear is significantly poorer, thereby resulting in an abnormally large asymmetry between the two ears. Amblyaudia is emerging as a distinct subtype of auditory processing disorder (APD).[citation needed] ## Treatments[edit] A number of computer-based auditory training programs exist for children with generalized Auditory Processing Disorders (APD). In the visual system, it has been proven that adults with amblyopia can improve their visual acuity with targeted brain training programs (perceptual learning).[37] A focused perceptual training protocol for children with amblyaudia called Auditory Rehabilitation for Interaural Asymmetry (ARIA) was developed in 2001[38] which has been found to improve dichotic listening performance in the non-dominant ear and enhance general listening skills. ARIA is now available in a number of clinical sites in the U.S., Canada, Australia and New Zealand. It is also undergoing clinical research trials involving electrophysiologic measures and activation patterns acquired through functional magnetic resonance imaging (fMRI) techniques to further establish its efficacy to remediate amblyaudia.[citation needed] ## See also[edit] * Amblyopia * Auditory processing disorder * Binaural fusion * Hearing * Otitis media * Aural atresia ## References[edit] 1. ^ Moncrieff, Keith, Abramson, & Swann (2016) Diagnosis of amblyaudia in children referred for auditory processing assessment. International journal of audiology, 55(6), 333-345. 2. ^ Whitton JP, Polley DB (October 2011). "Evaluating the perceptual and pathophysiological consequences of auditory deprivation in early postnatal life: a comparison of basic and clinical studies". J. Assoc. Res. Otolaryngol. 12 (5): 535–47. doi:10.1007/s10162-011-0271-6. PMC 3173557. PMID 21607783. 3. ^ Morell RJ, Brewer CC, Ge D, et al. (August 2007). "A twin study of auditory processing indicates that dichotic listening ability is a strongly heritable trait". Hum. Genet. 122 (1): 103–11. doi:10.1007/s00439-007-0384-5. PMID 17533509. S2CID 2692071. 4. ^ Miccio AW, Gallagher E, Grossman CB, Yont KM, Vernon-Feagans L (2001). "Influence of chronic otitis media on phonological acquisition". Clin Linguist Phon. 15 (1–2): 47–51. doi:10.3109/02699200109167629. PMID 21269097. S2CID 35288270. 5. ^ Besing JM, Koehnke J (April 1995). "A test of virtual auditory localization". Ear Hear. 16 (2): 220–9. doi:10.1097/00003446-199504000-00009. PMID 7789673. S2CID 15538878. 6. ^ a b Hall JW, Grose JH, Pillsbury HC (August 1995). "Long-term effects of chronic otitis media on binaural hearing in children". Arch. Otolaryngol. Head Neck Surg. 121 (8): 847–52. doi:10.1001/archotol.1995.01890080017003. PMID 7619408. 7. ^ Moore DR, Hutchings ME, Meyer SE (1991). "Binaural masking level differences in children with a history of otitis media". Audiology. 30 (2): 91–101. doi:10.3109/00206099109072874. PMID 1877902. 8. ^ Gravel JS, Wallace IF, Ruben RJ (March 1996). "Auditory consequences of early mild hearing loss associated with otitis media". Acta Otolaryngol. 116 (2): 219–21. doi:10.3109/00016489609137827. PMID 8725518. 9. ^ Pillsbury HC, Grose JH, Hall JW (July 1991). "Otitis media with effusion in children. Binaural hearing before and after corrective surgery". Arch. Otolaryngol. Head Neck Surg. 117 (7): 718–23. doi:10.1001/archotol.1991.01870190030008. PMID 1863436. 10. ^ Hogan SC, Moore DR (June 2003). "Impaired binaural hearing in children produced by a threshold level of middle ear disease". J. Assoc. Res. Otolaryngol. 4 (2): 123–9. doi:10.1007/s10162-002-3007-9. PMC 3202709. PMID 12943367. 11. ^ Moncrieff, DW (Sep 2002). "Interaural asymmetries revealed by dichotic listening tests in normal and dyslexic children". J Am Acad Audiol. 13 (8): 428–37. PMID 12371660. 12. ^ Moncrieff, DW (Sep 2006). "Identification of binaural integration deficits in children with the Competing Words Subtest: standard score versus interaural asymmetry". Int J Audiol. 45 (9): 546–54, discussion 554–8. doi:10.1080/14992020601003196. PMID 17005498. S2CID 22794514. 13. ^ Moncrieff, DW (Feb 2008). "Dichotic listening deficits in children with dyslexia". Dyslexia. 14 (1): 54–75. doi:10.1002/dys.344. PMID 17647215. 14. ^ Pennie RA (September 1998). "Prospective study of antibiotic prescribing for children". Can Fam Physician. 44: 1850–6. PMC 2277846. PMID 9789665. 15. ^ Teele DW, Klein JO, Rosner B (July 1989). "Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study". J. Infect. Dis. 160 (1): 83–94. doi:10.1093/infdis/160.1.83. PMID 2732519. 16. ^ Freid VM, Makuc DM, Rooks RN (May 1998). "Ambulatory health care visits by children: principal diagnosis and place of visit" (PDF). Vital Health Stat 13 (137): 1–23. PMID 9631643. 17. ^ Owen MJ, Norcross-Nechay K, Howie VM (January 1993). "Brainstem auditory evoked potentials in young children before and after tympanostomy tube placement". Int. J. Pediatr. Otorhinolaryngol. 25 (1–3): 105–17. doi:10.1016/0165-5876(93)90014-T. PMID 8436453. 18. ^ Eric Lupo J, Koka K, Thornton JL, Tollin DJ (February 2011). "The effects of experimentally induced conductive hearing loss on spectral and temporal aspects of sound transmission through the ear". Hear. Res. 272 (1–2): 30–41. doi:10.1016/j.heares.2010.11.003. PMC 3073683. PMID 21073935. 19. ^ Wilmington D, Gray L, Jahrsdoerfer R (April 1994). "Binaural processing after corrected congenital unilateral conductive hearing loss". Hear. Res. 74 (1–2): 99–114. doi:10.1016/0378-5955(94)90179-1. PMID 8040103. S2CID 4762842. 20. ^ Webster DB, Webster M (July 1977). "Neonatal sound deprivation affects brain stem auditory nuclei". Arch Otolaryngol. 103 (7): 392–6. doi:10.1001/archotol.1977.00780240050006. PMID 880104. 21. ^ Webster DB, Webster M (1979). "Effects of neonatal conductive hearing loss on brain stem auditory nuclei". Ann. Otol. Rhinol. Laryngol. 88 (5 Pt 1): 684–8. doi:10.1177/000348947908800515. PMID 496200. S2CID 10194727. 22. ^ Coleman JR, O'Connor P (June 1979). "Effects of monaural and binaural sound deprivation on cell development in the anteroventral cochlear nucleus of rats". Exp. Neurol. 64 (3): 553–66. doi:10.1016/0014-4886(79)90231-0. PMID 467549. S2CID 38143118. 23. ^ Conlee, John W.; Parks, Thomas N. (1981). "Age- and position-dependent effects of monaural acoustic deprivation in nucleus magnocellularis of the chicken". The Journal of Comparative Neurology. 202 (3): 373–384. doi:10.1002/cne.902020307. PMID 7298905. 24. ^ Conlee JW, Parks TN (June 1983). "Late appearance and deprivation-sensitive growth of permanent dendrites in the avian cochlear nucleus (nuc. magnocellularis)". J. Comp. Neurol. 217 (2): 216–26. doi:10.1002/cne.902170208. PMID 6886053. 25. ^ Gray L, Smith Z, Rubel EW (July 1982). "Developmental and experimental changes in dendritic symmetry in n. laminaris of the chick". Brain Res. 244 (2): 360–4. doi:10.1016/0006-8993(82)90098-1. PMID 7116181. S2CID 33997388. 26. ^ Smith ZD, Gray L, Rubel EW (October 1983). "Afferent influences on brainstem auditory nuclei of the chicken: n. laminaris dendritic length following monaural conductive hearing loss". J. Comp. Neurol. 220 (2): 199–205. doi:10.1002/cne.902200207. PMID 6315783. 27. ^ Silverman MS, Clopton BM (November 1977). "Plasticity of binaural interaction. I. Effect of early auditory deprivation". J. Neurophysiol. 40 (6): 1266–74. doi:10.1152/jn.1977.40.6.1266. PMID 925728. 28. ^ Clopton BM, Silverman MS (November 1977). "Plasticity of binaural interaction. II. Critical period and changes in midline response". J. Neurophysiol. 40 (6): 1275–80. doi:10.1152/jn.1977.40.6.1275. PMID 925729. 29. ^ Moore DR, Irvine DR (March 1981). "Plasticity of binaural interaction in the cat inferior colliculus". Brain Res. 208 (1): 198–202. doi:10.1016/0006-8993(81)90632-6. PMID 7470922. S2CID 6730028. 30. ^ Popescu MV, Polley DB (March 2010). "Monaural deprivation disrupts development of binaural selectivity in auditory midbrain and cortex". Neuron. 65 (5): 718–31. doi:10.1016/j.neuron.2010.02.019. PMC 2849994. PMID 20223206. 31. ^ Moncrieff, DW (Jul 2004). "ERP evidence of a dichotic left-ear deficit in some dyslexic children". J Am Acad Audiol. 15 (7): 518–34. doi:10.3766/jaaa.15.7.6. PMID 15484601. 32. ^ Moncrieff, D (Jan 2008). "Hemodynamic differences in children with dichotic listening deficits: preliminary results from an fMRI study during a cued listening task". J Am Acad Audiol. 19 (1): 33–45. doi:10.3766/jaaa.19.1.4. PMID 18637408. 33. ^ Moncrieff, DW (Jan 2009). "Recognition of randomly presented one-, two-, and three-pair dichotic digits by children and young adults". J Am Acad Audiol. 20 (1): 58–70. doi:10.3766/jaaa.20.1.6. PMID 19927683. 34. ^ Moncrieff, D (Jul 2015). "Age- and Gender-Specific Normative Information from Children Assessed with a Dichotic Words Test". J Am Acad Audiol. 26 (7): 632–44. doi:10.3766/jaaa.14096. PMID 26218052. 35. ^ Moncrieff, Keith, Abramson, & Swann, 2016. Diagnosis of amblyaudia in children referred for auditory processing assessment. International journal of audiology, 55(6), 333-345. 36. ^ Moncrieff DW (July 2011). "Dichotic listening in children: age-related changes in direction and magnitude of ear advantage". Brain Cogn. 76 (2): 316–22. doi:10.1016/j.bandc.2011.03.013. PMID 21530051. S2CID 37665256. 37. ^ Levi DM, Li RW (October 2009). "Perceptual learning as a potential treatment for amblyopia: a mini-review". Vision Res. 49 (21): 2535–49. doi:10.1016/j.visres.2009.02.010. PMC 2764839. PMID 19250947. 38. ^ Moncrieff DW, Wertz D (February 2008). "Auditory rehabilitation for interaural asymmetry: preliminary evidence of improved dichotic listening performance following intensive training". Int J Audiol. 47 (2): 84–97. doi:10.1080/14992020701770835. PMID 18236240. S2CID 22268018. ## External links[edit] * Temporary Hearing Loss Affects Brain's Wiring [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Amblyaudia	None	6,456	wikipedia	https://en.wikipedia.org/wiki/Amblyaudia	2021-01-18T18:32:00	{"wikidata": ["Q4741549"]}
"IMID" redirects here. For IMiD, see immunomodulatory imide drug. An immune-mediated inflammatory disease (IMID) is any of a group of conditions or diseases that lack a definitive etiology, but which are characterized by common inflammatory pathways leading to inflammation, and which may result from, or be triggered by, a dysregulation of the normal immune response. All IMIDs can cause end organ damage, and are associated with increased morbidity and/or mortality. Inflammation is an important and growing area of biomedical research and health care because inflammation mediates and is the primary driver of many medical disorders and autoimmune diseases, including ankylosing spondylitis, psoriasis, psoriatic arthritis, Behcet's disease, arthritis, inflammatory bowel disease (IBD), and allergy, as well as many cardiovascular, neuromuscular, and infectious diseases. Some current research even suggests that aging is a consequence, in part, of inflammatory processes. ## Contents * 1 Characterization * 2 See also * 3 Bibliography * 4 References ## Characterization[edit] IMID is characterized by immune disregulation, and one underlying manifestation of this immune disregulation is the inappropriate activation of inflammatory cytokines, such as IL-12, IL-6 or TNF alpha, whose actions lead to pathological consequences. ## See also[edit] * Immune mediated polygenic arthritis ## Bibliography[edit] * Shurin, Michael R. and Yuri S. Smolkin (editors). Immune Mediated Diseases: From Theory to Therapy (Advances in Experimental Medicine and Biology). Springer, 2007. ## References[edit] * idid.us: immune mediated inflammatory diseases, inflammatory diseases of immune dysregulation [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Immune-mediated inflammatory diseases	None	6,457	wikipedia	https://en.wikipedia.org/wiki/Immune-mediated_inflammatory_diseases	2021-01-18T19:05:00	{"wikidata": ["Q6005412"]}
Cockayne syndrome is a rare disease which causes short stature, premature aging (progeria), severe photosensitivity, and moderate to severe learning delay. This syndrome also includes failure to thrive in the newborn, very small head (microcephaly), and impaired nervous system development. Other symptoms may include hearing loss, tooth decay, vision problems, and bone abnormalities. There are three subtypes according to the severity of the disease and the onset of the symptoms: * Cockayne syndrome type 1 (type A), sometimes called “classic” or "moderate" Cockayne syndrome, diagnosed during early childhood * Cockayne syndrome type 2 (type B), sometimes referred to as the “severe” or "early-onset" type, presenting with growth and developmental abnormalities at birth * Cockayne syndrome type 3 (type C), a milder form of the disorder Cockayne syndrome is caused by mutations in either the ERCC8 (CSA) or ERCC6 (CSB) genes. Inheritance is autosomal recessive. Type 2 is the most severe and affected people usually do not survive past childhood. Those with type 3 live into middle adulthood. There is no cure yet. Treatment is supportive and may include educational programs for developmental delay, physical therapy, gastrostomy tube placement as needed; medications for spasticity and tremor as needed; use of sunscreens and sunglasses; treatment of hearing loss and cataracts; and other forms of treatment, as needed. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Cockayne syndrome type III	c0751037	6,458	gard	https://rarediseases.info.nih.gov/diseases/1417/cockayne-syndrome-type-iii	2021-01-18T18:01:15	{"mesh": ["D003057"], "omim": ["216411"], "umls": ["C0751037"], "orphanet": ["90324"], "synonyms": ["Cockayne syndrome type C", "Cockayne syndrome type 3"]}
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inherited condition that affects many of the body's organs. It is one of many autoimmune diseases, which are disorders that occur when the immune system malfunctions and attacks the body's own tissues and organs by mistake. In most cases, the signs and symptoms of APECED begin in childhood or adolescence. This condition commonly involves three characteristic features: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal gland insufficiency. Affected individuals typically have at least two of these features, and many have all three. CMC is a tendency to develop infections of the skin, the nails, and the moist lining of body cavities (mucous membranes) caused by a type of fungus called Candida. These infections, which are commonly known as yeast infections, are chronic, which means they recur and can last a long time. CMC is usually the first of the three characteristic features of APECED to become apparent in people with this disorder. Almost all affected individuals develop infections of the oral cavity (known as thrush). Infections of the tube that carries food from the mouth to the stomach (the esophagus) are also common, while the skin and nails are affected less often. In women, vaginal infections frequently occur. Other features of APECED result from the body's immune system attacking the network of hormone-producing glands (the endocrine system). The second characteristic feature of the disorder is hypoparathyroidism, which is a malfunction of the parathyroid glands. These glands secrete a hormone that regulates the body's use of calcium and phosphorus. Damage to the parathyroid glands leads to reduced parathyroid hormone production (hypoparathyroidism). Hypoparathyroidism can cause a tingling sensation in the lips, fingers, and toes; muscle pain and cramping; weakness; and fatigue. Serious effects of hypoparathyroidism, such spasms of the voicebox (larynx) leading to breathing problems and seizures, can be life-threatening. Damage to the small hormone-producing glands on top of each kidney (adrenal glands) results in a third major feature of APECED, adrenal gland insufficiency (autoimmune Addison disease). Reduced hormone production by the adrenal glands leads to signs and symptoms that can include fatigue, muscle weakness, loss of appetite, weight loss, low blood pressure, and changes in skin coloring. Other endocrine problems that can occur in APECED include type 1 diabetes resulting from impaired production of the hormone insulin; a shortage of growth hormone leading to short stature; problems affecting the internal reproductive organs (ovaries or testes) that can cause inability to conceive children (infertility); and dysfunction of the thyroid gland (a butterfly-shaped tissue in the lower neck), which can result in many symptoms including weight gain and fatigue. Autoimmune problems affecting non-endocrine tissues can lead to a variety of additional signs and symptoms in people with APECED. These features occur more often in North American populations than in European populations. Rashes that resemble hives (urticarial eruptions) are common and often occur in infancy and early childhood. Other early signs and symptoms may include thin enamel on the teeth (enamel hypoplasia) and chronic diarrhea or constipation associated with difficulty in absorbing nutrients from food. Additional features that occur in people with APECED, many of which can lead to permanent organ and tissue damage if left untreated, include stomach irritation (gastritis), liver inflammation (hepatitis), lung irritation (pneumonitis), dry mouth and dry eyes (Sjogren-like syndrome), inflammation of the eyes (keratitis), kidney problems (nephritis), vitamin B12 deficiency, hair loss (alopecia), loss of skin color in blotches (vitiligo), high blood pressure (hypertension), or a small (atrophic) or absent spleen (asplenia). ## Frequency APECED occurs in about 1 in 90,000 to 200,000 people in most populations studied, which have been mainly in Europe. This condition occurs more frequently in certain populations, affecting about 1 in 9,000 to 25,000 people among Iranian Jews, Sardinians, and Finns. ## Causes Mutations in the AIRE gene cause APECED. The AIRE gene provides instructions for making a protein called the autoimmune regulator. As its name suggests, this protein plays a critical role in regulating certain aspects of immune system function. Specifically, it helps the body distinguish its own proteins and cells from those of foreign invaders (such as bacteria, fungi, and viruses). This distinction is critical because to remain healthy, a person's immune system must be able to identify and destroy potentially harmful invaders while sparing the body's normal tissues. Mutations in the AIRE gene reduce or eliminate the function of the autoimmune regulator protein. Without enough of this protein function, the immune system's ability to distinguish between the body's proteins and foreign invaders is impaired, and it may attack the body's own organs. This reaction, which is known as autoimmunity, results in inflammation and can damage otherwise healthy cells and tissues. Autoimmune damage to the adrenal glands, parathyroid glands, and other organs underlies many of the major features of APECED. Studies suggest that AIRE gene mutations also result in immune substances (antibodies) mistakenly attacking proteins involved in an immune process called the IL-17 pathway, which is important in the body's defense against Candida. This pathway, which depends on specialized proteins called IL-17 cytokines for signaling, creates inflammation, sending additional cytokines and white blood cells to fight foreign invaders and promote tissue repair. In addition, the IL-17 pathway promotes the production of certain antimicrobial protein segments (peptides) that control growth of Candida on the surface of mucous membranes. By damaging IL-17 cytokines, AIRE gene mutations are thought to impair the IL-17 pathway's function, resulting in CMC in people with APECED. Researchers believe that differences in the effects of specific AIRE gene mutations as well as variations in other genes that have not been identified may help explain why the signs and symptoms of APECED can vary among affected individuals and populations. ### Learn more about the gene associated with Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy * AIRE ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. In rare cases, people with one copy of certain AIRE gene mutations in each cell have some features of APECED, such as CMC, hypoparathyroidism, or vitamin B12 deficiency, but do not have the full pattern of signs and symptoms that typically characterize the disorder. These individuals usually have one similarly-affected parent. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy	c1855869	6,459	medlineplus	https://medlineplus.gov/genetics/condition/autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy/	2021-01-27T08:24:33	{"gard": ["8466"], "mesh": ["C538275"], "omim": ["240300"], "synonyms": []}
Fitzsimmons et al. (1988) presented a family in which at least 4 persons had evidence of an inherited disorder manifested by variable spastic paraplegia, bilateral sensorineural deafness, intellectual retardation, and progressive nephropathy. Focal segmental proliferative lesions with sclerosis suggestive of mesangial IgA nephropathy (Berger disease; 161950) were found on renal biopsy in 2 affected persons. The glomerular basement membrane showed none of the changes characteristic of Alport syndrome. A mother and her 2 sons and 1 daughter by 2 different fathers were affected. By history, her deceased mother and maternal uncle were also affected. GU \- Progressive nephropathy Inheritance \- Autosomal dominant Neuro \- Variable spastic paraplegia \- Mental retardation Lab \- Focal segmental proliferative lesions with sclerosis suggestive of mesangial IgA nephropathy on renal biopsy Ears \- Bilateral sensorineural deafness ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	SPASTIC PARAPLEGIA, SENSORINEURAL DEAFNESS, MENTAL RETARDATION, AND PROGRESSIVE NEPHROPATHY	c2931667	6,460	omim	https://www.omim.org/entry/182690	2019-09-22T16:34:46	{"mesh": ["C537937"], "omim": ["182690"], "orphanet": ["2820"]}
Flystrike in sheep is a myiasis condition, in which domestic sheep are infected by one of several species of flies which are external parasites of sheep. Sheep are particularly susceptible to flystrike because their thick wool, if sufficiently contaminated with urine and faecal material, can provide effective breeding ground for maggots even in the relative absence of wounds. ## Contents * 1 Causes * 2 Identification of infected sheep * 3 Prevention * 4 See also * 5 References ## Causes[edit] Flystrike in sheep is a condition where parasitic flies lay eggs on soiled wool or open wounds. After hatching, the maggots bury themselves in the sheep's wool and eventually under the sheep's skin, feeding off their flesh. Once the larvae develop, flies continue to deposit eggs on to new or already infected sheep, starting the infection process over again. Sheep display symptoms such as agitation, poor doing, odour and matted wool, all of which further encourage the attraction of flies. Fly strike can be lethal for sheep due to ammonia poisoning.[1] Fly strike is problematic, not only causing loss or degradation of stock, but also requiring expenditure of both money and time for effective management. In Australia, Lucilia cuprina causes about 90% of infestations, and Chrysomya rufifacies is the most common secondary pest that targets wounds caused by L. cuprina.[2] ## Identification of infected sheep[edit] Flystrike sheep are identified in the flock by characteristic green or wet-looking patches in the sheep's fleece, usually around the haunches or tail, or at the site of an open wound, where wool can create a damper area which is more attractive to flies. In male sheep the penile region is also a common area for flystrike to occur. When the flock settle, infected sheep will display signs of agitation, such as foot stamping or turning to nibble their body. Flystruck animals often have a strong characteristic odour and in severe cases, the wet-looking wool can begin to shed. [3] Fly strike is more likely to be found in favorable environmental conditions such as temperatures between 15–38 °C (59–100 °F), recent rain, and wind speeds below 9 kilometres per hour (5.6 mph).[2] The peak UK Green Bottle breeding season tends to be in late June or July, but Flystrike can occur at any time warm damp conditions prevail and Green Bottles are active. ## Prevention[edit] There are several preventative measures which are used to reduce the occurrence of flystrike in sheep flocks, these include:[2] * Controlling intestinal parasites to prevent scours and a suitable surface for flystrike * Scheduled shearing and crutching * Removing the tails of lambs at weaning * Mulesing * Preventative chemical treatments before fly infestation risk is high * Breeding for traits that reduce the likelihood of infestation * Removing or avoiding large manure heaps or other sites attractive to the flies * Using fly traps near the flock to attract and kill any local flies, helping to minimise the local populations. NB: Traps often emit a pungent smell and are best placed away from human activity. None of these measures completely stop the occurrence of fly strike in sheep, and regular treatment is still necessary.[4] ## See also[edit] * Mange * Sarcoptes scabiei * Sheep dip ## References[edit] 1. ^ "Flystrike (Myiasis)". 2. ^ a b c "Managing flystrike in sheep". Retrieved July 24, 2016. 3. ^ Fahy, L., Lauber, M., & Suter, R. (2011). Flystrike. Retrieved 10 2013, from Department of Environment and Primary Industries.[1] 4. ^ Fahy, L., Lauber, M., & Suter, R. (2011). Flystrike. Retrieved 10 2013, from Department of Environment and Primary Industries. [2] [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Fly strike in sheep	None	6,461	wikipedia	https://en.wikipedia.org/wiki/Fly_strike_in_sheep	2021-01-18T19:08:27	{"wikidata": ["Q16251787"]}
This article lacks ISBNs for the books listed in it. Please make it easier to conduct research by listing ISBNs. If the {{Cite book}} or {{citation}} templates are in use, you may add ISBNs automatically, or discuss this issue on the talk page. (July 2017) Boanthropy is a psychological disorder in which a human believes themself to be a bovine.[1] ## Contents * 1 Historical accounts * 2 Contemporary * 2.1 Totemism * 3 In popular culture * 4 See also * 5 References ## Historical accounts[edit] The most famous sufferer of this disorder was Nebuchadnezzar II, who in the Book of Daniel "was driven from men, and did eat grass as oxen". Carl Jung would subsequently instance 'Nebuchadnezzar...[as] a complete regressive degeneration of a man who has overreached himself'.[2] According to Persian traditions, the Buyid prince Majd al-Dawla was suffering from an illusion that he is a cow, making the sound of a cow and asking that to be killed so that his flesh could be consumed. He was cured by Avicenna.[3] ## Contemporary[edit] Boanthropy 'still occurs today when a person, in a delusional state, believes themselves to be an ox or cow...and attempts to live and behave accordingly'.[4] It has been suggested that hypnotism, suggestion and auto-suggestion may contribute to such beliefs.[5] Dreams may also play an important part. Jung for example records how a stubborn woman 'dreamed she was attending an important social occasion. She was greeted by the hostess with the words: "How nice that you could come. All your friends are here, and they are waiting for you." The hostess then led her to the door and opened it, and the dreamer stepped through – into a cowshed!'.[6] Freud had long since noted 'cases in which a mental disease has started with a dream and in which a delusion originating in the dream has persisted'.[7] R. D. Laing offers an autobiographical account of a brief reactive psychosis in which the protagonist had a 'real feeling of regression in time...I actually seemed to be wandering in a kind of landscape with – um – desert landscape – as if I were an animal, rather – rather a large animal..a kind of rhinoceros or something like that and emitting sounds like a rhinoceros'.[8] ### Totemism[edit] Eric Berne considered the first years of life as a time when the child 'is dealing with magical people who can perhaps on occasion turn themselves into animals,' and thought that even in later life 'a great many people have an animal...which recurs again and again in their dreams. This is their totem[9] – something which may offer a route back for early regressive identifications. Derogatory cultural identifications of people 'like cattle, with their eyes always looking down, and their heads stooping to the earth, that is, to the dining table...they kick and butt at each other with horns and hoofs that are made of iron'[10] go back at least as far as Plato; while the 'direct identification of woman and cow'[11] in folk humor offers another potential source for delusional identification. Anthropological evidence such as 'a Burmese buffalo dance in which masked dancers are possessed by the buffalo spirit'[12] would seem to confirm such totemic/cultural influences. ## In popular culture[edit] * The Cow, an Iranian movie by Dariush Mehrjui * In an episode of the Anime Revolutionary Girl Utena, the young girl Nanami comes to believe she is a cow after receiving a cowbell as a gift and falsely believing it to be jewelry. The themes of the episode are primarily feminist, using a rendition of the famous song Dona Dona in the context of Nanami being a Cow to narrate the poor social treatment of women. ## See also[edit] * Clinical lycanthropy (or zoanthropy) * Hathor * Io * Therianthropy ## References[edit] 1. ^ Onions, C.T., ed. (1933). The Shorter Oxford English Dictionary On Historical Principles Vol.1. Oxford: Oxford University Press. p. 195. 2. ^ C. G. Jung, Analytical Psychology (1976) p. 123 3. ^ "معالجه کردن بوعلی سینا / آن صاحب مالیخولیا را" (in Arabic). 2009-08-22. Retrieved 24 July 2017. 4. ^ M. S. Stanford, Grace for the Afflicted (2008) p. 122-3 5. ^ Frank Harrel, Human Animals (2003) p. 293 6. ^ C. G. Jung, Man and his Symbols (1978) p. 33 7. ^ Sigmund Freud, Introductory Lectures on Psychoanalysis (PFL 1) p. 113 8. ^ R. D. Laing, The Politics of Experience (1984)p. 123 9. ^ Eric Berne, What Do You Say After You Say Hello? (1974) p. 39 and p. 167 10. ^ B. Jowett transl., The Essential Plato (1999) p. 268-9 11. ^ G. Legman, Rationale of the Dirty Joke I (1973) p. 217 12. ^ C. G. Jung, Man and his Symbols (1978) p. 262 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Boanthropy	None	6,462	wikipedia	https://en.wikipedia.org/wiki/Boanthropy	2021-01-18T18:53:37	{"wikidata": ["Q4931259"]}
A rare congenital disorder of copper metabolism that is principally characterized by bony exostoses (including the pathognomonic occipital horns), and connective tissue manifestations with cutis laxa and bladder diverticula. Central nervous system involvement is variable. ## Epidemiology Occipital horn syndrome (OHS) is a very rare X-linked disease and the exact prevalence is unknown. To date approximately 35 cases have been reported and all but one were male. ## Clinical description Age of onset ranges from infancy to childhood. Observations at birth may include cephalhematoma (12% of cases), loose and wrinkled skin, and umbilical or inguinal hernias. About one third of all patients primarily present with central nervous system involvement (hypotonia, developmental delay and/or seizures). Initial clinical presentation may occur later with bladder diverticula or skeletal manifestations. Bladder diverticula affects the majority of patients (>80%) and may manifest through recurrent urinary tract infections or pollakisuria. The most typical skeletal manifestation (present in 96% of all patients) is an exostosis on the occiput at the insertion of the trapezoid muscle (occipital horn), but exostoses may also occur on the tibia and radius. Other, more variable, skeletal features are hammer-shaped claviculae, scoliosis, pectus deformity, coxa valga, genua valga as well as dislocations of the radial head. Less frequently reported skeletal manifestations include bowing of the long bones, mid-diaphyseal broadening, metaphyseal spurring, rounding of the iliac wings and, rarely, osteopenia. Facial features become distinctive with age and includes a long face (46%), large ears (38%), sagging cheeks (45%) and coarse hair (74%). Trichoscopy may show pili torti. The skin is often hyperextensible and soft with fine wrinkling on the hands and feet. Skin redundancy is remarkable on the belly. Vascular tortuosity is common in the intracranial arteries (65%), but may also affect the cervical, splenic and splanchnic circulation and imposes a risk for aneurysm formation. Aortic root dilatation and dissection may rarely occur. Dysautonomia with postural orthostatic hypotension, temperature instability and chronic diarrhea is present in most patients (>90%). About half of all patients show a delayed motor development due to muscle hypotonia and joint hypermobility, and may report unusual clumsiness. Distal motor neuropathy has been recorded in at least one patient. About half of all patients have intellectual disability (ID) which is usually mild, but moderate to severe impairment may occur. ## Etiology OHS is due to pathogenic variants (missense, frameshift and splice variants) in the ATP7A gene (Xq21.1) encoding the copper-transport ATPase 1. OHS is allelic with Menkes disease; there are no clear genotype-phenotype correlations, nor a correlation between the type or location of the variant and serum copper levels. However, certain variants may lead to a partially functional protein or reduced amounts of an otherwise normal protein. ## Diagnostic methods Diagnosis is based on clinical features. Radiography shows the characteristic occipital horns. Diagnosis is confirmed by identification of a pathogenic variant. ## Differential diagnosis Menkes disease is the main differential diagnosis and allelic to OHS. Other conditions to be considered include other forms of cutis laxa, including autosomal dominant cutis laxa, and autosomal recessive cutis laxa type 1a and 1c, Ehlers-Danlos syndrome, dermatosparaxis type, and hereditary multiple exostoses. ## Antenatal diagnosis Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. ## Genetic counseling Transmission is X-linked recessive. Genetic counseling should be offered to couples where the mother is a carrier of a pathogenic variant, informing them that the risk for a male fetus to be affected is 50% at each pregnancy. The possibility of germ-line mosaicism should be discussed when counselling non-carrier mothers of singleton cases; although not yet described for OHS it has been described for Menkes disease. ## Management and treatment Treatment is symptomatic. No data exist on early parenteral copper-histidine supplementation. Notably, individuals with OHS are at increased risk for post-surgery apnea, and should benefit from prolonged post-surgery monitoring. ## Prognosis Prognosis is variable in OHS. Most patients reach adulthood. Risks for early demise include seizures, bladder rupture, vascular ruptures and postsurgical apnea. Inguinal hernia often recur after surgery. * European Reference Network [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Occipital horn syndrome	c0268353	6,463	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=198	2021-01-23T18:27:50	{"gard": ["4017"], "mesh": ["C537860"], "omim": ["304150"], "umls": ["C0268353", "C1096660"], "icd-10": ["E83.0"]}
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Autoimmune optic neuropathy" – news · newspapers · books · scholar · JSTOR (September 2013) (Learn how and when to remove this template message) Autoimmune optic neuropathy (AON), sometimes called autoimmune optic neuritis, may be a forme fruste of systemic lupus erythematosus (SLE) associated optic neuropathy. AON is more than the presence of any optic neuritis in a patient with an autoimmune process, as it describes a relatively specific clinical syndrome. AON is characterized by chronically progressive or recurrent vision loss associated with serological evidence of autoimmunity. Specifically, this term has been suggested for cases of optic neuritis with serological evidence of vasculitis by positive ANA, despite the lack of meeting criteria for SLE. The clinical manifestations include progressive vision loss that tends to be steroid-responsive and steroid dependent. Patients with defined SLE that go on to develop optic neuritis should be better identified as lupus optic neuritis. ## Contents * 1 Signs and symptoms * 2 Pathogenesis * 3 Diagnosis * 4 Treatment * 5 References ## Signs and symptoms[edit] AON was first described in 1982.[1] It presents with visual loss and signs of optic nerve dysfunction, such as loss of color vision, afferent pupil defect, and sometimes abnormalities of the optic disc. The clinical features of AON can be variable and present in several unilateral or bilateral forms: * Acute anterior or retrobulbar optic neuritis sometimes associated with pain. * Anterior or retrobulbar ischemic optic neuropathy not associated with pain. * Chronic progressive vision loss that mimics a compressive lesion. The main features that differentiate AON from the more common typical demyelinating optic neuritis is the poor recovery of vision and the chronic or recurrent or bilateral course of AON.[2] Furthermore, the workup for multiple sclerosis including MRI, will be negative. Thus, it may be necessary to diagnose AON after a period of observation, noting the problem is not behaving as expected for demyelinative disease.[3] ## Pathogenesis[edit] Approximately 1-2% of patients with defined SLE develop an optic neuropathy during the course of their disease.[4][5] SLE-associated optic neuritis is rarely the presenting sign of the disease. The molecular pathogenesis is hypothesized, based on clinical features and the emerging understanding of mechanisms in SLE.[6] Inflammation resulting from auto-antibodies, immune complexes, T-cells and complement, probably damages the components of the optic nerve, as well as the blood vessels (vasculitis). The resulting vasculitis causes a loss of blood supply to the nerve (ischemia). This combination of inflammation and ischemia may produce reversible changes such as demyelination alone, or more permanent damage axonal (necrosis), or a combination. The poor recovery of vision in AON despite anti-inflammatory treatment suggests that ischemia from the underlying vasculitis is an important component, but the details have not been established. It may be reasonable to consider that AON pathogenesis represents an incomplete expression of the SLE-associated optic neuropathy disease process.[citation needed] ## Diagnosis[edit] This section is empty. You can help by adding to it. (September 2017) ## Treatment[edit] AON is a rare disease and the natural history of the disease process is not well defined.[7] Unlike typical optic neuritis, there is no association with multiple sclerosis, but the visual prognosis for AON is worse than typical optic neuritis. Thus AON patients have different treatment, and often receive chronic immunosuppression. No formal recommendation can be made regarding the best therapeutic approach. However, the available evidence to date supports treatment with corticosteroids and other immunosuppressive agents.[citation needed] Early diagnosis and prompt treatment with systemic corticosteroids may restore some visual function but the patient may remain steroid dependent; vision often worsens when corticosteroids are tapered. As such, long-term steroid-sparing immunosuppressive agents may be required to limit the side-effects of steroids and minimize the risk of worsening vision.[citation needed] ## References[edit] 1. ^ Dutton, JJ; Burde, RM; Klingele, TG (1982). "Autoimmune retrobulbar optic neuritis". American Journal of Ophthalmology. 94 (1): 11–7. doi:10.1016/0002-9394(82)90184-2. PMID 6979934. 2. ^ Kupersmith, M J; Burde, R M; Warren, F A; Klingele, T G; Frohman, L P; Mitnick, H (1988). "Autoimmune optic neuropathy: Evaluation and treatment". Journal of Neurology, Neurosurgery & Psychiatry. 51 (11): 1381–1386. doi:10.1136/jnnp.51.11.1381. PMC 1032806. PMID 3266235. 3. ^ Riedel, Patrick; Wall, Michael; Grey, Allen; Cannon, Thomas; Folberg, Robert; Thompson, H. Stanley (1998). "Autoimmune optic neuropathy". Archives of Ophthalmology. 116 (8): 1121–4. PMID 9715702. 4. ^ Estes, Dorothy; Christian, Charles L. (1971). "The Natural History of Systemic Lupus Erythematosus by Prospective Analysis". Medicine. 50 (2): 85–96. doi:10.1097/00005792-197103000-00001. 5. ^ Siatkowski, R. Michael; Scott, Ingrid U.; Verm, Alan M.; Warn, Ann A.; Farris, Bradley K.; Strominger, Mitchell B.; Sklar, Evelyn M.L. (2001). "Optic Neuropathy and Chiasmopathy in the Diagnosis of Systemic Lupus Erythematosus". Journal of Neuro-Ophthalmology. 21 (3): 193–8. doi:10.1097/00041327-200109000-00006. PMID 11725184. 6. ^ Tsokos, George C. (2011). "Systemic Lupus Erythematosus". New England Journal of Medicine. 365 (22): 2110–21. doi:10.1056/NEJMra1100359. PMID 22129255. 7. ^ Frohman, L; Dellatorre, K; Turbin, R; Bielory, L (2009). "Clinical characteristics, diagnostic criteria and therapeutic outcomes in autoimmune optic neuropathy". British Journal of Ophthalmology. 93 (12): 1660–6. doi:10.1136/bjo.2009.159350. PMID 19692378. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Autoimmune optic neuropathy	None	6,464	wikipedia	https://en.wikipedia.org/wiki/Autoimmune_optic_neuropathy	2021-01-18T18:46:58	{"wikidata": ["Q17080979"]}
Dentinogenesis imperfecta is a disorder of tooth development. This condition causes the teeth to be discolored (most often a blue-gray or yellow-brown color) and translucent. Teeth are also weaker than normal, making them prone to rapid wear, breakage, and loss. These problems can affect both primary (baby) teeth and permanent teeth. Researchers have described three types of dentinogenesis imperfecta with similar dental abnormalities. Type I occurs in people who have osteogenesis imperfecta, a genetic condition in which bones are brittle and easily broken. Dentinogenesis imperfecta type II and type III usually occur in people without other inherited disorders. A few older individuals with type II have had progressive high-frequency hearing loss in addition to dental abnormalities, but it is not known whether this hearing loss is related to dentinogenesis imperfecta. Some researchers believe that dentinogenesis imperfecta type II and type III, along with a condition called dentin dysplasia type II, are actually forms of a single disorder. The signs and symptoms of dentin dysplasia type II are very similar to those of dentinogenesis imperfecta. However, dentin dysplasia type II affects the primary teeth much more than the permanent teeth. ## Frequency Dentinogenesis imperfecta affects an estimated 1 in 6,000 to 8,000 people. ## Causes Mutations in the DSPP gene have been identified in people with dentinogenesis imperfecta type II and type III. Mutations in this gene are also responsible for dentin dysplasia type II. Dentinogenesis imperfecta type I occurs as part of osteogenesis imperfecta, which is caused by mutations in one of several other genes (most often the COL1A1 or COL1A2 genes). The DSPP gene provides instructions for making two proteins that are essential for normal tooth development. These proteins are involved in the formation of dentin, which is a bone-like substance that makes up the protective middle layer of each tooth. DSPP gene mutations alter the proteins made from the gene, leading to the production of abnormally soft dentin. Teeth with defective dentin are discolored, weak, and more likely to decay and break. It is unclear whether DSPP gene mutations are related to the hearing loss found in a few older individuals with dentinogenesis imperfecta type II. ### Learn more about the gene associated with Dentinogenesis imperfecta * DSPP ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Dentinogenesis imperfecta	c0399380	6,465	medlineplus	https://medlineplus.gov/genetics/condition/dentinogenesis-imperfecta/	2021-01-27T08:25:12	{"gard": ["6258", "12796", "10144"], "mesh": ["D003784"], "omim": ["125420", "125490", "125500"], "synonyms": []}
Radiation colitis SpecialtyGastroenterology CausesRadiation therapy Radiation colitis is injury to the colon caused by radiation therapy.[1] It is usually associated with treatment for prostate cancer or cervical cancer.[1] Common symptoms are diarrhea, a feeling of being unable to empty the bowel,[2] gastrointestinal bleeding, and abdominal pain.[1] If symptoms of radiation colitis onset within 60 days of exposure to radiation, it is referred to as acute; otherwise, it is classified as chronic.[1] Acute radiation colitis may onset within a few hours of radiation exposure, and may clear up within two or three months after radiation ends.[1] Between 5 and 15% of individuals who receive radiation to the pelvis may have chronic radiation colitis.[1]Radiation therapy can also affect the bowel at the small intestine (radiation enteritis) or the rectum (radiation proctitis).[2] ## References[edit] 1. ^ a b c d e f Odze RD, Goldblum JF (2014). Odze and Goldblum surgical pathology of the GI tract, liver, biliary tract and pancreas. Elsevier Health Sciences. p. 480. ISBN 9781455733248. 2. ^ a b Kennedy GD, Heise CP (February 2007). "Radiation colitis and proctitis". Clin Colon Rectal Surg. 20 (1): 64–72. doi:10.1055/s-2007-970202. PMC 2780150. PMID 20011363. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Radiation colitis	c0341339	6,466	wikipedia	https://en.wikipedia.org/wiki/Radiation_colitis	2021-01-18T18:57:39	{"umls": ["C0341339"], "icd-10": ["K52.0"], "wikidata": ["Q2353003"]}
Type 1 plasminogen deficiency is a genetic condition associated with inflammed growths on the mucous membranes, the moist tissues that line body openings such as the eye, mouth, nasopharynx, trachea, and female genital tract. The growths may be triggered by local injury and/or infection and often recur after removal. The growths are caused by the deposition of fibrin (a protein involved in blood clotting) and by inflammation. The most common clinical finding is ligneous ('wood-like') conjunctivitis, a condition marked by redness and subsequent formation of pseudomembranes of part of the eye that progresses to white, yellow-white or red thick masses with a wood-like consistency that replace the normal mucosa. This can lead to vision loss. Growths in other areas can also lead to medical problems; those that occur in the gastrointestinal tract can cause ulcers, and growth in the windpipe can lead to breathing problems. Hydrocephalus may be present at birth in a small number of individuals. Type 1 plasminogen deficiency is caused by mutations in the PLG gene. It is inherited in an autosomal recessive pattern. Management depends upon the sites involved, but mainly focuses on managing the ligneous conjunctivitis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Type 1 plasminogen deficiency	c0398621	6,467	gard	https://rarediseases.info.nih.gov/diseases/4380/type-1-plasminogen-deficiency	2021-01-18T17:57:16	{"mesh": ["C580017"], "omim": ["217090"], "umls": ["C0398621"], "orphanet": ["722"], "synonyms": ["Hypoplasminogenemia"]}
Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades. ## Epidemiology Prevalence of RP is reported to be 1/3,000 to 1/5,000. No ethnic specificities have been reported although founder effects are possible. ## Clinical description Retinitis pigmentosa is slowly progressive but relentless. There is however broad variability in age of onset, rate of progression and secondary clinical manifestations. Affected individuals generally first develop night blindness (nyctalopia) due to loss of rod function, often in adolescence or earlier. They then develop peripheral visual field impairment, and over time loss of central vision, usually at late stages, often around midlife. Central visual acuity loss may occur at any age as a result of cystoid macular edema or photoreceptor loss. Posterior subcapsular cataracts are common and severity is age dependent. Reduced color vision may also be found. Fundus examination reveals bone spicule pigment deposits, attenuated retinal vessels, retinal atrophy and waxy optic nerve pallor. Severity is partly correlated with the pattern of inheritance with X-linked cases having the most severe course, autosomal recessive and single occurrence cases having intermediate severity, and autosomal dominant the most favorable course. ## Etiology More than 3,000 mutations in over 57 different genes or loci are currently known to cause non-syndromic RP. ## Diagnostic methods The diagnosis of RP is based on peripheral visual field loss, pigment deposits in fundus, loss of photoreceptors at the optical coherence tomography (OCT) scan of the retina and decreased or abolished responses as measured by electroretinography (ERG). Molecular genetic testing using single-gene testing, an RP multi-gene panel or exome sequencing allows for genetic subtype classification. ## Differential diagnosis Besides non syndromic forms, there are syndromic forms of RP of which the most frequent are Usher syndrome (RP and deafness) and BardetBiedl syndrome (RP and metabolic impairment). RP is to be distinguished from macular dystrophies (peripheral visual field is normal) and Leber congenital amaurosis (congenital retinal dystrophy) (see these terms). ## Antenatal diagnosis Prenatal diagnosis for at-risk pregnancies is possible by DNA analysis following amniocentesis or chorionic villus sampling. ## Genetic counseling RP may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. X-linked RP mutations generally only affect men. Genetic counseling should be provided to affected individuals and their families once the mode of inheritance has been determined through family history or molecular testing. Identical mutations may however produce different clinical manifestations. In X-linked familial cases, carrier testing for female relatives can be performed. ## Management and treatment Treatment is primarily aimed at slowing progression of the disease. Vitamin A palmitate and lutein-DHA may be provided as protecting antioxydants. Oral acetazolamide or topical dorzolamide are used to reduce cystoid macular edema. Lens extraction is required when cataracts reduce visual acuity. Sunglasses with short wavelength filtering improve visual performance and optical aids are recommended. Rehabilitation for reading and moving can be proposed in end-stage patients. ## Prognosis Except for mild cases or sectorial RP, most cases progress to legal blindness (visual acuity < 1/20 and visual field < 5 degrees). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Retinitis pigmentosa	c0035334	6,468	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=791	2021-01-23T17:13:41	{"gard": ["5694"], "mesh": ["D012174"], "omim": ["180100", "180104", "180105", "180210", "268000", "268025", "268060", "300029", "300155", "300424", "300605", "312600", "312612", "400004", "600059", "600105", "600132", "600138", "600852", "601414", "601718", "602594", "602772", "604232", "604393", "606068", "607921", "608133", "608380", "609913", "609923", "610282", "610359", "610599", "611131", "612095", "612165", "612572", "612712", "612943", "613194", "613341", "613428", "613464", "613575", "613581", "613582", "613617", "613660", "613731", "613750", "613756", "613758", "613767", "613769", "613794", "613801", "613809", "613810", "613827", "613861", "613862", "613983", "614180", "614181", "614494", "614500", "615233", "615434", "615565", "615725", "615780", "615922", "616188", "616394", "616469", "616544", "616562", "617023", "617123", "617304", "617433", "617460", "617781", "618173", "618195", "618220", "618345", "618613", "618697", "618826"], "umls": ["C0035334"], "icd-10": ["H35.5"]}
Cystic leukoencephalopathy without megalencephaly is characterised by non-progressive leukoencephalopathy, bilateral cysts in the anterior part of the temporal lobe, cerebral white matter anomalies and severe psychomotor impairment. Less than 50 patients have been described in the literature so far. Inheritance is most likely autosomal recessive. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Cystic leukoencephalopathy without megalencephaly	c2751843	6,469	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85136	2021-01-23T17:30:28	{"mesh": ["C567845"], "omim": ["612951"], "umls": ["C2751843"], "icd-10": ["E75.2"], "synonyms": ["CLWM"]}
A rare genetic neurovascular malformation characterized by sac-like bulging of cerebral arteries due to weakening of the endothelial layer. Familial occurrence is suspected when two or more affected first- to third-degree relatives are present in a family. Aneurysms may remain asymptomatic throughout life, or rupture and thereby cause potentially life-threatening subarachnoid hemorrhage. Patients with familial cerebral saccular aneurysm are more likely to develop more than one brain aneurysm, are at greater risk of rupture, and tend to have poorer outcome after rupture than patients with sporadic cerebral aneurysms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Familial cerebral saccular aneurysm	c1862932	6,470	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=231160	2021-01-23T18:59:52	{"mesh": ["C566284"], "omim": ["105800", "300870", "608542", "609122", "610213", "611892", "612161", "612162", "612586", "612587", "614252", "618734"], "icd-10": ["I67.1"], "synonyms": ["Familial berry aneurysm", "Familial intracranial saccular aneurysm"]}
Legal since 1937 Abortion in Puerto Rico is legal. Attitudes and laws in Puerto Rico relating to abortion have been significantly impacted by decisions of the federal government of the United States. Abortion effectively became legal in 1937 after a series of changes in the law by the Puerto Rico legislature based on introduction of Malthusian clinics introduced from US-initiated eugenic policies. During the 1960s and early 1970s, women from the mainland of the United States would travel to the island for legal abortions, with the practice largely ending in 1973 as a result of the US Supreme Court's decision in Roe v. Wade. Women have continued to travel to Puerto Rico from other parts of the Caribbean since the 1990s to obtain abortions illegal in their home countries. The total number of abortion clinics on the island has been in decline since a peak of over a dozen in the 1990s. Abortion statistics provided by the government have been criticized as unreliable. There were 19,200 abortions in 1991–1992, and 15,600 in 2001. There is an abortion rights community on the island, which is supported by a number of organizations. In 2019, International Women's Day in Puerto Rico revolved around women taking to the streets en masse to support abortion rights. There is also an anti-abortion movement in Puerto Rico, and it is notable for being much less violent than in the mainland United States. ## Contents * 1 Context * 2 History * 2.1 Legislative history * 2.2 Judicial history * 2.3 Clinic history * 3 Statistics * 4 Public funding * 5 Abortion rights views and activities * 5.1 Organizations * 5.2 Views * 5.3 Protests * 6 Anti-abortion views and activities * 6.1 Views * 6.2 Protests * 7 Footnotes * 8 References ## Context[edit] Access to low or no-cost birth control, correlates with an overall reduction in both teen pregnancies and fewer abortions, according to a 2014 study published in New England Journal of Medicine.[1] A 2011 study by the Center for Reproductive Rights and Ibis Reproductive Health found that states with more abortion restrictions were more likely to lack access to prenatal healthcare and had higher rates of maternal death, infant mortality as well as teen drug and alcohol abuse.[2] According to a 2017 report from the Center for Reproductive Rights and Ibis Reproductive Health, states that tried to pass additional constraints on a women's ability to access legal abortions had fewer policies supporting women's health, maternal health and children's health. These states also tended to resist expanding Medicaid, family leave, medical leave, and sex education in public schools.[3] According to Megan Donovan, a senior policy manager at the Guttmacher Institute, states have legislation seeking to protect a woman's right to access abortion services have the lowest rates of infant mortality in the United States.[3] Hurricane Maria made landfall in Puerto Rico on September 20, 2017 and had a major impact on the overall public health situation on the island that was still being felt years later. Healthcare infrastructure was severely damaged, including hospitals, dialysis centers and HIV support centers.[4] Zika risks were also increased because of an increase in the number of mosquitoes.[4] There was also an increase in demand but a decrease in supply of mental health services.[4] ## History[edit] Puerto Rico became a United States territory in 1898.[5] American colonial powers in Puerto Rico had a major impact on the island's relationship with women's reproductive rights and on abortion laws.[6] In 1937, modeled after US-initiated eugenic policies, Puerto Rico adopted more liberal abortion policies which saw the introduction of Malthusian clinics. Prior to this, abortion in Puerto Rico had been all but illegal. The changes meant medical doctors effectively became the arbitrators of when it was legal for women to be given an abortion.[6] There was no move by the legislature of Puerto Rico to make change abortion legislation prior to the 1973 Roe v. Wade US Supreme Court ruling.[6] Prior to the Roe v. Wade ruling, it was often a bit cheaper and easier for women to obtain abortions in Puerto Rico than it was for women to obtain abortions in the mainland United States. White women were one of the largest groups of women to travel to the island to get an abortion.[7] The Society for Humane Abortions (SHA) assisted in facilitating women from the mainland traveling to Puerto Rico and other locations like Japan and Mexico for abortions during the 1960s and early 1970s.[8] Research on abortion on the island only began in 1983.[6] Pregnant women in Puerto Rico in 2016 were at risk of getting the Zika virus, which causes major fetal defects. These defects may lead some women choose to terminate their pregnancy.[9] In 2018 and 2019, the effects of Hurricane Maria hampered women's ability on the island to get access to abortion services.[7] ### Legislative history[edit] Abortion effectively became legal in Puerto Rico in 1937 after the territory's legislature repealed existing laws around reproductive care and treatment. These reforms included allowing interstate transportation of information about contraceptives and birth control methods, legalized contraceptive sterilization, and introduced a therapeutic exemption for abortions to protect the life or health of the woman who was pregnant.[10] In 1964, there was a legislative effort to try to repeal the 1937 reforms by amending Puerto Rico's penal code, though it was only partially effective in totally criminalizing abortion; one consequence of these efforts though was it resulted in a large drop in the number of abortions performed in Puerto Rico.[10] There was no move by the legislature of Puerto Rico to make abortion legal prior to the 1973 Roe v. Wade US Supreme Court ruling.[6][7] In 2012, the Puerto Rico Penal Code was revised in Section II, Articles 99 to 101 that relate to abortion. Changes were made that made having an abortion a felony. This legislation was largely pushed through by the New Progressive Party who were trying to win votes among conservative voters on the island, even if the legislation could not withstand judicial review.[11] As of 2016, the law required that women seeking an abortion must have a pelvic exam performed by the doctor providing the abortion at the clinic. The law also required women have their blood testing for anemia and to determine their RH factor. The law also required doctors to offer any other exams or tests that may be needed prior to performing the abortion so a woman is fully informed, including a sonogram to determine how far along the pregnancy is.[12] Prior to 2019, minors did not require consent before getting an abortion so long as the doctor had provided the minor woman with adequate information to allow her to make an informed decision.[12] An evangelical minister Senator named Nayda Venegas put forth a proposed law on March 4, 2019 that would require women under the age of 21 to get parental consent before being allowed to have an abortion. This effort failed.[13] On May 7, 2018, Puerto Rico legislature proposed a series of abortion restrictions that were signed into law by the territory's governor on March 7, 2019.[13] The restrictions included girls under the age of 18 being required to get parental consent before being allowed to get an abortion. An exception was allowed saying, “the minor can go to court if she insists on having an abortion to present their claims to getting an abortion."[13][5] PS950 was vetoed on the same day, March 7, 2019 by Governor Ricardo Rosselló who said the legislation imposed “onerous restrictions” on a woman's ability to access abortion services. The House then overrrode the veto of PS950.[7] Pre-natal care for women under the age of 18 does not require similar parental consent.[5] ### Judicial history[edit] The US Supreme Court's decision in 1973's Roe v. Wade ruling meant the state could no longer regulate abortion in the first trimester.[14] Abortion also became legal in Puerto Rico as a consequence of this decision.[6] The Puerto Rican Supreme Court oversaw the case of the People of Puerto Rico v. Pablo Duarte Mendoza in 1980. Their ruling was effectively a territory specific answer to a question already answered by the US Supreme Court in the earlier Roe v. Wade.[11] The 1980 cases involved Dr. Pablo Duarte Mendoza being charged in 1973 for allegedly performing an illegal abortion on a 16-year-old girl in violation of Puerto Rico's 1937 abortion laws. Duarte was given a sentence of two to four years around the time that the 1937 law was being repealed and replaced with a law that provided women with greater access to abortion services. Duarte appealed the sentence to the Puerto Rico Supreme Court, which overturned the sentence given by the Puerto Rico Superior Court, citing the needs of the doctor to be able to consider a woman's health issues in the first trimester, with the women's health being a primary factor in whether or not an abortion should occur. The Supreme Court said that the issues of the health of the pregnant woman trumped any concern about her age.[11] ### Clinic history[edit] During the 1930s when abortion was illegal, Puerto Rican midwives and nurses who had training related to prenatal care and delivering babies would also sometimes perform abortions; Puerto Rican women were willing to pay a premium to use these medical practitioners to have safer abortions.[10] The passage of the 1937 revisions in law did not result in an immediate increase in the number of abortion providers as the new laws were not widely shared.[10] In the early 1990s, there were over a dozen abortion clinics in Puerto Rico.[5] In 1993, there were thirteen private clinics on the island offering abortion services.[15][6] Women in the 1990s in the Caribbean had few options for where they could get legal abortions, with Puerto Rico and Cuba being two of the places offering women the easiest legal access.[16] This continued into the 2000s and 2010s.[5] Women coming to Puerto Rico in 2016 for abortions included women from the Dominican Republic.[5] In 2016, there were seven abortion clinics in the territory.[12] The type of informed consent materials and documentation that minors were given in 2016 varied from clinic to clinic. This was because the law did not, by law, require informed consent for minors.[12] In 2016, the price of an abortion at a family planning clinic generally cost around $225 to $325 for a first trimester abortion.[12] In 2019, there were only six abortion clinics left on the island.[5] ## Statistics[edit] Reliable statistics about the number of legal abortions in Puerto Rico are difficult to ascertain because the Department of Health has historically failed to use reliable methodologies to attain numbers.[11] 23 out of every 1,000 pregnancies in 1999 were terminated as a result of an abortion.[7][16] In the period between 1991 and 1992, there were an estimated 19,200 legal abortions in the territory, with a rate of 22.7 and a ratio of 23.0 for a total abortion rate of 0.68.[16] These rates were among some of the lowest in the world.[16] In 2016, 98% of abortions were performed in the first trimester, in the period between 7 and 13 weeks of pregnancy. Most of these abortions used one of two procedures, suction or the aspiration method.[12] Only 2% of abortions in 2016 occurred in the second trimester, defined as week 13 to week 22. All abortions second trimester abortions took place before week 20. The most commonly used method in Puerto Rico for second trimester abortions is dilation and extraction.[12] Number, rate, and ratio of reported abortions, by reporting area of residence and occurrence and by percentage of abortions obtained by out-of-state residents Location Residence Occurrence % obtained by out-of-state residents Year Ref No. Rate Ratio No. Rate Ratio Puerto Rico 22 1991 [11] Puerto Rico 19,200 22.7 23.0 1991–1992 [16] Puerto Rico 15,600 18 2001 [11] Puerto Rico 3,622[note 1] 2009–2010 [11] ## Public funding[edit] Federal funding through Medicare is available to women in Puerto Rico in cases of rape, incest or risk of health or life to the mother. For women seeking abortions as a result of rape, the Department of Health's Rape Victims’ Assistance Center (CAVV) provides assistance in seeking public funds.[12] ## Abortion rights views and activities[edit] ### Organizations[edit] Clergy Consultation Service was an organization the promoted abortion rights on the island during the 1950s and 1960s. They were an outside organization.[10] Taller Salud is one of the organizations supporting abortion rights.[7] Amnesty International Puerto Rico also works on abortion rights in Puerto Rico.[5] ### Views[edit] Taller Salud's Michel Collado said in 2019, “Over the last few years, we’ve been struggling with a government that has eliminated access to sex education and gender perspective in public schools; they also cut funding to the NGOs [non-government organizations] that work with those issues."[7] ### Protests[edit] See also: Fourth-wave feminism and International Women's Day In 2019, International Women's Day in Puerto Rico revolved around women taking to the streets en masse to support abortion. Their efforts this day on abortion rights were part of broader 8M efforts to combat gender violence.[13] 107 women in Puerto Rico were killed between 2007 and 2011 as a result of partner violence. Of these 30 were killed in 2011 alone. In 2018, 23 women were murdered by intimate partners with 53 total women killed as a result of domestic violence that year.[13] ## Anti-abortion views and activities[edit] Anti-abortion activities in Puerto Rico tend to be more subdued than anti-abortion activities in the mainland United States, and are much less likely to include violence.[11] ### Views[edit] Senator Venegas Brown said during the debate around PS950, “I wish this was a bill to ban abortion." Brown said the only reason Senators were not able to do so was because of Roe v. Wade .[5] ### Protests[edit] An anti-abortion rally was held in 1974 in San Juan following revisions in Puerto Rican law earlier that year.[11] ## Footnotes[edit] 1. ^ This number is from the Department of Health, which uses a methodology that has been described as health academics as questionable. ## References[edit] 1. ^ https://www.nejm.org/doi/full/10.1056/NEJMoa1400506 2. ^ Castillo, Stephanie (2014-10-03). "States With More Abortion Restrictions Hurt Women's Health, Increase Risk For Maternal Death". Medical Daily. Retrieved 2019-05-27. 3. ^ a b "States pushing abortion bans have highest infant mortality rates". NBC News. Retrieved 2019-05-25. 4. ^ a b c 2017 (2017-11-17). "Public Health in Puerto Rico after Hurricane Maria - Issue Brief". The Henry J. Kaiser Family Foundation. Retrieved 2019-06-08.CS1 maint: numeric names: authors list (link) 5. ^ a b c d e f g h i "How Puerto Rico Became The Latest Battleground For Abortion Rights". www.yahoo.com. Retrieved 2019-06-08. 6. ^ a b c d e f g Azize-Vargas, Yamila; Avilés, Luis A. (1997). "Abortion in Puerto Rico: The Limits of Colonial Legality". Reproductive Health Matters. 5 (9): 56–65. doi:10.1016/S0968-8080(97)90006-9. ISSN 0968-8080. JSTOR 3775136. 7. ^ a b c d e f g MTV News Staff. "As Activists Rebuild Puerto Rico, Lawmakers Are Trying To Restrict Abortion". MTV News. Retrieved 2019-06-08. 8. ^ "The Forgotten History of Women Traveling Abroad for Abortions". Bitch Media. Retrieved 2019-06-08. 9. ^ Gani, Aisha (2016-01-29). "Zika virus: the options facing pregnant women across Latin America". The Guardian. ISSN 0261-3077. Retrieved 2019-05-29. 10. ^ a b c d e Marchand-Arias, R. E. (March 1998). "[Legal secrecy: abortion in Puerto Rico from 1937 to 1970]". Puerto Rico Health Sciences Journal. 17 (1): 15–26. ISSN 0738-0658. PMID 9642717. 11. ^ a b c d e f g h i Méndez-Méndez, Serafín; Fernandez, Ronald (2015-07-14). Puerto Rico Past and Present: An Encyclopedia, 2nd Edition: An Encyclopedia. ABC-CLIO. ISBN 9781440828324. 12. ^ a b c d e f g h "Servicios de Aborto en Puerto Rico". Salud Pro Mujer (in Spanish). Retrieved 2019-06-08. 13. ^ a b c d e "Puerto Ricans fight against women's rights setbacks on International Women's Day". NBC News. Retrieved 2019-05-23. 14. ^ Buell, Samuel (1991-01-01). "Criminal Abortion Revisited". New York University Law Review. 66: 1774–1831. 15. ^ Azize-Vargas, Yamila; Avilés, Luis A. (1997-05-01). "Abortion in Puerto Rico: The limits of colonial legality". Reproductive Health Matters. 5 (9): 56–65. doi:10.1016/S0968-8080(97)90006-9. ISSN 0968-8080. 16. ^ a b c d e Henshaw, Stanley K.; Singh, Susheela; Haas, Taylor (1999). "The Incidence of Abortion Worldwide". International Family Planning Perspectives. 25: S30–S38. doi:10.2307/2991869. ISSN 0190-3187. JSTOR 2991869. Abortion in the United States by state States * Alabama * Alaska * Arizona * Arkansas * California * Colorado * Connecticut * Delaware * Florida * Georgia * Hawaii * Idaho * Illinois * Indiana * Iowa * Kansas * Kentucky * Louisiana * Maine * Maryland * Massachusetts * Michigan * Minnesota * Mississippi * Missouri * Montana * Nebraska * Nevada * New Hampshire * New Jersey * New Mexico * New York * North Carolina * North Dakota * Ohio * Oklahoma * Oregon * Pennsylvania * Rhode Island * South Carolina * South Dakota * Tennessee * Texas * Utah * Vermont * Virginia * Washington * West Virginia * Wisconsin * Wyoming Federal district Washington, D.C. Insular areas * American Samoa * Guam * Northern Mariana Islands * Puerto Rico * U.S. Virgin Islands [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Abortion in Puerto Rico	None	6,471	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Puerto_Rico	2021-01-18T18:54:51	{"wikidata": ["Q64876951"]}
Cerebral creatine deficiency Other namesCCD SpecialtyPediatrics, medical genetics, neurology Symptomsintellectual disability, developmental delay, seziures Usual onsetearly childhood CausesGenetic Diagnostic methodBlood, and urine tests, genetic testing, brain MRS Treatmentdietary modification, creatine supplementation Prognosisvariable; early treatment for AGAT and GAMT deficiency results in significantly improved outcomes Cerebral creatine deficiencies are a small group of inherited disorders that result from defects in creatine biosynthesis and utilization. Commonly affected tissues include the brain and muscles. There are three distinct CCDs. The most common is creatine transporter defect (CTD), an X-linked disorder caused by pathogenic variants in SLC6A8. The main symptoms of CTD are intellectual disability and developmental delay, and these are caused by a lack of creatine in the brain, due to the defective transporter. There are also two enzymatic defects of creatine biosynthesis, arginine:glycine amidinotransferase deficiency (AGAT deficiency), caused by variants in GATM and guanidinoacetate methyltransferase deficiency (GAMT deficiency), caused by variants in GAMT. The single enzyme defects are both inherited in an autosomal recessive manner.[1] Creatine is synthesized in the kidney and liver, by a two step enzymatic process. In the first step, glycine and arginine are combined by arginine:glycine amidinotransferase to form guanidinoacetate. This step also results in the production of ornithine. Creatine is produced by the enzyme guanidinoacetate methyltransferase. After production in the liver and kidneys, creatine is transported to organs and tissues with high energy demands, most commonly the brain and skeletal muscles. In addition to endogenous production, creatine can be obtained from dietary sources or supplementation. Ornithine aminotransferase deficiency can cause secondary creatine deficiency, however it does not result in cerebral creatine deficiency.[2] ## Contents * 1 Signs and symptoms * 2 Pathogenesis * 3 References ## Signs and symptoms[edit] The clinical findings in all three CCDs result from the consequences of decreased levels of creatine in tissues where it is required. In affected individuals with all three disorders, there is an almost complete absence of creatine and phosphocreatine in the brain.[2] The two tissues with the highest demands for creatine are the brain and skeletal muscles. Muscular findings usually include weakness and decreased endurance. Other clinical findings include seizures, intellectual disability and developmental delay. Most affected individuals appear normal at birth, with clinical findings becoming apparent during the first year of life, and progressing. ## Pathogenesis[edit] Creatine is synthesized primarily in the liver and kidneys via a two-step enzymatic process. Defects in either of these two enzymes can cause a CCD. In order to pass the blood brain barrier, creatine requires a specialized transporter, encoded for by SLC6A8. A defect in this transporter is responsible for the third CCD.[2] ## References[edit] 1. ^ Braissant, O.; Henry, H.; Béard, E.; Uldry, J. P. (2011). "Creatine deficiency syndromes and the importance of creatine synthesis in the brain" (PDF). Amino Acids. 40 (5): 1315–1324. doi:10.1007/s00726-011-0852-z. PMID 21390529. 2. ^ a b c Schulze, Andreas (2009). "Creatine Deficiency Syndromes". In Sarafoglou, Kiriakie; Hoffmann, Georg F.; Roth, Karl S. (eds.). Pediatric Endocrinology and Inborn Errors of Metabolism (1st ed.). New York: McGraw-Hill Medical. pp. 153–161. ISBN 978-0-07-143915-2. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Cerebral creatine deficiency	c0268238	6,472	wikipedia	https://en.wikipedia.org/wiki/Cerebral_creatine_deficiency	2021-01-18T18:55:27	{"mesh": ["C536560"], "icd-10": ["E72.8"], "orphanet": ["79172"], "synonyms": ["CCDS", "CDS", "Cerebral creatine deficiency syndrome"], "wikidata": ["Q16908143"]}
Group of conditions resulting from maternal alcohol consumption during pregnancy "FASD" redirects here. For other uses, see FASD (disambiguation). Fetal alcohol spectrum disorders Other namesFoetal alcohol spectrum disorders Baby with fetal alcohol syndrome, showing some of the characteristic facial features SpecialtyPsychiatry, pediatrics, toxicology SymptomsAbnormal appearance, short height, low body weight, small head size, poor coordination, behavior problems, learning problems [1][2] ComplicationsBabies: Miscarriage, stillbirth Adults: Alcoholism, substance use disorder, substance abuse DurationLong term[1][3] TypesFetal alcohol syndrome, Partial fetal alcohol syndrome, Alcohol-related neurodevelopmental disorder, Static Encephalopathy, Alcohol-related birth defects[1] CausesDrinking alcohol during pregnancy[1] Diagnostic methodBased on symptoms[1] PreventionAvoiding drinking alcohol during pregnancy[4] TreatmentParent-child interaction therapy, efforts to modify child behavior, possibly medications[5] PrognosisModerate. Death age range from 31 to 37. Average death age is 34.[6] Frequency1–5% (US, EU)[7] Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person whose mother drank alcohol during pregnancy.[1] Symptoms can include an abnormal appearance, short height, low body weight, small head size, poor coordination, behavior problems, learning difficulties and problems with hearing or sight.[1][2] Those affected are more likely to have trouble in school, legal problems, participate in high-risk activities and have problems with alcohol or other drugs.[8] The most severe form of the condition is known as fetal alcohol syndrome (FAS).[1] Other types include Partial Fetal Alcohol Syndrome (pFAS), Alcohol-Related Neurodevelopmental Disorder (ARND), Static Encephalopathy,[9] Alcohol-Related Birth Defects (ARBD),[1][10] and Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure (ND-PAE).[11] Some accept only FAS as a diagnosis, seeing the evidence as inconclusive with respect to other types.[12] Fetal alcohol spectrum disorders are caused by a mother drinking alcohol during pregnancy.[1] Surveys from the United States found that about 10% of pregnant women drank alcohol in the past month, and 20% to 30% drank at some point during the pregnancy.[13] About 3.6% of pregnant American women are alcoholics.[14] The risk of FASD depends on the amount consumed and the frequency of consumption as well as at what point in pregnancy the alcohol was consumed.[13] Other risk factors include older age of the mother, smoking, and poor diet.[15][13] There is no known safe amount or time to drink alcohol during pregnancy.[1][16] While drinking small amounts does not cause abnormalities in the face, it may cause behavioral issues.[14] Alcohol crosses the blood–brain barrier and both directly and indirectly affects a developing fetus.[17] Diagnosis is based on the signs and symptoms in the person.[1] Fetal alcohol spectrum disorders are preventable by avoiding alcohol.[4] For this reason, medical authorities recommend no alcohol during pregnancy or while trying to become pregnant.[18][19][20] While the condition is permanent, treatment can improve outcomes.[1][3] Interventions may include parent–child interaction therapy, efforts to modify child behavior, and possibly medications.[5] FASD is estimated to affect between 1% and 5% of people in the United States and Western Europe.[7] FAS is believed to occur in between 0.2 and 9 per 1,000 live births in the United States.[7] In South Africa, some populations have rates as high as 9%.[10] The negative effects of alcohol during pregnancy have been described since ancient times.[10] The lifetime cost per child with FAS in the US was $2,000,000 in 2002.[7] The term fetal alcohol syndrome was first used in 1973.[10] ## Contents * 1 Types * 2 Signs and symptoms * 2.1 Growth * 2.2 Facial features * 2.3 Central nervous system * 2.3.1 Structural * 2.3.2 Neurological * 2.3.3 Functional * 2.4 Related signs * 3 Cause * 4 Mechanism * 5 Diagnosis * 5.1 Fetal alcohol syndrome * 5.2 Partial FAS * 5.3 Fetal alcohol effects * 5.3.1 Alcohol-related neurodevelopmental disorder * 5.3.2 Alcohol-related birth defects * 5.4 Exposure * 5.4.1 Confirmed exposure * 5.4.2 Unknown exposure * 5.4.3 Confirmed absence of exposure * 5.4.4 Biomarkers * 5.5 Ten brain domains * 5.6 Differential diagnosis * 6 Prevention * 7 Treatment * 7.1 Medication * 7.2 Behavioral interventions * 7.3 Developmental framework * 7.4 Advocacy model * 7.5 Public health and policy * 8 Prognosis * 8.1 Primary disabilities * 8.2 Secondary disabilities * 8.3 Protective factors and strengths * 8.4 Lifespan * 9 Epidemiology * 9.1 Australia * 10 History * 10.1 Historical references * 10.2 Recognition as a syndrome * 11 In fiction * 12 See also * 13 References * 14 External links ## Types[edit] FASDs encompass a range of physical and neurodevelopmental problems that can result from prenatal alcohol exposure.[1] The most severe condition is called fetal alcohol syndrome (FAS),[1] which refers to individuals who have a specific set of birth defects and neurodevelopmental disorders characteristic of the diagnosis.[21] Some accept only FAS as a diagnosis, seeing the evidence as inconclusive with respect to other types.[12] Partial fetal alcohol syndrome (pFAS) refers to individuals with a known, or highly suspected, history of prenatal alcohol exposure who have alcohol-related physical and neurodevelopmental deficits that do not meet the full criteria for FAS.[21] The subtypes of pFAS are alcohol-related neurodevelopmental disorder (ARND) and alcohol-related birth defects (ARBD).[21] In addition to FAS, pFAS, ARND, and ARBD, any other conditions believed to be related to prenatal alcohol exposure, such as spontaneous abortion and sudden infant death syndrome (SIDS), are also considered to be on the spectrum of related disorders.[21] It is unclear as of 2017[update] if identifying a FASD-related condition benefits the individual.[12] In 2013, the American Psychiatric Association introduced, neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE) into the DSM-V as a "condition for further study" and as a specified condition under, "other specified neurodevelopmental disorders" as a way to better study the behavioral aspects of all FASD disorders. Though similar sounding ND-PAE is the spectrum-wide term for the psychiatric, behavioral, and neurological symptoms of all FASD's, where as ARND, is the specific diagnosis of the non-dysmorphic type of FASD where a majority of the symptoms are witnessed.[22] ## Signs and symptoms[edit] Facial characteristics of a child with FAS The key of FASD can vary between individuals exposed to alcohol during pregnancy. While consensus exists for the definition and diagnosis of FAS, minor variations among the systems lead to differences in definitions and diagnostic cut-off criteria for other diagnoses across the FASD continuum. The central nervous system damage criteria particularly lacks clear consensus. A working knowledge of the key features is helpful in understanding FASD diagnoses and conditions, and each is reviewed with attention to similarities and differences across the four diagnostic systems. More than 400 problems, however, can occur with FASD.[23] ### Growth[edit] In terms of FASD, growth deficiency is defined as significantly below average height, weight or both due to prenatal alcohol exposure, and can be assessed at any point in the lifespan. Growth measurements must be adjusted for parental height, gestational age (for a premature infant), and other postnatal insults (e.g., poor nutrition), although birth height and weight are the preferred measurements.[24] Deficiencies are documented when height or weight falls at or below the 10th percentile of standardized growth charts appropriate to the population.[25] Prenatal or postnatal presentation of growth deficits can occur, but are most often postnatal.[26] Criteria for FASD are least specific in the IOM[clarification needed] diagnostic system ("low birth weight..., decelerating weight not due to nutrition..., [or] disproportional low weight to height" p. 4 of executive summary),[19] while the CDC and Canadian guidelines use the 10th percentile as a cut-off to determine growth deficiency.[2][27] The "4-Digit Diagnostic Code" allows for mid-range gradations in growth deficiency (between the 3rd and 10th percentiles) and severe growth deficiency at or below the 3rd percentile.[24] Growth deficiency (at severe, moderate, or mild levels) contributes to diagnoses of FAS and pFAS, but not ARND or static encephalopathy. Growth deficiency is ranked as follows by the "4-Digit Diagnostic Code":[24] * Severe: Height and weight at or below the 3rd percentile. * Moderate: Either height or weight at or below the 3rd percentile, but not both. * Mild: Either height or weight or both between the 3rd and 10th percentiles. * None: Height and weight both above the 10th percentile. In the initial studies that discovered FAS, growth deficiency was a requirement for inclusion in the studies; thus, all the original people with FAS had growth deficiency as an artifact of sampling characteristics used to establish criteria for the syndrome.[citation needed] That is, growth deficiency is a key feature of FASD because growth deficiency was a criterion for inclusion in the study that defined FAS. This suggests growth deficiency may be less critical for understanding the disabilities of FASD than the neurobehavioral sequelae to the brain damage.[19] ### Facial features[edit] Several characteristic craniofacial abnormalities are often visible in individuals with FAS.[28] The presence of FAS facial features indicates brain damage, although brain damage may also exist in their absence. FAS facial features (and most other visible, but non-diagnostic, deformities) are believed to be caused mainly during the 10th to 20th week of gestation.[29] Refinements in diagnostic criteria since 1975 have yielded three distinctive and diagnostically significant facial features known to result from prenatal alcohol exposure and distinguishes FAS from other disorders with partially overlapping characteristics.[30][31] The three FAS facial features are: * A smooth philtrum: The divot or groove between the nose and upper lip flattens with increased prenatal alcohol exposure. * Thin vermilion: The upper lip thins with increased prenatal alcohol exposure. * Small palpebral fissures: Eye width decreases with increased prenatal alcohol exposure. Measurement of FAS facial features uses criteria developed by the University of Washington. The lip and philtrum are measured by a trained physician with the Lip-Philtrum Guide,[32] a five-point Likert Scale with representative photographs of lip and philtrum combinations ranging from normal (ranked 1) to severe (ranked 5). Palpebral fissure length (PFL) is measured in millimeters with either calipers or a clear ruler and then compared to a PFL growth chart, also developed by the University of Washington.[33] Ranking FAS facial features is complicated because the three separate facial features can be affected independently by prenatal alcohol. A summary of the criteria follows:[24][34] * Severe: All three facial features ranked independently as severe (lip ranked at 4 or 5, philtrum ranked at 4 or 5, and PFL two or more standard deviations below average). * Moderate: Two facial features ranked as severe and one feature ranked as moderate (lip or philtrum ranked at 3, or PFL between one and two standard deviations below average). * Mild: A mild ranking of FAS facial features covers a broad range of facial feature combinations: * Two facial features ranked severe and one ranked within normal limits, * One facial feature ranked severe and two ranked moderate, or * One facial feature ranked severe, one ranked moderate and one ranked within normal limits. * None: All three facial features ranked within normal limits. ### Central nervous system[edit] Central nervous system (CNS) damage is the primary feature of any FASD diagnosis. Prenatal alcohol exposure, which is classified as a teratogen, can damage the brain across a continuum of gross to subtle impairments, depending on the amount, timing, and frequency of the exposure as well as genetic predispositions of the fetus and mother.[19][35] While functional abnormalities are the behavioral and cognitive expressions of the FASD disability, CNS damage can be assessed in three areas: structural, neurological, and functional impairments. All four diagnostic systems allow for assessment of CNS damage in these areas, but criteria vary. The IOM system requires structural or neurological impairment for a diagnosis of FAS, but also allows a "complex pattern" of functional anomalies for diagnosing PFAS and ARND.[19] The "4-Digit Diagnostic Code" and CDC guidelines allow for a positive CNS finding in any of the three areas for any FASD diagnosis, but functional anomalies must measure at two standard deviations or worse in three or more functional domains for a diagnosis of FAS, PFAS, and ARND.[24][27] The "4-Digit Diagnostic Code" also allows for an FASD diagnosis when only two functional domains are measured at two standard deviations or worse.[24] The "4-Digit Diagnostic Code" further elaborates the degree of CNS damage according to four ranks: * Definite: Structural impairments or neurological impairments for FAS or static encephalopathy. * Probable: Significant dysfunction of two standard deviations or worse in three or more functional domains. * Possible: Mild to moderate dysfunction of two standard deviations or worse in one or two functional domains or by judgment of the clinical evaluation team that CNS damage cannot be dismissed. * Unlikely: No evidence of CNS damage. #### Structural[edit] Structural abnormalities of the brain are observable, physical damage to the brain or brain structures caused by prenatal alcohol exposure. Structural impairments may include microcephaly (small head size) of two or more standard deviations below the average, or other abnormalities in brain structure (e.g., agenesis of the corpus callosum, cerebellar hypoplasia).[19] Microcephaly is determined by comparing head circumference (often called occipitofrontal circumference, or OFC) to appropriate OFC growth charts.[25] Other structural impairments must be observed through medical imaging techniques by a trained physician. Because imaging procedures are expensive and relatively inaccessible to most people, diagnosis of FAS is not frequently made via structural impairments, except for microcephaly. Evidence of a CNS structural impairment due to prenatal alcohol exposure will result in a diagnosis of FAS, and neurological and functional impairments are highly likely.[2][19][24][27] During the first trimester of pregnancy, alcohol interferes with the migration and organization of brain cells, which can create structural deformities or deficits within the brain.[36] During the third trimester, damage can be caused to the hippocampus, which plays a role in memory, learning, emotion, and encoding visual and auditory information, all of which can create neurological and functional CNS impairments as well.[37] As of 2002, there were 25 reports of autopsies on infants known to have FAS. The first was in 1973, on an infant who died shortly after birth.[38] The examination revealed extensive brain damage, including microcephaly, migration anomalies, callosal dysgenesis, and a massive neuroglial, leptomeningeal heterotopia covering the left hemisphere.[39] In 1977, Dr. Clarren described a second infant whose mother was a binge drinker. The infant died ten days after birth. The autopsy showed severe hydrocephalus, abnormal neuronal migration, and a small corpus callosum (which connects the two brain hemispheres) and cerebellum.[39] FAS has also been linked to brainstem and cerebellar changes, agenesis of the corpus callosum and anterior commissure, neuronal migration errors, absent olfactory bulbs, meningomyelocele, and porencephaly.[39] #### Neurological[edit] When structural impairments are not observable or do not exist, neurological impairments are assessed. In the context of FASD, neurological impairments are caused by prenatal alcohol exposure which causes general neurological damage to the central nervous system (CNS), the peripheral nervous system, or the autonomic nervous system. A determination of a neurological problem must be made by a trained physician, and must not be due to a postnatal insult, such as meningitis, concussion, traumatic brain injury, etc. All four diagnostic systems show virtual agreement on their criteria for CNS damage at the neurological level, and evidence of a CNS neurological impairment due to prenatal alcohol exposure will result in a diagnosis of FAS or pFAS, and functional impairments are highly likely.[2][19][24][27] Neurological problems are expressed as either hard signs, or diagnosable disorders, such as epilepsy or other seizure disorders, or soft signs. Soft signs are broader, nonspecific neurological impairments, or symptoms, such as impaired fine motor skills, neurosensory hearing loss, poor gait, clumsiness, and poor hand - eye coordination. Many soft signs have norm-referenced criteria, while others are determined through clinical judgment. "Clinical judgment" is only as good as the clinician, and soft signs should be assessed by either a pediatric neurologist, a pediatric neuropsychologist, or both. #### Functional[edit] When structural or neurological impairments are not observed, all four diagnostic systems allow CNS damage due to prenatal alcohol exposure to be assessed in terms of functional impairments.[2][19][24][27] Functional impairments are deficits, problems, delays, or abnormalities due to prenatal alcohol exposure (rather than hereditary causes or postnatal insults) in observable and measurable domains related to daily functioning, often referred to as developmental disabilities. There is no consensus on a specific pattern of functional impairments due to prenatal alcohol exposure[19] and only CDC guidelines label developmental delays as such,[27] so criteria (and FASD diagnoses) vary somewhat across diagnostic systems. The four diagnostic systems list various CNS domains that can qualify for functional impairment that can determine an FASD diagnosis: * Evidence of a complex pattern of behavior or cognitive abnormalities inconsistent with developmental level in the following CNS domains – Sufficient for a pFAS or ARND diagnosis using IOM guidelines[19] * Learning disabilities, academic achievement, impulse control, social perception, communication, abstraction, math skills, memory, attention, judgment * Performance at two or more standard deviations on standardized testing in three or more of the following CNS domains – Sufficient for an FAS, pFAS or static encephalopathy diagnosis using 4-Digit Diagnostic Code[24] * Executive functioning, memory, cognition, social/adaptive skills, academic achievement, language, motor skills, attention, activity level * General cognitive deficits (e.g., IQ) at or below the 3rd percentile on standardized testing – Sufficient for an FAS diagnosis using CDC guidelines[27] * Performance at or below the 16th percentile on standardized testing in three or more of the following CNS domains – Sufficient for an FAS diagnosis using CDC guidelines[27] * Cognition, executive functioning, motor functioning, attention and hyperactive problems, social skills, sensory processing disorder, social communication, memory, difficulties responding to common parenting practices * Performance at two or more standard deviations on standardized testing in three or more of the following CNS domains – Sufficient for an FAS diagnosis using Canadian guidelines * Cognition, communication, academic achievement, memory, executive functioning, adaptive behavior, motor skills, social skills, social communication ### Related signs[edit] Other conditions may commonly co-occur with FAS, stemming from prenatal alcohol exposure. However, these conditions are considered alcohol-related birth defects[19] and not diagnostic criteria for FAS. * Heart: A heart murmur that frequently disappears by one year of age. Ventricular septal defect most commonly seen, followed by an atrial septal defect. * Bones: Joint anomalies including abnormal position and function, altered palmar crease patterns, small distal phalanges, and small fifth fingernails. * Kidneys: Horseshoe, aplastic, dysplastic, or hypoplastic kidneys. * Eyes: Strabismus, optic nerve hypoplasia[40] (which may cause light sensitivity, decreased visual acuity, or involuntary eye movements). * Occasional problems: ptosis of the eyelid, microphthalmia, cleft lip with or without a cleft palate, webbed neck, short neck, tetralogy of Fallot, coarctation of the aorta, spina bifida, and hydrocephalus. ## Cause[edit] Fetal alcohol syndrome 1) Alcohol consumed (EtOH) 2) Alcohol crosses into the placenta 3) Alcohol metabolizes 4) fatty acid ethyl esters (FAEE) detected in meconium Fetal Alcohol Spectrum Disorder is caused by a woman consuming alcohol while pregnant.[1] Alcohol crosses through the placenta to the unborn child and can interfere with normal development. Alcohol is a teratogen (causes birth defects) and there is no known safe amount of alcohol to consume while pregnant and there is no known safe time during pregnancy to consume alcohol to prevent birth defects such as FASD.[1][41] Evidence of harm from low levels of alcohol consumption is not clear and since there are not known safe amounts of alcohol, women are suggested to completely abstain from drinking when trying to get pregnant and while pregnant.[42][43][44][41] Small amounts of alcohol may not cause an abnormal appearance, however, small amounts of alcohol consumption while pregnant may cause milder symptoms such as behavioral problems and also increases the risk of miscarriage.[14][43][45] Among those women who are alcoholic, an estimated one-third of their children have FAS.[43] There is evidence supporting the theory that the father can cause FAS through long term epigenetic mutation of the father's sperm.[43][46] ## Mechanism[edit] Despite intense research efforts, the exact mechanism for the development of FAS or FASD is unknown. On the contrary, clinical and animal studies have identified a broad spectrum of pathways through which maternal alcohol can negatively affect the outcome of a pregnancy. Clear conclusions with universal validity are difficult to draw, since different ethnic groups show considerable genetic polymorphism for the hepatic enzymes responsible for ethanol detoxification.[47] Genetic examinations have revealed a continuum of long-lasting molecular effects that are not only timing specific but are also dosage specific; with even moderate amounts being able to cause alterations.[48] A human fetus appears to be at triple risk from maternal alcohol consumption:[49][50] 1. The placenta allows free entry of ethanol and toxic metabolites like acetaldehyde into the fetal compartment. The so-called placental barrier is practically absent with respect to ethanol. 2. The developing fetal nervous system appears particularly sensitive to ethanol toxicity. The latter interferes with proliferation, differentiation, neuronal migration, axonic outgrowth, integration, and fine-tuning of the synaptic network. In short, all major processes in the developing central nervous system appear compromised. 3. Fetal tissues are quite different from adult tissues in function and purpose. For example, the main detoxicating organ in adults is the liver, whereas the fetal liver is incapable of detoxifying ethanol, as the ADH and ALDH enzymes have not yet been brought to expression at this early stage. Up to term, fetal tissues do not have significant capacity for the detoxification of ethanol, and the fetus remains exposed to ethanol in the amniotic fluid for periods far longer than the decay time of ethanol in the maternal circulation. The lack of significant quantities of ADH and ALDH means that fetal tissues have much lower quantities of antioxidant enzymes, like SOD, glutathione transferases, and glutathion peroxidases, resulting in antioxidant protection being much less effective. ## Diagnosis[edit] Because admission of alcohol use during pregnancy can stigmatize birth mothers, many are reluctant to admit drinking or to provide an accurate report of the quantity they drank. This complicates diagnosis and treatment of the syndrome.[27] As a result, diagnosis of the severity of FASD relies on protocols of observation of the child's physiology and behavior rather than maternal self-reporting. Presently, four FASD diagnostic systems that diagnose FAS and other FASD conditions have been developed in North America: * The Institute of Medicine's guidelines for FAS, the first system to standardize diagnoses of individuals with prenatal alcohol exposure;[19] * The University of Washington's "The 4-Digit Diagnostic Code", which ranks the four key features of FASD on a Likert scale of one to four and yields 256 descriptive codes that can be categorized into 22 distinct clinical categories, ranging from FAS to no findings;[24] * The Centers for Disease Control's "Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis", which established consensus on the diagnosis FAS in the U.S. but deferred addressing other FASD conditions;[27] and * Canadian guidelines for FASD diagnoses, which established criteria for diagnosing FASD in Canada and harmonized most differences between the IOM and University of Washington's systems.[2] Each diagnostic system requires that a complete FASD evaluation includes an assessment of the four key features of FASD, described below. A positive finding on all four features is required for a diagnosis of FAS. However, prenatal alcohol exposure and central nervous system damage are the critical elements of the spectrum of FASD, and a positive finding in these two features is sufficient for an FASD diagnosis that is not "full-blown FAS". While the four diagnostic systems essentially agree on criteria for fetal alcohol syndrome (FAS), there are still differences when full criteria for FAS are not met. This has resulted in differing and evolving nomenclature for other conditions across the spectrum of FASD, which may account for such a wide variety of terminology. Most individuals with deficits resulting from prenatal alcohol exposure do not express all features of FAS and fall into other FASD conditions.[19] The Canadian guidelines recommend the assessment and descriptive approach of the "4-Digit Diagnostic Code" for each key feature of FASD and the terminology of the IOM in diagnostic categories, excepting ARBD.[2] Thus, other FASD conditions are partial expressions of FAS. However, these other FASD conditions may create disabilities similar to FAS if the key area of central nervous system damage shows clinical deficits in two or more of ten domains of brain functioning. Essentially, even though growth deficiency and/or FAS facial features may be mild or nonexistent in other FASD conditions, yet clinically significant brain damage of the central nervous system is present. In these other FASD conditions, an individual may be at greater risk for adverse outcomes because brain damage is present without associated visual cues of poor growth or the "FAS face" that might ordinarily trigger an FASD evaluation. Such individuals may be misdiagnosed with primary mental health disorders such as ADHD or oppositional defiance disorder without appreciation that brain damage is the underlying cause of these disorders, which requires a different treatment paradigm than typical mental health disorders. While other FASD conditions may not yet be included as an ICD or DSM-IV-TR diagnosis, they nonetheless pose significant impairment in functional behavior because of underlying brain damage. ### Fetal alcohol syndrome[edit] The following criteria must be fully met for an FAS diagnosis:[2][19][24][27] 1. Growth deficiency: Prenatal or postnatal height or weight (or both) at or below the 10th percentile[25] 2. FAS facial features: All three FAS facial features present[33] 3. Central nervous system damage: Clinically significant structural neurological, or functional impairment 4. Prenatal alcohol exposure: Confirmed or Unknown prenatal alcohol exposure Fetal alcohol syndrome (FAS) is the first diagnosable condition of FASD that was discovered. FAS is the only expression of FASD that has garnered consensus among experts to become an official ICD-9 and ICD-10 diagnosis. To make this diagnosis or determine any FASD condition, a multi-disciplinary evaluation is necessary to assess each of the four key features for assessment. Generally, a trained physician will determine growth deficiency and FAS facial features. While a qualified physician may also assess central nervous system structural abnormalities and/or neurological problems, usually central nervous system damage is determined through psychological, speech-language, and occupational therapy assessments to ascertain clinically significant impairments in three or more of the Ten Brain Domains.[51] Prenatal alcohol exposure risk may be assessed by a qualified physician, psychologist, social worker, or chemical health counselor. These professionals work together as a team to assess and interpret data of each key feature for assessment and develop an integrative, multi-disciplinary report to diagnose FAS (or other FASD conditions) in an individual. ### Partial FAS[edit] Partial FAS (pFAS) was previously known as atypical FAS in the 1997 edition of the "4-Digit Diagnostic Code". People with pFAS have a confirmed history of prenatal alcohol exposure, but may lack growth deficiency or the complete facial stigmata. Central nervous system damage is present at the same level as FAS. These individuals have the same functional disabilities but "look" less like FAS. The following criteria must be fully met for a diagnosis of Partial FAS:[2][19][24] 1. Growth deficiency: Growth or height may range from normal to deficient[25] 2. FAS facial features: Two or three FAS facial features present[33] 3. Central nervous system damage: Clinically significant structural, neurological, or functional impairment in three or more of the Ten Brain Domains[51] 4. Prenatal alcohol exposure: Confirmed prenatal alcohol exposure ### Fetal alcohol effects[edit] Fetal alcohol effects (FAE) is a previous term for alcohol-related neurodevelopmental disorder and alcohol-related birth defects.[1] It was initially used in research studies to describe humans and animals in whom teratogenic effects were seen after confirmed prenatal alcohol exposure (or unknown exposure for humans), but without obvious physical anomalies.[52] Smith (1981) described FAE as an "extremely important concept" to highlight the debilitating effects of brain damage, regardless of the growth or facial features.[53] This term has fallen out of favor with clinicians because it was often regarded by the public as a less severe disability than FAS, when in fact its effects can be just as detrimental.[54] #### Alcohol-related neurodevelopmental disorder[edit] Alcohol-related neurodevelopmental disorder (ARND) was initially suggested by the Institute of Medicine to replace the term FAE and focus on central nervous system damage, rather than growth deficiency or FAS facial features. The Canadian guidelines also use this diagnosis and the same criteria. While the "4-Digit Diagnostic Code" includes these criteria for three of its diagnostic categories, it refers to this condition as static encephalopathy. The behavioral effects of ARND are not necessarily unique to alcohol however, so use of the term must be within the context of confirmed prenatal alcohol exposure.[55] ARND may be gaining acceptance over the terms FAE and ARBD to describe FASD conditions with central nervous system abnormalities or behavioral or cognitive abnormalities or both due to prenatal alcohol exposure without regard to growth deficiency or FAS facial features.[55][56] The following criteria must be fully met for a diagnosis of ARND or static encephalopathy:[2][19][24] 1. Growth deficiency: Growth or height may range from normal to minimally deficient[25] 2. FAS facial features: Minimal or no FAS facial features present[33] 3. Central nervous system damage: Clinically significant structural, neurological, or functional impairment in three or more of the Ten Brain Domains[51] 4. Prenatal alcohol exposure: Confirmed prenatal alcohol exposure;0 #### Alcohol-related birth defects[edit] Alcohol-related birth defects (ARBD), formerly known as possible fetal alcohol effect (PFAE),[52] was a term proposed as an alternative to FAE and PFAE[57] The IOM presents ARBD as a list of congenital anomalies that are linked to maternal alcohol use but have no key features of FASD.[19] PFAE and ARBD have fallen out of favor because these anomalies are not necessarily specific to maternal alcohol consumption and are not criteria for diagnosis of FASD.[55] The Canadian guidelines recommend that ARBD should not be used as an umbrella term or diagnostic category for FASD. ### Exposure[edit] Prenatal alcohol exposure is determined by interview of the biological mother or other family members knowledgeable of the mother's alcohol use during the pregnancy (if available), prenatal health records (if available), and review of available birth records, court records (if applicable), chemical dependency treatment records (if applicable), chemical biomarkers,[58] or other reliable sources. Exposure level is assessed as confirmed exposure, unknown exposure, and confirmed absence of exposure by the IOM, CDC and Canadian diagnostic systems. The "4-Digit Diagnostic Code" further distinguishes confirmed exposure as High Risk and Some Risk: * High Risk: Confirmed use of alcohol during pregnancy known to be at high blood alcohol levels (100 mg/dL or greater) delivered at least weekly in early pregnancy. * Some Risk: Confirmed use of alcohol during pregnancy with use less than High Risk or unknown usage patterns. * Unknown Risk: Unknown use of alcohol during pregnancy. * No Risk: Confirmed absence of prenatal alcohol exposure. #### Confirmed exposure[edit] Amount, frequency, and timing of prenatal alcohol use can dramatically impact the other three key features of FASD. While consensus exists that alcohol is a teratogen, there is no clear consensus as to what level of exposure is toxic.[19] The CDC guidelines are silent on these elements diagnostically. The IOM and Canadian guidelines explore this further, acknowledging the importance of significant alcohol exposure from regular or heavy episodic alcohol consumption in determining, but offer no standard for diagnosis. Canadian guidelines discuss this lack of clarity and parenthetically point out that "heavy alcohol use" is defined by the National Institute on Alcohol Abuse and Alcoholism as five or more drinks per episode on five or more days during a 30-day period.[59] "The 4-Digit Diagnostic Code" ranking system distinguishes between levels of prenatal alcohol exposure as high risk and some risk. It operationalizes high risk exposure as a blood alcohol concentration (BAC) greater than 100 mg/dL delivered at least weekly in early pregnancy. This BAC level is typically reached by a 55 kg female drinking six to eight beers in one sitting.[24] #### Unknown exposure[edit] For many adopted or adults and children in foster care, records or other reliable sources may not be available for review. Reporting alcohol use during pregnancy can also be stigmatizing to birth mothers, especially if alcohol use is ongoing.[27] In these cases, all diagnostic systems use an unknown prenatal alcohol exposure designation. A diagnosis of FAS is still possible with an unknown exposure level if other key features of FASD are present at clinical levels. #### Confirmed absence of exposure[edit] Confirmed absence of exposure would apply to planned pregnancies in which no alcohol was used or pregnancies of women who do not use alcohol or report no use during the pregnancy. This designation is relatively rare, as most people presenting for an FASD evaluation are at least suspected to have had a prenatal alcohol exposure due to presence of other key features of FASD.[24][27] #### Biomarkers[edit] Evidence is insufficient for the use of chemical biomarkers to detect prenatal alcohol exposure.[60] Biomarkers being studied include fatty acid ethyl esters (FAEE) detected in the meconium (first feces of an infant) and hair. FAEE may be present if chronic alcohol exposure occurs during the 2nd and 3rd trimester since this is when the meconium begins to form. Concentrations of FAEE can be influence by medication use, diet, and individual genetic variations in FAEE metabolism however.[61][62] ### Ten brain domains[edit] A recent effort to standardize assessment of functional CNS damage has been suggested by an experienced FASD diagnostic team in Minnesota. The proposed framework attempts to harmonize IOM, 4-Digit Diagnostic Code, CDC, and Canadian guidelines for measuring CNS damage vis-à-vis FASD evaluations and diagnosis. The standardized approach is referred to as the Ten Brain Domains and encompasses aspects of all four diagnostic systems' recommendations for assessing CNS damage due to prenatal alcohol exposure. The framework provides clear definitions of brain dysfunction, specifies empirical data needed for accurate diagnosis, and defines intervention considerations that address the complex nature of FASD with the intention to avoid common secondary disabilities.[51] The proposed Ten Brain Domains include:[51] * Achievement, adaptive behavior, attention, cognition, executive functioning, language, memory, motor skills, multisensory integration or soft neurological problems, social communication[51] The Fetal Alcohol Diagnostic Program (FADP) uses unpublished Minnesota state criteria of performance at 1.5 or more standard deviations on standardized testing in three or more of the Ten Brain Domains to determine CNS damage. However, the Ten Brain Domains are easily incorporated into any of the four diagnostic systems' CNS damage criteria, as the framework only proposes the domains, rather than the cut-off criteria for FASD.[63] ### Differential diagnosis[edit] The CDC reviewed nine syndromes that have overlapping features with FAS; however, none of these syndromes include all three FAS facial features, and none are the result of prenatal alcohol exposure:[27] * Aarskog syndrome * Williams syndrome * Noonan syndrome * Dubowitz syndrome * Brachman-DeLange syndrome * Toluene syndrome * Fetal hydantoin syndrome * Fetal valproate syndrome * Maternal PKU fetal effects Other disorders that have similar symptoms may include:[64] * Attention deficit hyperactive disorder * Autism spectrum disorder * Reactive attachment disorder * Oppositional defiant disorder * Sensory integration dysfunction * Bipolar disorder * Depression * Asperger's syndrome ## Prevention[edit] See also: Alcohol and pregnancy The only certain way to prevent FAS is to avoid drinking alcohol during pregnancy.[55][65] In the United States, the Surgeon General recommended in 1981, and again in 2005, that women abstain from alcohol use while pregnant or while planning a pregnancy, the latter to avoid damage even in the earliest stages (even weeks) of a pregnancy, as the woman may not be aware that she has conceived.[18] The Centers for Disease Control and the American College of Obstetricians and Gynecologists also recommend no alcohol during pregnancy.[62] In the United States, federal legislation has required that warning labels be placed on all alcoholic beverage containers since 1988 under the Alcoholic Beverage Labeling Act. There is some controversy surrounding the "zero-tolerance" approach taken by many countries when it comes to alcohol consumption during pregnancy. The assertion that moderate drinking causes FAS is said to lack strong evidence and, in fact, the practice of equating a responsible level of drinking with potential harm to the fetus may have negative social, legal, and health impacts.[66] In addition, special care should be taken when considering statistics on this disease, as prevalence and causation is often linked with FASD, which is more common and causes less harm, as opposed to FAS.[67] ## Treatment[edit] There is no cure for FASD, but treatment is possible. Early intervention from birth to age 3 has been shown to improve the development of a child born with FASD.[62] Because CNS damage, symptoms, secondary disabilities, and needs vary widely by individual, there is no one treatment type that works for everyone. ### Medication[edit] Psychoactive drugs are frequently tried on those with FASD as many FASD symptoms are mistaken for or overlap with other disorders, most notably ADHD.[68] ### Behavioral interventions[edit] Behavioral interventions are based on the learning theory, which is the basis for many parenting and professional strategies and interventions.[56] Along with ordinary parenting styles, such strategies are frequently used by default for treating those with FAS, as the diagnoses oppositional defiance disorder (ODD), conduct disorder, reactive attachment disorder (RAD) often overlap with FAS (along with ADHD), and these are sometimes thought to benefit from behavioral interventions. Frequently, a person's poor academic achievement results in special education services, which also utilizes principles of learning theory, behavior modification, and outcome-based education. ### Developmental framework[edit] Many books and handouts on FAS recommend a developmental approach, based on developmental psychology, even though most do not specify it as such and provide little theoretical background. Optimal human development generally occurs in identifiable stages (e.g., Jean Piaget's theory of cognitive development, Erik Erikson's stages of psychosocial development, John Bowlby's attachment framework, and other developmental stage theories). FAS interferes with normal development,[69] which may cause stages to be delayed, skipped, or immaturely developed. Over time, an unaffected child can negotiate the increasing demands of life by progressing through stages of development normally, but not so for a child with FAS.[69] By knowing what developmental stages and tasks children follow, treatment and interventions for FAS can be tailored to helping a person meet developmental tasks and demands successfully.[69] If a person is delayed in the adaptive behavior domain, for instance, then interventions would be recommended to target specific delays through additional education and practice (e.g., practiced instruction on tying shoelaces), giving reminders, or making accommodations (e.g., using slip-on shoes) to support the desired functioning level. This approach is an advance over behavioral interventions, because it takes the person's developmental context into account while developing interventions.[citation needed] ### Advocacy model[edit] The advocacy model takes the point of view that someone is needed to actively mediate between the environment and the person with FAS.[55] Advocacy activities are conducted by an advocate (for example, a family member, friend, or case manager) and fall into three basic categories. An advocate for FAS: (1) interprets FAS and the disabilities that arise from it and explains it to the environment in which the person operates, (2) engenders change or accommodation on behalf of the person, and (3) assists the person in developing and reaching attainable goals.[55] The advocacy model is often recommended, for example, when developing an Individualized Education Program (IEP) for the person's progress at school.[68] An understanding of the developmental framework would presumably inform and enhance the advocacy model, but advocacy also implies interventions at a systems level as well, such as educating schools, social workers, and so forth on best practices for FAS. However, several organizations devoted to FAS also use the advocacy model at a community practice level as well.[70] ### Public health and policy[edit] Treating FAS at the public health and public policy level promotes FAS prevention and diversion of public resources to assist those with FAS.[55] It is related to the advocacy model but promoted at a systems level (rather than with the individual or family), such as developing community education and supports, state or province level prevention efforts (e.g., screening for maternal alcohol use during OB/GYN or prenatal medical care visits), or national awareness programs. Several organizations and state agencies in the U.S. are dedicated to this type of intervention.[70] The US Centers for Disease Control estimates 3 million women in the United States are at risk of having a baby with FASD, and recommended that women of child-bearing age should be on birth control or abstain from drinking alcohol as the safest way to avoid this.[71] ## Prognosis[edit] ### Primary disabilities[edit] The primary disabilities of FAS are the functional difficulties with which the child is born as a result of CNS damage due to prenatal alcohol exposure.[72] Often, primary disabilities are mistaken as behavior problems, but the underlying CNS damage is the originating source of a functional difficulty,[73] rather than a mental health condition, which is considered a secondary disability. The exact mechanisms for functional problems of primary disabilities are not always fully understood, but animal studies have begun to shed light on some correlates between functional problems and brain structures damaged by prenatal alcohol exposure.[55] Representative examples include: * Learning impairments are associated with impaired dendrites of the hippocampus[74] * Impaired motor development and functioning are associated with reduced size of the cerebellum[75] * Hyperactivity is associated with decreased size of the corpus callosum[76] Functional difficulties may result from CNS damage in more than one domain, but common functional difficulties by domain include:[55][56][69][73] Note that this is not an exhaustive list of difficulties. * Achievement: Learning disabilities * Adaptive behavior: Poor impulse control, poor personal boundaries, poor anger management, stubbornness, intrusive behavior, too friendly with strangers, poor daily living skills, developmental delays * Attention: Attention-Deficit/Hyperactivity Disorder (ADHD), poor attention or concentration, distractible * Cognition: Intellectual disability, confusion under pressure, poor abstract skills, difficulty distinguishing between fantasy and reality, slower cognitive processing * Executive functioning: Poor judgment, Information-processing disorder, poor at perceiving patterns, poor cause and effect reasoning, inconsistent at linking words to actions, poor generalization ability * Language: Expressive or receptive language disorders, grasp parts but not whole concepts, lack understanding of metaphor, idioms, or sarcasm * Memory: Poor short-term memory, inconsistent memory and knowledge base * Motor skills: Poor handwriting, poor fine motor skills, poor gross motor skills, delayed motor skill development (e.g., riding a bicycle at appropriate age) * Sensory processing and soft neurological problems: sensory processing disorder, sensory defensiveness, undersensitivity to stimulation * Social communication: Intrude into conversations, inability to read nonverbal or social cues, "chatty" but without substance ### Secondary disabilities[edit] The secondary disabilities of FAS are those that arise later in life secondary to CNS damage. These disabilities often emerge over time due to a mismatch between the primary disabilities and environmental expectations; secondary disabilities can be ameliorated with early interventions and appropriate supportive services.[72] Six main secondary disabilities were identified in a University of Washington research study of 473 subjects diagnosed with FAS, PFAS (partial fetal alcohol syndrome), and ARND (alcohol-related neurodevelopmental disorder):[55][72] * Mental health problems: Diagnosed with ADHD, Clinical Depression, or other mental illness, experienced by over 90% of the subjects * Disrupted school experience: Suspended or expelled from school or dropped out of school, experienced by 60% of the subjects (age 12 and older) * Trouble with the law: Charged or convicted with a crime, experienced by 60% of the subjects (age 12 and older) * Confinement: For inpatient psychiatric care, inpatient chemical dependency care, or incarcerated for a crime, experienced by about 50% of the subjects (age 12 and older) * Inappropriate sexual behavior: Sexual advances, sexual touching, or promiscuity, experienced by about 50% of the subjects (age 12 and older) * Alcohol and drug problems: Abuse or dependency, experienced by 35% of the subjects (age 12 and older) Two additional secondary disabilities exist for adults:[55][72] * Dependent living: Group home, living with family or friends, or some sort of assisted living, experienced by 80% of the subjects (age 21 and older) * Problems with employment: Required ongoing job training or coaching, could not keep a job, unemployed, experienced by 80% of the subjects (age 21 and older) ### Protective factors and strengths[edit] Eight factors were identified in the same study as universal protective factors that reduced the incidence rate of the secondary disabilities:[55][72] * Living in a stable and nurturing home for over 73% of life * Being diagnosed with FAS before age six * Never having experienced violence * Remaining in each living situation for at least 2.8 years * Experiencing a "good quality home" (meeting 10 or more defined qualities) from age 8 to 12 years old * Having been found eligible for developmental disability (DD) services * Having basic needs met for at least 13% of life * Having a diagnosis of FAS (rather than another FASD condition) Malbin (2002) has identified the following areas of interests and talents as strengths that often stand out for those with FASD and should be utilized, like any strength, in treatment planning:[56] * Music, playing instruments, composing, singing, art, spelling, reading, computers, mechanics, woodworking, skilled vocations (welding, electrician, etc.), writing, poetry * Participation in non-impact sport or physical fitness activities ### Lifespan[edit] One study found that the people with FASD had a significantly shorter life expectancy.[77] With the average life span of 34 years old, a study found that 44% of the deaths were of "external cause", with 15% of deaths being suicides. ## Epidemiology[edit] FASD is estimated to affect between 2% and 5% of people in the United States and Western Europe.[7] FAS is believed to occur in between 0.2 and 9 per 1000 live births in the United States.[7] The lifetime costs of an individual with FAS were estimated to be two million USD in 2002.[7] Drinking any quantity during pregnancy, the risk of giving birth to a child with FASD is about 15%, and to a child with FAS about 1.5%. Drinking large quantities, defined as 2 standard drinks a day, or 6 standard drinks in a short time, carries a 50% risk of a FAS birth.[78] ### Australia[edit] See also: Drinking culture in Australia FASD among Australian youth is more common in indigenous Australians.[79] The only states that have registered birth defects in Australian youth are Western Australia, New South Wales, Victoria and South Australia.[80] In Australia, only 12% of Australian health professionals are aware of the diagnostics and symptoms of FASD.[79] In Western Australia, the rate of births resulting in FASD is 0.02 per 1,000 births for non-Indigenous Australians, however among indigenous births the rate is 2.76 per 1,000 births.[80] In Victoria, there have been no registered FASD related births for indigenous Australians, but the rate for the general population in Victoria is 0.01–0.03 per 1000 births.[80] There have been no dedicated FASD clinics within Western Australia, but there are also no nationally supported diagnostic criteria anywhere in Australia.[81] Passive surveillance is a prevention technique used within Australia to assist in monitoring and establishing detectable defects during pregnancy and childhood.[80] ## History[edit] From the 1960s to the 1980s, alcohol was commonly used as a tocolytic, a method to stop preterm labor. The method originated with Dr. Fritz Fuchs, the chairman of the department of obstetrics and gynecology at Cornell University Medical College.[82][83] Doctors recommended a small amount of alcohol to calm the uterus during contractions in early pregnancy or Braxton Hicks contractions. In later stages of pregnancy, the alcohol was administered intravenously and often in large amounts. "Women experienced similar effects as occur with oral ingestion, including intoxication, nausea and vomiting, and potential alcohol poisoning, followed by hangovers when the alcohol was discontinued."[84] Vomiting put the mother at a high risk for aspiration and was "a brutal procedure for all involved."[82] Because the alcohol was being given intravenously, the doctor could continue giving the treatment to the mother long after she had passed out, resulting in her being more intoxicated than would otherwise be possible. Such heavy intoxication is highly likely to contribute to FASD.[82] ### Historical references[edit] Anecdotal accounts of prohibitions against maternal alcohol use from Biblical, ancient Greek, and ancient Roman sources[85] imply a historical awareness of links between maternal alcohol use and negative child outcomes.[38] For example, in the Bible, Judges 13:4 (addressed to a woman who was going to have a baby) reads: "Therefore be careful and drink no wine or strong drink, and eat nothing unclean" (ESV). In 1725 British physicians petitioned the House of Commons on the effects of strong drink when consumed by pregnant women saying that such drinking is “… too often the cause of weak, feeble, and distempered children, who must be, instead of an advantage and strength, a charge to their country.”[86] There are many other such historical references. In Gaelic Scotland, the mother and nurse were not allowed to consume ale during pregnancy and breastfeeding (Martin Martin). Claims that alcohol consumption caused idiocy were part of the Teetotalism's message in the 19th century,[87] but such claims, despite some attempts to offer evidence, were ignored because no mechanism could be advanced.[88] The earliest recorded observation of possible links between maternal alcohol use and fetal damage was made in 1899 by Dr. William Sullivan, a Liverpool prison physician who noted higher rates of stillbirth for 120 alcoholic female prisoners than their sober female relatives; he suggested the causal agent to be alcohol use.[89] This contradicted the predominating belief at the time that heredity caused intellectual disability, poverty, and criminal behavior, which contemporary studies on the subjects usually concluded.[55] A case study by Henry H. Goddard of the Kallikak family—popular in the early 1900s—represents this earlier perspective,[90] though later researchers have suggested that the Kallikaks almost certainly had FAS.[91] General studies and discussions on alcoholism throughout the mid-1900s were typically based on a heredity argument.[92] Prior to fetal alcohol syndrome being specifically identified and named in 1973, only a few studies had noted differences between the children of mothers who used alcohol during pregnancy or breast-feeding and those who did not, and identified alcohol use as a possible contributing factor rather than heredity.[55] ### Recognition as a syndrome[edit] Fetal alcohol syndrome was named in 1973 by two dysmorphologists, Drs. Kenneth Lyons Jones and David Weyhe Smith of the University of Washington Medical School in Seattle, United States. They identified a pattern of "craniofacial, limb, and cardiovascular defects associated with prenatal onset growth deficiency and developmental delay" in eight unrelated children of three ethnic groups, all born to mothers who were alcoholics.[93] The pattern of malformations indicated that the damage was prenatal. News of the discovery shocked some, while others were skeptical of the findings.[94] Dr. Paul Lemoine of Nantes, France had already published a study in a French medical journal in 1968 about children with distinctive features whose mothers were alcoholics,[95] and in the U.S., Christy Ulleland and colleagues at the University of Washington Medical School had conducted an 18-month study in 1968–1969 documenting the risk of maternal alcohol consumption among the offspring of 11 alcoholic mothers.[96] The Washington and Nantes findings were confirmed by a research group in Gothenburg, Sweden in 1979.[97] Researchers in France, Sweden, and the United States were struck by how similar these children looked, though they were not related, and how they behaved in the same unfocused and hyperactive manner.[97] Within nine years of the Washington discovery, animal studies, including non-human monkey studies carried out at the University of Washington Primate Center by Dr. Sterling Clarren, had confirmed that alcohol was a teratogen. By 1978, 245 cases of FAS had been reported by medical researchers, and the syndrome began to be described as the most frequent known cause of intellectual disability. While many syndromes are eponymous, i.e. named after the physician first reporting the association of symptoms, Dr. Smith named FAS after the causal agent of the symptoms.[98] He reasoned that doing so would encourage prevention, believing that if people knew maternal alcohol consumption caused the syndrome, then abstinence during pregnancy would follow from patient education and public awareness.[98] At the time, nobody was aware of the full range of possible birth defects from FAS or its rate of prevalence.[98] Over time, as subsequent research and clinical experience suggested that a range of effects (including physical, behavioral, and cognitive) could arise from prenatal alcohol exposure, the term Fetal Alcohol Spectrum Disorder (FASD) was developed to include FAS as well as other conditions resulting from prenatal alcohol exposure.[98] Currently, FAS[19][52][93] is the only expression of prenatal alcohol exposure defined by the International Statistical Classification of Diseases and Related Health Problems and assigned ICD-9 and diagnoses. ## In fiction[edit] In Aldous Huxley's 1932 novel Brave New World (where all fetuses are gestated in vitro in a factory), lower caste fetuses are created by receiving alcohol transfusions to reduce intelligence and height, thus conditioning them for simple, menial tasks. Connections between alcohol and incubating embryos are made multiple times in the novel. [99] The main character of the 2009 film Defendor is implied to have the condition.[citation needed] ## See also[edit] * Alcohol and pregnancy * Smoking and pregnancy * Environmental toxicants and fetal development ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r "Facts about FASDs". 16 April 2015. Archived from the original on 23 May 2015. Retrieved 10 June 2015. 2. ^ a b c d e f g h i j k Chudley; et al. (2005). "Fetal alcohol spectrum disorder: Canadian guidelines for diagnosis". CMAJ. 172 (5 Suppl): S1–S21. doi:10.1503/cmaj.1040302. PMC 557121. PMID 15738468. 3. ^ a b Rasmussen, Carmen; Andrew, Gail; Zwaigenbaum, Lonnie; Tough, Suzanne (20 November 2016). "Neurobehavioural outcomes of children with fetal alcohol spectrum disorders: A Canadian perspective". Paediatrics & Child Health. 13 (3): 185–191. ISSN 1205-7088. PMC 2529423. PMID 19252695. 4. ^ a b "Alcohol Use in Pregnancy". 17 April 2014. Archived from the original on 28 June 2015. Retrieved 10 June 2015. 5. ^ a b Roszel, EL (13 April 2015). "Central nervous system deficits in fetal alcohol spectrum disorder". The Nurse Practitioner. 40 (4): 24–33. doi:10.1097/01.npr.0000444650.10142.4f. PMID 25774812. 6. ^ Thanh, Nguyen Xuan; Jonsson, Egon (2016). "Life Expectancy of People with Fetal Alcohol Syndrome". Journal of Population Therapeutics and Clinical Pharmacology = Journal de la Therapeutique des Populations et de la Pharmacologie Clinique. 23 (1): e53-9. PMID 26962962. Retrieved 17 July 2020. 7. ^ a b c d e f g "Data & Statistics Prevalence of FASDs". Center for Disease Control and Prevention. 16 April 2015. Archived from the original on 29 June 2015. Retrieved 10 June 2015. 8. ^ Coriale, G; Fiorentino, D; Di Lauro, F; Marchitelli, R; Scalese, B; Fiore, M; Maviglia, M; Ceccanti, M (2013). "Fetal Alcohol Spectrum Disorder (FASD): neurobehavioral profile, indications for diagnosis and treatment". Rivista di Psichiatria. 48 (5): 359–69. doi:10.1708/1356.15062. PMID 24326748. 9. ^ "FASD Fact #1: FASD = Fetal Alcohol Spectrum Disorder". Families Affected by Fetal Alcohol Spectrum Disorder FAFASD. Retrieved 4 December 2020. 10. ^ a b c d Riley, EP; Infante, MA; Warren, KR (June 2011). "Fetal alcohol spectrum disorders: an overview". Neuropsychology Review. 21 (2): 73–80. doi:10.1007/s11065-011-9166-x. PMC 3779274. PMID 21499711. 11. ^ Hagan, Joseph F.; Balachova, Tatiana; Bertrand, Jacquelyn; Chasnoff, Ira; Dang, Elizabeth; Fernandez-Baca, Daniel; Kable, Julie; Kosofsky, Barry; Senturias, Yasmin N.; Singh, Natasha; Sloane, Mark; Weitzman, Carol; Zubler, Jennifer (2016). "Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure". Pediatrics. AAP Publications. 138 (4): e20151553. doi:10.1542/peds.2015-1553. PMC 5477054. PMID 27677572. Retrieved 4 December 2020. 12. ^ a b c "Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Spectrum Disorders (FASD) – conditions and interventions". www.sbu.se. Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU). 14 December 2016. Archived from the original on 6 June 2017. Retrieved 8 June 2017. 13. ^ a b c "Fetal Alcohol Exposure". April 2015. Archived from the original on 10 June 2015. Retrieved 10 June 2015. 14. ^ a b c McHugh, RK; Wigderson, S; Greenfield, SF (June 2014). "Epidemiology of substance use in reproductive-age women". Obstetrics and Gynecology Clinics of North America. 41 (2): 177–89. doi:10.1016/j.ogc.2014.02.001. PMC 4068964. PMID 24845483. 15. ^ Gupta, Keshav Kumar; Gupta, Vinay Kumar; Shirasaka, Tomohiro (2016). "An Update on Fetal Alcohol Syndrome—Pathogenesis, Risks, and Treatment". Alcoholism: Clinical and Experimental Research. 40 (8): 1594–1602. doi:10.1111/acer.13135. PMID 27375266. 16. ^ Williams, J. F.; Smith, V. C. (19 October 2015). "Fetal Alcohol Spectrum Disorders". Pediatrics. 136 (5): e1395–e1406. doi:10.1542/peds.2015-3113. PMID 26482673. S2CID 23752340. 17. ^ Fetal Alcohol Spectrum Disorder: Management and Policy Perspectives of FASD. John Wiley & Sons. 2011. pp. 73–75. ISBN 9783527632565. Archived from the original on 10 September 2017. 18. ^ a b Vice Admiral Richard H. Carmona (2005). "A 2005 Message to Women from the U.S. Surgeon General" (PDF). Archived (PDF) from the original on 24 September 2015. Retrieved 12 June 2015. 19. ^ a b c d e f g h i j k l m n o p q r s t Institute of Medicine; Committee to Study Fetal Alcohol Syndrome (1995). Stratton, Kathleen; Howe, Cynthia; Battaglia, Frederick C. (eds.). Fetal alcohol syndrome: diagnosis, epidemiology, prevention, and treatment. Washington, D.C.: National Academy Press. ISBN 978-0-309-05292-4. Archived from the original on 11 March 2016. 20. ^ "Australian Government National Health and Medical Research Council". Archived from the original on 5 November 2012. Retrieved 4 November 2012. 21. ^ a b c d Kingdon; et al. (2016), "Research Review: Executive function deficits in fetal alcohol spectrum disorders and attention-deficit/hyperactivity disorder – a meta-analysis", Journal of Child Psychology and Psychiatry, 57 (2): 116–131, doi:10.1111/jcpp.12451, PMC 5760222, PMID 26251262 22. ^ Zubler, MD, FAAP, Jennifer; Weitzman, MD, FAAP, Carol; Sloane, DO, Mark; Singh, MPA, Natasha; Senturias, MD, FAAP, Yasmin N.; Kosofsky, MD, PhD, Barry; Kable, PhD, Julie; Fernandez-Baca, MA, Daniel; Dang, MPH, Elizabeth; Chasnoff, MD, FAAP, Ira; Bertrand PhD, Jacquelyn; Balachova PhD, Tatiana; Hagan Jr. MD, FAAP, Joseph F. (2016). "Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure" (PDF). Pediatrics. American Journal of Pediatrics. 138 (4): e20151553. doi:10.1542/peds.2015-1553. PMC 5477054. PMID 27677572. Retrieved 30 March 2020.CS1 maint: multiple names: authors list (link) 23. ^ "CAMH: More than 400 conditions co-occur with Fetal Alcohol Spectrum Disorders (FASD), CAMH study finds". www.camh.ca. Archived from the original on 21 November 2016. Retrieved 20 November 2016. 24. ^ a b c d e f g h i j k l m n o p Astley, S.J. (2004). Diagnostic Guide for Fetal Alcohol Spectrum Disorders: The 4-Digit Diagnostic Code. Seattle: University of Washington. PDF available at FAS Diagnostic and Prevention Network Archived 16 December 2006 at the Wayback Machine. Retrieved on 2007-04-11. 25. ^ a b c d e Clinical growth charts. Archived 3 December 2010 at the Wayback Machine National Center for Growth Statistics. Retrieved on 2007-04-10 26. ^ del Campo, Miguel; Jones, Kenneth Lyons (1 January 2017). "A review of the physical features of the fetal alcohol spectrum disorders". European Journal of Medical Genetics. Special issue on Environmental Teratogens. 60 (1): 55–64. doi:10.1016/j.ejmg.2016.10.004. ISSN 1769-7212. PMID 27729236. 27. ^ a b c d e f g h i j k l m n Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis (PDF). CDC (July 2004). Retrieved on 2019-10-19 28. ^ Jones K, Smith D (1975). "The fetal alcohol syndrome". Teratology. 12 (1): 1–10. doi:10.1002/tera.1420120102. PMID 1162620. 29. ^ Renwick J, Asker R (1983). "Ethanol-sensitive times for the human conceptus". Early Hum Dev. 8 (2): 99–111. doi:10.1016/0378-3782(83)90065-8. PMID 6884260. 30. ^ Astley SJ, Clarren SK (1996). "Most FAS children have a smaller brain then other children "A case definition and photographic screening tool for the facial phenotype of fetal alcohol syndrome"". Journal of Pediatrics. 129 (1): 33–41. doi:10.1016/s0022-3476(96)70187-7. PMID 8757560. 31. ^ Astley SJ, Stachowiak J, Clarren SK, Clausen C (2002). "Application of the fetal alcohol syndrome facial photographic screening tool in a foster care population". Journal of Pediatrics. 141 (5): 712–717. doi:10.1067/mpd.2002.129030. PMID 12410204. 32. ^ Lip-philtrum guides Archived 8 February 2007 at the Wayback Machine. FAS Diagnostic and Prevention Network, University of Washington. Retrieved on 2007-04-10. 33. ^ a b c d FAS facial features Archived 27 October 2007 at the Wayback Machine. FAS Diagnostic and Prevention Network, University of Washington. Retrieved on 2007-04-10 34. ^ Astley, Susan. Backside of Lip-Philtrum Guides (2004) (PDF) Archived 19 June 2007 at the Wayback Machine. University of Washington, Fetal Alcohol Syndrome Diagnostic and Prevention Network. Retrieved on 2007-04-11 35. ^ West, J.R. (Ed.) (1986). Alcohol and Brain Development. New York: Oxford University Press.[page needed] 36. ^ Clarren S, Alvord E, Sumi S, Streissguth A, Smith D (1978). "Brain malformations related to prenatal exposure to ethanol". J Pediatr. 92 (1): 64–7. doi:10.1016/S0022-3476(78)80072-9. PMID 619080. 37. ^ Coles C, Brown R, Smith I, Platzman K, Erickson S, Falek A (1991). "Effects of prenatal alcohol exposure at school age. I. Physical and cognitive development". Neurotoxicol Teratol. 13 (4): 357–67. doi:10.1016/0892-0362(91)90084-A. PMID 1921915. 38. ^ a b Jones K.L.; Smith D.W. (1973). "Recognition of the fetal alcohol syndrome in early infancy". Lancet. 2 (7836): 999–1001. doi:10.1016/s0140-6736(73)91092-1. PMID 4127281. 39. ^ a b c Mattson, S.N., & Riley, E.P. (2002). "Neurobehavioral and Neuroanatomical Effects of Heavy Prenatal Exposure to Alcohol," in Streissguth and Kantor. (2002). p. 10. 40. ^ Strömland K, Pinazo-Durán M (2002). "Ophthalmic involvement in the fetal alcohol syndrome: clinical and animal model studies". Alcohol Alcohol. 37 (1): 2–8. doi:10.1093/alcalc/37.1.2. PMID 11825849. 41. ^ a b Mamluk, Loubaba; Edwards, Hannah B.; Savović, Jelena; Leach, Verity; Jones, Timothy; Moore, Theresa H. M.; Ijaz, Sharea; Lewis, Sarah J.; Donovan, Jenny L.; Lawlor, Debbie; Smith, George Davey (3 August 2017). "Low alcohol consumption and pregnancy and childhood outcomes: time to change guidelines indicating apparently 'safe' levels of alcohol during pregnancy? A systematic review and meta-analyses". BMJ Open. 7 (7): e015410. doi:10.1136/bmjopen-2016-015410. ISSN 2044-6055. PMC 5642770. PMID 28775124. 42. ^ Mamluk, Loubaba; Edwards, Hannah B.; Savović, Jelena; Leach, Verity; Jones, Timothy; Moore, Theresa H. M.; Ijaz, Sharea; Lewis, Sarah J.; Donovan, Jenny L.; Lawlor, Debbie; Smith, George Davey (1 July 2017). "Low alcohol consumption and pregnancy and childhood outcomes: time to change guidelines indicating apparently 'safe' levels of alcohol during pregnancy? A systematic review and meta-analyses". BMJ Open. 7 (7): e015410. doi:10.1136/bmjopen-2016-015410. ISSN 2044-6055. PMID 28775124. S2CID 2941340. 43. ^ a b c d Yaffe, Sumner J. (2011). Drugs in pregnancy and lactation : a reference guide to fetal and neonatal risk (9 ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 527. ISBN 9781608317080. Archived from the original on 10 September 2017. 44. ^ "Pregnancy and alcohol: occasional, light drinking may be safe". Prescrire Int. 21 (124): 44–50. February 2012. PMID 22413723. 45. ^ Sundermann, Alexandra C.; Zhao, Sifang; Young, Chantay L.; Lam, LeAnn; Jones, Sarah H.; Velez Edwards, Digna R.; Hartmann, Katherine E. (August 2019). "Alcohol Use in Pregnancy and Miscarriage: A Systematic Review and Meta-Analysis". Alcoholism, Clinical and Experimental Research. 43 (8): 1606–1616. doi:10.1111/acer.14124. ISSN 1530-0277. PMC 6677630. PMID 31194258. 46. ^ Zachariah,V.L & Harding,K.(2019)'Genetic and Epigenetic Perspectives on the Role of Fathers in Fetal Alcohol Spectrum Disorder', CanFASD, retrieved from https://canfasd.ca/wp-content/uploads/publications/Fathers-Role-1-Issue-Paper-Final.pdf 47. ^ Warren K.; Li T-K (2005). "Genetic polymorphisms: Impact on the risk of fetal alcohol spectrum disorders". Birth Defects Research Part A: Clinical and Molecular Teratology. 73 (4): 195–203. doi:10.1002/bdra.20125. PMID 15786496. 48. ^ Laufer BI, Mantha K, Kleiber ML, Diehl EJ, Addison SM, Singh SM (July 2013). "Long-lasting alterations to DNA methylation and ncRNAs could underlie the effects of fetal alcohol exposure in mice". Disease Models & Mechanisms. 6 (4): 977–92. doi:10.1242/dmm.010975. PMC 3701217. PMID 23580197. 49. ^ Brien J.; et al. (1983). "Disposition of ethanol in human maternal venous blood and amniotic fluid". Am J Obstet Gynecol. 146 (2): 181–186. doi:10.1016/0002-9378(83)91050-5. PMID 6846436. 50. ^ Nava-Ocampo A.; et al. (2004). "Elimination kinetics of ethanol in pregnant women". Reproduct Toxicol. 18 (4): 613–617. doi:10.1016/j.reprotox.2004.02.012. PMID 15135856. 51. ^ a b c d e f Lang, Jeannette (2006). "Ten Brain Domains: A Proposal for Functional Central Nervous System Parameters for Fetal Alcohol Spectrum Disorder Diagnosis and Follow-up" (PDF). Journal of the FAS Institute. 4: 1–11. Archived from the original (PDF) on 26 September 2006. Retrieved 4 February 2007. 52. ^ a b c Clarren S.K.; Smith D.W. (1978). "Fetal alcohol syndrome". New England Journal of Medicine. 298 (19): 1063–1067. doi:10.1056/NEJM197805112981906. PMID 347295. 53. ^ Smith D.W. (1981). "Fetal alcohol syndrome and fetal alcohol effects". Neurobehavioral Toxicology and Teratology. 3 (2): 127. PMID 7254460. 54. ^ Aase J.M.; Jones K.L.; Clarren S.K. (1995). "Do we need the term FAE?". Pediatrics. 95 (3): 428–430. PMID 7862486. 55. ^ a b c d e f g h i j k l m n Streissguth, A. (1997). Fetal Alcohol Syndrome: A Guide for Families and Communities. Baltimore: Brookes Publishing. ISBN 1-55766-283-5. 56. ^ a b c d Malbin, D. (2002). Fetal Alcohol Spectrum Disorders: Trying Differently Rather Than Harder. Portland, Oregon: FASCETS, Inc. ISBN 0-9729532-0-5. 57. ^ Sokol, R. J.; Clarren, S. K. (1989). "Guidelines for use of terminology describing the impact of prenatal alcohol on the offspring". Alcoholism: Clinical and Experimental Research. 13 (4): 597–598. doi:10.1111/j.1530-0277.1989.tb00384.x. PMID 2679217. 58. ^ Bager, Heidi; Christensen, Lars Porskjaer; Husby, Steffen; Bjerregaard, Lene (February 2017). "Biomarkers for the Detection of Prenatal Alcohol Exposure: A Review". Alcoholism: Clinical and Experimental Research. 41 (2): 251–261. doi:10.1111/acer.13309. PMID 28098942. S2CID 2595225. 59. ^ U.S. Department of Health and Human Services. (2000). National Institute on Alcohol Abuse and Alcoholism. Tenth special report to the U.S Congress on alcohol and health: Highlights frfom current research. Washington, DC: The Institute. 60. ^ McQuire, C.; Paranjothy, S.; Hurt, L.; Mann, M.; Farewell, D.; Kemp, A. (1 September 2016). "Objective Measures of Prenatal Alcohol Exposure: A Systematic Review". Pediatrics. 138 (3): e20160517. doi:10.1542/peds.2016-0517. ISSN 0031-4005. PMID 27577579. S2CID 420106. 61. ^ Bager, Heidi; Christensen, Lars Porskjær; Husby, Steffen; Bjerregaard, Lene (2017). "Biomarkers for the Detection of Prenatal Alcohol Exposure: A Review". Alcoholism: Clinical and Experimental Research. 41 (2): 251–261. doi:10.1111/acer.13309. ISSN 1530-0277. PMID 28098942. S2CID 2595225. 62. ^ a b c Dejong, Katherine; Olyaei, Amy; Lo, Jamie O. (March 2019). "Alcohol Use in Pregnancy". Clinical Obstetrics and Gynecology. 62 (1): 142–155. doi:10.1097/GRF.0000000000000414. ISSN 0009-9201. PMC 7061927. PMID 30575614. 63. ^ FADP – Fetal Alcohol Diagnostic Program Archived 23 February 2007 at the Wayback Machine 64. ^ "Overlapping Behavioral Characteristics of FASD's & Related Mental Health Diagnosis". www.fasdfamilies.com. Cathy Bruer-Thompson. Retrieved 28 July 2019. 65. ^ "Alcohol and Pregnancy Questions and Answers \| FASD \| NCBDDD \| CDC". www.cdc.gov. 4 August 2017. Retrieved 25 September 2017. 66. ^ Armstrong, E. M. (1 May 2000). "Fetal alcohol syndrome: the origins of a moral panic". Alcohol and Alcoholism. 35 (3): 276–282. doi:10.1093/alcalc/35.3.276. PMID 10869248. 67. ^ "Fetal Alcohol Spectrum Disorders (FASDs)". Center for Disease Control. Archived from the original on 28 July 2017. Retrieved 9 September 2017. 68. ^ a b Buxton, B. (2005). Damaged Angels: An Adoptive Mother Discovers the Tragic Toll of Alcohol in Pregnancy. New York: Carroll & Graf. ISBN 0-7867-1550-2. 69. ^ a b c d McCreight, B. (1997). Recognizing and Managing Children with Fetal Alcohol Syndrome/Fetal Alcohol Effects: A Guidebook. Washington, DC: CWLA. ISBN 0-87868-607-X. 70. ^ a b National Organization on Fetal Alcohol Syndrome, Archived 5 April 2007 at the Wayback Machine Minnesota Organization on Fetal Alcohol Syndrome. Archived 5 April 2007 at the Wayback Machine Retrieved on 2007-04-11 71. ^ "More than 3 million US women at risk for alcohol-exposed pregnancy \| CDC Online Newsroom \| CDC". www.cdc.gov. 2 February 2016. Archived from the original on 21 November 2016. Retrieved 20 November 2016. 72. ^ a b c d e Streissguth, A.P., Barr, H.M., Kogan, J., & Bookstein, F.L. (1996). Understanding the occurrence of secondary disabilities in clients with fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE): Final report to the Centers for Disease Control and Prevention on Grant No. RO4/CCR008515 (Tech. Report No. 96-06). Seattle: University of Washington, Fetal Alcohol and Drug Unit. 73. ^ a b Malbin, D. (1993). Fetal Alcohol Syndrome, Fetal Alcohol Effects: Strategies for Professionals. Center City, MN: Hazelden. ISBN 0-89486-951-5 74. ^ Abel EL, Jacobson S, Sherwin BT (1983). "In utero alcohol exposure: Functional and structural brain damage". Neurobehavioral Toxicology and Teratology. 5 (3): 363–366. PMID 6877477. 75. ^ Meyer L, Kotch L, Riley E (1990). "Neonatal ethanol exposure: functional alterations associated with cerebellar growth retardation". Neurotoxicol Teratol. 12 (1): 15–22. doi:10.1016/0892-0362(90)90107-N. PMID 2314357. 76. ^ Zimmerberg B, Mickus LA (1990). "Sex differences in corpus callosum: Influence of prenatal alcohol exposure and maternal undernutrition". Brain Research. 537 (1–2): 115–122. doi:10.1016/0006-8993(90)90347-e. PMID 2085766. S2CID 21989095. 77. ^ Thanh, Nguyen Xuan; Jonsson, Egon (2016). "Life Expectancy of People with Fetal Alcohol Syndrome". Journal of Population Therapeutics and Clinical Pharmacology = Journal de la Therapeutique des Populations et de la Pharmacologie Clinique. 23 (1): e53–59. ISSN 2561-8741. PMID 26962962. 78. ^ Popova S.; Lange S.; Probst C.; Gmel G.; Rehm J. (2017). "Estimation of national, regional, and global prevalence of alcohol use during pregnancy and fetal alcohol syndrome: a systematic review and meta-analysis". The Lancet Global Health. 5 (3): E290–E299. doi:10.1016/S2214-109X(17)30021-9. PMID 28089487. 79. ^ a b Elliot, E. J; Payne, J; Hann, E; Bower, C (2006). "Diagnosis of fetal alcohol syndrome and alcohol use in pregnancy: A survey of Paediatricians' knowledge, attitudes and practice". Journal of Paediatrics and Child Health. 42 (1): 698–703. doi:10.1111/j.1440-1754.2006.00954.x. PMID 17044897. S2CID 22479922. 80. ^ a b c d Burns, L; Breen, C; Bower, C; O'Leary, C; Elliiot, E. J (2015). "Counting fetal alcohol spectrum disorders in Australia:The evidence and the challenges". Drug and Alcohol Review. 32 (5): 461–467. doi:10.1111/dar.12047. PMID 23617437. 81. ^ Mutch, R. C; Watkins, R; Bower, C (2014). "Fetal alcohol spectrum disorders: Notifications to Western Australian register of developmental anomalies". Journal of Paediatrics and Child Health. 51 (4): 433–436. doi:10.1111/jpc.12746. PMID 25412883. S2CID 25740666. 82. ^ a b c Armstrong, E. M. (2003). Conceiving risk, bearing responsibility: Fetal alcohol syndrome & the diagnosis of moral disorder. Baltimore: The Johns Hopkins University Press. 83. ^ Saxon, Wolfgang (4 March 1995). "Dr. Fritz Fuchs, 76, Who Advanced Obstetrics". The New York Times. Archived from the original on 27 June 2017. Retrieved 16 February 2017. 84. ^ King, T. L., & Brucker, M. C. (2011). Pharmacology for women's health. Sudbury, MA: Jones and Bartlett. 85. ^ Oba, Peggy Seo (2007). "History of FASD". FAS Aware UK. Archived from the original on 4 January 2017. Retrieved 20 November 2016. 86. ^ Jackson, Randle (24 April 1828). Valpy, Abraham John (ed.). "Considerations on the Increase of Crime, and the Degree of its Extent". The Pamphleteer. London: John Hatchard and Son ... and T. and G. Underwood ... 29 (57): 325. OCLC 1761801. "[Alcohol consumption is] too often the cause of weak, feeble, and distempered children, who must be, instead of an advantage and strength, a charge to their country". Biography of author Randle Jackson 87. ^ Jonathan Townley Crane, Arts of Intoxication: The Aim and the Results. (New York:Carlton & Lanahan, 1870), 173–175 88. ^ Jennifer L. Tait The Poisoned Chalice (Tuscaloosa, AL: University of Alabama Press, 2010), 27,28. 89. ^ Sullivan W.C. (1899). "A note on the influence of maternal inebriety on the offspring". Journal of Mental Science. 45 (190): 489–503. doi:10.1192/bjp.45.190.489. 90. ^ Goddard, H.H. (1912). The Kallikak Family: A Study in the Heredity of Feeble-Mindedness. New York: Macmillan. 91. ^ Karp R.J.; Qazi Q.H.; Moller K.A.; Angelo W.A.; Davis J.M. (1995). "Fetal alcohol syndrome at the turn of the century: An unexpected explanation of the Kallikak family". Archives of Pediatrics and Adolescent Medicine. 149 (1): 45–48. doi:10.1001/archpedi.1995.02170130047010. PMID 7827659. 92. ^ Haggard, H.W., & Jellinek, E.M. (1942). Alcohol Explored. New York: Doubleday. 93. ^ a b Jones K.L.; Smith D.W; Ulleland C.N.; Streissguth A.P. (1973). "Pattern of malformation in offspring of chronic alcoholic mothers". Lancet. 1 (7815): 1267–1271. doi:10.1016/S0140-6736(73)91291-9. PMID 4126070. 94. ^ Streissguth, A.P. (2002). In A. Streissguth, & J. Kanter (Eds.), The Challenge in Fetal Alcohol Syndrome: Overcoming Secondary Disabilities. Seattle: University of WA Press. ISBN 0-295-97650-0. 95. ^ Lemoine P.; Harousseau H.; Borteyru J.B.; Menuet J.C. (1968). "Les enfants de parents alcooliques. Anomalies observées, à propos de 127 cas". Quest Medical. 21: 476–482. Reprinted in Lemoine P, Harousseau H, Borteyru JP, Menuet JC (April 2003). "Children of alcoholic parents--observed anomalies: discussion of 127 cases". Ther Drug Monit. 25 (2): 132–6. doi:10.1097/00007691-200304000-00002. PMID 12657907. S2CID 8894309.CS1 maint: multiple names: authors list (link) 96. ^ Ulleland C.N. (1972). "The offspring of alcoholic mothers". Annals of the New York Academy of Sciences. 197 (1): 167–169. Bibcode:1972NYASA.197..167U. doi:10.1111/j.1749-6632.1972.tb28142.x. PMID 4504588. S2CID 84514766. 97. ^ a b Olegard R.; Sabel K.G.; Aronsson M. Sandin; Johannsson P.R.; Carlsson C.; Kyllerman M.; Iversen K.; Hrbek A. (1979). "Effects on the child of alcohol abuse during pregnancy". Acta Paediatrica Scandinavica. 275: 112–121. doi:10.1111/j.1651-2227.1979.tb06170.x. PMID 291283. S2CID 2799171. 98. ^ a b c d Clarren, S.K. (2005). A thirty year journey from tragedy to hope. Foreword to Buxton, B. (2005). Damaged Angels: An Adoptive Mother Discovers the Tragic Toll of Alcohol in Pregnancy. New York: Carroll & Graf. ISBN 0-7867-1550-2. 99. ^ Brown, Jasmine M; Bland, Roger; Jonsson, Egon; Greenshaw, Andrew J (March 2019). "A Brief History of Awareness of the Link Between Alcohol and Fetal Alcohol Spectrum Disorder". Canadian Journal of Psychiatry. 64 (3): 166. doi:10.1177/0706743718777403. PMC 6405809. PMID 29807454. ## External links[edit] Classification D * ICD-10: Q86.0 * ICD-9-CM: 760.71 * MeSH: D005310 * DiseasesDB: 32957 External resources * MedlinePlus: 000911 * eMedicine: ped/767 * Patient UK: Fetal alcohol spectrum disorder Wikimedia Commons has media related to Fetal alcohol syndrome. * Fetal alcohol spectrum disorder at Curlie * Center for Disease Control's page on Fetal Alcohol Spectrum Disorders (FASDs) * v * t * e Pregnancy and childbirth Planning * Birth control * Natural family planning * Pre-conception counseling Conception * Assisted reproductive technology * Artificial insemination * Fertility medication * In vitro fertilisation * Fertility awareness * Unintended pregnancy Testing * 3D ultrasound * Obstetric ultrasonography * Pregnancy test * Home testing * Prenatal diagnosis Prenatal Anatomy * Amniotic fluid * Amniotic sac * Endometrium * Placenta Development * Fundal height * Gestational age * Human embryogenesis * Maternal physiological changes * Postpartum physiological changes Care * Nutrition * Environmental toxicants * In pregnancy * Prenatal * Concomitant conditions * Drinking * Diabetes mellitus * Smoking * Vaping * SLE * Sexual activity during pregnancy Procedures * Amniocentesis * Cardiotocography * Chorionic villus sampling * Nonstress test * Abortion Childbirth Preparation * Bradley method * Hypnobirthing * Lamaze * Nesting instinct Roles * Doula * Birth attendant * Men's roles * Midwife * Obstetrician * Perinatal nurse * Traditional birth attendant Delivery * Bloody show * Childbirth positions * Home birth * Multiple birth * Natural childbirth * Pelvimetry / Bishop score * Cervical dilation * Cervical effacement * Position * Presentation * Breech * Cephalic * Shoulder * Rupture of membranes * Unassisted childbirth * Uterine contraction * Water birth Postpartum Maternal * Postpartum confinement * Sex after pregnancy * Psychiatric disorders of childbirth * Postpartum physiological changes Roles * Doula * Health visitor * Lactation consultant * Monthly nurse * Confinement nanny Infant * Adaptation to extrauterine life * Child care * Congenital disorders Obstetric history * Gravidity and parity * v * t * e Psychoactive substance-related disorder General * SID * Substance intoxication / Drug overdose * Substance-induced psychosis * Withdrawal: * Craving * Neonatal withdrawal * Post-acute-withdrawal syndrome (PAWS) * SUD * Substance abuse / Substance-related disorders * Physical dependence / Psychological dependence / Substance dependence Combined substance use * SUD * Polysubstance dependence * SID * Combined drug intoxication (CDI) Alcohol SID Cardiovascular diseases * Alcoholic cardiomyopathy * Alcohol flush reaction (AFR) Gastrointestinal diseases * Alcoholic liver disease (ALD): * Alcoholic hepatitis * Auto-brewery syndrome (ABS) Endocrine diseases * Alcoholic ketoacidosis (AKA) Nervous system diseases * Alcohol-related dementia (ARD) * Alcohol intoxication * Hangover Neurological disorders * Alcoholic hallucinosis * Alcoholic polyneuropathy * Alcohol-related brain damage * Alcohol withdrawal syndrome (AWS): * Alcoholic hallucinosis * Delirium tremens (DTs) * Fetal alcohol spectrum disorder (FASD) * Fetal alcohol syndrome (FAS) * Korsakoff syndrome * Positional alcohol nystagmus (PAN) * Wernicke–Korsakoff syndrome (WKS, Korsakoff psychosis) * Wernicke encephalopathy (WE) Respiratory tract diseases * Alcohol-induced respiratory reactions * Alcoholic lung disease SUD * Alcoholism (alcohol use disorder (AUD)) * Binge drinking Caffeine * SID * Caffeine-induced anxiety disorder * Caffeine-induced sleep disorder * Caffeinism * SUD * Caffeine dependence Cannabis * SID * Cannabis arteritis * Cannabinoid hyperemesis syndrome (CHS) * SUD * Amotivational syndrome * Cannabis use disorder (CUD) * Synthetic cannabinoid use disorder Cocaine * SID * Cocaine intoxication * Prenatal cocaine exposure (PCE) * SUD * Cocaine dependence Hallucinogen * SID * Acute intoxication from hallucinogens (bad trip) * Hallucinogen persisting perception disorder (HPPD) Nicotine * SID * Nicotine poisoning * Nicotine withdrawal * SUD * Nicotine dependence Opioids * SID * Opioid overdose * SUD * Opioid use disorder (OUD) Sedative / hypnotic * SID * Kindling (sedative–hypnotic withdrawal) * benzodiazepine: SID * Benzodiazepine overdose * Benzodiazepine withdrawal * SUD * Benzodiazepine use disorder (BUD) * Benzodiazepine dependence * barbiturate: SID * Barbiturate overdose * SUD * Barbiturate dependence Stimulants * SID * Stimulant psychosis * amphetamine: SUD * Amphetamine dependence Volatile solvent * SID * Sudden sniffing death syndrome (SSDS) * Toluene toxicity * SUD * Inhalant abuse * v * t * e Congenital malformation due to substance exposure * Fetal alcohol spectrum disorder * Fetal hydantoin syndrome * Fetal warfarin syndrome * Prenatal amphetamine exposure * Prenatal cannabis exposure * Prenatal cocaine exposure * Prenatal nicotine exposure Other * Substance use disorder [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Fetal alcohol spectrum disorder	c0814154	6,473	wikipedia	https://en.wikipedia.org/wiki/Fetal_alcohol_spectrum_disorder	2021-01-18T18:28:18	{"mesh": ["D063647"], "icd-9": ["12"], "icd-10": ["Q86.0"], "orphanet": ["1915"], "wikidata": ["Q400277"]}
A number sign (#) is used with this entry because of evidence that Seckel syndrome-6 (SCKL6) can be caused by homozygous mutation in the CEP63 gene (614724) on chromosome 3q22. One such family has been reported. For a general phenotypic description and a discussion of genetic heterogeneity of Seckel syndrome, see SCKL1 (210600). Clinical Features Sir et al. (2011) ascertained a consanguineous Pakistani family in which 3 female cousins were born with microcephaly, with head circumferences of -4 SD to -6 SD. All had speech delay, but learned to speak by 3 years of age; by age 5 years there was clear evidence of cognitive delay, but there was no motor delay. At the time of examination they were 18 years, 16 years, and 7.5 years of age, and all had head circumferences of 9 to 15 cm below the 3rd centile. All 3 had short stature, with heights that ranged from -2 SD to -4 SD. There was no history of seizures, and there were no other malformations. Mapping In 3 affected female cousins from a consanguineous Pakistani family with microcephaly and short stature, Sir et al. (2011) performed autozygosity mapping and identified a single 24-Mb locus of homozygosity on chromosome 3, between markers D3S3513 at 137 cM and D3S1569 at 158 cM. Molecular Genetics In 3 female cousins from a consanguineous Pakistani family with microcephaly and short stature mapping to chromosome 3q22, Sir et al. (2011) sequenced 3 candidate genes and identified homozygosity for a nonsense mutation in the CEP63 gene (614724.0001). INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly NEUROLOGIC Central Nervous System \- Mental retardation MOLECULAR BASIS \- Caused by mutation in the centrosomal protein, 63-KD gene (CEP63, 614724.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	SECKEL SYNDROME 6	c3553582	6,474	omim	https://www.omim.org/entry/614728	2019-09-22T15:54:22	{"omim": ["614728"]}
Injury to the main nerve bundle in the back of humans Spinal cord injury MRI of fractured and dislocated neck vertebra that is compressing the spinal cord SpecialtyNeurosurgery TypesComplete, incomplete[1] Diagnostic methodBased on symptoms, medical imaging[1] TreatmentSpinal motion restriction, intravenous fluids, vasopressors[1] Frequencyc. 12,000 per year (USA)[2] A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. Symptoms may include loss of muscle function, sensation, or autonomic function in the parts of the body served by the spinal cord below the level of the injury. Injury can occur at any level of the spinal cord and can be complete, with a total loss of sensation and muscle function at lower sacral segments, or incomplete, meaning some nervous signals are able to travel past the injured area of the cord up to the Sacral S4-5 spinal cord segments. Depending on the location and severity of damage, the symptoms vary, from numbness to paralysis, including bowel or bladder incontinence. Long term outcomes also range widely, from full recovery to permanent tetraplegia (also called quadriplegia) or paraplegia. Complications can include muscle atrophy, loss of voluntary motor control, spasticity, pressure sores, infections, and breathing problems. In the majority of cases the damage results from physical trauma such as car accidents, gunshot wounds, falls, or sports injuries, but it can also result from nontraumatic causes such as infection, insufficient blood flow, and tumors. Just over half of injuries affect the cervical spine, while 15% occur in each of the thoracic spine, border between the thoracic and lumbar spine, and lumbar spine alone.[1] Diagnosis is typically based on symptoms and medical imaging.[1] Efforts to prevent SCI include individual measures such as using safety equipment, societal measures such as safety regulations in sports and traffic, and improvements to equipment. Treatment starts with restricting further motion of the spine and maintaining adequate blood pressure.[1] Corticosteroids have not been found to be useful.[1] Other interventions vary depending on the location and extent of the injury, from bed rest to surgery. In many cases, spinal cord injuries require long-term physical and occupational therapy, especially if it interferes with activities of daily living. In the United States, about 12,000 people a year survive a spinal cord injury.[2] The most commonly affected group are young adult males.[2] SCI has seen great improvements in its care since the middle of the 20th century. Research into potential treatments includes stem cell implantation, engineered materials for tissue support, epidural spinal stimulation, and wearable robotic exoskeletons.[3] ## Contents * 1 Classification * 1.1 Complete and incomplete injuries * 1.2 Spinal cord injury without radiographic abnormality * 1.3 Central cord syndrome * 1.4 Anterior cord syndrome * 1.5 Brown-Séquard syndrome * 1.6 Posterior cord syndrome * 1.7 Conus medullaris and cauda equina syndromes * 2 Signs and symptoms * 2.1 Lumbosacral * 2.2 Thoracic * 2.3 Cervical * 2.4 Complications * 3 Causes * 4 Prevention * 5 Diagnosis * 6 Management * 6.1 Prehospital treatment * 6.2 Early hospital treatment * 6.3 Rehabilitation * 7 Prognosis * 8 Epidemiology * 9 History * 10 Research directions * 11 See also * 12 References * 13 Bibliography * 14 External links ## Classification[edit] The effects of injury depend on the level along the spinal column (left). A dermatome is an area of the skin that sends sensory messages to a specific spinal nerve (right). Spinal nerves exit the spinal cord between each pair of vertebrae. Spinal cord injury can be traumatic or nontraumatic,[4] and can be classified into three types based on cause: mechanical forces, toxic, and ischemic (from lack of blood flow).[5] The damage can also be divided into primary and secondary injury: the cell death that occurs immediately in the original injury, and biochemical cascades that are initiated by the original insult and cause further tissue damage.[6] These secondary injury pathways include the ischemic cascade, inflammation, swelling, cell suicide, and neurotransmitter imbalances.[6] They can take place for minutes or weeks following the injury.[7] At each level of the spinal column, spinal nerves branch off from either side of the spinal cord and exit between a pair of vertebrae, to innervate a specific part of the body. The area of skin innervated by a specific spinal nerve is called a dermatome, and the group of muscles innervated by a single spinal nerve is called a myotome. The part of the spinal cord that was damaged corresponds to the spinal nerves at that level and below. Injuries can be cervical 1–8 (C1–C8), thoracic 1–12 (T1–T12), lumbar 1–5 (L1–L5),[8] or sacral (S1–S5).[9] A person's level of injury is defined as the lowest level of full sensation and function.[10] Paraplegia occurs when the legs are affected by the spinal cord damage (in thoracic, lumbar, or sacral injuries), and tetraplegia occurs when all four limbs are affected (cervical damage).[11] SCI is also classified by the degree of impairment. The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), published by the American Spinal Injury Association (ASIA), is widely used to document sensory and motor impairments following SCI.[12] It is based on neurological responses, touch and pinprick sensations tested in each dermatome, and strength of the muscles that control key motions on both sides of the body.[13] Muscle strength is scored on a scale of 0–5 according to the table on the right, and sensation is graded on a scale of 0–2: 0 is no sensation, 1 is altered or decreased sensation, and 2 is full sensation.[14] Each side of the body is graded independently.[14] Muscle strength[15] ASIA Impairment Scale for classifying spinal cord injury[13][16] Grade Muscle function Grade Description 0 No muscle contraction A Complete injury. No motor or sensory function is preserved in the sacral segments S4 or S5. 1 Muscle flickers B Sensory incomplete. Sensory but not motor function is preserved below the level of injury, including the sacral segments. 2 Full range of motion, gravity eliminated C Motor incomplete. Motor function is preserved below the level of injury, and more than half of muscles tested below the level of injury have a muscle grade less than 3 (see muscle strength scores, left). 3 Full range of motion, against gravity D Motor incomplete. Motor function is preserved below the level of injury and at least half of the key muscles below the neurological level have a muscle grade of 3 or more. 4 Full range of motion against resistance E Normal. No motor or sensory deficits, but deficits existed in the past. 5 Normal strength ### Complete and incomplete injuries[edit] Level and completeness of injuries[17] Complete Incomplete Tetraplegia 18.3% 34.1% Paraplegia 23.0% 18.5% In a "complete" spinal injury, all functions below the injured area are lost, whether or not the spinal cord is severed.[9] An "incomplete" spinal cord injury involves preservation of motor or sensory function below the level of injury in the spinal cord.[18] To be classed as incomplete, there must be some preservation of sensation or motion in the areas innervated by S4 to S5,[19] e.g. voluntary external anal sphincter contraction.[18] The nerves in this area are connected to the very lowest region of the spinal cord, and retaining sensation and function in these parts of the body indicates that the spinal cord is only partially damaged. Incomplete injury by definition includes a phenomenon known as sacral sparing: some degree of sensation is preserved in the sacral dermatomes, even though sensation may be more impaired in other, higher dermatomes below the level of the lesion.[20] Sacral sparing has been attributed to the fact that the sacral spinal pathways are not as likely as the other spinal pathways to become compressed after injury due to the lamination of fibers within the spinal cord.[20] ### Spinal cord injury without radiographic abnormality[edit] Spinal cord injury without radiographic abnormality exists when SCI is present but there is no evidence of spinal column injury on radiographs.[21] Spinal column injury is trauma that causes fracture of the bone or instability of the ligaments in the spine; this can coexist with or cause injury to the spinal cord, but each injury can occur without the other.[22] Abnormalities might show up on magnetic resonance imaging (MRI), but the term was coined before MRI was in common use.[23] ### Central cord syndrome[edit] Incomplete lesions of the spinal cord: Central cord syndrome (top), Anterior cord syndrome (middle), and Brown-Séquard syndrome (bottom). Central cord syndrome, almost always resulting from damage to the cervical spinal cord, is characterized by weakness in the arms with relative sparing of the legs, and spared sensation in regions served by the sacral segments.[24] There is loss of sensation of pain, temperature, light touch, and pressure below the level of injury.[25] The spinal tracts that serve the arms are more affected due to their central location in the spinal cord, while the corticospinal fibers destined for the legs are spared due to their more external location.[25] The most common of the incomplete SCI syndromes, central cord syndrome usually results from neck hyperextension in older people with spinal stenosis. In younger people, it most commonly results from neck flexion.[26] The most common causes are falls and vehicle accidents; however other possible causes include spinal stenosis and impingement on the spinal cord by a tumor or vertebral disk.[27] ### Anterior cord syndrome[edit] Anterior cord syndrome, due to damage to the front portion of the spinal cord or reduction in the blood supply from the anterior spinal artery, can be caused by fractures or dislocations of vertebrae or herniated disks.[25] Below the level of injury, motor function, pain sensation, and temperature sensation are lost, while sense of touch and proprioception (sense of position in space) remain intact.[28][26] These differences are due to the relative locations of the spinal tracts responsible for each type of function.[25] ### Brown-Séquard syndrome[edit] Brown-Séquard syndrome occurs when the spinal cord is injured on one side much more than the other.[29] It is rare for the spinal cord to be truly hemisected (severed on one side), but partial lesions due to penetrating wounds (such as gunshot or knife wounds) or fractured vertebrae or tumors are common.[30] On the ipsilateral side of the injury (same side), the body loses motor function, proprioception, and senses of vibration and touch.[29] On the contralateral (opposite side) of the injury, there is a loss of pain and temperature sensations.[27][29] ### Posterior cord syndrome[edit] Posterior cord syndrome, in which just the dorsal columns of the spinal cord are affected, is usually seen in cases of chronic myelopathy but can also occur with infarction of the posterior spinal artery.[31] This rare syndrome causes the loss of proprioception and sense of vibration below the level of injury[26] while motor function and sensation of pain, temperature, and touch remain intact.[32] Usually posterior cord injuries result from insults like disease or vitamin deficiency rather than trauma.[33] Tabes dorsalis, due to injury to the posterior part of the spinal cord caused by syphilis, results in loss of touch and proprioceptive sensation.[34] ### Conus medullaris and cauda equina syndromes[edit] Conus medullaris syndrome is an injury to the end of the spinal cord, located at about the T12–L2 vertebrae in adults.[29] This region contains the S4–S5 spinal segments, responsible for bowel, bladder, and some sexual functions, so these can be disrupted in this type of injury.[29] In addition, sensation and the Achilles reflex can be disrupted.[29] Causes include tumors, physical trauma, and ischemia.[35] Cauda equina syndrome (CES) results from a lesion below the level at which the spinal cord splits into the cauda equina,[33] at levels L2–S5 below the conus medullaris.[36] Thus it is not a true spinal cord syndrome since it is nerve roots that are damaged and not the cord itself; however, it is common for several of these nerves to be damaged at the same time due to their proximity.[35] CES can occur by itself or alongside conus medullaris syndrome.[36] It can cause low back pain, weakness or paralysis in the lower limbs, loss of sensation, bowel and bladder dysfunction, and loss of reflexes.[36] Unlike in conus medullaris syndrome, symptoms often occur on only one side of the body.[35] The cause is often compression, e.g. by a ruptured intervertebral disk or tumor.[35] Since the nerves damaged in CES are actually peripheral nerves because they have already branched off from the spinal cord, the injury has better prognosis for recovery of function: the peripheral nervous system has a greater capacity for healing than the central nervous system.[36] ## Signs and symptoms[edit] Actions of the spinal nerves Level Motor Function C1–C6 Neck flexors C1–T1 Neck extensors C3, C4, C5 Supply diaphragm (mostly C4) C5, C6 Move shoulder, raise arm (deltoid); flex elbow (biceps) C6 externally rotate (supinate) the arm C6, C7 Extend elbow and wrist (triceps and wrist extensors); pronate wrist C7, T1 Flex wrist; supply small muscles of the hand T1–T6 Intercostals and trunk above the waist T7–L1 Abdominal muscles L1–L4 Flex thigh L2, L3, L4 Adduct thigh; Extend leg at the knee (quadriceps femoris) L4, L5, S1 abduct thigh; Flex leg at the knee (hamstrings); Dorsiflex foot (tibialis anterior); Extend toes L5, S1, S2 Extend leg at the hip (gluteus maximus); Plantar flex foot and flex toes Further information: Dermatome (anatomy) Signs (observed by a clinician) and symptoms (experienced by a patient) vary depending on where the spine is injured and the extent of the injury. A section of skin innervated through a specific part of the spine is called a dermatome, and injury to that part of the spine can cause pain, numbness, or a loss of sensation in the related areas. Paraesthesia, a tingling or burning sensation in affected areas of the skin, is another symptom.[37] A person with a lowered level of consciousness may show a response to a painful stimulus above a certain point but not below it.[38] A group of muscles innervated through a specific part of the spine is called a myotome, and injury to that part of the spinal cord can cause problems with movements that involve those muscles. The muscles may contract uncontrollably (spasticity), become weak, or be completely paralysed. Spinal shock, loss of neural activity including reflexes below the level of injury, occurs shortly after the injury and usually goes away within a day.[39] Priapism, an erection of the penis may be a sign of acute spinal cord injury.[40] The specific parts of the body affected by loss of function are determined by the level of injury. Some signs, such as bowel and bladder dysfunction can occur at any level. Neurogenic bladder involves a compromised ability to empty the bladder and is a common symptom of spinal cord injury. This can lead to high pressures in the bladder that can damage the kidneys.[41] ### Lumbosacral[edit] The effects of injuries at or above the lumbar or sacral regions of the spinal cord (lower back and pelvis) include decreased control of the legs and hips, genitourinary system, and anus. People injured below level L2 may still have use of their hip flexor and knee extensor muscles.[42] Bowel and bladder function are regulated by the sacral region. It is common to experience sexual dysfunction after injury, as well as dysfunction of the bowel and bladder, including fecal and urinary incontinence.[9] ### Thoracic[edit] In addition to the problems found in lower-level injuries, thoracic (chest height) spinal lesions can affect the muscles in the trunk. Injuries at the level of T1 to T8 result in inability to control the abdominal muscles. Trunk stability may be affected; even more so in higher level injuries.[43] The lower the level of injury, the less extensive its effects. Injuries from T9 to T12 result in partial loss of trunk and abdominal muscle control. Thoracic spinal injuries result in paraplegia, but function of the hands, arms, and neck are not affected.[44] One condition that occurs typically in lesions above the T6 level is autonomic dysreflexia (AD), in which the blood pressure increases to dangerous levels, high enough to cause potentially deadly stroke.[8][45] It results from an overreaction of the system to a stimulus such as pain below the level of injury, because inhibitory signals from the brain cannot pass the lesion to dampen the excitatory sympathetic nervous system response.[5] Signs and symptoms of AD include anxiety, headache, nausea, ringing in the ears, blurred vision, flushed skin, and nasal congestion.[5] It can occur shortly after the injury or not until years later.[5] Other autonomic functions may also be disrupted. For example, problems with body temperature regulation mostly occur in injuries at T8 and above.[42] Another serious complication that can result from lesions above T6 is neurogenic shock, which results from an interruption in output from the sympathetic nervous system responsible for maintaining muscle tone in the blood vessels.[5][45] Without the sympathetic input, the vessels relax and dilate.[5][45] Neurogenic shock presents with dangerously low blood pressure, low heart rate, and blood pooling in the limbs—which results in insufficient blood flow to the spinal cord and potentially further damage to it.[46] ### Cervical[edit] Spinal cord injuries at the cervical (neck) level result in full or partial tetraplegia (also called quadriplegia).[24] Depending on the specific location and severity of trauma, limited function may be retained. Additional symptoms of cervical injuries include low heart rate, low blood pressure, problems regulating body temperature, and breathing dysfunction.[47] If the injury is high enough in the neck to impair the muscles involved in breathing, the person may not be able to breathe without the help of an endotracheal tube and mechanical ventilator.[9] Function after complete cervical spinal cord injury[48] Level Motor Function Respiratory function C1–C4 Full paralysis of the limbs Cannot breathe without mechanical ventilation C5 Paralysis of the wrists, hands, and triceps Difficulty coughing, may need help clearing secretions C6 Paralysis of the wrist flexors, triceps, and hands C7–C8 Some hand muscle weakness, difficulty grasping and releasing ### Complications[edit] Complications of spinal cord injuries include pulmonary edema, respiratory failure, neurogenic shock, and paralysis below the injury site. In the long term, the loss of muscle function can have additional effects from disuse, including atrophy of the muscle. Immobility can lead to pressure sores, particularly in bony areas, requiring precautions such as extra cushioning and turning in bed every two hours (in the acute setting) to relieve pressure.[49] In the long term, people in wheelchairs must shift periodically to relieve pressure.[50] Another complication is pain, including nociceptive pain (indication of potential or actual tissue damage) and neuropathic pain, when nerves affected by damage convey erroneous pain signals in the absence of noxious stimuli.[51] Spasticity, the uncontrollable tensing of muscles below the level of injury, occurs in 65–78% of chronic SCI.[52] It results from lack of input from the brain that quells muscle responses to stretch reflexes.[53] It can be treated with drugs and physical therapy.[53] Spasticity increases the risk of contractures (shortening of muscles, tendons, or ligaments that result from lack of use of a limb); this problem can be prevented by moving the limb through its full range of motion multiple times a day.[54] Another problem lack of mobility can cause is loss of bone density and changes in bone structure.[55][56] Loss of bone density (bone demineralization), thought to be due to lack of input from weakened or paralysed muscles, can increase the risk of fractures.[57] Conversely, a poorly understood phenomenon is the overgrowth of bone tissue in soft tissue areas, called heterotopic ossification.[58] It occurs below the level of injury, possibly as a result of inflammation, and happens to a clinically significant extent in 27% of people.[58] Muscle mass is reduced as muscles atrophy with disuse. People with SCI are at especially high risk for respiratory and cardiovascular problems, so hospital staff must be watchful to avoid them.[59] Respiratory problems (especially pneumonia) are the leading cause of death in people with SCI, followed by infections, usually of pressure sores, urinary tract infections and respiratory infections.[60] Pneumonia can be accompanied by shortness of breath, fever, and anxiety.[24] Another potentially deadly threat to respiration is deep venous thrombosis (DVT), in which blood forms a clot in immobile limbs; the clot can break off and form a pulmonary embolism, lodging in the lung and cutting off blood supply to it.[61] DVT is an especially high risk in SCI, particularly within 10 days of injury, occurring in over 13% in the acute care setting.[62] Preventative measures include anticoagulants, pressure hose, and moving the patient's limbs.[62] The usual signs and symptoms of DVT and pulmonary embolism may be masked in SCI cases due to effects such as alterations in pain perception and nervous system functioning.[62] Urinary tract infection (UTI) is another risk that may not display the usual symptoms (pain, urgency, and frequency); it may instead be associated with worsened spasticity.[24] The risk of UTI, likely the most common complication in the long term, is heightened by use of indwelling urinary catheters.[49] Catheterization may be necessary because SCI interferes with the bladder's ability to empty when it gets too full, which could trigger autonomic dysreflexia or damage the bladder permanently.[49] The use of intermittent catheterization to empty the bladder at regular intervals throughout the day has decreased the mortality due to kidney failure from UTI in the first world, but it is still a serious problem in developing countries.[57] An estimated 24–45% of people with SCI suffer disorders of depression, and the suicide rate is as much as six times that of the rest of the population.[63] The risk of suicide is worst in the first five years after injury.[64] In young people with SCI, suicide is the leading cause of death.[65] Depression is associated with an increased risk of other complications such as UTI and pressure ulcers that occur more when self-care is neglected.[65] ## Causes[edit] Falling as a part of recreational activities can cause spinal cord injuries. Spinal cord injuries are most often caused by physical trauma.[21] Forces involved can be hyperflexion (forward movement of the head); hyperextension (backward movement); lateral stress (sideways movement); rotation (twisting of the head); compression (force along the axis of the spine downward from the head or upward from the pelvis); or distraction (pulling apart of the vertebrae).[66] Traumatic SCI can result in contusion, compression, or stretch injury.[4] It is a major risk of many types of vertebral fracture.[67] Pre-existing asymptomatic congenital anomalies can cause major neurological deficits, such as hemiparesis, to result from otherwise minor trauma.[68] In the US, Motor vehicle accidents are the most common cause of SCIs; second are falls, then violence such as gunshot wounds, then sports injuries.[69] In some countries falls are more common, even surpassing vehicle crashes as the leading cause of SCI.[70] The rates of violence-related SCI depend heavily on place and time.[70] Of all sports-related SCIs, shallow water dives are the most common cause; winter sports and water sports have been increasing as causes while association football and trampoline injuries have been declining.[71] Hanging can cause injury to the cervical spine, as may occur in attempted suicide.[72] Military conflicts are another cause, and when they occur they are associated with increased rates of SCI.[73] Another potential cause of SCI is iatrogenic injury, caused by an improperly done medical procedure such as an injection into the spinal column.[74] SCI can also be of a nontraumatic origin. Nontraumatic lesions cause anywhere from 30 to 80% of all SCI;[75] the percentage varies by locale, influenced by efforts to prevent trauma.[76] Developed countries have higher percentages of SCI due to degenerative conditions and tumors than developing countries.[77] In developed countries, the most common cause of nontraumatic SCI is degenerative diseases, followed by tumors; in many developing countries the leading cause is infection such as HIV and tuberculosis.[78] SCI may occur in intervertebral disc disease, and spinal cord vascular disease.[79] Spontaneous bleeding can occur within or outside of the protective membranes that line the cord, and intervertebral disks can herniate.[11] Damage can result from dysfunction of the blood vessels, as in arteriovenous malformation, or when a blood clot becomes lodged in a blood vessel and cuts off blood supply to the cord.[80] When systemic blood pressure drops, blood flow to the spinal cord may be reduced, potentially causing a loss of sensation and voluntary movement in the areas supplied by the affected level of the spinal cord.[81] Congenital conditions and tumors that compress the cord can also cause SCI, as can vertebral spondylosis and ischemia.[4] Multiple sclerosis is a disease that can damage the spinal cord, as can infectious or inflammatory conditions such as tuberculosis, herpes zoster or herpes simplex, meningitis, myelitis, and syphilis.[11] ## Prevention[edit] Vehicle-related SCI is prevented with measures including societal and individual efforts to reduce driving under the influence of drugs or alcohol, distracted driving, and drowsy driving.[82] Other efforts include increasing road safety (such as marking hazards and adding lighting) and vehicle safety, both to prevent accidents (such as routine maintenance and antilock brakes) and to mitigate the damage of crashes (such as head restraints, air bags, seat belts, and child safety seats).[82] Falls can be prevented by making changes to the environment, such as nonslip materials and grab bars in bathtubs and showers, railings for stairs, child and safety gates for windows.[83] Gun-related injuries can be prevented with conflict resolution training, gun safety education campaigns, and changes to the technology of guns (such as trigger locks) to improve their safety.[83] Sports injuries can be prevented with changes to sports rules and equipment to increase safety, and education campaigns to reduce risky practices such as diving into water of unknown depth or head-first tackling in association football.[84] ## Diagnosis[edit] X-rays (left) are more available, but can miss details like herniated disks that MRIs can show (right).[85] A person's presentation in context of trauma or non-traumatic background determines suspicion for a spinal cord injury. The features are namely paralysis, sensory loss, or both at any level. Other symptoms may include incontinence.[86] A radiographic evaluation using an X-ray, CT scan, or MRI can determine if there is damage to the spinal column and where it is located.[9] X-rays are commonly available[85] and can detect instability or misalignment of the spinal column, but do not give very detailed images and can miss injuries to the spinal cord or displacement of ligaments or disks that do not have accompanying spinal column damage.[9] Thus when X-ray findings are normal but SCI is still suspected due to pain or SCI symptoms, CT or MRI scans are used.[85] CT gives greater detail than X-rays, but exposes the patient to more radiation,[87] and it still does not give images of the spinal cord or ligaments; MRI shows body structures in the greatest detail.[9] Thus it is the standard for anyone who has neurological deficits found in SCI or is thought to have an unstable spinal column injury.[88] Neurological evaluations to help determine the degree of impairment are performed initially and repeatedly in the early stages of treatment; this determines the rate of improvement or deterioration and informs treatment and prognosis.[89][90] The ASIA Impairment Scale outlined above is used to determine the level and severity of injury.[9] ## Management[edit] ### Prehospital treatment[edit] Spine motion restriction with a long spine board The first stage in the management of a suspected spinal cord injury is geared toward basic life support and preventing further injury: maintaining airway, breathing, and circulation and restricting further motion of the spine.[23] In the emergency setting, most people who has been subjected to forces strong enough to cause SCI are treated as though they have instability in the spinal column and have spinal motion restricted to prevent damage to the spinal cord.[91] Injuries or fractures in the head, neck, or pelvis as well as penetrating trauma near the spine and falls from heights are assumed to be associated with an unstable spinal column until it is ruled out in the hospital.[9] High-speed vehicle crashes, sports injuries involving the head or neck, and diving injuries are other mechanisms that indicate a high SCI risk.[92] Since head and spinal trauma frequently coexist, anyone who is unconscious or has a lowered level of consciousness as a result of a head injury is spinal motion restricted.[93] A rigid cervical collar is applied to the neck, and the head is held with blocks on either side and the person is strapped to a backboard.[91] Extrication devices are used to move people without excessively moving the spine[94] if they are still inside a vehicle or other confined space. The use of a cervical collar has been shown to increase mortality in people with penetrating trauma and is thus not routinely recommended in this group.[95] Modern trauma care includes a step called clearing the cervical spine, ruling out spinal cord injury if the patient is fully conscious and not under the influence of drugs or alcohol, displays no neurological deficits, has no pain in the middle of the neck and no other painful injuries that could distract from neck pain.[33] If these are all absent, no spinal motion restriction is necessary.[94] If an unstable spinal column injury is moved, damage may occur to the spinal cord.[96] Between 3 and 25% of SCIs occur not at the time of the initial trauma but later during treatment or transport.[23] While some of this is due to the nature of the injury itself, particularly in the case of multiple or massive trauma, some of it reflects the failure to adequately restrict motion of the spine. SCI can impair the body's ability to keep warm, so warming blankets may be needed.[97] ### Early hospital treatment[edit] Initial care in the hospital, as in the prehospital setting, aims to ensure adequate airway, breathing, cardiovascular function, and spinal motion restriction.[98] Imaging of the spine to determine the presence of a SCI may need to wait if emergency surgery is needed to stabilize other life-threatening injuries.[99] Acute SCI merits treatment in an intensive care unit, especially injuries to the cervical spinal cord.[98] People with SCI need repeated neurological assessments and treatment by neurosurgeons.[100] People should be removed from the spine board as rapidly as possible to prevent complications from its use.[101] If the systolic blood pressure falls below 90 mmHg within days of the injury, blood supply to the spinal cord may be reduced, resulting in further damage.[46] Thus it is important to maintain the blood pressure which may be done using intravenous fluids and vasopressors.[102] Vasopressors used include phenylephrine, dopamine, or norepinephrine.[1] Mean arterial blood pressure is measured and kept at 85 to 90 mmHg for seven days after injury.[103] The treatment for shock from blood loss is different from that for neurogenic shock, and could harm people with the latter type, so it is necessary to determine why someone is in shock.[102] However it is also possible for both causes to exist at the same time.[1] Another important aspect of care is prevention of insufficient oxygen in the bloodstream, which could deprive the spinal cord of oxygen.[104] People with cervical or high thoracic injuries may experience a dangerously slowed heart rate; treatment to speed it may include atropine.[1] The corticosteroid medication methylprednisolone has been studied for use in SCI with the hope of limiting swelling and secondary injury.[105] As there does not appear to be long term benefits and the medication is associated with risks such as gastrointestinal bleeding and infection its use is not recommended as of 2018.[1][105] Its use in traumatic brain injury is also not recommended.[101] Surgery may be necessary, e.g. to relieve excess pressure on the cord, to stabilize the spine, or to put vertebrae back in their proper place.[103] In cases involving instability or compression, failing to operate can lead to worsening of the condition.[103] Surgery is also necessary when something is pressing on the cord, such as bone fragments, blood, material from ligaments or intervertebral discs,[106] or a lodged object from a penetrating injury.[85] Although the ideal timing of surgery is still debated, studies have found that earlier surgical intervention (within 24 hours of injury) is associated with better outcomes.[103][107] Sometimes a patient has too many other injuries to be a surgical candidate this early.[103] Surgery is controversial because it has potential complications (such as infection), so in cases where it is not clearly needed (e.g. the cord is being compressed), doctors must decide whether to perform surgery based on aspects of the patient's condition and their own beliefs about its risks and benefits.[108] In cases where a more conservative approach is chosen, bed rest, cervical collars, motion restriction devices, and optionally traction are used.[109] Surgeons may opt to put traction on the spine to remove pressure from the spinal cord by putting dislocated vertebrae back into alignment, but herniation of intervertebral disks may prevent this technique from relieving pressure.[110] Gardner-Wells tongs are one tool used to exert spinal traction to reduce a fracture or dislocation and to reduce motion to the affected areas.[111] ### Rehabilitation[edit] Main article: Rehabilitation in spinal cord injury SCI patients often require extended treatment in specialized spinal unit or an intensive care unit.[112] The rehabilitation process typically begins in the acute care setting. Usually, the inpatient phase lasts 8–12 weeks and then the outpatient rehabilitation phase lasts 3–12 months after that, followed by yearly medical and functional evaluation.[8] Physical therapists, occupational therapists, recreational therapists, nurses, social workers, psychologists, and other health care professionals work as a team under the coordination of a physiatrist[9] to decide on goals with the patient and develop a plan of discharge that is appropriate for the person's condition. Orthopedic devices such as ankle-foot orthoses can aid in walking. In the acute phase physical therapists focus on the patient's respiratory status, prevention of indirect complications (such as pressure ulcers), maintaining range of motion, and keeping available musculature active.[113] For people whose injuries are high enough to interfere with breathing, there is great emphasis on airway clearance during this stage of recovery.[114] Weakness of respiratory muscles impairs the ability to cough effectively, allowing secretions to accumulate within the lungs.[115] As SCI patients suffer from reduced total lung capacity and tidal volume,[116] physical therapists teach them accessory breathing techniques (e.g. apical breathing, glossopharyngeal breathing) that typically are not taught to healthy individuals. Physical therapy treatment for airway clearance may include manual percussions and vibrations, postural drainage,[114] respiratory muscle training, and assisted cough techniques.[115] Patients are taught to increase their intra-abdominal pressure by leaning forward to induce cough and clear mild secretions.[115] The quad cough technique is done lying on the back with the therapist applying pressure on the abdomen in the rhythm of the cough to maximize expiratory flow and mobilize secretions.[115] Manual abdominal compression is another technique used to increase expiratory flow which later improves coughing.[114] Other techniques used to manage respiratory dysfunction include respiratory muscle pacing, use of a constricting abdominal binder, ventilator-assisted speech, and mechanical ventilation.[115] The amount of functional recovery and independence achieved in terms of activities of daily living, recreational activities, and employment is affected by the level and severity of injury.[117] The Functional Independence Measure (FIM) is an assessment tool that aims to evaluate the function of patients throughout the rehabilitation process following a spinal cord injury or other serious illness or injury.[118] It can track a patient's progress and degree of independence during rehabilitation.[118] People with SCI may need to use specialized devices and to make modifications to their environment in order to handle activities of daily living and to function independently. Weak joints can be stabilized with devices such as ankle-foot orthoses (AFOs) and knee-AFOs, but walking may still require a lot of effort.[119] Increasing activity will increase chances of recovery.[120] ## Prognosis[edit] Holly Koester incurred a spinal injury as a result of a motor vehicle collision and is now a wheelchair racer. Spinal cord injuries generally result in at least some incurable impairment even with the best possible treatment. The best predictor of prognosis is the level and completeness of injury, as measured by the ASIA impairment scale.[121] The neurological score at the initial evaluation done 72 hours after injury is the best predictor of how much function will return.[75] Most people with ASIA scores of A (complete injuries) do not have functional motor recovery, but improvement can occur.[121][122] Most patients with incomplete injuries recover at least some function.[122] Chances of recovering the ability to walk improve with each AIS grade found at the initial examination; e.g. an ASIA D score confers a better chance of walking than a score of C.[75] The symptoms of incomplete injuries can vary and it is difficult to make an accurate prediction of the outcome. A person with a mild, incomplete injury at the T5 vertebra will have a much better chance of using his or her legs than a person with a severe, complete injury at exactly the same place. Of the incomplete SCI syndromes, Brown-Séquard and central cord syndromes have the best prognosis for recovery and anterior cord syndrome has the worst.[28] People with nontraumatic causes of SCI have been found to be less likely to suffer complete injuries and some complications such as pressure sores and deep vein thrombosis, and to have shorter hospital stays.[11] Their scores on functional tests were better than those of people with traumatic SCI upon hospital admission, but when they were tested upon discharge, those with traumatic SCI had improved such that both groups' results were the same.[11] In addition to the completeness and level of the injury, age and concurrent health problems affect the extent to which a person with SCI will be able to live independently and to walk.[8] However, in general people with injuries to L3 or below will likely be able to walk functionally, T10 and below to walk around the house with bracing, and C7 and below to live independently.[8] New therapies are beginning to provide hope for better outcomes in patients with SCI, but most are in the experimental/translational stage.[3] One important predictor of motor recovery in an area is presence of sensation there, particularly pain perception.[36] Most motor recovery occurs in the first year post-injury, but modest improvements can continue for years; sensory recovery is more limited.[123] Recovery is typically quickest during the first six months.[124] Spinal shock, in which reflexes are suppressed, occurs immediately after the injury and resolves largely within three months but continues resolving gradually for another 15.[125] Sexual dysfunction after spinal injury is common. Problems that can occur include erectile dysfunction, loss of ability to ejaculate, insufficient lubrication of the vagina, and reduced sensation and impaired ability to orgasm.[52] Despite this, many people learn ways to adapt their sexual practices so they can lead satisfying sex lives.[126] Although life expectancy has improved with better care options, it is still not as good as the uninjured population. The higher the level of injury, and the more complete the injury, the greater the reduction in life expectancy.[80] Mortality is very elevated within a year of injury.[80] ## Epidemiology[edit] Breakdown of age at time of injury in the US from 1995–1999.[127] 0–15 (3.0%) 16–30 (42.1%) 31–45 (28.1%) 46–60 (15.1%) 61–75 (8.5%) 76+ (3.2%) Worldwide, the number of new cases since 1995 of SCI ranges from 10.4 to 83 people per million per year.[103] This wide range of numbers is probably partly due to differences among regions in whether and how injuries are reported.[103] In North America, about 39 people per every million incur SCI traumatically each year, and in Western Europe, the incidence is 16 per million.[107][128] In the United States, the incidence of spinal cord injury has been estimated to be about 40 cases per 1 million people per year or around 12,000 cases per year.[129] In China, the incidence is approximately 60,000 per year.[130] The estimated number of people living with SCI in the world ranges from 236 to 4187 per million.[103] Estimates vary widely due to differences in how data are collected and what techniques are used to extrapolate the figures.[131] Little information is available from Asia, and even less from Africa and South America.[103] In Western Europe the estimated prevalence is 300 per million people and in North America it is 853 per million.[128] It is estimated at 440 per million in Iran, 526 per million in Iceland, and 681 per million in Australia.[131] In the United States there are between 225,000 and 296,000 individuals living with spinal cord injuries,[132] and different studies have estimated prevalences from 525 to 906 per million.[131] SCI is present in about 2% of all cases of blunt force trauma.[96] Anyone who has undergone force sufficient to cause a thoracic spinal injury is at high risk for other injuries also.[99] In 44% of SCI cases, other serious injuries are sustained at the same time; 14% of SCI patients also suffer head trauma or facial trauma.[21] Other commonly associated injuries include chest trauma, abdominal trauma, pelvic fractures, and long bone fractures.[90] Males account for four out of five traumatic spinal cord injuries.[24] Most of these injuries occur in men under 30 years of age.[9] The average age at the time of injury has slowly increased from about 29 years in the 1970s to 41.[24] Rates of injury are at their lowest in children, at their highest in the late teens to early twenties, then get progressively lower in older age groups; however rates may rise in the elderly.[133] In Sweden between 50 and 70% of all cases of SCI occur in people under 30, and 25% occur in those over 50.[70] While SCI rates are highest among people age 15–20,[134] fewer than 3% of SCIs occur in people under 15.[135] Neonatal SCI occurs in one in 60,000 births, e.g. from breech births or injuries by forceps.[136] The difference in rates between the sexes diminishes in injuries at age 3 and younger; the same number of girls are injured as boys, or possibly more.[137] Another cause of pediatric injury is child abuse such as shaken baby syndrome.[136] For children, the most common cause of SCI (56%) is vehicle crashes.[138] High numbers of adolescent injuries are attributable in a large part to traffic accidents and sports injuries.[139] For people over 65, falls are the most common cause of traumatic SCI.[4] The elderly and people with severe arthritis are at high risk for SCI because of defects in the spinal column.[140] In nontraumatic SCI, the gender difference is smaller, the average age of occurrence is greater, and incomplete lesions are more common.[75] ## History[edit] The ancient Egyptian Edwin Smith Papyrus is the earliest known description of SCI.[141] SCI has been known to be devastating for millennia; the ancient Egyptian Edwin Smith Papyrus from 2500 BC, the first known description of the injury, says it is "not to be treated".[141] Hindu texts dating back to 1800 BC also mention SCI and describe traction techniques to straighten the spine.[141] The Greek physician Hippocrates, born in the fifth century BC, described SCI in his Hippocratic Corpus and invented traction devices to straighten dislocated vertebrae.[142] But it was not until Aulus Cornelius Celsus, born 30 BC, noted that a cervical injury resulted in rapid death that the spinal cord itself was implicated in the condition.[141] In the second century AD the Greek physician Galen experimented on monkeys and reported that a horizontal cut through the spinal cord caused them to lose all sensation and motion below the level of the cut.[143] The seventh-century Greek physician Paul of Aegina described surgical techniques for treatment of broken vertebrae by removing bone fragments, as well as surgery to relieve pressure on the spine.[141] Little medical progress was made during the Middle Ages in Europe; it was not until the Renaissance that the spine and nerves were accurately depicted in human anatomy drawings by Leonardo da Vinci and Andreas Vesalius.[143] In 1762 a surgeon named Andre Louis removed a bullet from the lumbar spine of a patient, who regained motion in the legs.[143] In 1829 the surgeon Gilpin Smith performed a successful laminectomy that improved the patient's sensation.[144] However, the idea that SCI was untreatable remained predominant until the early 20th century.[145] In 1934, the mortality rate in the first two years after injury was over 80%, mostly due to infections of the urinary tract and pressure sores.[146] It was not until the latter half of the century that breakthroughs in imaging, surgery, medical care, and rehabilitation medicine contributed to a substantial improvement in SCI care.[145] The relative incidence of incomplete compared to complete injuries has improved since the mid-20th century, due mainly to the emphasis on faster and better initial care and stabilization of spinal cord injury patients.[147] The creation of emergency medical services to professionally transport people to the hospital is given partial credit for an improvement in outcomes since the 1970s.[148] Improvements in care have been accompanied by increased life expectancy of people with SCI; survival times have improved by about 2000% since 1940.[149] In 2015/2016 23% of people in nine spinal injury centres in England had their discharge delayed because of disputes about who should pay for the equipment they needed.[150] ## Research directions[edit] Main article: Spinal cord injury research Scientists are investigating various avenues for treatment of spinal cord injury. Therapeutic research is focused on two main areas: neuroprotection and neuroregeneration.[73] The former seeks to prevent the harm that occurs from secondary injury in the minutes to weeks following the insult, and the latter aims to reconnect the broken circuits in the spinal cord to allow function to return.[73] Neuroprotective drugs target secondary injury effects including inflammation, damage by free radicals, excitotoxicity (neuronal damage by excessive glutamate signaling), and apoptosis (cell suicide).[73] Several potentially neuroprotective agents that target pathways like these are under investigation in human clinical trials.[73] Human bone marrow derived mesenchymal stem cells seen under phase contrast microscope (63 x magnification) Stem cell transplantation is an important avenue for SCI research: the goal is to replace lost spinal cord cells, allow reconnection in broken neural circuits by regrowing axons, and to create an environment in the tissues that is favorable to growth.[73] A key avenue of SCI research is research on stem cells, which can differentiate into other types of cells—including those lost after SCI.[73] Types of cells being researched for use in SCI include embryonic stem cells, neural stem cells, mesenchymal stem cells, olfactory ensheathing cells, Schwann cells, activated macrophages, and induced pluripotent stem cells.[151] Hundreds of stem cell studies have been done in humans, with promising but inconclusive results.[139] An ongoing Phase 2 trial in 2016 presented data[152] showing that after 90 days, 2 out of 4 subjects had already improved two motor levels and had thus already achieved its endpoint of 2/5 patients improving two levels within 6–12 months. Six-month data is expected in January 2017.[153] Another type of approach is tissue engineering, using biomaterials to help scaffold and rebuild damaged tissues.[73] Biomaterials being investigated include natural substances such as collagen or agarose and synthetic ones like polymers and nitrocellulose.[73] They fall into two categories: hydrogels and nanofibers.[73] These materials can also be used as a vehicle for delivering gene therapy to tissues.[73] One avenue being explored to allow paralyzed people to walk and to aid in rehabilitation of those with some walking ability is the use of wearable powered robotic exoskeletons.[154] The devices, which have motorized joints, are put on over the legs and supply a source of power to move and walk.[154] Several such devices are already available for sale, but investigation is still underway as to how they can be made more useful.[154] Preliminary studies of epidural spinal cord stimulators for motor complete injuries have demonstrated some improvement.[155] In 2014 Darek Fidyka underwent pioneering spinal surgery that used nerve grafts, from his ankle, to 'bridge the gap' in his severed spinal cord and olfactory ensheathing cells (OECs) to stimulate the spinal cord cells. The surgery was performed in Poland in collaboration with Prof. Geoff Raisman, chair of neural regeneration at University College London's Institute of Neurology, and his research team. The OECs were taken from the patient's olfactory bulbs in his brain and then grown in the lab, these cells were then injected above and below the impaired spinal tissue.[156] ## See also[edit] * Paralyzed Veterans of America ## References[edit] 1. ^ a b c d e f g h i j k ATLS – Advanced Trauma Life Support – Student Course Manual (10th ed.). American College of Surgeons. 2018. pp. 129–144. ISBN 9780996826235. 2. ^ a b c "Spinal Cord Injury Facts and Figures at a Glance" (PDF). 2012. Retrieved 16 May 2018. 3. ^ a b Krucoff MO, Miller JP, Saxena T, Bellamkonda R, Rahimpour S, Harward SC, Lad SP, Turner DA (January 2019). "Toward Functional Restoration of the Central Nervous System: A Review of Translational Neuroscience Principles". Neurosurgery. 84 (1): 30–40. doi:10.1093/neuros/nyy128. PMC 6292792. PMID 29800461. 4. ^ a b c d Sabapathy V, Tharion G, Kumar S (2015). "Cell Therapy Augments Functional Recovery Subsequent to Spinal Cord Injury under Experimental Conditions". Stem Cells International. 2015: 1–12. doi:10.1155/2015/132172. PMC 4512598. PMID 26240569. 5. ^ a b c d e f Newman, Fleisher & Fink 2008, p. 348. 6. ^ a b Newman, Fleisher & Fink 2008, p. 335. 7. ^ Yu WY, He DW (September 2015). "Current trends in spinal cord injury repair" (PDF). European Review for Medical and Pharmacological Sciences. 19 (18): 3340–4. PMID 26439026. Archived (PDF) from the original on 2015-12-08. 8. ^ a b c d e Cifu & Lew 2013, p. 197. 9. ^ a b c d e f g h i j k Office of Communications and Public Liaison, National Institute of Neurological Disorders and Stroke, ed. (2013). Spinal Cord Injury: Hope Through Research. National Institutes of Health. Archived from the original on 2015-11-19. 10. ^ Miller & Marini 2012, p. 138. 11. ^ a b c d e Field-Fote 2009, p. 5. 12. ^ Marino RJ, Barros T, Biering-Sorensen F, Burns SP, Donovan WH, Graves DE, Haak M, Hudson LM, Priebe MM (2003). "International standards for neurological classification of spinal cord injury". The Journal of Spinal Cord Medicine. 26 Suppl 1: S50–6. doi:10.1080/10790268.2003.11754575. PMID 16296564. 13. ^ a b "Standard Neurological Classification of Spinal Cord Injury" (PDF). American Spinal Injury Association & ISCOS. Archived from the original on June 18, 2011. Retrieved 5 November 2015.CS1 maint: unfit URL (link) 14. ^ a b Weiss 2010, p. 307. 15. ^ Harvey 2008, p. 7. 16. ^ Teufack, Harrop & Ashwini 2012, p. 67. 17. ^ Field-Fote, pp. 7–8. sfn error: no target: CITEREFField-Fote (help) 18. ^ a b Ho CH, Wuermser LA, Priebe MM, Chiodo AE, Scelza WM, Kirshblum SC (March 2007). "Spinal cord injury medicine. 1. Epidemiology and classification". Archives of Physical Medicine and Rehabilitation. 88 (3 Suppl 1): S49–54. doi:10.1016/j.apmr.2006.12.001. PMID 17321849. 19. ^ Sabharwal 2014, p. 840. 20. ^ a b Lafuente DJ, Andrew J, Joy A (June 1985). "Sacral sparing with cauda equina compression from central lumbar intervertebral disc prolapse". Journal of Neurology, Neurosurgery, and Psychiatry. 48 (6): 579–81. doi:10.1136/jnnp.48.6.579. PMC 1028376. PMID 4009195. 21. ^ a b c Peitzman, Fabian & Rhodes 2012, p. 288. sfn error: no target: CITEREFPeitzmanFabianRhodes2012 (help) 22. ^ Peitzman, Fabian & Rhodes 2012, pp. 288–89. sfn error: no target: CITEREFPeitzmanFabianRhodes2012 (help) 23. ^ a b c Peitzman, Fabian & Rhodes 2012, p. 289. sfn error: no target: CITEREFPeitzmanFabianRhodes2012 (help) 24. ^ a b c d e f Sabharwal 2014, p. 839. 25. ^ a b c d Snell 2010, p. 170. 26. ^ a b c Namdari, Pill & Mehta 2014, p. 297. 27. ^ a b Marx, Walls & Hockberger 2013, p. 1420. sfn error: no target: CITEREFMarxWallsHockberger2013 (help) 28. ^ a b Field-Fote 2009, p. 9. 29. ^ a b c d e f Field-Fote 2009, p. 10. 30. ^ Snell 2010, p. 171. 31. ^ Roos 2012, pp. 249–50. 32. ^ Ilyas & Rehman 2013, p. 389. 33. ^ a b c Peitzman, Fabian & Rhodes 2012, p. 294. sfn error: no target: CITEREFPeitzmanFabianRhodes2012 (help) 34. ^ Snell 2010, p. 167. 35. ^ a b c d Marx, Walls & Hockberger 2013, p. 1422. sfn error: no target: CITEREFMarxWallsHockberger2013 (help) 36. ^ a b c d e Field-Fote 2009, p. 11. 37. ^ Augustine 2011, p. 199. 38. ^ Sabharwal 2013, p. 39. 39. ^ Snell 2010, p. 169. 40. ^ Augustine 2011, p. 200. 41. ^ Schurch, Brigitte; Tawadros, Cécile; Carda, Stefano (2015), "Dysfunction of lower urinary tract in patients with spinal cord injury", Handbook of Clinical Neurology, Elsevier, 130: 247–267, doi:10.1016/b978-0-444-63247-0.00014-6, ISBN 9780444632470, PMID 26003248 42. ^ a b Weiss 2010, p. 313. 43. ^ Weiss 2010, pp. 311, 313. 44. ^ Weiss 2010, p. 311. 45. ^ a b c Dimitriadis F, Karakitsios K, Tsounapi P, Tsambalas S, Loutradis D, Kanakas N, Watanabe NT, Saito M, Miyagawa I, Sofikitis N (June 2010). "Erectile function and male reproduction in men with spinal cord injury: a review". Andrologia. 42 (3): 139–65. doi:10.1111/j.1439-0272.2009.00969.x. PMID 20500744. 46. ^ a b Holtz & Levi 2010, p. 63. 47. ^ Sabharwal 2013, pp. 53–54. 48. ^ Sabharwal 2014, p. 843. 49. ^ a b c Holtz & Levi 2010, p. 70. 50. ^ Weiss 2010, p. 314–15. 51. ^ Field-Fote 2009, p. 17. 52. ^ a b Hess MJ, Hough S (July 2012). "Impact of spinal cord injury on sexuality: broad-based clinical practice intervention and practical application". The Journal of Spinal Cord Medicine. 35 (4): 211–8. doi:10.1179/2045772312Y.0000000025. PMC 3425877. PMID 22925747. 53. ^ a b Selzer, M.E. (January 2010). Spinal Cord Injury. ReadHowYouWant.com. pp. 23–24. ISBN 978-1-4587-6331-0. Archived from the original on 2014-07-07. 54. ^ Weiss 2010, p. 315. 55. ^ Frontera, Silver & Rizzo 2014, p. 407. 56. ^ Qin W, Bauman WA, Cardozo C (November 2010). "Bone and muscle loss after spinal cord injury: organ interactions". Annals of the New York Academy of Sciences. 1211 (1): 66–84. Bibcode:2010NYASA1211...66Q. doi:10.1111/j.1749-6632.2010.05806.x. PMID 21062296. 57. ^ a b Field-Fote 2009, p. 16. 58. ^ a b Field-Fote 2009, p. 15. 59. ^ Fehlings MG, Cadotte DW, Fehlings LN (August 2011). "A series of systematic reviews on the treatment of acute spinal cord injury: a foundation for best medical practice". Journal of Neurotrauma. 28 (8): 1329–33. doi:10.1089/neu.2011.1955. PMC 3143392. PMID 21651382. 60. ^ Sabharwal 2013, p. 26. 61. ^ Field-Fote 2009, p. 13. 62. ^ a b c Holtz & Levi 2010, p. 69. 63. ^ Burns SM, Mahalik JR, Hough S, Greenwell AN (2008). "Adjustment to changes in sexual functioning following spinal cord injury: The contribution of men's adherence to scripts for sexual potency". Sexuality and Disability. 26 (4): 197–205. doi:10.1007/s11195-008-9091-y. ISSN 0146-1044. 64. ^ Sabharwal 2013, p. 27. 65. ^ a b Pollard C, Kennedy P (September 2007). "A longitudinal analysis of emotional impact, coping strategies and post-traumatic psychological growth following spinal cord injury: a 10-year review". British Journal of Health Psychology. 12 (Pt 3): 347–62. doi:10.1348/135910707X197046. PMID 17640451. 66. ^ Augustine 2011, p. 198. 67. ^ Clark West, Stefan Roosendaal, Joost Bot and Frank Smithuis. "Spine injury – TLICS Classification". Radiology Assistant. Archived from the original on 2017-10-27. Retrieved 2017-10-26.CS1 maint: multiple names: authors list (link) 68. ^ Kuchner EF, Anand AK, Kaufman BM (April 1985). "Cervical diastematomyelia: a case report with operative management". Neurosurgery. 16 (4): 538–42. doi:10.1097/00006123-198504000-00016. PMID 3990933. 69. ^ Sabharwal 2013, pp. 24–25. 70. ^ a b c Holtz & Levi 2010, p. 10. 71. ^ Sabharwal 2013, p. 34. 72. ^ Brown et al. 2008, p. 1132. 73. ^ a b c d e f g h i j k Kabu S, Gao Y, Kwon BK, Labhasetwar V (December 2015). "Drug delivery, cell-based therapies, and tissue engineering approaches for spinal cord injury". Journal of Controlled Release. 219: 141–154. doi:10.1016/j.jconrel.2015.08.060. PMC 4656085. PMID 26343846. 74. ^ Frontera, Silver & Rizzo 2014, p. 39. 75. ^ a b c d Scivoletto G, Tamburella F, Laurenza L, Torre M, Molinari M (2014). "Who is going to walk? A review of the factors influencing walking recovery after spinal cord injury". Frontiers in Human Neuroscience. 8: 141. doi:10.3389/fnhum.2014.00141. PMC 3952432. PMID 24659962. 76. ^ Celani MG, Spizzichino L, Ricci S, Zampolini M, Franceschini M (May 2001). "Spinal cord injury in Italy: A multicenter retrospective study". Archives of Physical Medicine and Rehabilitation. 82 (5): 589–96. doi:10.1053/apmr.2001.21948. PMID 11346833. 77. ^ New PW, Cripps RA, Bonne Lee B (February 2014). "Global maps of non-traumatic spinal cord injury epidemiology: towards a living data repository". Spinal Cord. 52 (2): 97–109. doi:10.1038/sc.2012.165. PMID 23318556. 78. ^ Sabharwal 2013, p. 24. 79. ^ van den Berg ME, Castellote JM, de Pedro-Cuesta J, Mahillo-Fernandez I (August 2010). "Survival after spinal cord injury: a systematic review". Journal of Neurotrauma. 27 (8): 1517–28. doi:10.1089/neu.2009.1138. PMID 20486810. 80. ^ a b c Fulk, Behrman & Schmitz 2013, p. 890. 81. ^ Moore 2006, pp. 530–31. 82. ^ a b Sabharwal 2013, p. 31. 83. ^ a b Sabharwal 2013, p. 32. 84. ^ Sabharwal 2013, p. 33. 85. ^ a b c d Wyatt et al. 2012, p. 384. 86. ^ "How is SCI diagnosed?". National Institute of Child Health and Human Development. 2016. Retrieved 2019-01-01. 87. ^ Holtz & Levi 2010, p. 78. 88. ^ DeKoning 2014, p. 389. 89. ^ Holtz & Levi 2010, pp. 64–65. 90. ^ a b Sabharwal 2013, p. 55. 91. ^ a b Sabharwal 2013, p. 38. 92. ^ Augustine 2011, p. 207. 93. ^ Cameron et al. 2014. 94. ^ a b Sabharwal 2013, p. 37. 95. ^ "EMS spinal precautions and the use of the long backboard" (PDF). Prehospital Emergency Care. 17 (3): 392–3. 2013. doi:10.3109/10903127.2013.773115. PMID 23458580. 96. ^ a b Ahn H, Singh J, Nathens A, MacDonald RD, Travers A, Tallon J, Fehlings MG, Yee A (August 2011). "Pre-hospital care management of a potential spinal cord injured patient: a systematic review of the literature and evidence-based guidelines". Journal of Neurotrauma. 28 (8): 1341–61. doi:10.1089/neu.2009.1168. PMC 3143405. PMID 20175667. 97. ^ Cameron & Jelinek 2014. sfn error: no target: CITEREFCameronJelinek2014 (help) 98. ^ a b Sabharwal 2013, p. 53. 99. ^ a b Bigelow & Medzon 2011, p. 173. 100. ^ DeKoning 2014, p. 373. 101. ^ a b Campbell J (2018). International Trauma Life Support for Emergency Care Providers (8th Global ed.). Pearson. pp. 221–248. ISBN 9781292170848. 102. ^ a b Holtz & Levi 2010, pp. 63–64. 103. ^ a b c d e f g h i Witiw CD, Fehlings MG (July 2015). "Acute Spinal Cord Injury". Journal of Spinal Disorders & Techniques. 28 (6): 202–10. doi:10.1097/BSD.0000000000000287. PMID 26098670. 104. ^ Bigelow & Medzon 2011, pp. 167, 176. 105. ^ a b Rouanet C, Reges D, Rocha E, Gagliardi V, Silva GS (June 2017). "Traumatic spinal cord injury: current concepts and treatment update". Arquivos de Neuro-Psiquiatria. 75 (6): 387–393. doi:10.1590/0004-282X20170048. PMID 28658409. 106. ^ Holtz & Levi 2010, p. 65. 107. ^ a b Liu JM, Long XH, Zhou Y, Peng HW, Liu ZL, Huang SH (March 2016). "Is Urgent Decompression Superior to Delayed Surgery for Traumatic Spinal Cord Injury? A Meta-Analysis". World Neurosurgery. 87: 124–31. doi:10.1016/j.wneu.2015.11.098. PMID 26724625. 108. ^ Holtz & Levi 2010, pp. 65–69. 109. ^ Holtz & Levi 2010, p. 67. 110. ^ Bigelow & Medzon 2011, p. 177. 111. ^ Krag MH, Byrt W, Pope M (March 1989). "Pull-off strength of gardner-Wells tongs from cadaveric crania". Spine. 14 (3): 247–50. doi:10.1097/00007632-198903000-00001. PMID 2711238. 112. ^ "Management of acute spinal cord injuries in an intensive care unit or other monitored setting". Neurosurgery. 50 (3 Suppl): S51–7. March 2002. doi:10.1097/00006123-200203001-00011. PMID 12431287. 113. ^ Fulk G; Schmitz T; Behrman A (2007). "Traumatic Spinal Cord Injury". In O'Sullivan S; Schmitz T (eds.). Physical Rehabilitation (5th ed.). Philadelphia: F.A. Davis. pp. 937–96. 114. ^ a b c Reid WD, Brown JA, Konnyu KJ, Rurak JM, Sakakibara BM (2010). "Physiotherapy secretion removal techniques in people with spinal cord injury: a systematic review". The Journal of Spinal Cord Medicine. 33 (4): 353–70. doi:10.1080/10790268.2010.11689714. PMC 2964024. PMID 21061895. 115. ^ a b c d e Brown R, DiMarco AF, Hoit JD, Garshick E (August 2006). "Respiratory dysfunction and management in spinal cord injury". Respiratory Care. 51 (8): 853–68, discussion 869–70. PMC 2495152. PMID 16867197. 116. ^ Winslow C, Rozovsky J (October 2003). "Effect of spinal cord injury on the respiratory system". American Journal of Physical Medicine & Rehabilitation. 82 (10): 803–14. doi:10.1097/01.PHM.0000078184.08835.01. PMID 14508412. 117. ^ Weiss 2010, p. 306. 118. ^ a b Chumney D, Nollinger K, Shesko K, Skop K, Spencer M, Newton RA (2010). "Ability of Functional Independence Measure to accurately predict functional outcome of stroke-specific population: systematic review". Journal of Rehabilitation Research and Development. 47 (1): 17–29. doi:10.1682/JRRD.2009.08.0140. PMID 20437324. 119. ^ del-Ama AJ, Koutsou AD, Moreno JC, de-los-Reyes A, Gil-Agudo A, Pons JL (2012). "Review of hybrid exoskeletons to restore gait following spinal cord injury". Journal of Rehabilitation Research and Development. 49 (4): 497–514. doi:10.1682/JRRD.2011.03.0043. PMID 22773254. 120. ^ Frood RT (2011). "The use of treadmill training to recover locomotor ability in patients with spinal cord injury". Bioscience Horizons. 4: 108–117. doi:10.1093/biohorizons/hzr003. 121. ^ a b Peitzman, Fabian & Rhodes 2012, p. 293. sfn error: no target: CITEREFPeitzmanFabianRhodes2012 (help) 122. ^ a b Waters RL, Adkins RH, Yakura JS (November 1991). "Definition of complete spinal cord injury". Paraplegia. 29 (9): 573–81. doi:10.1038/sc.1991.85. PMID 1787981. 123. ^ Field-Fote 2009, p. 8. 124. ^ Yakura, J.S. (Dec 22, 1996). "Recovery following spinal cord injury". American Rehabilitation. Retrieved 5 November 2015. 125. ^ Cortois & Charvier 2015, p. 236. 126. ^ Elliott 2010. 127. ^ Data from the National Spinal Cord Injury Statistical Center. Committee on Spinal Cord Injury; Board on Neuroscience and Behavioral Health; Institute of Medicine (27 July 2005). Spinal Cord Injury: Progress, Promise, and Priorities. National Academies Press. p. 15. ISBN 978-0-309-16520-4. Archived from the original on 6 November 2017. 128. ^ a b Chéhensse C, Bahrami S, Denys P, Clément P, Bernabé J, Giuliano F (2013). "The spinal control of ejaculation revisited: a systematic review and meta-analysis of anejaculation in spinal cord injured patients". Human Reproduction Update. 19 (5): 507–26. doi:10.1093/humupd/dmt029. PMID 23820516. 129. ^ "Spinal Cord Injury Facts". Foundation for Spinal Cord Injury Prevention, Care & Cure. June 2009. Archived from the original on 2 November 2015. Retrieved 5 November 2015. 130. ^ Qiu J (July 2009). "China Spinal Cord Injury Network: changes from within". The Lancet. Neurology. 8 (7): 606–7. doi:10.1016/S1474-4422(09)70162-0. PMID 19539234. 131. ^ a b c Singh A, Tetreault L, Kalsi-Ryan S, Nouri A, Fehlings MG (2014). "Global prevalence and incidence of traumatic spinal cord injury". Clinical Epidemiology. 6: 309–31. doi:10.2147/CLEP.S68889. PMC 4179833. PMID 25278785. 132. ^ Field-Fote 2009, p. 3. 133. ^ Devivo MJ (May 2012). "Epidemiology of traumatic spinal cord injury: trends and future implications". Spinal Cord. 50 (5): 365–72. doi:10.1038/sc.2011.178. PMID 22270188. 134. ^ Pellock & Myer 2013, p. 124. 135. ^ Hammell 2013, p. 274. 136. ^ a b Sabharwal 2013, p. 388. 137. ^ Schottler J, Vogel LC, Sturm P (December 2012). "Spinal cord injuries in young children: a review of children injured at 5 years of age and younger". Developmental Medicine and Child Neurology. 54 (12): 1138–43. doi:10.1111/j.1469-8749.2012.04411.x. PMID 22998495. 138. ^ Augustine 2011, p. 197. 139. ^ a b Aghayan HR, Arjmand B, Yaghoubi M, Moradi-Lakeh M, Kashani H, Shokraneh F (2014). "Clinical outcome of autologous mononuclear cells transplantation for spinal cord injury: a systematic review and meta-analysis". Medical Journal of the Islamic Republic of Iran. 28: 112. PMC 4313447. PMID 25678991. 140. ^ Augustine 2011, pp. 197–98. 141. ^ a b c d e Lifshutz J, Colohan A (January 2004). "A brief history of therapy for traumatic spinal cord injury". Neurosurgical Focus. 16 (1): E5. doi:10.3171/foc.2004.16.1.6. PMID 15264783. 142. ^ Holtz & Levi 2010, pp. 3–4. 143. ^ a b c Holtz & Levi 2010, p. 5. 144. ^ Holtz & Levi 2010, p. 6. 145. ^ a b Morganti-Kossmann, Raghupathi & Maas 2012, p. 229. 146. ^ Fallah, Dance & Burns 2012, p. 235. 147. ^ Sekhon LH, Fehlings MG (December 2001). "Epidemiology, demographics, and pathophysiology of acute spinal cord injury". Spine. 26 (24 Suppl): S2–12. doi:10.1097/00007632-200112151-00002. PMID 11805601. 148. ^ Sabharwal 2013, p. 35. 149. ^ Holtz & Levi 2010, p. 7. 150. ^ "Revealed: Patients stranded in hospital for months as officials 'squabble' over equipment". Health Service Journal. 12 January 2018. Retrieved 15 February 2018. 151. ^ Silva NA, Sousa N, Reis RL, Salgado AJ (March 2014). "From basics to clinical: a comprehensive review on spinal cord injury". Progress in Neurobiology. 114: 25–57. doi:10.1016/j.pneurobio.2013.11.002. PMID 24269804. 152. ^ Wirth, Edward (September 14, 2016). "Initial Clinical Trials of hESC-Derived Oligodendrocyte Progenitor Cells in Subacute Spinal Cord Injury" (PDF). ISCoS Meeting presentation. Asterias Biotherapeutics. Archived (PDF) from the original on September 21, 2016. Retrieved September 14, 2016. 153. ^ "Asterias Biotherapeutics Announces Positive Efficacy Data in Patients with Complete Cervical Spinal Cord Injuries Treated with AST-OPC1". asteriasbiotherapeutics.com. Archived from the original on 2016-09-20. Retrieved 2016-09-15. 154. ^ a b c Louie DR, Eng JJ, Lam T (October 2015). "Gait speed using powered robotic exoskeletons after spinal cord injury: a systematic review and correlational study". Journal of Neuroengineering and Rehabilitation. 12: 82. doi:10.1186/s12984-015-0074-9. PMC 4604762. PMID 26463355. 155. ^ Young W (2015). "Electrical stimulation and motor recovery". Cell Transplantation. 24 (3): 429–46. doi:10.3727/096368915X686904. PMID 25646771. 156. ^ https://www.theguardian.com/science/2014/oct/21/paralysed-darek-fidyka-pioneering-surgery ## Bibliography[edit] * Adams JG (5 September 2012). Emergency Medicine: Clinical Essentials. Elsevier Health Sciences. ISBN 978-1-4557-3394-1. * Augustine JJ (21 November 2011). "Spinal trauma". In Campbell JR (ed.). International Trauma Life Support for Emergency Care Providers. Pearson Education. ISBN 978-0-13-300408-3. * Bigelow S, Medzon R (16 June 2011). "Injuries of the spine: Nerve". In Legome E, Shockley LW (eds.). Trauma: A Comprehensive Emergency Medicine Approach. Cambridge University Press. ISBN 978-1-139-50072-2. * Brown J, Wyatt JP, Illingworth RN, Clancy MJ, Munro P (6 June 2008). Oxford American Handbook of Emergency Medicine. Oxford University Press. ISBN 978-0-19-977948-2. * Cameron P, Jelinek G, Kelly AM, Brown AF, Little M (1 April 2014). Textbook of Adult Emergency Medicine: Expert Consult. Elsevier Health Sciences UK. ISBN 978-0-7020-5438-9. * Cifu DK, Lew HL (10 September 2013). Handbook of Polytrauma Care and Rehabilitation. Demos Medical Publishing. ISBN 978-1-61705-100-5. * Cortois F, Charvier K (21 May 2015). "Sexual dysfunction in patients with spinal cord lesions". In Vodusek DB, Boller F (eds.). Neurology of Sexual and Bladder Disorders: Handbook of Clinical Neurology. Elsevier Science. ISBN 978-0-444-63254-8. * DeKoning EP (10 January 2014). "Cervical spine injuries". In Sherman, S., Weber, J., Schindlbeck, M., Patwari, R. (eds.). Clinical Emergency Medicine. McGraw-Hill Education. ISBN 978-0-07-179461-9. * Elliott S (19 March 2010). "Sexual dysfunction in women with spinal cord injury". In Bono CM, Cardenas DD, Frost FS (eds.). Spinal Cord Medicine, Second Edition: Principles & Practice. Demos Medical Publishing. pp. 429–38. ISBN 978-1-935281-77-1. * Field-Fote E (26 March 2009). "Spinal cord injury: An overview". In Field-Fote E (ed.). Spinal Cord Injury Rehabilitation. F.A. Davis. ISBN 978-0-8036-2319-4. * Fallah A, Dance D, Burns AS (29 October 2012). "Rehabilitation of the individual with spinal cord injury". In Fehlings, M.G., Vaccaro, A.R., Maxwell B. (eds.). Essentials of Spinal Cord Injury: Basic Research to Clinical Practice. Thieme. ISBN 978-1-60406-727-9. * Frontera WR, Silver JK, Rizzo TD (5 September 2014). Essentials of Physical Medicine and Rehabilitation. Elsevier Health Sciences. ISBN 978-0-323-22272-3. * Fulk GD, Behrman AL, Schmitz TJ (23 July 2013). "Traumatic Spinal Cord Injury". In O'Sullivan S, Schmitz T (eds.). Physical Rehabilitation. F.A. Davis. ISBN 978-0-8036-4058-0. * Hammell KW (11 December 2013). Spinal Cord Injury Rehabilitation. Springer. ISBN 978-1-4899-4451-1. * Harvey L (2008). Management of Spinal Cord Injuries: A Guide for Physiotherapists. Elsevier Health Sciences. ISBN 978-0-443-06858-4. * Holtz A, Levi R (6 July 2010). Spinal Cord Injury. Oxford University Press. ISBN 978-0-19-970681-5. * Ilyas A, Rehman S (31 March 2013). Contemporary Surgical Management of Fractures and Complications. JP Medical Ltd. ISBN 978-93-5025-964-1. * Marx J, Walls R (1 August 2013). Rosen's Emergency Medicine: Concepts and Clinical Practice. Elsevier Health Sciences. ISBN 978-1-4557-4987-4. * Miller E, Marini I (24 February 2012). "Sexuality and spinal cord injury counseling implications". In Marini I, Stebnicki MA (eds.). The Psychological and Social Impact of Illness and Disability, 6th Edition. Springer Publishing Company. ISBN 978-0-8261-0655-1. * Moore K (2006). Clinically Oriented Anatomy. Lippincott Williams & Wilkins. ISBN 978-0-7817-3639-8. * Morganti-Kossmann C, Raghupathi R, Maas A (19 July 2012). Traumatic Brain and Spinal Cord Injury: Challenges and Developments. Cambridge University Press. ISBN 978-1-107-00743-7. * Namdari S, Pill S, Mehta S (21 October 2014). Orthopedic Secrets. Elsevier Health Sciences. ISBN 978-0-323-17285-1. * Newman MF, Fleisher LA, Fink MP (2008). Perioperative Medicine: Managing for Outcome. Elsevier Health Sciences. ISBN 978-1-4160-2456-9. * Peitzman AB, Fabian TC, Rhodes M, Schwab CW, Yealy DM (2012). The Trauma Manual: Trauma and Acute Care Surgery. Lippincott Williams & Wilkins. ISBN 978-1-4511-1679-3. * Pellock JM, Myer EC (22 October 2013). Neurologic Emergencies in Infancy and Childhood. Elsevier Science. ISBN 978-1-4831-9392-2. * Roos KL (7 March 2012). Emergency Neurology. Springer Science & Business Media. ISBN 978-0-387-88585-8. * Sabharwal S (10 December 2013). Essentials of Spinal Cord Medicine. Demos Medical Publishing. ISBN 978-1-61705-075-6. * Sabharwal S (5 September 2014). "Spinal cord injury (Cervical)". In Frontera WR, Silver JK, Rizzo TD (eds.). Essentials of Physical Medicine and Rehabilitation. Elsevier Health Sciences. ISBN 978-0-323-22272-3. * Shah KH, Egan D, Quaas J (17 February 2012). Essential Emergency Trauma. Lippincott Williams & Wilkins. ISBN 978-1-4511-5318-7. * Snell, R.S. (2010). "The spinal cord and the ascending and descending tracts". Clinical Neuroanatomy. Lippincott Williams & Wilkins. ISBN 978-0-7817-9427-5. * Teufack S, Harrop JS, Ashwini DS (29 October 2012). "Spinal Cord Injury Classification". In Fehlings MG, Vaccaro AR, Maxwell B (eds.). Essentials of Spinal Cord Injury: Basic Research to Clinical Practice. Thieme. ISBN 978-1-60406-727-9. * Weiss JM (15 March 2010). "Spinal cord injury". In Weiss, L.D., Weiss, J.M., Pobre, T. (eds.). Oxford American Handbook of Physical Medicine and Rehabilitation. Oxford University Press, USA. ISBN 978-0-19-970999-1. * Wyatt JP, Illingworth RN, Graham CA, Hogg K, Robertson C, Clancy M (9 February 2012). Oxford Handbook of Emergency Medicine. OUP Oxford. ISBN 978-0-19-101605-9. ## External links[edit] * Spinal cord injury at Curlie Classification D * ICD-10: G95.9, S14, S24, S34, T06.0, T06.1, T09.3 * MeSH: D013119 * DiseasesDB: 12327 External resources * MedlinePlus: 001066 * eMedicine: emerg/553 neuro/711 pmr/182 pmr/183 orthoped/425 * v * t * e Neurotrauma Traumatic brain injury * Intracranial hemorrhage * Intra-axial * Intraparenchymal hemorrhage * Intraventricular hemorrhage * Extra-axial * Subdural hematoma * Epidural hematoma * Subarachnoid hemorrhage * Brain herniation * Cerebral contusion * Cerebral laceration * Concussion * Post-concussion syndrome * Second-impact syndrome * Dementia pugilistica * Chronic traumatic encephalopathy * Diffuse axonal injury * Abusive head trauma * Penetrating head injury Spinal cord injury * Anterior spinal artery syndrome * Brown-Séquard syndrome * Cauda equina syndrome * Central cord syndrome * Paraplegia * Posterior cord syndrome * Spinal cord injury without radiographic abnormality * Tetraplegia (Quadriplegia) Peripheral nerves * Nerve injury * Peripheral nerve injury * classification * Wallerian degeneration * Injury of accessory nerve * Brachial plexus injury * Traumatic neuroma * v * t * e Trauma Principles * Polytrauma * Major trauma * Traumatology * Triage * Resuscitation * Trauma triad of death Assessment Clinical prediction rules * Revised Trauma Score * Injury Severity Score * Abbreviated Injury Scale * NACA score Investigations * Diagnostic peritoneal lavage * Focused assessment with sonography for trauma Management Principles * Advanced trauma life support * Trauma surgery * Trauma center * Trauma team * Damage control surgery * Early appropriate care Procedures * Resuscitative thoracotomy Pathophysiology Injury * MSK * Bone fracture * Joint dislocation * Degloving * Soft tissue injury * Resp * Flail chest * Pneumothorax * Hemothorax * Diaphragmatic rupture * Pulmonary contusion * Cardio * Internal bleeding * Thoracic aorta injury * Cardiac tamponade * GI * Blunt kidney trauma * Ruptured spleen * Neuro * Penetrating head injury * Traumatic brain injury * Intracranial hemorrhage Mechanism * Blast injury * Blunt trauma * Burn * Penetrating trauma * Crush injury * Stab wound * Ballistic trauma * Electrocution Region * Abdominal trauma * Chest trauma * Facial trauma * Head injury * Spinal cord injury Demographic * Geriatric trauma * Pediatric trauma Complications * Posttraumatic stress disorder * Wound healing * Acute lung injury * Crush syndrome * Rhabdomyolysis * Compartment syndrome * Contracture * Volkmann's contracture * Embolism * air * fat * Chronic traumatic encephalopathy * Subcutaneous emphysema Authority control * NDL: 01222576 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Spinal cord injury	c0037929	6,475	wikipedia	https://en.wikipedia.org/wiki/Spinal_cord_injury	2021-01-18T18:37:11	{"mesh": ["D013119"], "umls": ["90058"], "icd-10": ["T09.3", "G95.9"], "orphanet": ["90058"], "wikidata": ["Q1415275"]}
Sotos syndrome is a condition characterized mainly by distinctive facial features; overgrowth in childhood; and learning disabilities or delayed development. Facial features may include a long, narrow face; a high forehead; flushed (reddened) cheeks; a small, pointed chin; and down-slanting palpebral fissures. Affected infants and children tend to grow quickly; they are significantly taller than their siblings and peers and have a large head. Other signs and symptoms may include intellectual disability; behavioral problems; problems with speech and language; and/or weak muscle tone (hypotonia). Sotos syndrome is usually caused by a mutation in the NSD1 gene and is inherited in an autosomal dominant manner. About 95% of cases are due to a new mutation in the affected person and occur sporadically (are not inherited). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Sotos syndrome	c0175695	6,476	gard	https://rarediseases.info.nih.gov/diseases/10091/sotos-syndrome	2021-01-18T17:57:40	{"mesh": ["D058495"], "omim": ["117550"], "umls": ["C0175695"], "orphanet": ["821"], "synonyms": ["Cerebral gigantism", "Distinctive facial appearance, overgrowth in childhood, and learning disabilities or delayed development"]}
Bartter syndrome is a group of very similar kidney disorders that cause an imbalance of potassium, sodium, chloride, and related molecules in the body. In some cases, Bartter syndrome becomes apparent before birth. The disorder can cause polyhydramnios, which is an increased volume of fluid surrounding the fetus (amniotic fluid). Polyhydramnios increases the risk of premature birth. Beginning in infancy, affected individuals often fail to grow and gain weight at the expected rate (failure to thrive). They lose excess amounts of salt (sodium chloride) in their urine, which leads to dehydration, constipation, and increased urine production (polyuria). In addition, large amounts of calcium are lost through the urine (hypercalciuria), which can cause weakening of the bones (osteopenia). Some of the calcium is deposited in the kidneys as they are concentrating urine, leading to hardening of the kidney tissue (nephrocalcinosis). Bartter syndrome is also characterized by low levels of potassium in the blood (hypokalemia), which can result in muscle weakness, cramping, and fatigue. Rarely, affected children develop hearing loss caused by abnormalities in the inner ear (sensorineural deafness). Two major forms of Bartter syndrome are distinguished by their age of onset and severity. One form begins before birth (antenatal) and is often life-threatening. The other form, often called the classical form, begins in early childhood and tends to be less severe. Once the genetic causes of Bartter syndrome were identified, researchers also split the disorder into different types based on the genes involved. Types I, II, and IV have the features of antenatal Bartter syndrome. Because type IV is also associated with hearing loss, it is sometimes called antenatal Bartter syndrome with sensorineural deafness. Type III usually has the features of classical Bartter syndrome. This disease summary is from MedlinePlus Genetics, an online health information resource from the National Institutes of Health. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Bartter syndrome	c0004775	6,477	gard	https://rarediseases.info.nih.gov/diseases/5893/bartter-syndrome	2021-01-18T18:01:53	{"mesh": ["D001477"], "omim": ["601678", "241200", "607364", "602522", "613090"], "umls": ["C0004775"], "orphanet": ["112"], "synonyms": ["Potassium wasting", "Bartter's syndrome", "Hypokalemic alkalosis with hypercalciuria"]}
Toluene toxicity Chemical structure of toluene SpecialtyEmergency medicine Toluene toxicity refers to the harmful effects caused by toluene on the body. ## Contents * 1 Metabolism in humans * 2 Environmental influences * 3 Measure of exposure * 4 Effects of long-term exposure * 5 References * 6 External links ## Metabolism in humans[edit] While a significant amount of toluene, 25%–40%, is exhaled unchanged via the lungs, a greater proportion is metabolised and excreted via other pathways. The primary route of toluene metabolism is by hydroxylation to benzyl alcohol by members of the cytochrome P450 (CYP) superfamily.[1] There are five CYPs which are important in toluene metabolism, CYP1A2, CYP2B6, CYP2E1, CYP2C8, and CYP1A1.[2] The first four seem to be involved in the hydroxylation of toluene to benzyl alcohol. CYP2E1 seems to be the primary enzyme in the hydroxylation of toluene, accounting for roughly 44% of toluene metabolism;[1] however, there is a great deal of ethnic variability, in the Finnish population for example the primary enzyme is CYP2B6. CYP2E1 catalyses the formation of benzyl alcohol and p-cresol,[1][2] while CYP2B6 produces comparatively little p-cresol.[2] It is believed that in humans, benzyl alcohol is metabolised to benzaldehyde by CYP rather than alcohol dehydrogenase;[3] however, this belief does not appear to be universal.[4][5] Benzaldehyde is in turn metabolised to benzoic acid, primarily by mitochondrial aldehyde dehydrogenase-2 (ALDH-2), while only a small percentage is metabolised by cytosolic ALDH-1.[5] Benzoic acid is metabolised to either benzoyl glucuronide or hippuric acid.[4][6] Benzoyl glucuronide is produced by the reaction of benzoic acid with glucuronic acid, which accounts for 10–20% of benzoic acid elimination. Hippuric acid is also known as benzoylglycine and is produced from benzoic acid in two steps: first benzoic acid is converted to benzoyl-CoA by the enzyme benzoyl-CoA synthase; then benzoyl-CoA is converted to hippuric acid by benzoyl-CoA:glycine N-acyltransferase.[7] Hippuric acid is the primary urinary metabolite of toluene.[4] Ring hydroxylation to cresols is a minor pathway in the metabolism of toluene. The majority of the cresol is excreted unchanged in urine; however, some of the p-cresol and o-cresol is excreted as a conjugate. Studies in rats have shown that p-cresol is primarily conjugated with glucuronide to produce p-cresylglucuronide, though this may not be applicable to humans.[8] o-cresol appears to be excreted mostly unchanged in urine or as the glucuronide or sulfate conjugate.[9] There appears to be some dispute over whether m-cresol is produced as a metabolite of toluene or not.[4][10] ## Environmental influences[edit] When exposure to toluene occurs there is usually simultaneous exposure to several other chemicals.[4] Often toluene exposure occurs in conjunction with benzene and since they are to some degree metabolised by the same enzymes, the relative concentrations will determine their rate of elimination.[4] Of course the longer it takes for toluene to be eliminated the more harm it is likely to do. The smoking and drinking habits of those exposed to toluene will partially determine the elimination of toluene. Studies have shown that even a modest amount of acute ethanol consumption can significantly decrease the distribution or elimination of toluene from the blood resulting in increased tissue exposure.[11] Other studies have shown that chronic ethanol consumption can enhance toluene metabolism via the induction of CYP2E1.[12] Smoking has been shown to enhance the elimination rate of toluene from the body, perhaps as a result of enzyme induction.[13] The diet can also influence toluene elimination. Both a low-carbohydrate diet and fasting have been shown to induce CYP2E1 and as a result increase toluene metabolism.[12] A low protein diet may decrease total CYP content and thereby reduce the elimination rate of the drug.[12] ## Measure of exposure[edit] Hippuric acid has long been used as an indicator of toluene exposure;[14] however, there appears to be some doubt about its validity.[15] There is significant endogenous hippuric acid production by humans; which shows inter- and intra-individual variation influenced by factors such as diet, medical treatment, alcohol consumption, etc.[15] This suggests that hippuric acid may be an unreliable indicator of toluene exposure.[15][16] It has been suggested that urinary hippuric acid, the traditional marker of toluene exposure is simply not sensitive enough to separate the exposed from the non-exposed.[17] This has led to the investigation of other metabolites as markers for toluene exposure.[16] Urinary o-cresol may be more reliable for the biomonitoring of toluene exposure because, unlike hippuric acid, o-cresol is not found at detectable levels in unexposed subjects.[16] o-Cresol may be a less sensitive marker of toluene exposure than hippuric acid.[18] o-Cresol excretion may be an unreliable method for measuring toluene exposure because o-cresol makes up <1% of total toluene elimination.[14] Benzylmercapturic acid, a minor metabolite of toluene, is produced from benzaldehyde.[19] In more recent years, studies have suggested the use of urinary benzylmercapturic acid as the best marker for toluene exposure, because: it is not detected in non-exposed subjects; it is more sensitive than hippuric acid at low concentrations; it is not affected by eating or drinking; it can detect toluene exposure down to approximately 15 ppm; and it shows a better quantitative relationship with toluene than hippuric acid or o-cresol.[20][21] ## Effects of long-term exposure[edit] Serious adverse behavioural effects are often associated with chronic occupational exposure [22] and toluene abuse related to the deliberate inhalation of solvents.[23] Long-term toluene exposure is often associated with effects such as: psychoorganic syndrome;[24] visual evoked potential (VEP) abnormality;[24] toxic polyneuropathy, cerebellar, cognitive, and pyramidal dysfunctions;[23][24] optic atrophy; hearing disorders[25][26] and brain lesions.[23] The neurotoxic effects of long-term use (in particular repeated withdrawals) of toluene may cause postural tremors by downregulating GABA receptors within the cerebellar cortex.[23] Treatment with GABA agonists such as benzodiazepines provide some relief from toluene-induced tremor and ataxia.[23] An alternative to drug treatment is ventral intermediate nucleus (vim) thalamotomy.[23] The tremors associated with toluene misuse do not seem to be a transient symptom, but an irreversible and progressive symptom which continues after solvent abuse has been discontinued.[23] There is some evidence that low-level toluene exposure may cause disruption in the differentiation of astrocyte precursor cells.[27] This does not appear to be a major hazard to adults; however, exposure of pregnant women to toluene during critical stages of fetal development could cause serious disruption to neuronal development.[27] ## References[edit] 1. ^ a b c Shou, M; Lu T; Krausz KW; Sai Y; Yang T; Korzekwa KR; Gonzalez FJ; Gelboin HV (2000-04-14). "Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes P450 to human drug metabolism". European Journal of Pharmacology. 394 (2–3): 199–209. doi:10.1016/S0014-2999(00)00079-0. PMID 10771285. 2. ^ a b c Nakajima, T; Wang RS; Elovaara E; Gonzalez FJ; Gelboin HV; Raunio H; Pelkonen O; Vainio H; Aoyama T (1997-02-07). "Toluene metabolism by cDNA-expressed human hepatic cytochrome P450". Biochemical Pharmacology. 53 (3): 271–7. doi:10.1016/S0006-2952(96)00652-1. PMID 9065730. 3. ^ Chapman, DE; Moore TJ; Michener SR; Powis G (November–December 1990). "Metabolism and covalent binding of [14C]toluene by human and rat liver microsomal fractions and liver slices". Drug Metabolism and Disposition. 18 (6): 929–36. PMID 1981539. 4. ^ a b c d e f Agency for Toxic Substances and Disease Registry (September 2000). Toxicological profile for toluene. Atlanta, GA: Agency for Toxic Substances and Disease Registry. OCLC 47129207. 5. ^ a b Kawamoto, T; Matsuno K; Kodama Y; Murata K; Matsuda S (September–October 1994). "ALDH2 polymorphism and biological monitoring of toluene". Archives of Environmental Health. 49 (5): 332–6. doi:10.1080/00039896.1994.9954983. PMID 7944563. 6. ^ World Health Organization (1985). Environmental Health Criteria No. 52 (Toluene). Geneva: World Health Organization. ISBN 978-92-4-154192-3. 7. ^ Gregus, Z; Fekete T; Halászi E; Klaassen CD (June 1996). "Lipoic acid impairs glycine conjugation of benzoic acid and renal excretion of benzoylglycine". Drug Metabolism and Disposition. 24 (6): 682–8. PMID 8781786. 8. ^ Lesaffer G, De Smet R, D'Heuvaert T, Belpaire FM, Lameire N, Vanholder R (October 2003). "Comparative kinetics of the uremic toxin p-cresol versus creatinine in rats with and without renal failure". Kidney International. 64 (4): 1365–73. doi:10.1046/j.1523-1755.2003.00228.x. PMID 12969155. 9. ^ Wilkins-Haug, L (February 1997). "Teratogen update: toluene". Teratology. 55 (2): 145–51. doi:10.1002/(SICI)1096-9926(199702)55:2<145::AID-TERA5>3.0.CO;2-2. PMID 9143096. 10. ^ Tassaneeyakul, W; Birkett DJ; Edwards JW; Veronese ME; Tassaneeyakul W; Tukey RH; Miners JO (January 1996). "Human cytochrome P450 isoform specificity in the regioselective metabolism of toluene and o-, m- and p-xylene". Journal of Pharmacology and Experimental Therapeutics. 276 (1): 101–8. PMID 8558417. 11. ^ Wallen, M; Näslund PH; Nordqvist MB (December 1984). "The effects of ethanol on the kinetics of toluene in man". Toxicology and Applied Pharmacology. 76 (3): 414–9. doi:10.1016/0041-008X(84)90345-4. PMID 6506069. 12. ^ a b c Nakajima, T; Wang RS; Murayama N (1993). "Immunochemical assessment of the influence of nutritional, physiological and environmental factors on the metabolism of toluene". International Archives of Occupational and Environmental Health. 65 (1 Supplement): S127–30. doi:10.1007/BF00381323. PMID 8406908. 13. ^ Hjelm, EW; Näslund PH; Wallén M (1988). "Influence of cigarette smoking on the toxicokinetics of toluene in humans". Journal of Toxicology and Environmental Health. 25 (2): 155–63. doi:10.1080/15287398809531197. PMID 3172270. 14. ^ a b Duydu, Y; Süzen S; Erdem N; Uysal H; Vural N (July 1999). "Validation of hippuric acid as a biomarker of toluene exposure". Bulletin of Environmental Contamination and Toxicology. 63 (1): 1–8. doi:10.1007/s001289900940. PMID 10423476. 15. ^ a b c Angerer, J (1985). "Occupational chronic exposure to organic solvents. XII. O-cresol excretion after toluene exposure". International Archives of Occupational and Environmental Health. 56 (4): 323–8. doi:10.1007/BF00405273. PMID 4066055. 16. ^ a b c Angerer, J; Krämer A (1997). "Occupational chronic exposure to organic solvents. XVI. Ambient and biological monitoring of workers exposed to toluene". International Archives of Occupational and Environmental Health. 69 (2): 91–6. doi:10.1007/s004200050121. PMID 9001914. 17. ^ Inoue, O; Seiji K; Watanabe T; Nakatsuka H; Jin C; Liu SJ; Ikeda M (1993). "Effects of smoking and drinking on excretion of hippuric acid among toluene-exposed workers". International Archives of Occupational and Environmental Health. 64 (6): 425–30. doi:10.1007/BF00517948. PMID 8458658. 18. ^ Inoue, O; Seiji K; Watanabe T; Chen Z; Huang MY; Xu XP; Qiao X; Ikeda M (May 1994). "Effects of smoking and drinking habits on urinary o-cresol excretion after occupational exposure to toluene vapor among Chinese workers". American Journal of Industrial Medicine. 25 (5): 697–708. doi:10.1002/ajim.4700250509. PMID 8030640. 19. ^ Laham, S; Potvin M (1987). "Biological conversion of benzaldehyde to benzylmercapturic acid in the Sprague-Dawley rat". Drug and Chemical Toxicology. 10 (3–4): 209–25. doi:10.3109/01480548709042983. PMID 3428183. 20. ^ Inoue, O; Kanno E; Kasai K; Ukai H; Okamoto S; Ikeda M (2004-03-01). "Benzylmercapturic acid is superior to hippuric acid and o-cresol as a urinary marker of occupational exposure to toluene". Toxicology Letters. 147 (2): 177–86. doi:10.1016/j.toxlet.2003.11.003. PMID 14757321. 21. ^ Inoue, O; Kanno E; Yusa T; Kakizaki M; Ukai H; Okamoto S; Higashikawa K; Ikeda M (June 2002). "Urinary benzylmercapturic acid as a marker of occupational exposure to toluene". International Archives of Occupational and Environmental Health. 75 (5): 341–7. doi:10.1007/s00420-002-0322-8. PMID 11981673. 22. ^ Feldman RG, Ratner MH, Ptak T (May 1999). "Chronic toxic encephalopathy in a painter exposed to mixed solvents". Environ Health Perspect. 107 (5): 417–22. doi:10.1289/ehp.99107417. PMC 1566426. PMID 10210698.CS1 maint: multiple names: authors list (link) 23. ^ a b c d e f g Miyagi, Y; Shima F; Ishido K; Yasutake T; Kamikaseda K (June 1999). "Tremor induced by toluene misuse successfully treated by a Vim thalamotomy". Journal of Neurology, Neurosurgery, and Psychiatry. 66 (6): 794–6. doi:10.1136/jnnp.66.6.794. PMC 1736379. PMID 10329759. 24. ^ a b c Urban, P; Lukáš E; Pelclová D; et al. (2003). "Neurological and neurophysiological follow-up on workers with severe chronic exposure to toluene". Neurotoxicity. P25 (s130). 25. ^ Schäper, Michael; Seeber, Andreas; van Thriel, Christoph (2008-01-01). "The Effects of Toluene Plus Noise on Hearing Thresholds: An Evaluation Based on Repeated Measurements in the German Printing Industry". International Journal of Occupational Medicine and Environmental Health. 21 (3): 191–200. doi:10.2478/v10001-008-0030-z. ISSN 1896-494X. PMID 19042192. 26. ^ Yılmaz, Omer Hinc; Kos, Mehmet; Basturk, Arzu; Kesici, Gulin Gokcen; Unlu, Ilhan (2014-11-01). "A comparison of the effects of solvent and noise exposure on hearing, together and separately". Noise and Health. 16 (73): 410–5. doi:10.4103/1463-1741.144422. ISSN 1463-1741. PMID 25387537. 27. ^ a b Yamaguchi, H; Kidachi Y; Ryoyama K (May–June 2002). "Toluene at environmentally relevant low levels disrupts differentiation of astrocyte precursor cells". Archives of Environmental Health. 57 (3): 232–8. doi:10.1080/00039890209602942. PMID 12507177. ## External links[edit] Classification D * ICD-10: T52.2 * ICD-9-CM: 982.0 * DiseasesDB: 31145 External resources * eMedicine: article/818939 * ATSDR - Case Studies in Environmental Medicine: Toluene Toxicity U.S. Department of Health and Human Services (public domain) * v * t * e Psychoactive substance-related disorder General * SID * Substance intoxication / Drug overdose * Substance-induced psychosis * Withdrawal: * Craving * Neonatal withdrawal * Post-acute-withdrawal syndrome (PAWS) * SUD * Substance abuse / Substance-related disorders * Physical dependence / Psychological dependence / Substance dependence Combined substance use * SUD * Polysubstance dependence * SID * Combined drug intoxication (CDI) Alcohol SID Cardiovascular diseases * Alcoholic cardiomyopathy * Alcohol flush reaction (AFR) Gastrointestinal diseases * Alcoholic liver disease (ALD): * Alcoholic hepatitis * Auto-brewery syndrome (ABS) Endocrine diseases * Alcoholic ketoacidosis (AKA) Nervous system diseases * Alcohol-related dementia (ARD) * Alcohol intoxication * Hangover Neurological disorders * Alcoholic hallucinosis * Alcoholic polyneuropathy * Alcohol-related brain damage * Alcohol withdrawal syndrome (AWS): * Alcoholic hallucinosis * Delirium tremens (DTs) * Fetal alcohol spectrum disorder (FASD) * Fetal alcohol syndrome (FAS) * Korsakoff syndrome * Positional alcohol nystagmus (PAN) * Wernicke–Korsakoff syndrome (WKS, Korsakoff psychosis) * Wernicke encephalopathy (WE) Respiratory tract diseases * Alcohol-induced respiratory reactions * Alcoholic lung disease SUD * Alcoholism (alcohol use disorder (AUD)) * Binge drinking Caffeine * SID * Caffeine-induced anxiety disorder * Caffeine-induced sleep disorder * Caffeinism * SUD * Caffeine dependence Cannabis * SID * Cannabis arteritis * Cannabinoid hyperemesis syndrome (CHS) * SUD * Amotivational syndrome * Cannabis use disorder (CUD) * Synthetic cannabinoid use disorder Cocaine * SID * Cocaine intoxication * Prenatal cocaine exposure (PCE) * SUD * Cocaine dependence Hallucinogen * SID * Acute intoxication from hallucinogens (bad trip) * Hallucinogen persisting perception disorder (HPPD) Nicotine * SID * Nicotine poisoning * Nicotine withdrawal * SUD * Nicotine dependence Opioids * SID * Opioid overdose * SUD * Opioid use disorder (OUD) Sedative / hypnotic * SID * Kindling (sedative–hypnotic withdrawal) * benzodiazepine: SID * Benzodiazepine overdose * Benzodiazepine withdrawal * SUD * Benzodiazepine use disorder (BUD) * Benzodiazepine dependence * barbiturate: SID * Barbiturate overdose * SUD * Barbiturate dependence Stimulants * SID * Stimulant psychosis * amphetamine: SUD * Amphetamine dependence Volatile solvent * SID * Sudden sniffing death syndrome (SSDS) * Toluene toxicity * SUD * Inhalant abuse * v * t * e * Poisoning * Toxicity * Overdose History of poison Inorganic Metals Toxic metals * Beryllium * Cadmium * Lead * Mercury * Nickel * Silver * Thallium * Tin Dietary minerals * Chromium * Cobalt * Copper * Iron * Manganese * Zinc Metalloids * Arsenic Nonmetals * Sulfuric acid * Selenium * Chlorine * Fluoride Organic Phosphorus * Pesticides * Aluminium phosphide * Organophosphates Nitrogen * Cyanide * Nicotine * Nitrogen dioxide poisoning CHO * alcohol * Ethanol * Ethylene glycol * Methanol * Carbon monoxide * Oxygen * Toluene Pharmaceutical Drug overdoses Nervous * Anticholinesterase * Aspirin * Barbiturates * Benzodiazepines * Cocaine * Lithium * Opioids * Paracetamol * Tricyclic antidepressants Cardiovascular * Digoxin * Dipyridamole Vitamin poisoning * Vitamin A * Vitamin D * Vitamin E * Megavitamin-B6 syndrome Biological1 Fish / seafood * Ciguatera * Haff disease * Ichthyoallyeinotoxism * Scombroid * Shellfish poisoning * Amnesic * Diarrhetic * Neurotoxic * Paralytic Other vertebrates * amphibian venom * Batrachotoxin * Bombesin * Bufotenin * Physalaemin * birds / quail * Coturnism * snake venom * Alpha-Bungarotoxin * Ancrod * Batroxobin Arthropods * Arthropod bites and stings * bee sting / bee venom * Apamin * Melittin * scorpion venom * Charybdotoxin * spider venom * Latrotoxin / Latrodectism * Loxoscelism * tick paralysis Plants / fungi * Cinchonism * Ergotism * Lathyrism * Locoism * Mushrooms * Strychnine 1 including venoms, toxins, foodborne illnesses. * Category * Commons * WikiProject [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Toluene toxicity	None	6,478	wikipedia	https://en.wikipedia.org/wiki/Toluene_toxicity	2021-01-18T18:52:57	{"icd-10": ["T52.2"], "wikidata": ["Q3153686"]}
Temtamy preaxial brachydactyly syndrome is a rare, genetic dysostosis syndrome characterized by bilateral, symmetrical, preaxial brachydactyly associated with hyperphalangy, motor developmental delay and intellectual disability, growth retardation, sensorineural hearing loss, dental abnormalities (incuding misalignment of teeth, talon cusps, microdontia), and facial dysmorphism that includes plagiocephaly, round face, hypertelorism, malar hypoplasia, malformed ears, microstomia and micro/retrognathia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Temtamy preaxial brachydactyly syndrome	c1854466	6,479	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=363417	2021-01-23T17:46:35	{"gard": ["9679"], "mesh": ["C536958"], "omim": ["605282"], "umls": ["C1854466"], "icd-10": ["Q87.2"]}
Often called "albino", this amelanistic python owes its yellow color to unaffected carotenoid pigments. Amelanism (also known as amelanosis) is a pigmentation abnormality characterized by the lack of pigments called melanins, commonly associated with a genetic loss of tyrosinase function. Amelanism can affect fish, amphibians, reptiles, birds, and mammals including humans. The appearance of an amelanistic animal depends on the remaining non-melanin pigments. The opposite of amelanism is melanism, a higher percentage of melanin. A similar condition, albinism, is a hereditary condition characterised in animals by the absence of pigment in the eyes, skin, hair, scales, feathers or cuticle.[1] This results in an all white animal, usually with pink or red eyes. ## Contents * 1 Melanins and melanin production * 2 In mammals * 3 In other vertebrates * 4 Aeumelanism * 5 Aphaeomelanism * 6 See also * 7 References ## Melanins and melanin production[edit] Melanin is a compound found in plants, animals, and protists, and is derived from the amino acid tyrosine. Melanin is a photoprotectant, absorbing the DNA-damaging ultraviolet radiation of the sun. Vertebrates have melanin in their skin and hair, feathers, or scales. They also have two layers of pigmented tissue in the eye: the stroma, at the front of the iris, and the iris pigment epithelium, a thin but critical layer of pigmented cells at the back of the iris. Melanin is also present in the inner ear, and is important for the early development of the auditory system.[2] Melanin is also found in parts of the brain and adrenal gland. The normal zebrafish embryo, above, shows the migration and maturation of melanocytes. The amelanistic embryo, below, has melanocytes but no melanin. Melanins are produced in organelles called melanosomes. The production of melanins is called melanogenesis. Melanosomes are found in specialized pigment cells called melanocytes, but may also be engulfed by other cells, which are then called melanophages. Hair acquires pigment from melanocytes in the root bulb, which deposit melanosomes into the growing hair structure. A critical step in the production of melanins is the catalysis of tyrosine by an enzyme called tyrosinase, producing dopaquinone. Dopaquinone may become eumelanin, or phaeomelanin. Eumelanin, meaning true black, is a dense compound that absorbs most wavelengths of light, and appears black or brown as a result. Phaeomelanin, meaning rufous-black, is characterized by the presence of sulfur-containing cysteine, and it appears reddish to yellowish as a result. Melanosomes containing eumelanin are eumelanosomes, while those containing phaeomelanin are phaeomelanosomes. Melanocyte-stimulating hormone (MSH) binds to the Melanocortin 1 receptor (MC1R) and commits melanocytes to the production of eumelanin. In the absence of this signal, melanocytes produce phaeomelanin. Another chemical, Agouti signalling peptide (ASP), can attach itself to MC1R and interfere with MSH/MC1R signalling. In many mammals, variation in the level of ASP switches melanocytes between eumelanin and phaeomelanin production, resulting in coloured patterns. Amelanistic laboratory mice, such as these, have no pigment in their skin, hair, or eyes. Their eyes are reddish. Melanocytes, and the parallel melanophores found in fishes, amphibians, and reptiles, are derived from a strip of tissue in the embryo called the neural crest. Stem cells in the neural crest give rise to the cells of the autonomic nervous system, supportive elements of the skeleton such as chondrocytes, cells of the endocrine system, and melanocytes. This strip of tissue is found along the dorsal midline of the embryo, and multipotent cells migrate down along the sides of the embryo, or through germ layers, to their ultimate destinations. Melanocyte stem cells are called melanoblasts. Conditions associated with abnormalities in the migration of melanoblasts are known collectively as piebaldism. Pigment cells of the iris pigment epithelium have a separate embryological origin.[3] Piebaldism and amelanism are distinct conditions. ## In mammals[edit] The only pigments that mammals produce are melanins. For a mammal to be unable to chemically manufacture melanin renders it completely pigmentless. This condition is more commonly called albinism. Amelanistic mammals have white hair, pink skin, and eyes that have a pink, red, or violet appearance. Reddish eyes are due to the lack of pigment in the iris pigment epithelium. When the stroma is unpigmented but the iris pigment epithelium is not, mammalian eyes appear blue. Melanin in the pigment epithelium is critical for visual acuity and contrast.[4] Loss of melanogenesis function is linked to the gene that encodes tyrosinase. Certain alleles of this gene, TYR, at the Color locus, cause oculocutaneous albinism type 1 in humans and the familiar red-eyed albino conditions in mice and other mammals. Amelanistic ("lutino") cockatiels retain their carotenoid-based red and yellow pigments. ## In other vertebrates[edit] Other vertebrates, such as fishes, amphibians, reptiles and birds, produce a variety of non-melanin pigments. Disruption of melanin production does not affect the production of these pigments. Non-melanin pigments in other vertebrates are produced by cells called chromatophores. Within this categorization, xanthophores are cells that contain primarily yellowish pteridines, while erythrophores contain primarily orangish carotenoids. Some species also possess iridophores or leucophores, which do not contain true pigments, but light-reflective structures that give iridescence. An extremely uncommon type of chromatophore, the cyanophore, produces a very vivid blue pigment.[5] Amelanism in fishes, amphibians, reptiles and birds has the same genetic etiology as in mammals: loss of tyrosinase function. However, due to the presence of other pigments, other amelanistic vertebrates are seldom white and red-eyed like amelanistic mammals. Without melanocortin 1 receptor to signal eumelanin production in melanocytes, this Labrador retriever has a yellow coat. His eyes and skin are normal. ## Aeumelanism[edit] Melanocytes depend on the Melanocortin 1 receptor (MC1R) to signal the production of eumelanin. Loss of melanocortin 1 receptor function or high activity of the MC1R-antagonist, Agouti signalling peptide, can cause the widespread absence of eumelanin. Loss of MC1R function, a recessive trait, has been observed in many species. In humans, various mutations of the MC1R gene result in red hair, blond hair, fair skin, and susceptibility to sundamaged skin and melanoma.[6] Aeumelanic hair coats, associated with mutations of the MC1R gene, have also been identified in mice,[7] cattle,[8] dogs,[9] and horses.[10] These coat colors are called "yellow" in mice and dogs, "red" in cattle and chestnut in horses. The loss of eumelanin in the coat is, in these species, harmless. The distinction between aeumelanism and hyperphaeomelanism – over abundance of phaeomelanin – is semantic. The bay horse, left, has both eumelanin and phaeomelanin in her coat; the agouti signaling peptide suppresses black color to the "points" v the mane, tail, ear tips, and legs. The horse at right lacks the agouti signalling protein, and has a uniformly black or aphaeomelanistic coat. In a chestnut horse, the solid red coat is created by a recessive aeumelanic mutation in MC1R and agouti, if present, is masked. In all cases, the eyes and skin are unaffected. ## Aphaeomelanism[edit] Aphaeomelanism is the abnormal absence of phaeomelanin from the integumentary system and/or eyes.[11] Phaeomelanin is produced by melanocytes in the absence of melanocortin 1 receptor. This absence is mediated by agouti signalling protein, which antagonizes melanocortin 1 receptor. Loss of function of agouti signalling protein can permit unmediated eumelanin production, producing a uniformly black-to-brown coat color. This condition can be observed in dogs,[12] cats,[13] and horses.[14] The appearance of mammals with recessive agouti mutations is typically dense black. As with aeumelanism, the difference between lack of phaeomelanin and abundance of eumelanin is one of words. Some agouti alleles in mice are associated with health defects, but this is not the case in dogs, cats, or horses. ## See also[edit] * Albinism * Dyschromia * Erythrism * Heterochromia iridum * Leucism * Melanism * Piebaldism * Vitiligo * Xanthochromism ## References[edit] 1. ^ "Albinism". Encyclopædia Britannica. Retrieved January 27, 2015. 2. ^ Robins, Ashley H. (1991). Biological perspectives on human pigmentation (1 ed.). Cambridge University Press. pp. 76–77. ISBN 0-521-36514-7. 3. ^ Robins, Ashley H. (1991) pg. 75 4. ^ Arun D. Singh; Harminder S. Dua (1997). "16 Retinal pigment epitheliopathies". In A. M. Peter Hamilton; Richard Gregson; Gary Edd Fish (eds.). Text Atlas of the Retina (1 ed.). Informa Health Care. p. 249. ISBN 1-85317-226-X. 5. ^ Fujii, R (October 2000). "The regulation of motile activity in fish chromatophores". Pigment Cell Res. 13 (5): 300–19. doi:10.1034/j.1600-0749.2000.130502.x. PMID 11041206. 6. ^ Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: {155555}: {5/15/2009}:. World Wide Web URL: https://www.ncbi.nlm.nih.gov/omim/ 7. ^ Robbins, L.S.; Nadeau, J. H.; Johnson, K. R.; Kelly, M. A.; Roselli-Rehfuss, L.; Baack, E.; Mountjoy, K. G.; Cone, R. D. (1993). "Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function". Cell. 72 (6): 827–834. doi:10.1016/0092-8674(93)90572-8. PMID 8458079. S2CID 12179800. 8. ^ Joerg, H; Fries, H. R.; Meijerink, E.; Stranzinger, G. F. (1996). "Red coat color in Holstein cattle is associated with a deletion in the MSHR gene". Mammalian Genome. 7 (4): 317–318. doi:10.1007/s003359900090. PMID 8661706. S2CID 2497765. 9. ^ Newton, JM; Wilkie, A. L.; He, L.; Jordan, S. A.; Metallinos, D. L.; Holmes, N. G.; Jackson, I. J.; Barsh, G. S. (2000). "Melanocortin 1 receptor variation in the domestic dog". Mammalian Genome. 11 (1): 24–30. doi:10.1007/s003350010005. PMID 10602988. S2CID 1755908. 10. ^ Marklund, L; Moller MJ; Sandberg K; Andersson L (Dec 1996). "A missense mutation in the gene for melanocyte-stimulating hormone receptor (MC1R) is associated with the chestnut coat color in horses". Mammalian Genome. 7 (12): 895–9. doi:10.1007/s003359900264. PMID 8995760. S2CID 29095360. 11. ^ Davis, Jeff N. (September–October 2007). "Color Abnormalities". Birding. American Birding Association. 39 (5): 36–46. 12. ^ Kerns, Julie A.; Newton, J.; Berryere, Tom G.; Rubin, Edward M.; Cheng, Jan-Fang; Schmutz, Sheila M.; Barsh, Gregory S. (October 2004). "Characterization of the dog Agouti gene and a nonagouti mutation in German Shepherd Dogs". Mammalian Genome. Springer New York. 15 (10): 798–808. doi:10.1007/s00335-004-2377-1. ISSN 1432-1777. PMID 15520882. S2CID 27945452. 13. ^ [1] Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: {600201}: {9/4/2008}:. World Wide Web URL: https://www.ncbi.nlm.nih.gov/omim/ 14. ^ Rieder, Stefan; Taourit, Sead; Mariat, Denis; Langlois, Bertrand; Guérin, Gérard (2001). "Mutations in the agouti (ASIP), the extension (MC1R), and the brown (TYRP1) loci and their association to coat color phenotypes in horses (Equus caballus)". Mammalian Genome. Springer-Verlag. 12 (6): 450–455. doi:10.1007/s003350020017. PMID 11353392. S2CID 2012676. * v * t * e Pigmentation disorders/Dyschromia Hypo-/ leucism Loss of melanocytes Vitiligo * Quadrichrome vitiligo * Vitiligo ponctué Syndromic * Alezzandrini syndrome * Vogt–Koyanagi–Harada syndrome Melanocyte development * Piebaldism * Waardenburg syndrome * Tietz syndrome Loss of melanin/ amelanism Albinism * Oculocutaneous albinism * Ocular albinism Melanosome transfer * Hermansky–Pudlak syndrome * Chédiak–Higashi syndrome * Griscelli syndrome * Elejalde syndrome * Griscelli syndrome type 2 * Griscelli syndrome type 3 Other * Cross syndrome * ABCD syndrome * Albinism–deafness syndrome * Idiopathic guttate hypomelanosis * Phylloid hypomelanosis * Progressive macular hypomelanosis Leukoderma w/o hypomelanosis * Vasospastic macule * Woronoff's ring * Nevus anemicus Ungrouped * Nevus depigmentosus * Postinflammatory hypopigmentation * Pityriasis alba * Vagabond's leukomelanoderma * Yemenite deaf-blind hypopigmentation syndrome * Wende–Bauckus syndrome Hyper- Melanin/ Melanosis/ Melanism Reticulated * Dermatopathia pigmentosa reticularis * Pigmentatio reticularis faciei et colli * Reticulate acropigmentation of Kitamura * Reticular pigmented anomaly of the flexures * Naegeli–Franceschetti–Jadassohn syndrome * Dyskeratosis congenita * X-linked reticulate pigmentary disorder * Galli–Galli disease * Revesz syndrome Diffuse/ circumscribed * Lentigo/Lentiginosis: Lentigo simplex * Liver spot * Centrofacial lentiginosis * Generalized lentiginosis * Inherited patterned lentiginosis in black persons * Ink spot lentigo * Lentigo maligna * Mucosal lentigines * Partial unilateral lentiginosis * PUVA lentigines * Melasma * Erythema dyschromicum perstans * Lichen planus pigmentosus * Café au lait spot * Poikiloderma (Poikiloderma of Civatte * Poikiloderma vasculare atrophicans) * Riehl melanosis Linear * Incontinentia pigmenti * Scratch dermatitis * Shiitake mushroom dermatitis Other/ ungrouped * Acanthosis nigricans * Freckle * Familial progressive hyperpigmentation * Pallister–Killian syndrome * Periorbital hyperpigmentation * Photoleukomelanodermatitis of Kobori * Postinflammatory hyperpigmentation * Transient neonatal pustular melanosis Other pigments Iron * Hemochromatosis * Iron metallic discoloration * Pigmented purpuric dermatosis * Schamberg disease * Majocchi's disease * Gougerot–Blum syndrome * Doucas and Kapetanakis pigmented purpura/Eczematid-like purpura of Doucas and Kapetanakis * Lichen aureus * Angioma serpiginosum * Hemosiderin hyperpigmentation Other metals * Argyria * Chrysiasis * Arsenic poisoning * Lead poisoning * Titanium metallic discoloration Other * Carotenosis * Tar melanosis Dyschromia * Dyschromatosis symmetrica hereditaria * Dyschromatosis universalis hereditaria See also * Skin color * Skin whitening * Tanning * Sunless * Tattoo * removal * Depigmentation [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Amelanism	None	6,480	wikipedia	https://en.wikipedia.org/wiki/Amelanism	2021-01-18T18:35:51	{"wikidata": ["Q4742182"]}
Fusarium wilt A tobacco plant suffering from Fusarium wilt Causal agentsFusarium oxysporum HostsTomato, tobacco, legumes, cucurbits, sweet potatoes and banana EPPO CodeFUSAOX Fusarium wilt is a common vascular wilt fungal disease, exhibiting symptoms similar to Verticillium wilt. This disease has been investigated extensively since the early years of this century. The pathogen that causes Fusarium wilt is Fusarium oxysporum (F. oxysporum).[1] The species is further divided into formae speciales based on host plant. ## Contents * 1 Hosts and symptoms * 2 Disease cycle * 3 Environment * 4 Management * 5 Importance * 6 Origin * 7 See also * 8 External links * 9 References ## Hosts and symptoms[edit] The fungal pathogen Fusarium oxysporum affects a wide variety of hosts of any age. Tomato, tobacco, legumes, cucurbits, sweet potatoes and banana are a few of the most susceptible plants, but it also infects other herbaceous plants.[2] F. oxysporum generally produces symptoms such as wilting, chlorosis, necrosis, premature leaf drop, browning of the vascular system, stunting and damping-off. The most important of these is vascular wilt.[3] Fusarium wilt starts out looking like vein clearing on the younger leaves and drooping of the older lower leaves, followed by stunting, yellowing of the lower leaves, defoliation, marginal necrosis and plant death. On older plants, symptoms are more distinct between the blossoming and fruit maturation stages.[4] F. oxysporum is split into divisions called formae speciales (singular forma specialis, abbreviated f.sp.). Over 100 formae speciales divisions are identified,[5] each with one or two different races. Each forma specialis within the species are host-specific (i.e. specific to a certain plant) and produce different symptoms: F. oxysporum f. sp. batatas affects sweet potato. The symptoms include leaf chlorosis, stunting, and leaf drop. It is transmitted through the soil and through vascular wounds in plant material. Fusarium oxysporum f. sp. canariensis causes wilt of Canary Island date palm and other propagated palms. The disease is spread through contaminated seed, soil and pruning tools.[6] F. oxysporum f. sp. cubense causes Panama disease on banana. It is found everywhere bananas are grown in Africa, Asia, Central and South America. It attacks banana plants of all ages and spreads mainly through the soil. It causes wilting and yellowing of the leaves.[7] F. oxysporum f. sp. lycopersici causes vascular wilt in tomato. The disease starts out as yellowing and drooping on one side of the plant. Leaf wilting, plant stunting, browning of the vascular system, leaf death and lack of fruit production also occur.[8] F. oxysporum f. sp. melonis attacks muskmelon and cantaloupe. It causes damping-off in seedlings and causes chlorosis, stunting and wilting in old plants. Necrotic streaks can appear on the stems.[9] ## Disease cycle[edit] F. oxysporum is the most widely dispersed of the Fusarium species and is found worldwide.[10] F. oxysporum has no known sexual stage, but produces three types of asexual spores: microconidia, macroconidia, and chlamydospores. The microconidia are the most abundantly produced spores. They are oval, elliptical or kidney shaped and produced on aerial mycelia. Macroconidia, which have three to five cells and have gradually pointed or curved edges, are found on sporodochia on the surface of diseased plant (in culture the sporodochia may be sparse or nonexistent). Chlamydospores are usually formed singly or in pairs, but can sometimes be found in clusters or in short chains. They are round thick walled spores produced within or terminally on an older mycelium or in macroconidia. Chlamydospores unlike the other spores can survive in the soil for a long period of time. F. oxysporum is a common soil pathogen and saprophyte that feeds on dead and decaying organic matter. It survives in the soil debris as a mycelium and all spore types, but is most commonly recovered from the soil as chlamydospores.[1] This pathogen spreads in two basic ways: it spreads short distances by water splash, and by planting equipment, and long distances by infected transplants and seeds. F. oxysporum infects a healthy plant by means of mycelia or by germinating spores penetrating the plant's root tips, root wounds, or lateral roots. The mycelium advances intracellularly through the root cortex and into the xylem. Once in the xylem, the mycelium remains exclusively in the xylem vessels and produces microconidia (asexual spores).[10] The microconidia are able to enter into the sap stream and are transported upward. Where the flow of the sap stops the microconidia germinate. Eventually the spores and the mycelia clog the vascular vessels, which prevents the plant from up-taking and translocating nutrients. In the end the plant transpires more than it can transport, the stomata close, the leaves wilt, and the plant dies. After the plant dies the fungus invades all tissues, sporulates, and continues to infect neighboring plants. ## Environment[edit] As previously stated F. oxysporum is a common soil saprophyte that infects a wide host range of plant species around the world. It has the ability to survive in most soil—arctic, tropical, desert, cultivated and non-cultivated.[1] Though Fusarium oxysporum may be found in many places and environments, development of the disease is favored by high temperatures and warm moist soils. The optimum temperature for growth on artificial media is between 25-30 °C, and the optimum soil temperature for root infection is 30 °C or above.[11] However, infection through the seed can occur at temperatures as low as 14 °C.[11] ## Management[edit] F. oxysporum is a major wilt pathogen of many economically important crop plants. It is a soil-borne pathogen, which can live in the soil for long periods of time, so rotational cropping is not a useful control method. It can also spread through infected dead plant material, so cleaning up at the end of the season is important. One control method is to improve soil conditions because F. oxysporum spreads faster through soils that have high moisture and bad drainage. Other control methods include planting resistant varieties, removing infected plant tissue to prevent overwintering of the disease, using soil and systemic fungicides to eradicate the disease from the soil, flood fallowing, and using clean seeds each year. Applying fungicides depends on the field environment. It is difficult to find a biological control method because research in a greenhouse can have different effects than testing in the field. The best control method found for F. oxysporum is planting resistant varieties, although not all have been bred for every forma specialis. F. oxysporum f. sp. batatas can be controlled by using clean seed, cleaning up infected leaf and plant material and breeding for resistance. Fungicides can also be used, but are not as effective as the other two because of field conditions during application. Fungicides can be used effectively by dip treating propagation material. Different races of F. oxysporum f. sp. cubense, Panama disease on banana, can be susceptible, resistant and partially resistant. It can be controlled by breeding for resistance and through eradication and quarantine of the pathogen by improving soil conditions and using clean plant material. Biological control can work using antagonists. Systemic and soil fungicides can also be used.[9] The main control method for F. oxysporum f. sp. lycopersici, vascular wilt on tomato, is resistance. Other effective control methods are fumigating the infected soil and raising the soil pH to 6.5-7.[8] The most effective way to control F. oxysporum f. sp. melonis is to graft a susceptible variety of melon to a resistant root-stock.[9] Resistant cultivars, liming the soil to change soil pH to 6-7, and reducing soil nitrogen levels also help control F. oxysporum f. sp. melonis.[12] The fungus Trichoderma viride is a proven biocontrol agent to control this disease in an environment friendly way. A company in India is manufacturing an Organic fungicide which can manage Fusarium wilt, the affected banana plants when treated the disease was managed and the plants bore fruits. The product is known by name Fungi-CeaZe and also known as Banana Care in parts of South America. The same product manages Fusarium wilt in cucumber, tomato and various other crops. ## Importance[edit] Because F. oxysporum is so widespread, it is a significant problem in many crops. It is economically damaging to the banana industry, and the threat of more virulent strains or mutations to damage previously resistant crops is of major concern. F. oxysporum also causes damage to many crops from the family Solanaceae, including potato, tomato, and pepper. Yield losses of effected crops can be high, up to 45% yield loss of tomato crop has been reported in India. Other commercially important plants affected include basil, beans, carnation, chrysanthemum, peas, and watermelon. Woody ornamentals are infected, but are usually not killed by Fusarium wilt alone. Palms, however, are the exception, and there are many species that can die from F. oxysporum infection.[13] Fusarium wilt's importance as a damaging disease on strawberry production is increasing. In South Korea, where Fusarium wilt is the most serious soil-borne disease of strawberry, losses in transplant production of up to 30% have been reported.[14] There is growing interest in using Fusarium wilt as a form of biological control. Certain pathogenic strains of F. oxysporum could be released to infect and control invasive weed species. This type of control (called a mycoherbicide) would be more targeted than herbicide applications, without the associated problems of chemical use. In addition. F. oxysporum may compete with other soil fungi that act as pathogens of important crops. Introducing specific strains of F. oxysporum that are not pathogenic (or non-infectious mutants of pathogens) to nearby crops could take nutrients from other potential disease-causing fungi.[1] Fusarium wilt (Panama disease) is the most serious disease of banana, threatening 80% of the world's banana production, most of which is planted with the susceptible Cavendish varieties. Bananas are a staple food in the diet of millions throughout the subtropics and tropics, and the spread of Panama disease could have devastating effects on both large scale production and subsistence farms.[15] ## Origin[edit] Members of F. oxysporum are present throughout the world's soils. However, before global transportation, many of the different varieties of the pathogen were isolated. Now, global trade has spread F. oxysporum inoculum with the crop. A recent example of this is the spread of Fusarium oxysporum f.sp. cubense which may have originated in Asia and just recently has appeared in banana producing areas in the South Pacific.[16] Inoculum can originate from many sources. F. oxysporum conidia and chlamydospores can attach to the outside of seeds. Commercial seed companies must practice proper sanitation techniques, or the seed can carry its own inoculum to the grower's field. This has been demonstrated with the seeds of various legumes, tomatoes, sugarbeet, aster, oil palm, and more. Vegetative cuttings can also carry inoculum or the live pathogen. Importantly, plants used for cuttings carrying no outward symptoms of infection may still transmit the pathogen. This has become a problem in some greenhouse floral crops like Chrysanthemum and Carnation. The pathogen's sporodochia and other inoculum sources may also be spread by soil movement and shipment of nonhost plants carried with infected soil. Certain rare soils are said to be "Fusarium-suppressive," that is, given two soils with high populations of infective F. oxysporum in the soil and the proper hosts, one soil will have a lower incidence of Fusarium wilt. Study of these soils is ongoing, but the decreased disease rate is thought to be due to other soil flora.[17] ## See also[edit] * Fusarium * Panama disease \- Fusarium wilt of banana * Fusarium Wilt \- A global threat to the banana ## External links[edit] * Fusarium and Verticillium Wilts of Tomato, Potato, Pepper, and Eggplant; * Fusarium oxysporum * Fusarium Wilt * Fusarium Wilt - A global threat to the banana ## References[edit] 1. ^ a b c d Snyder, W.C. and Hansen, H.N. 1940. The species concept in Fusarium. Am. J. Bot. 27:64-67. 2. ^ "Fusarium Wilt." Pan Germany. Pestizid Aktions-Netzwerk. Web. 23 Nov. 2010. 3. ^ Agrios, 1988; Smith et al., 1988 4. ^ Fusarium oxysporum. Andre K. Gonsalves and Stephen A. Ferreira. Department of Plant Pathology, CTAHR; University of Hawaii at Manoa. 5. ^ Gerlach, Wolfgang. Nirenberg, Helgard. Genus Fusarium: A Pictorial Atlas. Berlin-Dahlem. 1982 6. ^ Elliott, Monica. "Fusarium Wilt of Canary Island Date Palm". UF/IFAS Extension Service. Retrieved 2016-11-21. 7. ^ Booth, C. 1971. The Genus Fusarium. Commonwealth Agricultural Bureaux. 139. 8. ^ a b Fusarium oxysporum f. sp. lycopersici (Sacc.) W.C. Snyder and H.N. Hans. Prepared by Mui-Yun Wong. PP728 Soilborne Plant Pathogen Class Project, Spring 2003. 9. ^ a b c Booth, C. 1971. The Genus Fusarium. Commonwealth Agricultural Bureaux. 146. 10. ^ a b Agrios, George N. Plant Pathology. 5th ed. Amsterdam: Elsevier Academic, 2005. 522+. Print. 11. ^ a b W, Goss Russ. "FUSARIUM WILTS OF POTATO, THEIR DIFFERENTIATION AND THE EFFECT OF ENVIRONMENT UPON THEIR OCCURRENCE." American Potato Journal 7th ser. XIII (1936). Print. 12. ^ Fusarium Diseases of Cucurbits. Fact Sheet Page: 733.00 Date: 1-1998. Thomas A. Zitter, Department of Plant Pathology, Cornell University. 13. ^ Dreistadt, S.H. and Clark, J.K. 2004. Pests of Landscape Trees and Shrubs: an Integrated Pest Management Guide. ANR Publications. 233-34. 14. ^ Nam, M. H., et al. 2005\. Resistance analysis of cultivars and occurrence survey of Fusarium wilt on strawberry. Res. Plant Dis. 11: 35-38. 15. ^ Ploetz, Randy. 2005. Panama Disease: An Old Nemesis Rears its Ugly Head Part 2: The Cavendish Era and Beyond. 16. ^ Davis, Richard 2004. Fusarium wilt (Panama disease) of banana. Archived 2011-06-12 at the Wayback Machine Plant Protection Service. 17. ^ Mace, M.E. Bell, A.A. and Beckman, C.H. 1981. Fungal Wilt Diseases of Plants. Academic Press. 51-80. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Fusarium wilt	None	6,481	wikipedia	https://en.wikipedia.org/wiki/Fusarium_wilt	2021-01-18T18:57:58	{"wikidata": ["Q1475267"]}
Rickettsiosis SpecialtyInfectious disease A rickettsiosis is a disease caused by intracellular bacteria. ## Contents * 1 Cause * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Cause[edit] Rickettsioses can be divided into a spotted fever group (SPG) and typhus group (TG).[1] In the past, rickettsioses were considered to be caused by species of Rickettsia.[2] However, scrub typhus is still considered a rickettsiosis, even though the causative organism has been reclassified from Rickettsia tsutsugamushi to Orientia tsutsugamushi. Examples of rickettsioses include typhus, both endemic and epidemic, Rocky Mountain spotted fever, and Rickettsialpox. Organisms involved include Rickettsia parkeri.[3] Many new causative organisms have been identified in the last few decades.[4] Most are in the genus Rickettsia, but scrub typhus is in the genus Orientia.[5] ## Diagnosis[edit] No rapid laboratory tests are available to diagnose rickettsial diseases early in the course of illness, and serologic assays usually take 10–12 days to become positive. Research is indicating that swabs of eschars may be used for molecular detection of rickettsial infections.[6][7] ## Treatment[edit] Doxycycline has been used in the treatment of rickettsial infection.[8] ## References[edit] 1. ^ Choi YJ, Jang WJ, Ryu JS, et al. (February 2005). "Spotted fever group and typhus group rickettsioses in humans, South Korea". Emerging Infect. Dis. 11 (2): 237–44. doi:10.3201/eid1102.040603. PMC 3320442. PMID 15752441. 2. ^ Raoult D, Roux V (October 1997). "Rickettsioses as paradigms of new or emerging infectious diseases". Clin. Microbiol. Rev. 10 (4): 694–719. doi:10.1128/CMR.10.4.694. PMC 172941. PMID 9336669. 3. ^ Paddock CD, Finley RW, Wright CS, et al. (November 2008). "Rickettsia parkeri rickettsiosis and its clinical distinction from Rocky Mountain spotted fever". Clin. Infect. Dis. 47 (9): 1188–96. doi:10.1086/592254. PMID 18808353. 4. ^ Parola P, Paddock CD, Raoult D (October 2005). "Tick-Borne Rickettsioses around the World: Emerging Diseases Challenging Old Concepts". Clin. Microbiol. Rev. 18 (4): 719–56. doi:10.1128/CMR.18.4.719-756.2005. PMC 1265907. PMID 16223955. 5. ^ Unsworth NB, Stenos J, Faa AG, Graves SR (July 2007). "Three Rickettsioses, Darnley Island, Australia". Emerging Infect. Dis. 13 (7): 1105–7. doi:10.3201/eid1307.050088. PMC 2878210. PMID 18214193. 6. ^ Angelakis, Emmanouil; Richet, Hervé; Rolain, Jean-Marc; La Scola, Bernard; Raoult, Didier (2012). "Comparison of real-time quantitative PCR and culture for the diagnosis of emerging Rickettsioses". PLoS Neglected Tropical Diseases. 6 (3): e1540. doi:10.1371/journal.pntd.0001540. ISSN 1935-2735. PMC 3295807. PMID 22413026. 7. ^ Giulieri, Stefano; Jaton, Katia; Cometta, Alain; Trellu, Laurence T.; Greub, Gilbert (February 2012). "Development of a duplex real-time PCR for the detection of Rickettsia spp. and typhus group rickettsia in clinical samples" (PDF). FEMS Immunology and Medical Microbiology. 64 (1): 92–97. doi:10.1111/j.1574-695X.2011.00910.x. ISSN 1574-695X. PMID 22098502. 8. ^ "eMedicine - Rickettsial Infection : Article by Mobeen H Rathore". ## External links[edit] * Media related to Rickettsioses at Wikimedia Commons Classification D * ICD-10: A75-A79 * ICD-9-CM: 080-083 * MeSH: D012288 External resources * eMedicine: ped/2015 * v * t * e Proteobacteria-associated Gram-negative bacterial infections α Rickettsiales Rickettsiaceae/ (Rickettsioses) Typhus * Rickettsia typhi * Murine typhus * Rickettsia prowazekii * Epidemic typhus, Brill–Zinsser disease, Flying squirrel typhus Spotted fever Tick-borne * Rickettsia rickettsii * Rocky Mountain spotted fever * Rickettsia conorii * Boutonneuse fever * Rickettsia japonica * Japanese spotted fever * Rickettsia sibirica * North Asian tick typhus * Rickettsia australis * Queensland tick typhus * Rickettsia honei * Flinders Island spotted fever * Rickettsia africae * African tick bite fever * Rickettsia parkeri * American tick bite fever * Rickettsia aeschlimannii * Rickettsia aeschlimannii infection Mite-borne * Rickettsia akari * Rickettsialpox * Orientia tsutsugamushi * Scrub typhus Flea-borne * Rickettsia felis * Flea-borne spotted fever Anaplasmataceae * Ehrlichiosis: Anaplasma phagocytophilum * Human granulocytic anaplasmosis, Anaplasmosis * Ehrlichia chaffeensis * Human monocytotropic ehrlichiosis * Ehrlichia ewingii * Ehrlichiosis ewingii infection Rhizobiales Brucellaceae * Brucella abortus * Brucellosis Bartonellaceae * Bartonellosis: Bartonella henselae * Cat-scratch disease * Bartonella quintana * Trench fever * Either B. henselae or B. quintana * Bacillary angiomatosis * Bartonella bacilliformis * Carrion's disease, Verruga peruana β Neisseriales M+ * Neisseria meningitidis/meningococcus * Meningococcal disease, Waterhouse–Friderichsen syndrome, Meningococcal septicaemia M− * Neisseria gonorrhoeae/gonococcus * Gonorrhea ungrouped: * Eikenella corrodens/Kingella kingae * HACEK * Chromobacterium violaceum * Chromobacteriosis infection Burkholderiales * Burkholderia pseudomallei * Melioidosis * Burkholderia mallei * Glanders * Burkholderia cepacia complex * Bordetella pertussis/Bordetella parapertussis * Pertussis γ Enterobacteriales (OX−) Lac+ * Klebsiella pneumoniae * Rhinoscleroma, Pneumonia * Klebsiella granulomatis * Granuloma inguinale * Klebsiella oxytoca * Escherichia coli: Enterotoxigenic * Enteroinvasive * Enterohemorrhagic * O157:H7 * O104:H4 * Hemolytic-uremic syndrome * Enterobacter aerogenes/Enterobacter cloacae Slow/weak * Serratia marcescens * Serratia infection * Citrobacter koseri/Citrobacter freundii Lac− H2S+ * Salmonella enterica * Typhoid fever, Paratyphoid fever, Salmonellosis H2S− * Shigella dysenteriae/sonnei/flexneri/boydii * Shigellosis, Bacillary dysentery * Proteus mirabilis/Proteus vulgaris * Yersinia pestis * Plague/Bubonic plague * Yersinia enterocolitica * Yersiniosis * Yersinia pseudotuberculosis * Far East scarlet-like fever Pasteurellales Haemophilus: * H. influenzae * Haemophilus meningitis * Brazilian purpuric fever * H. ducreyi * Chancroid * H. parainfluenzae * HACEK Pasteurella multocida * Pasteurellosis * Actinobacillus * Actinobacillosis Aggregatibacter actinomycetemcomitans * HACEK Legionellales * Legionella pneumophila/Legionella longbeachae * Legionnaires' disease * Coxiella burnetii * Q fever Thiotrichales * Francisella tularensis * Tularemia Vibrionaceae * Vibrio cholerae * Cholera * Vibrio vulnificus * Vibrio parahaemolyticus * Vibrio alginolyticus * Plesiomonas shigelloides Pseudomonadales * Pseudomonas aeruginosa * Pseudomonas infection * Moraxella catarrhalis * Acinetobacter baumannii Xanthomonadaceae * Stenotrophomonas maltophilia Cardiobacteriaceae * Cardiobacterium hominis * HACEK Aeromonadales * Aeromonas hydrophila/Aeromonas veronii * Aeromonas infection ε Campylobacterales * Campylobacter jejuni * Campylobacteriosis, Guillain–Barré syndrome * Helicobacter pylori * Peptic ulcer, MALT lymphoma, Gastric cancer * Helicobacter cinaedi * Helicobacter cellulitis This infectious disease article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Rickettsiosis	c0035585	6,482	wikipedia	https://en.wikipedia.org/wiki/Rickettsiosis	2021-01-18T19:08:18	{"mesh": ["D012282", "D012288"], "icd-9": ["083", "083.9", "080"], "icd-10": ["A75", "A79"], "orphanet": ["102021"], "wikidata": ["Q646664"]}
Chondrodermatitis nodularis chronica helicis Other namesChondrodermatitis nodularis helicis[1]:782 Chondrodermatitis helicis nodularis in a 67-year-old man SpecialtyDermatology Chondrodermatitis nodularis chronica helicis is a small, nodular, tender, chronic inflammatory lesion occurring on the helix of the ear, most often in men.[2]:610 * Histopathology, showing an ulceration surrounded by acanthosis and parakeratosis, with absence of atypia. ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. This Dermal and subcutaneous growths article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Chondrodermatitis nodularis chronica helicis	c0271415	6,483	wikipedia	https://en.wikipedia.org/wiki/Chondrodermatitis_nodularis_chronica_helicis	2021-01-18T18:47:28	{"wikidata": ["Q1076057"]}
This article may be confusing or unclear to readers. Please help us clarify the article. There might be a discussion about this on the talk page. (January 2010) (Learn how and when to remove this template message) Focal dermal hypoplasia Other namesGoltz syndrome This condition is inherited in an X-linked dominant manner. SpecialtyMedical genetics Focal dermal hypoplasia is a form of ectodermal dysplasia.[1] It is a multisystem disorder characterized primarily by skin manifestations to the atrophic and hypoplastic areas of skin which are present at birth. These defects manifest as yellow-pink bumps on the skin and pigmentation changes.[2] The disorder is also associated with shortness of stature and some evidence suggests that it can cause epilepsy.[3] ## Contents * 1 Genetics * 2 Diagnosis * 3 Treatment * 4 Eponyms * 4.1 Jessner-Cole syndrome * 4.2 Goltz-Gorlin * 5 See also * 6 References * 7 External links ## Genetics[edit] The molecular Location of the PORCN gene on the X chromosome: base pairs 48,367,346 to 48,379,201 Focal dermal hypoplasia has been associated with PORCN gene mutations on the X chromosome.[4] 90% of the individuals who are affected with the syndrome are female: the commonly accepted, though unconfirmed, explanation for this is that the non-mosaic hemizygous males are not viable.[5] The differential diagnosis of focal dermal hypoplasia (Goltz) syndrome includes autosomal recessive Setleis syndrome due to TWIST2 gene mutations. It associated with morning glory anomaly, polymicrogyria, incontinentia pigmenti, oculocerebrocutaneous syndrome, Rothmund-Thomson syndrome and microphthalmia with linear skin defects (also known as MLS) syndrome because they are all caused by deletions or point mutations in the HCCS gene.[6] ## Diagnosis[edit] Goltz Syndrome is a very rare diagnosis. To date, there are under 25 cases of Goltz Syndrome in the United States.[7] ## Treatment[edit] Management is targeted toward the various soft tissue and skeletal anomalies, with the goal of achieving optimal functional and cosmetic results.[citation needed] ## Eponyms[edit] ### Jessner-Cole syndrome[edit] The disorder was first formally recognized by dermatologists, Max Jessner and Harold Newton Cole, in the early 20th century. Jessner and Cole's papers were referenced more than any others in the first half of the 20th century.[8][9] ### Goltz-Gorlin[edit] Besides its formal name, it is most commonly referred to as Goltz-Gorlin syndrome, after Robert Goltz and Robert Gorlin.[10] Goltz and Gorlin worked together at Columbia University [11] and are credited for describing the symptoms of the disorder in more detail than ever before and tracking its genetic trends. The name became popular during the second half of the 20th century. ## See also[edit] * List of cutaneous conditions * List of radiographic findings associated with cutaneous conditions ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. ISBN 978-0-7216-2921-6. 2. ^ Goltz RW, Henderson RR, Hitch JM, Ott JE (2008). "Focal dermal hypoplasia syndrome. A review of the literature and report of two cases". Archives of Dermatology. GeneReviews. 101 (1): 1–11. doi:10.1001/archderm.101.1.1. PMID 5416790. 3. ^ Kanemura H, Hatakeyama K, Sugita K, Aihara M (2011). "Epilepsy in a patient with focal dermal hypoplasia". Pediatric Neurology. 44 (2): 135–8. doi:10.1016/j.pediatrneurol.2010.08.003. PMID 21215914. 4. ^ Wang X, Reid Sutton V, Omar Peraza-Llanes J, et al. (July 2007). "Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia". Nat. Genet. 39 (7): 836–8. doi:10.1038/ng2057. PMID 17546030. S2CID 3184143. 5. ^ Sutton, Reid. Veyver; Ignatia B Van den Veyver (1970). "Focal Dermal Hypoplasia". Arch. Dermatol. 6. ^ Wimplinger I, Shaw GM, Kutsche K, et al. (Aug 2007). "HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations?". Mol Vis. 13: 1475–82. PMID 17893649. 7. ^ Carol, Koby (host) (January 7, 2015). "From Adversity Comes Invention: A Mother and Daughter's Story". All About Living. 12:00 minutes in. 97.7 FM Madison. 8. ^ Jessner: Naeviforme poikilodermieartige Hautveränderungen mit Missbildungen. Zentralblatt für Haut- und Geschlechtskrankheiten, 1928, 27: 468. 9. ^ H. N. Cole, et al: Ectodermal and mesodermal dysplasia with osseous involvement. Archiv für Dermatologie und Syphilis, Berlin, 1941, 44: 773-788. 10. ^ synd/1370 at Who Named It? 11. ^ R. W. Goltz, W. C. Peterson, R. J. Gorlin, H. G. Ravits: Focal dermal hypoplasia. Archives of Dermatology, Chicago, 1962, 86: 708-717. ## External links[edit] * http://www.orpha.net/consor/www/cgi-bin/OC_Exp.php?lng=EN&Expert=2092 * GeneReview/NIH/UW entry on Focal dermal hypoplasia Classification D * ICD-10: Q82.8 * ICD-9-CM: 759.89 * OMIM: 305600 * MeSH: D005489 * DiseasesDB: 29896 External resources * eMedicine: derm/155 * GeneReviews: Focal Dermal Hypoplasia * Orphanet: 2092 * v * t * e Congenital malformations and deformations of integument / skin disease Genodermatosis Congenital ichthyosis/ erythrokeratodermia AD * Ichthyosis vulgaris AR * Congenital ichthyosiform erythroderma: Epidermolytic hyperkeratosis * Lamellar ichthyosis * Harlequin-type ichthyosis * Netherton syndrome * Zunich–Kaye syndrome * Sjögren–Larsson syndrome XR * X-linked ichthyosis Ungrouped * Ichthyosis bullosa of Siemens * Ichthyosis follicularis * Ichthyosis prematurity syndrome * Ichthyosis–sclerosing cholangitis syndrome * Nonbullous congenital ichthyosiform erythroderma * Ichthyosis linearis circumflexa * Ichthyosis hystrix EB and related * EBS * EBS-K * EBS-WC * EBS-DM * EBS-OG * EBS-MD * EBS-MP * JEB * JEB-H * Mitis * Generalized atrophic * JEB-PA * DEB * DDEB * RDEB * related: Costello syndrome * Kindler syndrome * Laryngoonychocutaneous syndrome * Skin fragility syndrome Ectodermal dysplasia * Naegeli syndrome/Dermatopathia pigmentosa reticularis * Hay–Wells syndrome * Hypohidrotic ectodermal dysplasia * Focal dermal hypoplasia * Ellis–van Creveld syndrome * Rapp–Hodgkin syndrome/Hay–Wells syndrome Elastic/Connective * Ehlers–Danlos syndromes * Cutis laxa (Gerodermia osteodysplastica) * Popliteal pterygium syndrome * Pseudoxanthoma elasticum * Van der Woude syndrome Hyperkeratosis/ keratinopathy PPK * diffuse: Diffuse epidermolytic palmoplantar keratoderma * Diffuse nonepidermolytic palmoplantar keratoderma * Palmoplantar keratoderma of Sybert * Meleda disease * syndromic * connexin * Bart–Pumphrey syndrome * Clouston's hidrotic ectodermal dysplasia * Vohwinkel syndrome * Corneodermatoosseous syndrome * plakoglobin * Naxos syndrome * Scleroatrophic syndrome of Huriez * Olmsted syndrome * Cathepsin C * Papillon–Lefèvre syndrome * Haim–Munk syndrome * Camisa disease * focal: Focal palmoplantar keratoderma with oral mucosal hyperkeratosis * Focal palmoplantar and gingival keratosis * Howel–Evans syndrome * Pachyonychia congenita * Pachyonychia congenita type I * Pachyonychia congenita type II * Striate palmoplantar keratoderma * Tyrosinemia type II * punctate: Acrokeratoelastoidosis of Costa * Focal acral hyperkeratosis * Keratosis punctata palmaris et plantaris * Keratosis punctata of the palmar creases * Schöpf–Schulz–Passarge syndrome * Porokeratosis plantaris discreta * Spiny keratoderma * ungrouped: Palmoplantar keratoderma and spastic paraplegia * desmoplakin * Carvajal syndrome * connexin * Erythrokeratodermia variabilis * HID/KID Other * Meleda disease * Keratosis pilaris * ATP2A2 * Darier's disease * Dyskeratosis congenita * Lelis syndrome * Dyskeratosis congenita * Keratolytic winter erythema * Keratosis follicularis spinulosa decalvans * Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome * Keratosis pilaris atrophicans faciei * Keratosis pilaris Other * cadherin * EEM syndrome * immune system * Hereditary lymphedema * Mastocytosis/Urticaria pigmentosa * Hailey–Hailey see also Template:Congenital malformations and deformations of skin appendages, Template:Phakomatoses, Template:Pigmentation disorders, Template:DNA replication and repair-deficiency disorder Developmental anomalies Midline * Dermoid cyst * Encephalocele * Nasal glioma * PHACE association * Sinus pericranii Nevus * Capillary hemangioma * Port-wine stain * Nevus flammeus nuchae Other/ungrouped * Aplasia cutis congenita * Amniotic band syndrome * Branchial cyst * Cavernous venous malformation * Accessory nail of the fifth toe * Bronchogenic cyst * Congenital cartilaginous rest of the neck * Congenital hypertrophy of the lateral fold of the hallux * Congenital lip pit * Congenital malformations of the dermatoglyphs * Congenital preauricular fistula * Congenital smooth muscle hamartoma * Cystic lymphatic malformation * Median raphe cyst * Melanotic neuroectodermal tumor of infancy * Mongolian spot * Nasolacrimal duct cyst * Omphalomesenteric duct cyst * Poland anomaly * Rapidly involuting congenital hemangioma * Rosenthal–Kloepfer syndrome * Skin dimple * Superficial lymphatic malformation * Thyroglossal duct cyst * Verrucous vascular malformation * Birthmark * v * t * e X-linked disorders X-linked recessive Immune * Chronic granulomatous disease (CYBB) * Wiskott–Aldrich syndrome * X-linked severe combined immunodeficiency * X-linked agammaglobulinemia * Hyper-IgM syndrome type 1 * IPEX * X-linked lymphoproliferative disease * Properdin deficiency Hematologic * Haemophilia A * Haemophilia B * X-linked sideroblastic anemia Endocrine * Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy * KAL1 Kallmann syndrome * X-linked adrenal hypoplasia congenita Metabolic * Amino acid: Ornithine transcarbamylase deficiency * Oculocerebrorenal syndrome * Dyslipidemia: Adrenoleukodystrophy * Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency * Pyruvate dehydrogenase deficiency * Danon disease/glycogen storage disease Type IIb * Lipid storage disorder: Fabry's disease * Mucopolysaccharidosis: Hunter syndrome * Purine–pyrimidine metabolism: Lesch–Nyhan syndrome * Mineral: Menkes disease/Occipital horn syndrome Nervous system * X-linked intellectual disability: Coffin–Lowry syndrome * MASA syndrome * Alpha-thalassemia mental retardation syndrome * Siderius X-linked mental retardation syndrome * Eye disorders: Color blindness (red and green, but not blue) * Ocular albinism (1) * Norrie disease * Choroideremia * Other: Charcot–Marie–Tooth disease (CMTX2-3) * Pelizaeus–Merzbacher disease * SMAX2 Skin and related tissue * Dyskeratosis congenita * Hypohidrotic ectodermal dysplasia (EDA) * X-linked ichthyosis * X-linked endothelial corneal dystrophy Neuromuscular * Becker's muscular dystrophy/Duchenne * Centronuclear myopathy (MTM1) * Conradi–Hünermann syndrome * Emery–Dreifuss muscular dystrophy 1 Urologic * Alport syndrome * Dent's disease * X-linked nephrogenic diabetes insipidus Bone/tooth * AMELX Amelogenesis imperfecta No primary system * Barth syndrome * McLeod syndrome * Smith–Fineman–Myers syndrome * Simpson–Golabi–Behmel syndrome * Mohr–Tranebjærg syndrome * Nasodigitoacoustic syndrome X-linked dominant * X-linked hypophosphatemia * Focal dermal hypoplasia * Fragile X syndrome * Aicardi syndrome * Incontinentia pigmenti * Rett syndrome * CHILD syndrome * Lujan–Fryns syndrome * Orofaciodigital syndrome 1 * Craniofrontonasal dysplasia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Focal dermal hypoplasia	c0016395	6,484	wikipedia	https://en.wikipedia.org/wiki/Focal_dermal_hypoplasia	2021-01-18T18:53:29	{"gard": ["6457"], "mesh": ["D005489"], "umls": ["C0016395"], "icd-9": ["759.89"], "icd-10": ["Q82.8"], "orphanet": ["2092"], "wikidata": ["Q5463847"]}
A number sign (#) is used with this entry because of evidence that some patients with Cohen syndrome have homozygous or compound heterozygous mutations in the COH1 gene (VPS13B; 607817) on chromosome 8q22. Description Cohen syndrome is an autosomal recessive multisystem disorder characterized by many clinical features, including facial dysmorphism, microcephaly, truncal obesity, intellectual disability, progressive retinopathy, and intermittent congenital neutropenia (summary by Duplomb et al., 2014). Clinical Features Cohen syndrome is one of the rare autosomal recessive disorders that are overrepresented in the Finnish population (Norio, 2003). The phenotype in Finnish patients is highly homogeneous, consisting of nonprogressive mild to severe psychomotor retardation, motor clumsiness, microcephaly, characteristic facial features, childhood hypotonia and joint laxity, progressive retinochoroidal dystrophy, myopia, intermittent isolated neutropenia, and a cheerful disposition. Characteristic facial features include high-arched or wave-shaped eyelids, a short philtrum, thick hair, and low hairline. Kolehmainen et al. (2003) stated that in non-Finnish patients thought to have Cohen syndrome, a confusing phenotypic variability prevails. Obesity, although frequently mentioned as a characteristic finding, is insignificant. On the other hand, there is no proof of retinochoroidal dystrophy or intermittent neutropenia in reports of some patients. Chandler et al. (2003) studied 33 non-Finnish patients with Cohen syndrome and concluded that Cohen syndrome has a distinctive clinical phenotype identifiable not only in Finnish patients but also in other genetically diverse patient groups. Cohen et al. (1973) described a brother and sister and an unrelated patient with hypotonia, obesity, high nasal bridge, and prominent incisors as well as mental deficiency. Carey and Hall (1978) reported 4 additional patients. Sack and Friedman (1980) observed the syndrome in a 10-year-old girl with excessive height and floppy mitral valve. Intrafamilial variability suggested that the diagnosis may often be difficult. Kousseff (1981) described 4 affected sibs (2 of each sex) with moderate mental retardation, microcephaly, hypotonia, high nasal bridge, and narrow hands and feet with elongated fingers and toes. Three sibs were short of stature. Friedman and Sack (1982) reported 5 additional cases in 4 families, strengthening the conclusion of autosomal recessive inheritance. Mental retardation, high nasal bridge, prominent central incisors with open mouth, maxillary malar hypoplasia, and antimongoloid slant of the eyes were features. They suggested that the disorder may have a relatively high frequency in Ashkenazi Jews. Since 1968, Norio et al. (1984) had observed patients with the same disorder, known by them as the 'Pepper syndrome,' from the family name. By 1984, they found reports of 25 cases (Balestrazzi et al., 1980; Goecke et al., 1982) and added 6 Finnish patients. Norio et al. (1984) added chorioretinal dystrophy and granulocytopenia to the clinical features and observed parental consanguinity in 2 instances. Ophthalmologic findings included decreased visual acuity, hemeralopia (see 310500 for a discussion of the use of the terms hemeralopia and nyctalopia), constricted visual fields, chorioretinal dystrophy with bull's-eye-like maculae and pigmentary deposits, optic atrophy, and isoelectric electroretinogram. Fuhrmann-Rieger et al. (1984) pointed out the similarities of the Prader-Willi syndrome (176270) and Cohen syndrome. (See also Fraccaro et al., 1983). North et al. (1985) reported 6 cases in 4 sibships. Periureteric obstruction and epilepsy were reported as possible new features. In Israel, where the Cohen syndrome seems to be unusually frequent, Sack and Friedman (1986) studied 39 patients in 32 families. Neutropenia and chorioretinal dysplasia, 2 manifestations found in all Finnish patients by Norio et al. (1984), were not found in any of these patients. Incorrect diagnoses included Marfan syndrome, Sotos syndrome, hypothyroidism, minimal brain dysfunction, and, most frequently, 'mental retardation of an unknown cause,' illustrating the difficulty of being certain of the diagnosis. Young and Moore (1987) described 3 affected sibs. Abnormalities present in all 3 children included mental retardation, hypotonia, and short philtrum with open mouth and prominent lips. Whereas the 2 older sibs had similar facies and an engaging personality, the youngest had a different facial appearance and marked behavioral problems. Mehes et al. (1988) found mitral valve prolapse and severe gastroesophageal reflux with hiatal hernia in an affected girl aged 2 years and 4 months. These observations, along with others previously reported, suggested that Cohen syndrome may be a connective tissue disorder. Kondo et al. (1990) described 2 affected brothers from a consanguineous marriage who also had leukopenia and mottled retina. Kondo et al. (1990) pointed out that mottled retina had been observed in 22 of 87 patients and that it appears to be family- and ethnic-specific. Among 19 familial cases, mottled retina was observed in all affected sibs from 5 families, but in 13 families none of the affected sibs had mottled retinas. All Finnish patients had the mottled retina, but this was noted in only 1 of 39 Jewish patients. Based on these observations, Kondo et al. (1990) suggested that there are 2 alleles at the gene locus for the Cohen syndrome: one for a Finnish type with mottled retina and the other for a Jewish type without retinal anomalies. They concurred with Norio and Raitta (1986) that the Mirhosseini-Holmes-Walton syndrome (268050) is the same as Cohen syndrome, or at least an allelic disorder. Steinlein et al. (1991) described 2 brothers with findings fitting the diagnosis of both the Cohen and the Mirhosseini-Holmes-Walton syndromes but also showing severe ocular manifestations. Tapetoretinal degeneration was documented by histopathologic studies. The younger brother suffered total retinal detachment bilaterally, requiring enucleation. Warburg et al. (1990) were of the opinion that a retinitis pigmentosa-like tapetoretinal degeneration is an 'obligatory sign' in patients with Cohen syndrome. Their patient also had granulocytopenia. Massa et al. (1991) described isolated growth hormone deficiency in a girl with Cohen syndrome. Satisfactory catch-up growth occurred after treatment with biosynthetic human growth hormone. Fryns et al. (1991) reported a successful pregnancy in a 26-year-old woman with presumed Cohen syndrome. Her offspring had slight psychomotor retardation but was not thought to have the Cohen syndrome. Norio (1993) indicated that the diagnosis of Cohen syndrome is suggested by the short philtrum (which is unable to cover the upper incisors), prominent root of the nose, and prominent upper central incisors. The feet are often small, and there is usually an increased space between toes 1 and 2 ('sandal groove'). The neutropenia is intermittent and harmless. Higgins et al. (1994) demonstrated pyridoxine-responsive hyper-beta-alaninemia in a 4-year-old girl with some features of Cohen syndrome. She had crooked teeth, a small philtrum, narrow hands, and global developmental delay. Ophthalmic examination was not reported and there was no mention of obesity. Schlichtemeier et al. (1994) described probable Cohen syndrome in African American brother and sister. The brother, who presented at age 13 years with new-onset seizures, sagittal sinus thrombosis with cerebral hemorrhage, and extensive venous thrombosis of the lower limbs, showed combined deficiency of protein C, protein S, and antithrombin III. Carotid aneurysm and tortuous descending aorta were also present. Schlichtemeier et al. (1994) suggested that vasculopathy may be an integral part of the Cohen syndrome. North et al. (1995) reported the cases of identical female twins with Cohen syndrome. They presented with retinal degeneration, obesity, and mental retardation, and had the characteristic facial appearance. Unusual features of the twins included tall stature, macrocephaly, and transient cardiomyopathy during the first year of life. Precocious puberty was present in both girls; the development of breast buds and axillary hair was noted at the age 7.5 years. Kivitie-Kallio et al. (1997) reported hematologic data on 26 Finnish patients with Cohen syndrome. All had experienced periods of isolated granulocytopenia from an early age. Granulocytopenia was mild to moderate, noncyclic, and never fatal. Most patients suffered from prolonged or repeated gingival or skin infections. In 16 patients studied in detail, bone marrow examination showed a normo- or hypercellular marrow, with a left-shifted granulopoiesis in 8 of the 16 patients. The response to adrenaline stimulation was subnormal in 12 of 14 and to hydrocortisone in 8 of 16 patients, but administration of recombinant GCSF (138970) caused granulocytosis in the 3 patients studied. No bone marrow malignancies were seen. Olivieri et al. (1998) studied the bone marrow and the functional properties of neutrophils obtained from peripheral blood or skin window exudates from a patient with Cohen syndrome. Neutrophil adhesive capability was greatly increased in this patient. Cytofluorometric expression of CD11B (120980) and CD62L molecules were consistent with a generalized neutrophil activation in vivo. The patient was a 22-year-old girl with neutropenia and recurrent gingivitis. A tentative diagnosis of Prader-Willi syndrome had been made in childhood. However, her features, including obesity, hypotonia, microcephaly, chorioretinal dystrophy, high nasal bridge, narrow hands and feet, narrow and high-arched palate, and prominent central incisors, were more consistent with Cohen syndrome. In 3 patients with Cohen syndrome, Okamoto et al. (1998) found a remarkably high level of urinary hyaluronic acid. They pointed out that hyperhyaluronic aciduria is a characteristic finding in Werner syndrome (277700) and some other conditions. Okamoto et al. (1998) suggested that the basic defect in Cohen syndrome involves a metabolic abnormality in the extracellular matrix. Kivitie-Kallio et al. (1998) performed MRI on 18 patients with Cohen syndrome and 26 healthy volunteers. The main finding was a relatively enlarged corpus callosum. A relatively enlarged corpus callosum in a microcephalic head and normal signal intensities of the gray and white matters supports a clinical suspicion of Cohen syndrome. Kivitie-Kallio et al. (1999) evaluated cardiac, endocrine, and radiologic abnormalities in 22 patients of Finnish descent with Cohen syndrome. No evidence for clinically significant mitral prolapse was found; however, a decreased left ventricular function with advancing age was identified. No significant endocrine abnormalities were found in examination of pituitary, adrenal, and thyroid function. The patients were either of normal height or were moderately short at all ages, often associated with marked kyphosis. Truncal obesity was seen in 4 of the 22 patients. X-rays of the chest, lumbar and thoracic spine, long bones, ankles, and metacarpophalangeal pattern profiles revealed kyphosis, scoliosis, and calcaneo planovalgus as common features. Fingers of these patients were slender but short with a characteristic metacarpophalangeal pattern profile. Horn et al. (2000) reported 2 brothers and a cousin from a multiply consanguineous kindred of Lebanese descent with a syndrome of microcephaly, progressive postnatal growth deficiency, mental retardation, hypotonia, chorioretinal dystrophy, and myopia. The severity of the condition varied among the affected family members. Kivitie-Kallio et al. (2000) reported ophthalmologic findings from 22 Finnish patients with Cohen syndrome. Hurmerinta et al. (2002) pointed to the fact that Cohen syndrome is relatively common in Finland, where 35 patients had been diagnosed. They obtained anthropometric measurements of the head and face of 22 patients, and cephalometric radiographs of 14 patients. Anthropometric analysis confirmed and quantified the small head size. Width of the upper face was close to normal but width of the lower face was small. The philtrum was shorter than in healthy controls. Measurements from standardized radiographs showed short cranial base dimensions but normal cranial base angles. Most patients had forward-inclined upper incisors and maxillary prognathia. De Ravel et al. (2002) reevaluated a brother and sister, the offspring of first cousins, who were originally reported by Buntinx et al. (1991) as representing an apparently new syndrome of mental retardation, short stature, unusual face, radioulnar synostosis, and retinal pigment abnormalities. De Ravel et al. (2002) concluded that the 55-year-old brother and 52-year-old sister had Cohen syndrome. Both had neutropenia and the male had persistent fluctuating thrombocytopenia. De Ravel et al. (2002) stated that asymptomatic thrombocytopenia had not previously been reported in Cohen syndrome. In their series of 33 non-Finnish patients with Cohen syndrome, Chandler et al. (2003) identified laryngeal abnormalities, including laryngomalacia, laryngeal stenosis, and vocal cord paralysis, as an associated feature. Karpf et al. (2004) reported findings on cognitive, linguistic, and adaptive profiles in a group of 45 individuals clinically diagnosed with Cohen syndrome at ages varying from 4 to 49 years. Independence levels were generally poor, but socialization skills were relatively less impaired. This particular area of strength was thought to underlie the 'sociable' temperament typically associated with Cohen syndrome. The range of cognitive ability was wider in this study than reported in most previous studies, raising the issue of whether mental retardation should be considered a necessary component of the phenotype. Kolehmainen et al. (2004) undertook an extensive molecular assessment of 76 patients from 59 families with a provisional diagnosis of Cohen syndrome and correlated molecular and clinical findings. The patients were assessed for the following 8 clinical criteria: developmental delay, microcephaly, typical Cohen syndrome facial gestalt, truncal obesity with slender extremities, overly sociable behavior, joint hypermobility, high myopia and/or retinal dystrophy, and neutropenia. Patients fulfilling 6 or more criteria were considered likely to have true Cohen syndrome. Those with lower scores (5 of 8 or fewer) were considered provisionally to have a Cohen-like syndrome. Kolehmainen et al. (2004) found 22 different COH1 mutations, of which 19 were novel, in probands identified by these diagnostic criteria. In addition, they identified another 3 novel mutations in patients with incomplete clinical data. By contrast, no COH1 mutations were found in patients with a provisional diagnosis of Cohen syndrome who were labeled 'Cohen-like.' Falk et al. (2004) described 8 members of 2 large Amish kindreds who had early-onset pigmentary retinopathy and myopia, global developmental delay and mental retardation, microcephaly, short stature, hypotonia, joint hyperextensibility, small hands and feet, and a friendly disposition. Several of the children had intermittent granulocytopenia. Affected individuals shared a common facial appearance involving mild synophrys, hypertelorism, wide and wave-shaped palpebral fissures, low nasal bridge with a pinched root and bulbous tip, smooth philtrum, thin upper lip, and hypotonic facies. They appeared to grimace when smiling. Although the facial gestalt was considered inconsistent with the diagnosis of Cohen syndrome, sequencing of the COH1 gene revealed compound homozygosity in all affected individuals for both a frameshift (607817.0009) and a missense (607817.0010) mutation in the COH1 gene. Falk et al. (2004) concluded that facial gestalt is an unreliable indicator of Cohen syndrome between ethnic populations, although it is consistent among affected individuals within a particular ethnic group. Waite et al. (2010) reported 3 patients, including 2 patients of Pakistani descent from a consanguineous kindred who were distally related, with genetically confirmed Cohen syndrome. All had the typical facial appearance, developmental delay, and ocular anomalies, and all also had cerebellar hypoplasia on brain imaging, which Waite et al. (2010) concluded may be a feature of this disorder. Rivera-Brugues et al. (2011) reported 3 patients with genetically confirmed Cohen syndrome who were younger than 3 years of age. None had neutropenia, and only 1 had mildly increased pigmentation of the retina. Common features included hypotonic facial expression, almond-shaped eyes, prominent nose, short philtrum, delayed psychomotor development, and mental retardation. The authors noted that the facial phenotype and some additional features of the disorder change with time. ### Clinical Variability Gueneau et al. (2014) described a 33-year-old woman who had recurrent infections in infancy and childhood, and was diagnosed with chronic and intermittent neutropenia. Speech and motor development was normal. At 25 years of age, she had reduced visual fields and retinal abnormalities, and was diagnosed with retinal dystrophy. Upon examination at 33 years of age, she had short stature, borderline microcephaly, and the typical facial gestalt for Cohen syndrome: facial dysmorphism included moderate downslanting palpebral fissures, convex and high nasal bridge, malar hypoplasia, short philtrum, and mild ptosis. She had slender extremities but no joint hypermobility or truncal obesity. In addition, her intellectual development was normal; she had attended high school and had a reported IQ of 100. Funduscopy revealed moderate pigmentary retinopathy with rare bone spicule-shaped pigment deposits in the periphery and macular edema. Electroretinography revealed severely decreased responses in both scotopic and photopic conditions, indicating that both rod and cone photoreceptor responses were impaired. Megarbane et al. (2001) described a nonconsanguineous Lebanese family in which 2 brothers had a seemingly distinct syndrome comprising microcephaly, primary cutis verticis gyrata, progressive retinitis pigmentosa, cataracts, sensorineural hearing loss, and mental retardation. The brothers were 41 and 53 years of age. In the older brother the scalp features had appeared 10 years earlier. In the younger brother visual problems became obvious at age 12 and the auditory problem at age 30. Night blindness had been noted from age 20. By a genomewide scan in this family, Megarbane et al. (2009) found a region of homozygosity by descent in the region of chromosome 8 containing the VPS13B gene. Sequencing of this gene identified a homozygous mutation (607817.0016) in the affected brothers that segregated with the disorder in the family. Megarbane et al. (2009) noted that the features in the brothers were compatible with Cohen syndrome with the additional features of cutis verticis gyrata and sensorineural deafness. They also noted that the hearing loss and cutis verticis gyrata could be caused by mutations in a different gene and locus, but that their linkage data did not support the presence of another causative homozygous locus and no deafness gene or locus had been identified on chromosome 8q. Because cutis verticis gyrata is frequently associated with mental retardation, they suggested that it may be a rare manifestation of Cohen syndrome. Biochemical Features Duplomb et al. (2014) found that the serum proteins of 11 patients with genetically confirmed Cohen syndrome showed an unusual pattern of glycosylation characterized by a significant accumulation of agalactosylated fucosylated structures, as well as asialylated fucosylated structures, suggesting a defect of N-glycosylation in the Golgi. Glycosylation of the intracellular proteins ICAM1 (147840) and LAMP2 (309060) also showed an abnormal profile pattern. However, serum transferrin and a alpha-1-antitrypsin (SERPINA1; 107400) were normal. In vitro knockdown of VPS13B confirmed these glycosylation defects. Patient fibroblasts showed alterations in Golgi morphology, decreased or absent early endosomes, and abnormally enlarged lysosomes, suggesting a crucial role for VPS13B in endosomal-lysosomal trafficking. The findings indicated that Cohen syndrome is associated with major glycosylation defects, which may contribute to the phenotype. Diagnosis Kivitie-Kallio and Norio (2001) reported the results of their nationwide study of 29 patients with Cohen syndrome in Finland. They found the following features to be essential for the diagnosis: nonprogressive psychomotor retardation, motor clumsiness, and microcephaly; typical facial features including high-arched eyelids, short philtrum, thick hair, and low hairline; childhood hypotonia and hyperextensibility of the joints; ophthalmologic findings of retinochoroidal dystrophy and myopia in patients over 5 years of age; and periods of isolated granulocytopenia. They noted a changing phenotype with age. In their patients, psychomotor retardation was profound in 22%, severe in 61%, moderate in 6%, and mild in 11%. On the basis of a study of 33 non-Finnish patients with Cohen syndrome, Chandler et al. (2003) contended that the diagnostic criteria suggested by Kivitie-Kallio and Norio (2001) are important but not obligatory features. As an aid to diagnosis, they proposed the presence of at least 2 of the following major criteria in a child with significant learning difficulties: (1) facial gestalt, characterized by thick hair, eyebrows and eyelashes, wave-shaped, downward-slanting palpebral fissures, prominent, beak-shaped nose, short, upturned philtrum with grimacing expression on smiling; (2) pigmentary retinopathy; and (3) neutropenia. Less specific but supportive criteria included early-onset, progressive myopia; microcephaly; truncal obesity with slender extremities; and joint hyperextensibility. Pathogenesis Limoge et al. (2015) characterized the obesity phenotype in 14 patients with COH1 by examining clinical, glucose, and lipid metabolism features. All patients had truncal obesity, despite a normal BMI in most of them. Although triglyceride, total cholesterol, and LDL values were normal in most patients, HDL was abnormally low in 9 of 13 patients. Leptin was elevated in 8 of 11 patients in whom it was measured, 2 of whom were obese by BMI. Blood pressure was elevated (more than 130/85) in 4 of 8 patients. Fasting blood glucose was normal in 12 of 13 patients, but oral glucose tolerance test showed impaired glucose tolerance after 2 hours in 4 of 9 patients tested. Limoge et al. (2015) also studied primary fibroblasts from COH1 patients as well as SGBS (see 312870) preadipocytes in which expression of VPS13B was knocked down by RNAi, and observed accelerated differentiation into fat cells. This was confirmed by earlier and increased expression of specific adipogenic genes, consequent to the increased response of the cells to insulin stimulation. At the end of the differentiation protocol, these fat cells exhibited decreased AKT2 (164731) phosphorylation after insulin stimulation, suggestive of insulin resistance. Limoge et al. (2015) concluded that VPS13B is an important regulator of adipogenesis, and that defective VPS13B results in increased fat storage and a risk of type 2 diabetes mellitus in patients with COH1. Mapping In 2 brothers born of consanguineous parents, Kondo et al. (1990) found that Cohen syndrome was not linked to markers in the 15q11-q12 region. Tahvanainen et al. (1994) mapped the Cohen syndrome locus, symbolized CHS1 by them, to chromosome 8 in an interval of approximately 10 cM between D8S270 and D8S521. Both of these markers had been assigned to 8q22 (Wood et al., 1993). Their studies involved four 2-generation Finnish pedigrees showing uniform clinical features in the affected members. All the remaining 9 patients in Finland were isolated cases in their families. Although not of value for linkage studies, they would be fully informative for the analysis of linkage disequilibrium and haplotype associations. In the Finnish population, one might anticipate a single founding chromosome carrying the disease mutation. Tahvanainen et al. (1994) suggested that the linkage information may help establish or rule out genetic heterogeneity of Cohen syndrome, including answering the question as to whether the ocular findings and leukopenia indicate a separate entity. By linkage disequilibrium analysis, Kolehmainen et al. (1997) narrowed the COH1 region to the immediate vicinity of D8S1762. Haplotype analysis suggested the occurrence of 1 main COH1 mutation and possibly 1 or 2 rare ones in Finland. By homozygosity mapping in a consanguineous Lebanese kindred, Horn et al. (2000) localized the gene responsible for this condition to a 26.8-cM region on chromosome 8q21.3-q22.1. This region overlapped the refined gene region for Cohen syndrome (Kolehmainen et al., 1997). Horn et al. (2000) hypothesized that the syndrome in their family, Cohen syndrome, and Mirhosseini-Holmes-Walton syndrome may be allelic. Segregation analysis in 11 non-Finnish families with Cohen syndrome by Chandler et al. (2003) was consistent with linkage of the disorder to the COH1 critical region on chromosome 8. Cytogenetics Fryns et al. (1990) described a 15-year-old girl with features of Cohen syndrome and a de novo, apparently balanced reciprocal translocation t(5q;7p)(q33.1;p15.1). They suggested that the Cohen syndrome may be due to a mutation in a gene located at either 5q33.1 or 7p15.1. Molecular Genetics By haplotype analysis, Kolehmainen et al. (2003) refined the critical Cohen syndrome region on 8q22 and characterized a novel gene, COH1, that is mutated in patients with Cohen syndrome (see 607817.0001-607817.0003). In 1 non-Finnish patient with Cohen syndrome studied by Kolehmainen et al. (2003), no mutation was found in the COH1 gene, suggesting genetic heterogeneity. By segregation analysis in 11 non-Finnish families with Cohen syndrome, Chandler et al. (2003) demonstrated allele sharing in affected but not unaffected sibs within the COH1 critical region. Haplotype analysis suggested the presence of allelic heterogeneity. Seifert et al. (2006) studied 24 patients with Cohen syndrome from 16 families of varying ethnic backgrounds and identified 25 different mutations in the COH1 gene, including 9 nonsense mutations, 8 frameshift mutations, 4 verified splice site mutations, 3 larger in-frame deletions, and 1 missense mutation. There was marked variability of developmental and growth parameters, although the typical facial gestalt was seen in 23 of 24 patients. Early-onset progressive myopia was present in all the patients older than 5 years, with widespread pigmentary retinopathy seen in 12 of 14 patients assessed who were over 5 years of age. Katzaki et al. (2007) identified pathogenic mutations in the COH1 gene in 10 Italian patients with Cohen syndrome from 9 families. All patients had characteristic features of the disorder, although with greater variability than reported for Finnish patients. Heterozygous partial COH1 gene deletions were identified in 2 different families. In 14 individuals with Cohen syndrome from an isolated population on 2 small adjacent islands in the eastern part of the Greek archipelago, Bugiani et al. (2008) identified a large homozygous deletion of exon 6 through 16 in the VPS13B gene (607817.0011). Twelve of the patients belonged to a large consanguineous kindred. The phenotype was relatively homogeneous, with common features including moderate to severe mental retardation, slender extremities with narrow hands and feet, joint hypermobility, and the typical facial gestalt. Microcephaly was not as profound as reported in Finnish patients. Parri et al. (2010) used multiplex ligation-dependent probe amplification (MLPA) to analyze the VPS13B gene in 14 patients with Cohen syndrome from 11 families, including 4 patients from 3 families previously studied by Katzaki et al. (2007). All 14 patients displayed the typical Cohen facial gestalt, narrow extremities, and truncal adiposity, and microcephaly was present in 9 of the 14 patients. Parri et al. (2010) detected 12 different mutations, including 6 frameshift, 3 splice site, and 2 nonsense mutations, as well as 1 complex rearrangement. Four patients from 3 Italian families carried the same large deletion of exon 6 through 16 previously identified in Greek patients by Bugiani et al. (2008). Haplotype analysis of 1 of the Greek patients as well as the 4 Italian patients suggested that the recurrent deletion is due to an ancestral founder effect in the Mediterranean area. Using high-density oligonucleotide array data to analyze copy number variation (CNV), Rivera-Brugues et al. (2011) found that 3 of 1,523 patients with unexplained mental retardation had intragenic heterozygous deletions in the COH1 gene. Subsequent sequencing of the COH1 gene revealed point mutations in the second allele in all 3 patients. No CNVs involving the COH1 gene were found in 1,612 controls. The report was an example of how microarrays can be used to identify autosomal recessive syndromes and to extend the phenotypic and mutational spectrum of recessive disorders. In a 33-year-old woman who exhibited the typical facial gestalt of Cohen syndrome and had neutropenia and retinopathy, but who did not display truncal obesity or mental retardation, Gueneau et al. (2014) identified compound heterozygosity for 2 splice site mutations in the VPS13B gene (607817.0014; 607817.0015). The authors suggested that a dosage effect of residual normal VPS13B protein might explain the incomplete phenotype in this patient. Nomenclature The preferred symbol for Cohen syndrome is COH1 because the symbol CHS1 had already been established for Chediak-Higashi syndrome (214500). INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Weight \- Truncal obesity developing in midchildhood \- Low birth weight HEAD & NECK Head \- Microcephaly Face \- Short philtrum \- Maxillary hypoplasia \- Mild micrognathia \- Facial hypotonia Eyes \- Downslanting palpebral fissures \- Almond-shaped eyes \- Chorioretinal dystrophy \- Myopia \- Decreased visual acuity \- Optic atrophy Nose \- Prominent nasal bridge Mouth \- High, narrow palate \- Open mouth appearance Teeth \- Prominent upper central incisors CARDIOVASCULAR Heart \- Mitral valve prolapse SKELETAL Spine \- Mild lumbar lordosis \- Mild thoracic scoliosis Limbs \- Joint hyperextensibility \- Cubitus valgus \- Genu valgum Hands \- Narrow hands \- Mild shortening of metacarpals \- Transverse palmar creases Feet \- Narrow feet \- Mild shortening of metatarsals NEUROLOGIC Central Nervous System \- Mental retardation \- Hypotonia \- Seizures \- Delayed motor milestones \- Large corpus callosum \- Cerebellar hypoplasia ENDOCRINE FEATURES \- Delayed puberty \- Growth hormone deficiency HEMATOLOGY \- Leukopenia \- Neutropenia MISCELLANEOUS \- Cheerful disposition \- Increased frequency in Ashkenazi Jewish population and in Finland MOLECULAR BASIS \- Caused by mutation in the homolog of the yeast vacuolar protein sorting 13 gene (VPS13B, 607817.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	COHEN SYNDROME	c0265223	6,485	omim	https://www.omim.org/entry/216550	2019-09-22T16:29:31	{"mesh": ["C536438"], "omim": ["216550"], "orphanet": ["193"], "synonyms": ["Alternative titles", "COH", "HYPOTONIA, OBESITY, AND PROMINENT INCISORS", "PEPPER SYNDROME", "CHS1, FORMERLY"], "genereviews": ["NBK1482"]}
Mastocytoma Other namesMast cell tumor Mast cell tumor cytology SpecialtyOncology A mastocytoma or mast cell tumor is a type of round-cell tumor consisting of mast cells. It is found in humans and many animal species; it also can refer to an accumulation or nodule of mast cells that resembles a tumor. Mast cells originate from the bone marrow and are normally found throughout the connective tissue of the body as normal components of the immune system. As they release histamine, they are associated with allergic reactions. Mast cells also respond to tissue trauma. Mast cell granules contain histamine, heparin, platelet-activating factor, and other substances. Disseminated mastocytosis is rarely seen in young dogs and cats, while mast cell tumors are usually skin tumors in older dogs and cats. Although not always malignant, they do have the potential to be. Up to 25 percent of skin tumors in dogs are mast cell tumors,[1] with a similar number in cats.[2] ## Contents * 1 Signs and symptoms * 1.1 Humans * 1.2 Other animals * 2 Diagnosis * 3 Treatment and prognosis * 4 Other animals * 4.1 Dogs * 4.2 Cats * 5 References * 6 External links ## Signs and symptoms[edit] ### Humans[edit] When mastocytomas affect humans, they are typically found in skin.[3] They usually occur as a single lesion on the trunk or wrist. Although it is rare, mastocytomas are sometimes found in the lung.[3] It can also affect children.[4] ### Other animals[edit] Mast cell tumors are known among veterinary oncologists as 'the great pretenders' because their appearance can be varied, from a wart-like nodule to a soft subcutaneous lump (similar on palpation to a benign lipoma) to an ulcerated skin mass. Most mast cell tumors are small, raised lumps on the skin. They may be hairless, ulcerated, or itchy. They are usually solitary, but in about six percent of cases, there are multiple mast cell tumors[5] (especially in Boxers and Pugs).[6] Manipulation of the tumor may result in redness and swelling from release of mast cell granules, also known as Darier's sign, and prolonged local hemorrhage. In rare cases, a highly malignant tumor is present, and signs may include loss of appetite, vomiting, diarrhea, and anemia. The presence of these signs usually indicates mastocytosis, which is the spread of mast cells throughout the body. Release of a large amount of histamine at one time can result in ulceration of the stomach and duodenum (present in up to 25 percent of cases)[6] or disseminated intravascular coagulation. When metastasis does occur, it is usually to the liver, spleen, lymph nodes and bone marrow. * Mast cell tumor on the side of a dog * Mast cell tumor on the inner thigh of a dog * Mast cell tumor of the paw ## Diagnosis[edit] A needle aspiration biopsy of the tumor will typically show a large number of mast cells. This is sufficient to make the diagnosis of a mast cell tumor, although poorly differentiated mast cells may have few granules and thus are difficult to identify. The granules of the mast cell stain blue to dark purple with a Romanowsky stain, and the cells are medium-sized.[7] However, a surgical biopsy is required to find the grade of the tumor. The grade depends on how well the mast cells are differentiated, mitotic activity, location within the skin, invasiveness, and the presence of inflammation or necrosis.[8] * Grade I – well differentiated and mature cells with a low potential for metastasis * Grade II – intermediately differentiated cells with potential for local invasion and moderate metastatic behavior * Grade III – undifferentiated, immature cells with a high potential for metastasis[1] However, there is a significant amount of discordance between veterinary pathologists in assigning grades to mast cell tumors due to imprecise criteria.[9] The disease is also staged according to the WHO system: * Stage I - a single skin tumor with no spread to lymph nodes * Stage II - a single skin tumor with spread to lymph nodes in the surrounding area * Stage III - multiple skin tumors or a large tumor invading deep to the skin with or without lymph node involvement * Stage IV – a tumor with metastasis to the spleen, liver, or bone marrow, or with the presence of mast cells in the blood[10] X-rays, ultrasound, or lymph node, bone marrow, or organ biopsies may be necessary to stage the disease. ## Treatment and prognosis[edit] Removal of the mast cell tumor through surgery is the treatment of choice. Antihistamines, such as diphenhydramine, are given prior to surgery to protect against the effects of histamine released from the tumor. Wide margins (two to three centimeters) are required because of the tendency for the tumor cells to be spread out around the tumor. If complete removal is not possible due to the size or location, additional treatment, such as radiation therapy or chemotherapy, may be necessary. Prednisone is often used to shrink the remaining tumor portion. H2 blockers, such as cimetidine, protect against stomach damage from histamine. Vinblastine and CCNU are common chemotherapy agents used to treat mast cell tumors.[5] Toceranib and masitinib, examples of receptor tyrosine kinase inhibitors, are used in the treatment[11][12] of canine mast cell tumors. Both were recently approved by the U.S. Food and Drug Administration (FDA)[13][14] as dog-specific anticancer drugs.[15] Grade I or II mast cell tumors that can be completely removed have a good prognosis. One study showed about 23 percent of incompletely removed grade II tumors recurred locally.[16] Any mast cell tumor found in the gastrointestinal tract, paw, or on the muzzle has a guarded prognosis. Previous beliefs that tumors in the groin or perineum carried a worse prognosis have been discounted.[17] Tumors that have spread to the lymph nodes or other parts of the body have a poor prognosis. Any dog showing symptoms of mastocytosis or with a grade III tumor has a poor prognosis. Dogs of the Boxer breed have a better than average prognosis because of the relatively benign behavior of their mast cell tumors.[10] Multiple tumors that are treated similarly to solitary tumors do not seem to have a worse prognosis.[18] Mast cell tumors do not necessarily follow the histological prognosis. Further prognostic information can be provided by AgNOR stain of histological or cytological specimen.[19] Even then, there is a risk of unpredictable behavior. ## Other animals[edit] Mast cell tumors are an uncommon occurrence in horses. They usually occur as benign, solitary masses on the skin of the head, neck, trunk, and legs. Mineralization of the tumor is common.[20] In pigs and cattle, mast cell tumors are rare. They tend to be solitary and benign in pigs and multiple and malignant in cattle.[6] Mast cell tumors are found in the skin of cattle most commonly, but these may be metastases from tumors of the viscera.[21] Other sites in cattle include the spleen, muscle, gastrointestinal tract, omentum, and uterus.[22] ### Dogs[edit] Mast cell tumors mainly occur in older adult dogs, but have been known to occur on rare occasions in puppies. The following breeds are commonly affected by mast cell tumors: * Boxer * Staffordshire bull terrier * Bulldog * Basset hound * Weimaraner * Boston terrier * Great Dane * Golden retriever * Labrador retriever * Beagle * German shorthaired pointer * Scottish terrier[10] * Pug * Shar pei[23] * Rhodesian ridgeback[6] ### Cats[edit] Two types of mast cell tumors have been identified in cats, a mast cell type similar to dogs and a histiocytic type that appears as subcutaneous nodules and may resolve spontaneously. Young Siamese cats are at an increased risk for the histiocytic type,[2] although the mast cell type is the most common in all cats and is considered to be benign when confined to the skin.[6] Mast cell tumors of the skin are usually located on the head or trunk.[24] Gastrointestinal and splenic involvement is more common in cats than in dogs; 50 percent of cases in dogs primarily involved the spleen or intestines.[25] Gastrointestinal mast cell tumors are most commonly found in the muscularis layer of the small intestine, but can also be found in the large intestine.[26] It is the third most common intestinal tumor in cats, after lymphoma and adenocarcinoma.[27] Diagnosis and treatment are similar to that of the dog. Cases involving difficult to remove or multiple tumors have responded well to strontium-90 radiotherapy as an alternative to surgery.[28] The prognosis for solitary skin tumors is good, but guarded for tumors in other organs. Histological grading of tumors has little bearing on prognosis.[29] ## References[edit] 1. ^ a b Brière C (2002). "Use of a reverse saphenous skin flap for the excision of a grade II mast cell tumor on the hind limb of a dog". Can Vet J. 43 (8): 620–2. PMC 339404. PMID 12170840. 2. ^ a b Johnson T, Schulman F, Lipscomb T, Yantis L (2002). "Histopathology and biologic behavior of pleomorphic cutaneous mast cell tumors in fifteen cats". Vet Pathol. 39 (4): 452–7. doi:10.1354/vp.39-4-452. PMID 12126148. 3. ^ a b Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. (2013). "Less Common Hematologic Malignancies". Harrison's principles of internal medicine (18th ed.). New York: McGraw-Hill. ISBN 9780071748896. 4. ^ García Iglesias F, Sánchez García AM, García Lara GM. Mastocitoma solitario. Rev Pediatr Aten Primaria. 2014;16:35-7 5. ^ a b Moore, Anthony S. (2005). "Cutaneous Mast Cell Tumors in Dogs". Proceedings of the 30th World Congress of the World Small Animal Veterinary Association. Retrieved 2006-08-19. 6. ^ a b c d e "Cutaneous Mast Cell Tumors". The Merck Veterinary Manual. 2006. Retrieved 2007-01-27. 7. ^ "Common Cytology Results". The Merck Veterinary Manual. 2006. Retrieved 2007-01-27. 8. ^ Vandis, Maria; Knoll, Joyce S. (March 2007). "Cytological examination of a cutaneous mast cell tumor in a boxer". Veterinary Medicine. Advanstar Communications. 102 (3): 165–168. 9. ^ Strefezzi R, Xavier J, Catão-Dias J (2003). "Morphometry of canine cutaneous mast cell tumors". Vet Pathol. 40 (3): 268–75. doi:10.1354/vp.40-3-268. PMID 12724567. 10. ^ a b c Morrison, Wallace B. (1998). Cancer in Dogs and Cats (1st ed.). Williams and Wilkins. ISBN 0-683-06105-4. 11. ^ London CA, Malpas PB, Wood-Follis SL, et al. (June 2009). "Multi-center, Placebo-controlled, Double-blind, Randomized Study of Oral Toceranib Phosphate (SU11654), a Receptor Tyrosine Kinase Inhibitor, for the Treatment of Dogs with Recurrent (Either Local or Distant) Mast Cell Tumor Following Surgical Excision". Clin Cancer Res. 15 (11): 3856–65. doi:10.1158/1078-0432.CCR-08-1860. PMID 19470739. 12. ^ Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, Castéran N, Borge L, Hajem B, Lermet A, Sippl W, Voisset E, Arock M, Auclair C, Leventhal PS, Mansfield CD, Moussy A, Hermine O (September 2009). "Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT". PLoS ONE. 4 (9): e7258. doi:10.1371/journal.pone.0007258. PMC 2746281. PMID 19789626. 13. ^ FDA NEWS RELEASE 14. ^ [1] 15. ^ CBS News FDA Approves First-Ever Dog Cancer Drug 16. ^ Séguin B, Besancon M, McCallan J, Dewe L, Tenwolde M, Wong E, Kent M (2006). "Recurrence rate, clinical outcome, and cellular proliferation indices as prognostic indicators after incomplete surgical excision of cutaneous grade II mast cell tumors: 28 dogs (1994–2002)". J Vet Intern Med. 20 (4): 933–40. doi:10.1892/0891-6640(2006)20[933:RRCOAC]2.0.CO;2. PMID 16955819. 17. ^ Sfiligoi G, Rassnick K, Scarlett J, Northrup N, Gieger T (2005). "Outcome of dogs with mast cell tumors in the inguinal or perineal region versus other cutaneous locations: 124 cases (1990–2001)". J Am Vet Med Assoc. 226 (8): 1368–74. doi:10.2460/javma.2005.226.1368. PMID 15844431. 18. ^ Mullins M, Dernell W, Withrow S, Ehrhart E, Thamm D, Lana S (2006). "Evaluation of prognostic factors associated with outcome in dogs with multiple cutaneous mast cell tumors treated with surgery with and without adjuvant treatment: 54 cases (1998–2004)". J Am Vet Med Assoc. 228 (1): 91–5. doi:10.2460/javma.228.1.91. PMID 16426175. 19. ^ Scase T, Edwards D, Miller J, Henley W, Smith K, Blunden A, Murphy S (2006). "Canine mast cell tumors: correlation of apoptosis and proliferation markers with prognosis". J Vet Intern Med. 20 (1): 151–8. doi:10.1892/0891-6640(2006)20[151:CMCTCO]2.0.CO;2. hdl:10871/37694. PMID 16496935. 20. ^ Cole R, Chesen A, Pool R, Watkins J (2007). "Imaging diagnosis—equine mast cell tumor". Vet Radiol Ultrasound. 48 (1): 32–4. doi:10.1111/j.1740-8261.2007.00200.x. PMID 17236357. 21. ^ Smith B, Phillips L (2001). "Congenital mastocytomas in a Holstein calf". Can Vet J. 42 (8): 635–7. PMC 1476568. PMID 11519274. 22. ^ Ames T, O'Leary T (1984). "Mastocytoma in a cow: a case report". Can J Comp Med. 48 (1): 115–7. PMC 1236018. PMID 6424914. 23. ^ Miller D (1995). "The occurrence of mast cell tumors in young Shar-Peis". J Vet Diagn Invest. 7 (3): 360–363. doi:10.1177/104063879500700311. PMID 7578452. 24. ^ Litster A, Sorenmo K (2006). "Characterisation of the signalment, clinical and survival characteristics of 41 cats with mast cell neoplasia". J Feline Med Surg. 8 (3): 177–83. doi:10.1016/j.jfms.2005.12.005. PMID 16476559. 25. ^ Takahashi T, Kadosawa T, Nagase M, Matsunaga S, Mochizuki M, Nishimura R, Sasaki N (2000). "Visceral mast cell tumors in dogs: 10 cases (1982–1997)". J Am Vet Med Assoc. 216 (2): 222–6. doi:10.2460/javma.2000.216.222. PMID 10649758. 26. ^ "Gastrointestinal Neoplasia". The Merck Veterinary Manual. 2006. Retrieved 2007-01-27. 27. ^ Moriello, Karen A. (April 2007). "Clinical Snapshot". Compendium on Continuing Education for the Practicing Veterinarian. Veterinary Learning Systems. 29 (4): 204. 28. ^ Turrel J, Farrelly J, Page R, McEntee M (2006). "Evaluation of strontium 90 irradiation in treatment of cutaneous mast cell tumors in cats: 35 cases (1992–2002)". J Am Vet Med Assoc. 228 (6): 898–901. doi:10.2460/javma.228.6.898. PMID 16536702. 29. ^ Molander-McCrary H, Henry C, Potter K, Tyler J, Buss M (1998). "Cutaneous mast cell tumors in cats: 32 cases (1991–1994)". J Am Anim Hosp Assoc. 34 (4): 281–4. doi:10.5326/15473317-34-4-281. PMID 9657159. ## External links[edit] Classification D * ICD-10: C96.2, D47.0 * ICD-9-CM: 238.5 * ICD-O: M9740/1 * MeSH: D034801 * DiseasesDB: 34450 External resources * eMedicine: derm/258 * Mast Cell Tumors from The Pet Health Library * Mast Cell Tumors in Dogs from Pet Cancer Center * Mast Cell Tumors in Cats from Pet Cancer Center * v * t * e Myeloid-related hematological malignancy CFU-GM/ and other granulocytes CFU-GM Myelocyte AML: * Acute myeloblastic leukemia * M0 * M1 * M2 * APL/M3 MP * Chronic neutrophilic leukemia Monocyte AML * AMoL/M5 * Myeloid dendritic cell leukemia CML * Philadelphia chromosome * Accelerated phase chronic myelogenous leukemia Myelomonocyte AML * M4 MD-MP * Juvenile myelomonocytic leukemia * Chronic myelomonocytic leukemia Other * Histiocytosis CFU-Baso AML * Acute basophilic CFU-Eos AML * Acute eosinophilic MP * Chronic eosinophilic leukemia/Hypereosinophilic syndrome MEP CFU-Meg MP * Essential thrombocytosis * Acute megakaryoblastic leukemia CFU-E AML * Erythroleukemia/M6 MP * Polycythemia vera MD * Refractory anemia * Refractory anemia with excess of blasts * Chromosome 5q deletion syndrome * Sideroblastic anemia * Paroxysmal nocturnal hemoglobinuria * Refractory cytopenia with multilineage dysplasia CFU-Mast Mastocytoma * Mast cell leukemia * Mast cell sarcoma * Systemic mastocytosis Mastocytosis: * Diffuse cutaneous mastocytosis * Erythrodermic mastocytosis * Adult type of generalized eruption of cutaneous mastocytosis * Urticaria pigmentosa * Mast cell sarcoma * Solitary mastocytoma Systemic mastocytosis * Xanthelasmoidal mastocytosis Multiple/unknown AML * Acute panmyelosis with myelofibrosis * Myeloid sarcoma MP * Myelofibrosis * Acute biphenotypic leukaemia * v * t * e Connective/soft tissue tumors and sarcomas Not otherwise specified * Soft-tissue sarcoma * Desmoplastic small-round-cell tumor Connective tissue neoplasm Fibromatous Fibroma/fibrosarcoma: * Dermatofibrosarcoma protuberans * Desmoplastic fibroma Fibroma/fibromatosis: * Aggressive infantile fibromatosis * Aponeurotic fibroma * Collagenous fibroma * Diffuse infantile fibromatosis * Familial myxovascular fibromas * Fibroma of tendon sheath * Fibromatosis colli * Infantile digital fibromatosis * Juvenile hyaline fibromatosis * Plantar fibromatosis * Pleomorphic fibroma * Oral submucous fibrosis Histiocytoma/histiocytic sarcoma: * Benign fibrous histiocytoma * Malignant fibrous histiocytoma * Atypical fibroxanthoma * Solitary fibrous tumor Myxomatous * Myxoma/myxosarcoma * Cutaneous myxoma * Superficial acral fibromyxoma * Angiomyxoma * Ossifying fibromyxoid tumour Fibroepithelial * Brenner tumour * Fibroadenoma * Phyllodes tumor Synovial-like * Synovial sarcoma * Clear-cell sarcoma Lipomatous * Lipoma/liposarcoma * Myelolipoma * Myxoid liposarcoma * PEComa * Angiomyolipoma * Chondroid lipoma * Intradermal spindle cell lipoma * Pleomorphic lipoma * Lipoblastomatosis * Spindle cell lipoma * Hibernoma Myomatous general: * Myoma/myosarcoma smooth muscle: * Leiomyoma/leiomyosarcoma skeletal muscle: * Rhabdomyoma/rhabdomyosarcoma: Embryonal rhabdomyosarcoma * Sarcoma botryoides * Alveolar rhabdomyosarcoma * Leiomyoma * Angioleiomyoma * Angiolipoleiomyoma * Genital leiomyoma * Leiomyosarcoma * Multiple cutaneous and uterine leiomyomatosis syndrome * Multiple cutaneous leiomyoma * Neural fibrolipoma * Solitary cutaneous leiomyoma * STUMP Complex mixed and stromal * Adenomyoma * Pleomorphic adenoma * Mixed Müllerian tumor * Mesoblastic nephroma * Wilms' tumor * Malignant rhabdoid tumour * Clear-cell sarcoma of the kidney * Hepatoblastoma * Pancreatoblastoma * Carcinosarcoma Mesothelial * Mesothelioma * Adenomatoid tumor [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Mastocytoma	c0024897	6,486	wikipedia	https://en.wikipedia.org/wiki/Mastocytoma	2021-01-18T19:10:19	{"umls": ["C0024897"], "icd-9": ["238.5"], "wikidata": ["Q6785569"]}
Abortion in Lithuania is legal and available on request until the twelfth week of pregnancy, and up to 22 weeks for medical reasons.[1] [2] While Lithuania was a Republic of the Soviet Union (as the Lithuanian Soviet Socialist Republic), abortions were regulated by the Government of the Soviet Union.[1] ## History[edit] After becoming the Lithuanian Soviet Socialist Republic on 21 July 1940, Lithuania followed the abortions laws of the Soviet Union. On 27 June 1936, the Soviet Union banned abortions unless there was a danger to the life of the mother or the child would inherit a serious disease from the parents. Under this law abortions were meant to be performed in maternity homes and hospitals, and physicians who disregarded this risked one to two years' imprisonment.[1] On 23 November 1955, the Soviet Union issued a decree which allowed abortions to be available on request. Later that year abortion was restricted so that it could only be performed in the first three months of pregnancy unless the birth would endanger the mother. Physicians had to perform abortions in hospitals and, unless the mother was in danger, a fee was charged.[1] If the abortion was not performed in a hospital, the physician could be imprisoned for one year, while a person not in possession of a medical degree could be imprisoned for two years. The serious injury or death of a pregnant woman could result in the sentence being extended up to eight years.[1] The Government of the Soviet Union was concerned about the rate of illegal abortions and attempted to decrease their occurrence. On 31 December 1987, the Soviet Union announced that it would allow many medical institutions to perform abortions until the twenty-eighth week of pregnancy.[1] In 1989, there were 50,100 abortions and 55,782 live births in Lithuania. By 2010, the number of abortions decreased to 6,989 abortions and 35,626 live births.[3] As of 2010[update], the abortion rate was 9.8 abortions per 1000 women aged 15-44 years.[4] From 1995 to 2000, the total fertility rate in Lithuania was 1.4 children/per woman, which the government officially wants to increase.[1] Lithuania's low fertility rate, and its Catholic traditions make abortion a controversial political issue, and regular attempts to restrict it occur.[5] There have been several attempts in recent years to adopt a more restrictive law on abortion, especially after 2005. Such attempts are particularly associated with the Polish minority.[6][7] ## References[edit] 1. ^ a b c d e f g "Abortion in Lithuania (Word Document)". United Nations. Retrieved 8 July 2013. 2. ^ Worrell, Marc. "Abortion law Lithuania". Women on Waves. Retrieved 19 January 2019. 3. ^ "Statistics of Abortions in Lithuania". Johnston`s Archive. 2011. Retrieved 8 July 2013. 4. ^ "World Abortion Policies 2013". United Nations. 2013. Retrieved 3 March 2014. 5. ^ http://www.vitaelitera.lt/ojs/index.php/akuserija-ir-ginekologija/article/download/154/153. 6. ^ "Lithuanian Parliament to Debate Abortion Ban". Human Rights Monitoring Institute. 26 March 2018. Retrieved 19 January 2019. 7. ^ Platform, European Liberties. "Polish Minority Party Wants to Ban Abortions in Lithuania". Liberties.eu. Retrieved 19 January 2019. * Law portal * Lithuania portal * Medicine portal * v * t * e Abortion in Europe Sovereign states * Albania * Andorra * Armenia * Austria * Azerbaijan * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Cyprus * Czech Republic * Denmark * Estonia * Finland * France * Georgia * Germany * Greece * Hungary * Iceland * Ireland * * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Turkey * Ukraine * United Kingdom * England * Northern Ireland * Scotland * Wales * Vatican City States with limited recognition * Abkhazia * Artsakh * Kosovo * Northern Cyprus * South Ossetia * Transnistria * v * t * e Abortion Main topics * Definitions * History * Methods * Abortion debate * Philosophical aspects * Abortion law Movements * Abortion-rights movements * Anti-abortion movements Issues * Abortion and mental health * Beginning of human personhood * Beginning of pregnancy controversy * Abortion-breast cancer hypothesis * Anti-abortion violence * Abortion under communism * Birth control * Crisis pregnancy center * Ethical aspects of abortion * Eugenics * Fetal rights * Forced abortion * Genetics and abortion * Late-term abortion * Legalized abortion and crime effect * Libertarian perspectives on abortion * Limit of viability * Malthusianism * Men's rights * Minors and abortion * Natalism * One-child policy * Paternal rights and abortion * Prenatal development * Reproductive rights * Self-induced abortion * Sex-selective abortion * Sidewalk counseling * Societal attitudes towards abortion * Socialism * Toxic abortion * Unsafe abortion * Women's rights By country Africa * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde * Central African Republic * Chad * Egypt * Ghana * Kenya * Namibia * Nigeria * South Africa * Uganda * Zimbabwe Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor * Georgia * India * Iran * Israel * Japan * Kazakhstan * South Korea * Malaysia * Nepal * Northern Cyprus * Philippines * Qatar * Saudi Arabia * Singapore * Turkey * United Arab Emirates * Vietnam * Yemen Europe * Albania * Andorra * Austria * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Czech Republic * Denmark * Estonia * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Ukraine * United Kingdom North America * Belize * Canada * Costa Rica * Cuba * Dominican Republic * El Salvador * Guatemala * Mexico * Nicaragua * Panama * Trinidad and Tobago * United States Oceania * Australia * Micronesia * Fiji * Kiribati * Marshall Islands * New Zealand * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu South America * Argentina * Bolivia * Brazil * Chile * Colombia * Ecuador * Guyana * Paraguay * Peru * Suriname * Uruguay * Venezuela Law * Case law * Constitutional law * History of abortion law * Laws by country * Buffer zones * Conscientious objection * Fetal protection * Heartbeat bills * Informed consent * Late-term restrictions * Parental involvement * Spousal consent Methods * Vacuum aspiration * Dilation and evacuation * Dilation and curettage * Intact D&X * Hysterotomy * Instillation * Menstrual extraction * Abortifacient drugs * Methotrexate * Mifepristone * Misoprostol * Oxytocin * Self-induced abortion * Unsafe abortion Religion * Buddhism * Christianity * Catholicism * Hinduism * Islam * Judaism * Scientology * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Abortion in Lithuania	None	6,487	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Lithuania	2021-01-18T18:32:09	{"wikidata": ["Q16057982"]}
For a discussion of genetic heterogeneity of multiple sclerosis (MS), see MS1 (126200). Mapping In a genomewide association study of 45 patients with multiple sclerosis and 195 controls in a genetically isolated Dutch population, Aulchenko et al. (2008) found an association between MS and the C allele of rs10492972 in intron 5 of the KIF1B gene (605995) on chromosome 1p36. The findings were replicated in 3 larger cohorts from the Netherlands, Sweden, and Canada. Pooled data comprising 2,679 patients and 3,125 controls from all 4 groups yielded a p value of 2.5 x 10(-10) (odds ratio of 1.35). The International Multiple Sclerosis Genetics Consortium (2010) (IMSGC) was unable to replicate the association between MS and the C allele of rs10492972 reported by Aulchenko et al. (2008). Genotyping of the variant in 8 case-control and 3 trio-family collections, including a total of 8,391 cases, 8,052 controls, and 2,137 trio families, found that none of them had a statistically significant association with the variant. In fact, more than half of the studies showed a trend in the opposite direction. In addition, International Multiple Sclerosis Genetics Consortium (2010) found that the frequency of the C allele was 0.33 in their pooled control group, which included samples from Australia, Belgium, Finland, Norway, Italy, Sweden, the U.K., and U.S., which was significantly different from the frequency of 0.27 found in Dutch controls by Aulchenko et al. (2008). These results suggested population differences in allele frequencies which may have influenced the original findings. Hintzen et al. (2010) replied that they were surprised that the findings could not be replicated and defended their original findings (Aulchenko et al., 2008). Hintzen et al. (2010) noted that the U.K. and Italian control groups of International Multiple Sclerosis Genetics Consortium (2010) did not find the allele in Hardy-Weinberg equilibrium, which may have led to incorrect conclusions. Furthermore, the disparate results between the 2 studies may reflect a prevalence/incidence bias of MS in the Dutch population. Sombekke et al. (2011) found no association between rs10492972 and clinical or MRI findings of neurodegeneration among 214 patients with MS. They also found no association between this SNP and disease susceptibility. Alcina et al. (2010) attempted to replicate the risk contribution of 19 SNPs associated with MS identified by the Wellcome Trust Case Control Consortium (2007). Only 1 SNP, rs17368528 in exon 5 of the H6PD gene (138090) on chromosome 1p36.22, showed a significant disease association among 732 Spanish patients and 974 controls, with replication in 1,318 Canadian patients and 1,507 controls (odds ratio (OR) of 0.83, p = 0.04). This marker is 1 Mb away from KIF1B, and the association was independent of KIF1B. Alcina et al. (2010) noted that the H6PD gene is involved in the pentose phosphate pathway, which provides reducing equivalents for regeneration of the antioxidant glutathione. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO, 4	c2675476	6,488	omim	https://www.omim.org/entry/612596	2019-09-22T16:01:01	{"omim": ["612596"]}
A number sign (#) is used with this entry because of evidence that meconium ileus can be caused by homozygous mutation in the GUCY2C gene (601330) on chromosome 12p. Description Meconium ileus refers to intestinal obstruction due to inspissated meconium in the distal ileum and cecum, which develops in utero and presents shortly after birth as a failure to pass meconium (summary by Romi et al., 2012). Meconium ileus is a known clinical manifestation of cystic fibrosis (CF; 219700), and meconium ileus in the absence of CF is a rare phenomenon (summary by Tal et al., 1985). Clinical Features Tal et al. (1985) reported a consanguineous Bedouin family in which 4 of 12 sibs had meconium ileus with normal sweat electrolytes. Two of the affected sibs also developed chronic diarrhea in infancy, 1 of whom died at 4 months of age from sepsis and severe malnutrition; postmortem examination revealed no pathologic findings consistent with cystic fibrosis. During long-term follow-up of the 3 surviving affected sibs there was no clinical evidence of steatorrhea, repeat smears did not show fat in the stool, and trypsin activity in the stools was qualitatively normal. No pulmonary abnormalities suggestive of CF were found clinically, radiographically, histologically, or on lung function tests. The parents and 8 other sibs were healthy and had normal sweat electrolytes. Romi et al. (2012) stated that intestinal biopsy in 3 of the affected sibs demonstrated normal ganglions and cholinergic neurons. Mapping Using DNA from 11 affected and 26 unaffected members of the Bedouin kindred with meconium ileus, originally reported by Tal et al. (1985), Romi et al. (2012) first ruled out linkage to the CFTR (602421) locus. Subsequent genomewide linkage analysis revealed a single locus of homozygosity on chromosome 12p13, spanning 9.5 Mb between markers D12S366 and D12S310, and fine mapping narrowed the locus to 4 Mb between D12S1580 and Ch12_TG. A maximum 2-point lod score of 4.1 (theta = 0) was obtained at D12S1580. Molecular Genetics In a large Bedouin kindred with meconium ileus mapping to chromosome 12p13, originally reported by Tal et al. (1985), Romi et al. (2012) analyzed the candidate gene GUCY2C (601330) and identified homozygosity for a missense mutation (601330.0002) in all affected individuals. The mutation was also detected in homozygosity in 4 of 24 unaffected family members; however, partial penetrance of the phenotype was evident in 1 of those individuals: ultrasonography late in pregnancy demonstrated meconium ileus, although the infant did pass stools unassisted after birth. Penetrance of the postnatal meconium ileus phenotype in homozygous individuals was thus 73% (11 affected of 15 homozygous mutants). The mutation was found in heterozygosity in 3 of 240 unrelated Bedouin controls but was not reported in the HapMap or 1000 Genomes databases. In a sporadic patient with severe meconium ileus, born of first-cousin Bedouin parents and negative for homozygosity at the CFTR locus, Romi et al. (2012) identified homozygosity for a 1-bp insertion in the GUCY2C gene (601330.0003) that was not found in the proband's 2 healthy sibs. The authors noted that the sporadic Bedouin patient's haplotype at the GUCY2C locus was different than that of affected individuals from the large Bedouin kindred. INHERITANCE \- Autosomal recessive ABDOMEN Gastrointestinal \- Failure to pass meconium after birth \- Inspissated meconium in distal ileum \- Microcolon on contrast enema \- Prolonged diarrhea in infancy (in some patients) \- Meconium ileus on ultrasonography MISCELLANEOUS \- Normal sweat electrolytes \- No features consistent with cystic fibrosis found in these patients MOLECULAR BASIS \- Caused by mutation in the guanylate cyclase 2C gene (GUCY2C, 601330.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	MECONIUM ILEUS	c2939175	6,489	omim	https://www.omim.org/entry/614665	2019-09-22T15:54:35	{"mesh": ["D000074270"], "omim": ["614665"], "icd-10": ["P76.0"], "orphanet": ["314376"], "synonyms": ["Meconium ileus due to guanylate cyclase 2C deficiency"]}
A rare form of axonal peripheral sensorimotor neuropathy characterized by classical CMT2 signs and symptoms (progressive weakness and atrophy of distal limb muscles, mild sensory deficits of position, vibration and pain/temperature, pes cavus, and symmetrically absent or reduced muscle and sensory action potentials with relatively preserved nerve conduction velocities in neurophysiological studies) as well as pyramidal tract involvement (spasticity, hyperreflexia). Spasticity and pain may be the presenting symptoms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation	c4707173	6,490	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324611	2021-01-23T17:30:18	{"icd-10": ["G60.0"], "synonyms": ["CMT2 due to KIF5A mutation"]}
## Clinical Features Asch and Myers (1976) described 5 males in 2 generations of a family with occipitofrontal head circumferences greater than 2 SD above the mean. All were neurologically and mentally normal. A maternal uncle of the first generation was said to have a large head. All were dolichocephalic. By sonographic studies the ventricular system was enlarged in 3 of the 5. Similar families were reported by Platt and Nash (1972) and by Day and Shutt (1979). Arbour et al. (1996) measured head size in the parents and sibs of 23 patients with a head circumference more than 2 SD above the mean and with no evidence of hydrocephalus or syndromic associations. In 12 of the 23, some degree of psychomotor impairment was present. It was found that head circumference of parents and sibs had a mean significantly greater than the population norm and a unimodal distribution. Probands with psychomotor impairment had bigger heads, and more had a history of birth difficulty than did unimpaired probands. They noted that macrocephaly in a parent or sib of an unborn child may present a risk for birth injury to that child. In the course of a clinical study of Sotos syndrome (117550), Cole and Hughes (1991) found that 6 of 79 probands who failed to fit that phenotype showed remarkable similarities to each other and to some of their first- and second-degree relatives. In addition to macrocephaly, clinical features included typical facies characterized by square outline with frontal bossing, 'dished-out' midface, biparietal narrowing, and long philtrum. Birth weight and length were normal or near normal with subsequent obesity. Cole and Hughes (1991) were uncertain as to whether this represented a new entity or benign familial macrocephaly; see 605309. Diaz-Rodriguez et al. (2010) reported a mother and son with benign familial macrocephaly who displayed the characteristic square facial appearance with frontal bossing and dished-out midfacies. There was also an unaffected sister. Inheritance The pedigree pattern in the family with macrocephaly described by Asch and Myers (1976) suggested male-limited autosomal dominant inheritance. Arbour et al. (1996) concluded that the usual genetic basis for nonsyndromic macrocephaly is multifactorial with a polymorphic genetic basis, rather than autosomal dominance. A risk of recurrence appeared to be much more lower than it would be on the assumption of autosomal dominant inheritance. Head \- Macrocephaly \- Biparietal narrowing \- Dolichocephaly Radiology \- Enlarged ventricular system Facies \- Square facial outline \- Frontal bossing \- Dished-out midface \- Long philtrum Inheritance \- Male-limited autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	MACROCEPHALY, BENIGN FAMILIAL	c0220690	6,491	omim	https://www.omim.org/entry/153470	2019-09-22T16:38:46	{"mesh": ["C537717"], "omim": ["153470"], "synonyms": ["Alternative titles", "COLE-HUGHES SYNDROME"]}
## Clinical Features Smith (1972) documented 8 cases of midgut volvulus in 1 kindred. The propositus, his 2 sons and 3 daughters, and his 2 grandchildren demonstrated this midgut malrotation syndrome. The midgut volvulus caused great discomfort. Six of the affected had undergone a total of 24 operative procedures to alleviate problems caused by the malrotation of the midgut. The clinical course of the 5 sibs showed normal growth and development followed by the appearance of abdominal distention, pain, and constipation by the age of 6 years. The 2 affected grandchildren died at the age of 4 weeks, one of postoperative complications to repair the volvulus and the other from multiple congenital defects. This kindred also demonstrated a thick disc of fibromuscular tissue on the antrum of the stomach in 3 of the patients and major obstetrical abnormalities in 10 of 19 pregnancies produced by the 5 affected sibs. Carmi et al. (1981) reported father and daughter with congenital midgut volvulus and consequent intestinal obstruction, discovered soon after birth. The father's younger sister developed intestinal obstruction 2 days after birth and was found to have atresia of the ascending colon. The parents of these 2 sibs and a later-born son of the 'father' were normal by roentgenographic survey of the gastrointestinal tract. Budd and Powley (1988) reported the cases of 2 sibs with small bowel volvulus and malrotation. Stalker and Chitayat (1992) described 2 sisters with congenital midgut volvulus. Both had small intestinal malrotation. One had gangrene of the entire small intestine, suggesting that the intestinal volvulus was late in onset. In the second sister, the volvulus probably occurred at an earlier gestational age, causing intestinal atresia. Both sibs had an unusual facial appearance: a 'boxy' head, high forehead, frontal bossing, telecanthus, and long palpebral fissures. Both parents had normal barium meal roentgenograms, and they and 2 unaffected sibs had a different facial appearance. GU \- Major obstetrical abnormalities Inheritance \- Autosomal dominant Head \- Boxy head \- High forehead \- Frontal bossing GI \- Midgut volvulus \- Abdominal distention and pain \- Constipation \- Thick fibromuscular disc on stomach antrum \- Neonatal intestinal obstruction \- Atresia of ascending colon \- Intestinal malrotation Eyes \- Telecanthus \- Long palpebral fissures ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	VOLVULUS OF MIDGUT	c0221210	6,492	omim	https://www.omim.org/entry/193250	2019-09-22T16:31:54	{"mesh": ["C562456"], "omim": ["193250"], "synonyms": ["Alternative titles", "INTESTINAL MALROTATION, FAMILIAL"]}
## Clinical Features Lewkonia and Buxton (1973) described myositis in father and daughter. The daughter's illness resembled childhood dermatomyositis and progressed to systemic involvement with death less than 4 years after onset. The father's illness followed the course of adult polymyositis, with little evidence of systemic involvement. Proximal muscle weakness was a conspicuous feature in both. In both, the diagnosis of myositis was confirmed by muscle biopsy. The significance of the familial occurrence may be similar to that of familial SLE (152700) and familial autoimmune disorders (109100). Rider et al. (1998) described the clinical, serologic, and immunogenetic features of idiopathic inflammatory myopathy (IIM), observed in 16 unrelated families in which 2 or more blood relatives developed the disorder. In addition, findings in patients with familial IIM were compared with those in 181 patients with sporadic IIM. Families included 3 pairs of monozygotic twins with juvenile dermatomyositis, 11 families with other sibs or relatives with polymyositis or dermatomyositis, and 2 families with inclusion body myositis (147421). They found that the clinical features of familial IIM were similar to those of sporadic IIM, although the frequency of myositis-specific autoantibodies was lower in familial than in sporadic cases. In the HLA system, DRB10301 was a common genetic risk factor for familial and sporadic IIM, but contributed less to the genetic risk of familial IIM. Homozygosity at the HLA-DQA1 locus was found to be a genetic risk factor unique to familial IIM. Rider et al. (1998) concluded that familial muscle weakness is not always due to inherited metabolic defects or dystrophies, but may be the result of the development of IIM in several members of the same family, and that multiple genetic factors are probably important in the etiology and disease expression of familial IIM, with DQA1 homozygosity being a distinct risk factor for familial IIM. Muscle \- Proximal muscle weakness \- Myositis Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton	MYOSITIS	c3888318	6,493	omim	https://www.omim.org/entry/160750	2019-09-22T16:37:40	{"doid": ["633"], "mesh": ["C000598744"], "omim": ["160750"], "icd-10": ["M60.9", "M60", "G72.49"], "synonyms": ["Alternative titles", "MYOPATHY, FAMILIAL IDIOPATHIC INFLAMMATORY"]}
Congenital condition characterised by fusion of two or more vertebrae in the neck Klippel-Feil syndrome Other namesCongenital dystrophia brevicollis, cervical vertebral fusion syndrome Woman with Klippel–Feil syndrome Pronunciation * /ˌklɪ.pəl ˈfaɪl/ SpecialtyPaediatrics, orthopaedics SymptomsCervical spine fusion, scoliosis, spina bifida, heart defect, respiratory problems, other syndromic features Usual onsetCongenital CausesGenetic mutations Risk factorsFamily history PrognosisShorter life expectancy in some cases Frequency1 in 40,000 to 42,000 births, females more affected than males Klippel–Feil syndrome (KFS), also known as cervical vertebral fusion syndrome, is a rare congenital condition characterized by the abnormal fusion of any two of the seven bones in the neck (cervical vertebrae).[1]:578 It results in a limited ability to move the neck and shortness of the neck, resulting in the appearance of a low hairline.[2] The syndrome is difficult to diagnose, as it occurs in a group of patients affected with many different abnormalities who can only be unified by the presence of fused or segmental cervical vertebrae.[3] KFS is not always genetic and not always known the day of the birth. The disease was initially reported in 1884 by Maurice Klippel and André Feil from France.[4] In 1919, in his Doctor of Philosophy thesis,[5] André Feil suggested another classification of the syndrome, encompassing not only deformation of the cervical spine, but also deformation of the lumbar and thoracic spine. ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 3.1 Classification * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 Notable cases * 7.1 Ancient * 7.2 Contemporary * 8 References * 9 External links ## Signs and symptoms[edit] CT scan showing fused cervical vertebrae and Sprengel's deformity (arrow), as seen in Klippel–Feil syndrome KFS is associated with many other abnormalities of the body, hence thorough evaluation of all patients with fused cervical vertebrae at birth is required. Furthermore, it is unclear whether KFS is a unique disease, or if it is one part of a spectrum of congenital spinal deformities.[citation needed] KFS is usually diagnosed after birth. The most common signs of the disorder are restricted mobility of the neck and upper spine and a shortened neck with the appearance of a low hairline at the back of the head.[citation needed] Associated abnormalities may include:[6][7][8][9] * Scoliosis (sideways curvature of the spine) * Spina bifida * Problems with the kidneys and the ribs * Cleft palate * Dental problems (delayed dentition, cavities, missing teeth) * Respiratory problems * Heart defects * Short stature * Duane syndrome * Srb's anomaly * Sprengel's deformity The disorder also may be associated with abnormalities of the head and face, skeleton, sex organs, muscles, brain and spinal cord, arms, legs and fingers.[citation needed] ## Genetics[edit] See also: Dominance (genetics) Mutations of the GDF6, GDF3 and MEOX1 gene are associated with KFS.[2] The cause of the condition is unknown in individuals with KFS who do not have mutations of these two genes. GDF6 and GDF3 provide the body with instructions for making proteins involved in regulating the growth and maturation of bone and cartilage. GDF6 specifically is involved in the formation of vertebral bones, among others, and establishing boundaries between bones in skeletal development. GDF3 is involved with bone and cartilage growth. Mutations of GDF6, GDF3 and MEOX1 cause a reduced number of functional proteins that are coded by these genes, but it is unclear exactly how a shortage in these proteins leads to incomplete separation of the vertebrae in people with KFS.[10] However, when the GDF6 gene was removed in mice, the result was the fusion of bones.[11] These mutations can be inherited in two ways: * Autosomal dominant inheritance, where one copy of the altered gene in each cell is sufficient to cause the disorder, is especially associated with C2-C3 fusion.[10] * Autosomal recessive inheritance, where both copies of a gene contain mutations, is especially associated with C5-C6 fusion.[10] * Another autosomal dominant form (mapped on locus 8q22.2), known as KFS with laryngeal malformation, has been identified. It is also known as segmentation syndrome 1.[12][13] ## Diagnosis[edit] The heterogeneity of KFS has made it difficult to outline the diagnosis as well as the prognosis for this disease.[citation needed] ### Classification[edit] In 1912, Maurice Klippel and Andre Feil independently provided the first descriptions of KFS. They described patients who had a short, webbed neck; decreased range of motion (ROM) in the cervical spine; and a low hairline. Feil subsequently classified the syndrome into 3 categories:[citation needed] * Type I — Fusion of C2 and C3 with occipitalization of the atlas. In 1953, further complications were later reported by McRae; flexion and extension is concentrated within the C1 and C2 vertebrae. As with aging, the odontoid process can become hypermobile, narrowing the space where the spinal cord and brain stem travel (spinal stenosis). * Type II — Long fusion below C2 with an abnormal occipital-cervical junction. Similar to the C2-C3 fusion of McRae and could be viewed as a more elaborate variation. Flexion, extension, and rotation are all concentrated in the area of an abnormal odontoid process or poorly developed ring of C1 which cannot withstand the effects of aging. * Type III — A single open interspace between two fused segments. Cervical spine motion is concentrated at single open articulation. This hypermobility may lead to instability or degenerative osteoarthritis. This pattern can be recognized as the cervical spine is often seen to be at an angle or hinge at this open segment. A classification scheme for KFS was proposed in 1919 by Andre Feil, which accounted for cervical, thoracic, and lumbar spine malformations.[14] However, in 2006, Dino Samartzis and colleagues proposed three classification-types that specifically addressed the cervical spine anomalies and their associated cervical spine-related symptoms, with additional elaboration on various time-dependent factors regarding this syndrome.[15] ## Treatment[edit] Treatment for KFS is symptomatic and may include surgery to relieve cervical or craniocervical instability and constriction of the spinal cord, and to correct scoliosis.[citation needed] If symptomatic treatment fails, spinal surgery may provide relief. Adjacent segment disease and scoliosis are two examples of common symptoms associated with Klippel–Feil syndrome, and they may be treated surgically. The three categories treated for types of spinal cord deficiencies are massive fusion of the cervical spine (Type I), the fusion of 1 or 2 vertebrae (Type II), and the presence of thoracic and lumbar spine anomalies in association with type I or type II Klippel–Feil syndrome (Type III).[citation needed] Adjacent segment disease can be addressed by performing cervical disc arthroplasty using a device such as the Bryan cervical disc prosthesis.[16] The option of the surgery is to maintain range of motion and attenuate the rate of adjacent segment disease advancement without fusion.[17] Another type of arthroplasty that is becoming an alternate choice to spinal fusion is Total Disc Replacement. Total disc replacement objective is to reduce pain or eradicate it.[18] Spinal fusion is commonly used to correct spinal deformities such as scoliosis. Arthrodesis is the last resort in pain relieving procedures, usually when arthroplasties fail.[citation needed] ## Prognosis[edit] The prognosis for most individuals with KFS is good if the disorder is treated early and appropriately. Activities that can injure the neck should be avoided, as it may contribute to further damage. Other diseases associated with the syndrome can be fatal if not treated, or if found too late to be treatable.[19] In less than 30% of cases, individuals with KFS will present with heart defects.[20] If these heart defects are present, they often lead to a shortened life expectancy, the average being 35–45 years of age among males and 40–50 among females. This condition is similar to the heart failure seen in gigantism.[21] ## Epidemiology[edit] The prevalence of KFS is unknown due to the lack of studies to determine its prevalence.[22] It is estimated to occur 1 in 40,000 to 42,000 newborns worldwide. In addition, females seem to be affected slightly more often than males.[10] ## Notable cases[edit] ### Ancient[edit] * A case of a child in Switzerland was discovered in a necropolis dated between 4500 and 4000 BC.[23] * In 2009, archaeologists excavating at a Neolithic site of the Đa Bút culture of northern Vietnam discovered the remains of a young man around age 25, "Burial 9", living between 2000 BC and 1500 BC with Klippel–Feil syndrome, who had apparently been supported by his subsistence-level community for at least a decade before his death.[24][25][26] * The 18th Dynasty Egyptian pharaoh Tutankhamun is believed by some to have suffered from Klippel–Feil syndrome,[27] though others dispute this claim.[28] ### Contemporary[edit] * English cricketer Gladstone Small[29] * "Big" Ed Brown from the TLC series, 90 Day Fiancé. ## References[edit] 1. ^ Andrews, James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 2. ^ a b "Klippel-Feil syndrome". Genetics Home Reference. U.S. National Library of Medicine. Retrieved 2018-08-18. 3. ^ "Klippel-Feil Syndrome". HONselect. 4. ^ Belykh, Evgenii; Malik, Kashif; Simoneau, Isabelle; Yagmurlu, Kaan; Lei, Ting; Cavalcanti, Daniel D.; Byvaltsev, Vadim A.; Theodore, Nicholas; Preul, Mark C. (July 2016). "Monsters and the case of L. Joseph: André Feil's thesis on the origin of the Klippel-Feil syndrome and a social transformation of medicine". Neurosurgical Focus. 41 (1): E3. doi:10.3171/2016.3.FOCUS15488. ISSN 1092-0684. PMID 27364256. 5. ^ Feil A (1919). "These de medicine, Paris. L'absence et la diminution des vertèbres cervicales (étude clinique et pathogénique); le syndrome de réduction numérique cervicales". Cite journal requires `\|journal=` (help) 6. ^ Paradowska, Szeląg, Sławecki (2007). "Klippel−Feil Syndrome – Review of the Literature" (PDF). Dent. Med. Probl. Archived from the original (PDF) on 2015-10-01. Retrieved 2015-09-30.CS1 maint: multiple names: authors list (link) 7. ^ de Lima, Marina de Deus Moura; Ortega, Karem Lopez; Araújo, Luis Carlos Arias; Soares, Marcelo Melo; de Magalhães, Marina Helena Cury Gallottini (2009-12-01). "Dental team management for a patient with Klippel-Feil syndrome: case report". Special Care in Dentistry. 29 (6): 244–248. doi:10.1111/j.1754-4505.2009.00101.x. ISSN 1754-4505. PMID 19886936. 8. ^ Marchiori, Dennis (2004). Clinical Imaging - E-Book: With Skeletal, Chest and Abdomen Pattern Differentials. Elsevier Health Sciences. ISBN 978-0323071277. Retrieved 25 January 2018. 9. ^ Farsetti P, Weinstein SL, Caterini R, De Maio F, Ippolito E (May 2003). "Sprengel's deformity: long-term follow-up study of 22 cases". J Pediatr Orthop B. 12 (3): 202–10. doi:10.1097/01202412-200305000-00007. PMID 12703036. Sarwark, JF; LaBella, CR, eds. (2010). Pediatric Orthopaedics and Sports Injuries: A Quick Reference Guide. Elk Grove Village IL: American Academy of Pediatrics. pp. 231–4. 10. ^ a b c d [1] at NLM Genetics Home Reference 11. ^ Tassabehji M, Fang ZM, Hilton EN, et al. (August 2008). "Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome". Hum. Mutat. 29 (8): 1017–27. doi:10.1002/humu.20741. PMID 18425797. S2CID 5276691. 12. ^ Online Mendelian Inheritance in Man (OMIM): Klippel-Feil Syndrome 1, Autosomal Dominant; KFS1 - 118100 13. ^ "Segmentation syndrome 1 \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". 14. ^ Feil A. L'absence et la diminuaton des vertebres cervicales (etude cliniqueet pathogenique); le syndrome dereduction numerique cervicales. Theses de Paris; 1919. 15. ^ Samartzis DD, Herman J, Lubicky JP, Shen FH (2006). "Classification of congenitally fused cervical patterns in Klippel-Feil patients: epidemiology and role in the development of cervical spine-related symptoms". Spine. 31 (21): E798–804. doi:10.1097/01.brs.0000239222.36505.46. PMID 17023841. S2CID 19744236. 16. ^ Goffin J, Casey A, Kehr P, et al. (September 2002). "Preliminary clinical experience with the Bryan Cervical Disc Prosthesis". Neurosurgery. 51 (3): 840–5, discussion 845–7. doi:10.1227/00006123-200209000-00048. PMID 12188968. 17. ^ Papanastassiou ID, Baaj AA, Dakwar E, Eleraky M, Vrionis FD (March 2011). "Failure of cervical arthroplasty in a patient with adjacent segment disease associated with Klippel-Feil syndrome". Indian J Orthop. 45 (2): 174–7. doi:10.4103/0019-5413.77139. PMC 3051126. PMID 21430874. 18. ^ Phillips FM, Garfin SR (September 2005). "Cervical disc replacement". Spine. 30 (17 Suppl): S27–33. doi:10.1097/01.brs.0000175192.55139.69. PMID 16138062. S2CID 46420208. 19. ^ Cathy C. Cartwright; Donna C. Wallace (3 May 2007). Nursing care of the pediatric neurosurgery patient. pp. 205–. ISBN 978-3-540-29703-1. Retrieved 25 December 2010. 20. ^ https://rarediseases.info.nih.gov/diseases/10280/klippel-feil-syndrome 21. ^ McGaughran JM, Kuna P, Das V (October 1998). "Audiological abnormalities in the Klippel-Feil syndrome". Arch. Dis. Child. 79 (4): 352–5. doi:10.1136/adc.79.4.352. PMC 1717726. PMID 9875048. 22. ^ Angeli, E., Wagner, J., Lawrick, E., Moore, K., Anderson, M., Soderland, L., & Brizee, A. (2010, May 5). General format title. Retrieved from http://owl.english.purdue.edu/owl/resource/560/01/ 23. ^ "Aspects historiques". 24. ^ "Oldest Known Paralyzed Human Discovered". Archived from the original on 2012-07-10. Retrieved 2014-01-18.CS1 maint: bot: original URL status unknown (link) 25. ^ Tilley, Lorna; Oxenham, Marc F (March 2011). "Survival against the odds: Modeling the social implications of care provision to seriously disabled individuals". International Journal of Paleopathology. 1 (1): 35–42. doi:10.1016/j.ijpp.2011.02.003. PMID 29539340. 26. ^ Gorman, James (2012-12-17). "Ancient Bones That Tell a Story of Compassion". The New York Times (17 December 2012, New York edition, D1). The New York Times. Retrieved 12 April 2015. 27. ^ Barrow, Becky (2002-09-29). "Tutankhamun shows his face 80 years after tomb is opened". The Telegraph. London. Retrieved 2007-07-12. 28. ^ Boyer RS, Rodin EA, Grey TC, Connolly RC (2003). "The skull and cervical spine radiographs of Tutankhamen: a critical appraisal". AJNR. American Journal of Neuroradiology. 24 (6): 1142–7. PMID 12812942. 29. ^ Hughes, Simon (1997-09-05). "Small gains from wealth of partners". Cricinfo. Retrieved 2007-12-13. This article incorporates information in the public domain prepared by the National Institute of Neurological Disorders and Stroke. ## External links[edit] * Klippel–Feil syndrome at Curlie Classification D * ICD-10: Q76.1 * ICD-9-CM: 756.16 * OMIM: 118100 214300 * MeSH: D007714 * DiseasesDB: 7197 External resources * eMedicine: orthoped/408 * v * t * e Congenital malformations and deformations of musculoskeletal system / musculoskeletal abnormality Appendicular limb / dysmelia Arms clavicle / shoulder * Cleidocranial dysostosis * Sprengel's deformity * Wallis–Zieff–Goldblatt syndrome hand deformity * Madelung's deformity * Clinodactyly * Oligodactyly * Polydactyly Leg hip * Hip dislocation / Hip dysplasia * Upington disease * Coxa valga * Coxa vara knee * Genu valgum * Genu varum * Genu recurvatum * Discoid meniscus * Congenital patellar dislocation * Congenital knee dislocation foot deformity * varus * Club foot * Pigeon toe * valgus * Flat feet * Pes cavus * Rocker bottom foot * Hammer toe Either / both fingers and toes * Polydactyly / Syndactyly * Webbed toes * Arachnodactyly * Cenani–Lenz syndactylism * Ectrodactyly * Brachydactyly * Stub thumb reduction deficits / limb * Acheiropodia * Ectromelia * Phocomelia * Amelia * Hemimelia multiple joints * Arthrogryposis * Larsen syndrome * RAPADILINO syndrome Axial Skull and face Craniosynostosis * Scaphocephaly * Oxycephaly * Trigonocephaly Craniofacial dysostosis * Crouzon syndrome * Hypertelorism * Hallermann–Streiff syndrome * Treacher Collins syndrome other * Macrocephaly * Platybasia * Craniodiaphyseal dysplasia * Dolichocephaly * Greig cephalopolysyndactyly syndrome * Plagiocephaly * Saddle nose Vertebral column * Spinal curvature * Scoliosis * Klippel–Feil syndrome * Spondylolisthesis * Spina bifida occulta * Sacralization Thoracic skeleton ribs: * Cervical * Bifid sternum: * Pectus excavatum * Pectus carinatum Authority control * GND: 4367829-4 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Klippel–Feil syndrome	c0022738	6,494	wikipedia	https://en.wikipedia.org/wiki/Klippel%E2%80%93Feil_syndrome	2021-01-18T18:55:16	{"gard": ["10280"], "mesh": ["D007714"], "umls": ["C0022738"], "orphanet": ["2345"], "wikidata": ["Q1774751"]}
Smouldering myeloma Other namesSmoldering myeloma, Smoldering multiple myeloma, Indolent myeloma or Asymptomatic myeloma SpecialtyHematology/oncology Smouldering myeloma, is a disease classified as intermediate in a spectrum of step-wise progressive diseases termed plasma cell dyscrasias. In this spectrum of diseases, a clone of plasma cells secreting monoclonal paraprotein (also termed myeloma protein or M protein) causes the relatively benign disease of monoclonal gammopathy of undetermined significance. This clone proliferates and may slowly evolve into more aggressive sub-clones that cause smouldering multiple myeloma. Further and more rapid evolution causes the overtly malignant stage of multiple myeloma and can subsequently lead to the extremely malignant stage of secondary plasma cell leukemia.[1][2][3] Thus, some patients with smouldering myeloma progress to multiple myeloma and plasma cell leukemia. Smouldering myeloma, however, is not a malignant disease. It is characterised as a pre-malignant disease that lacks symptoms but is associated with bone marrow biopsy showing the presence of an abnormal number of clonal myeloma cells, blood and/or urine containing a myeloma protein, and a significant risk of developing into a malignant disease.[2] ## Contents * 1 Diagnosis * 2 Treatment * 3 Prognosis * 4 References * 5 Further reading ## Diagnosis[edit] Smouldering myeloma is characterised by:[4] * Serum paraprotein >30 g/l or urinary monoclonal protein ≥500 mg per 24 h AND/OR * Clonal plasma cells >10% and <60% on bone marrow biopsy AND * No evidence of end organ damage that can be attributed to plasma cell disorder AND * No myeloma-defining event (>60% plasma cells in bone marrow OR Involved/Uninvolved light chain ratio>100) ## Treatment[edit] Treatment for multiple myeloma is focused on therapies that decrease the clonal plasma cell population and consequently decrease the signs and symptoms of disease. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), as in smouldering myeloma, treatment is typically deferred, or restricted to clinical trials.[5] They are generally responsive to IL-1β neutralisation.[6] ## Prognosis[edit] Smouldering myeloma with an increasingly abnormal serum free light chain (FLC) ratio is associated with a higher risk for progression to active multiple myeloma.[7] ## References[edit] 1. ^ Agarwal, A; Ghobrial, IM (1 March 2013). "Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: a review of the current understanding of epidemiology, biology, risk stratification, and management of myeloma precursor disease". Clinical Cancer Research. 19 (5): 985–94. doi:10.1158/1078-0432.ccr-12-2922. PMC 3593941. PMID 23224402. 2. ^ a b Dutta, AK; Hewett, DR; Fink, JL; Grady, JP; Zannettino, ACW (2017). "Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma". British Journal of Haematology. 178 (2): 196–208. doi:10.1111/bjh.14649. PMID 28466550. 3. ^ van de Donk, N; et al. (21 March 2014). "The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network". Haematologica. 99 (6): 984–96. doi:10.3324/haematol.2013.100552. PMC 4040895. PMID 24658815. 4. ^ Rajkumar, SV; Dimopoulos, MA; Palumbo, A; Blade, J; Merlini, G; Mateos, MV; Kumar, S; Hillengass, J; Kastritis, E; Richardson, P; Landgren, O; Paiva, B; Dispenzieri, A; Weiss, B; LeLeu, X; Zweegman, S; Lonial, S; Rosinol, L; Zamagni, E; Jagannath, S; Sezer, O; Kristinsson, SY; Caers, J; Usmani, SZ; Lahuerta, JJ; Johnsen, HE; Beksac, M; Cavo, M; Goldschmidt, H; Terpos, E; Kyle, RA; Anderson, KC; Durie, BG; Miguel, JF (November 2014). "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma". The Lancet Oncology. 15 (12): e538–48. doi:10.1016/s1470-2045(14)70442-5. PMID 25439696. 5. ^ Korde N; Kristinsson SY; Landgren O (2011). "Monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies". Blood. 117 (21): 5573–5581. doi:10.1182/blood-2011-01-270140. PMC 3316455. PMID 21441462. 6. ^ Dinarello CA (2011). "Interleukin-1 in the pathogenesis and treatment of inflammatory diseases". Blood. 117 (14): 3720–32. doi:10.1182/blood-2010-07-273417. PMC 3083294. PMID 21304099. 7. ^ Ballew, C; Liu, K; Savage, P; Oberman, A; Smoak, C (1990). "The utility of indirect measures of obesity in racial comparisons of blood pressure. CARDIA Study Group". J Clin Epidemiol. 43 (8): 799–804. doi:10.1016/0895-4356(90)90240-p. PMID 2200851. ## Further reading[edit] * Barlogie B, van Rhee F, Shaughnessy JD, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB (Oct 15, 2008). "Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease". Blood. 112 (8): 3122–5. doi:10.1182/blood-2008-06-164228. PMC 2569167. PMID 18669874. * Pérez-Persona E, Vidriales MB, Mateo G, García-Sanz R, Mateos MV, de Coca AG, Galende J, Martín-Nuñez G, Alonso JM, de Las Heras N, Hernández JM, Martín A, López-Berges C, Orfao A, San Miguel JF (Oct 1, 2007). "New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells". Blood. 110 (7): 2586–92. doi:10.1182/blood-2007-05-088443. PMID 17576818. * Kyle RA, Durie BG, Rajkumar SV, Landgren O, Blade J, Merlini G, Kröger N, Einsele H, Vesole DH, Dimopoulos M, San Miguel J, Avet-Loiseau H, Hajek R, Chen WM, Anderson KC, Ludwig H, Sonneveld P, Pavlovsky S, Palumbo A, Richardson PG, Barlogie B, Greipp P, Vescio R, Turesson I, Westin J, Boccadoro M (Jun 2010). "Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management". Leukemia. 24 (6): 1121–7. doi:10.1038/leu.2010.60. PMC 7020664. PMID 20410922. * Dispenzieri, A; Kumar, S (Oct 31, 2013). "Treatment for high-risk smoldering myeloma". The New England Journal of Medicine. 369 (18): 1764. doi:10.1056/NEJMc1310911. PMID 24171529. * Dispenzieri A, Kumar S (31 October 2013). "Treatment for High-Risk Smoldering Myeloma". New England Journal of Medicine. 369 (18): 1762–1765. doi:10.1056/NEJMc1310911. PMID 24171529. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Smouldering myeloma	c1531608	6,495	wikipedia	https://en.wikipedia.org/wiki/Smouldering_myeloma	2021-01-18T18:33:57	{"mesh": ["D000075122"], "umls": ["C1531608"], "wikidata": ["Q17146000"]}
A hereditary disorder of hepatic bilirubin conjugation, characterized by severe neonatal unconjugated hyperbilirubinemia due to a complete absence of hepatic bilirubin glucuronosyltransferase (BGT). ## Epidemiology The prevalence of Crigler-Najjar syndrome type 1 (CNS1) is unknown. Crigler-Najjar syndrome (CNS) has an estimated annual incidence at birth of 1/1,000,000. ## Clinical description Infants present with persistent jaundice at or soon after birth. Bilirubin encephalopathy (kernicterus manifesting as hypotonia, deafness, oculomotor palsy and lethargy) due to hyperbilirubinemia is a permanent risk. Neurologic defects (injury to basal ganglia, cerebellar and likely hippocampal structures) can occur, generally associated with intellectual and motor impairment. ## Etiology Numerous mutations in the UGT1A1 gene (2q37) are linked to CNS1 and result in absent bilirubin GT activity with marked impairment of bilirubin conjugation. ## Diagnostic methods Diagnosis is based on findings of total serum bilirubin between 20 and 45 mg/dL and presence of traces of bilirubin glucuronides in bile. Diagnosis is confirmed by genomic DNA analysis (ruling out the need for liver biopsy). When liver biopsy was performed, it showed a total deficiency of hepatic BGT activity. ## Differential diagnosis Differential diagnosis includes disorders of excessive bilirubin production (hemolysis, infections). CNS2 can be excluded by the absence of GT activity and lack of response to phenobarbital treatment and by DNA analysis. ## Antenatal diagnosis Antenatal diagnosis is available (chorionic villi sampling). ## Genetic counseling Transmission is autosomal recessive. Genetic counseling is recommended when parents have a family history of CNS. Preimplantatory genetic diagnosis may also be discussed in affected couples. ## Management and treatment Treatment relies on phototherapy for 10-12 hours a day (to maintain levels of unconjugated hyperbilirubinemia below the neurotoxic threshold and the bilirubin/albumin molar ratio <0.7). Orthotopic liver transplantation may be considered and is more effective when performed before onset of neurologic damage. Bilirubin chelators (calcium salts, cholestyramine) may be used. Treatment with heme oxygenase inhibitors (tin-mesoporphyrin) can decrease plasma bilirubin concentrations but are not advised in the long term, because of their side effects (photosensitization). They may be useful for treating acute and severe hyperbilirubinemia. Prompt treatment of neurologic manifestations is required to avoid potentially devastating neurologic sequelae (intensive phototherapy, albumin infusions, and plasma exchanges). Unlike CNS2, patients with CNS1 do not respond to phenobarbital. Gene therapy projects are ongoing. ## Prognosis Without treatment, CNS1 is lethal as a result of kernicterus. With treatment and management children have a good prognosis and may follow normal schooling, even though the treatment is very restrictive. Adult patients who have not undergone liver transplantation still require phototherapy but may have ``near normal'' social and familial lives. A few adult women have given birth to normal children, provided their pregnancies have been carefully followed up. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Crigler-Najjar syndrome type 1	c0010324	6,496	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79234	2021-01-23T18:50:48	{"gard": ["47"], "mesh": ["D003414", "C536212"], "omim": ["218800"], "umls": ["C0010324", "C2931131"], "icd-10": ["E80.5"], "synonyms": ["Bilirubin uridinediphosphate glucuronosyltransferase deficiency type 1", "Bilirubin-UGT deficiency type 1", "Hereditary unconjugated hyperbilirubinemia type 1", "UGT deficiency type 1"]}
A number sign (#) is used with this entry because of evidence that cone-rod dystrophy-11 (CORD11) is caused by heterozygous mutation in the RAXL1 gene (RAX2, 610362) on chromosome 19p13. For a phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970. Clinical Features Yang et al. (2015) studied a 4-generation family in which 6 members had retinal dystrophy. All affected individuals presented with declining visual acuity, although the age at onset of symptoms varied widely, with vision loss reported as early as age 15 years and as late as age 60. Examination of all 4 living patients revealed relative central scotoma on kinetic visual fields and obvious macular changes consistent with cone or cone-rod dystrophy, including small yellow macular deposits and/or macular pigment mottling, as well as waxy disc pallor and attenuated vasculature indicating diffuse dystrophy. Central scotomas worsened as macular atrophy progressed. In older patients, mid- and far-peripheral scotomas were detected that correlated with retinal pigment epithelium changes and atrophy of the mid- and far-peripheral retina. Spectral-domain optical coherence tomography of the macula revealed subfoveal hyperreflective deposits and severe diffuse attenuation of the outer retina. In addition, all patients had abnormal electroretinograms (ERGs) demonstrating variable patterns of both cone- and rod-system dysfunction. Scotopic responses to bright flashes were attenuated and prolonged for both the a- and b-waves, but the b-wave was predominantly affected, producing electronegative waveforms as well as b-wave to a-wave amplitude ratios of less than 1.0 in all patients. No other cause of an electronegative ERG was identified in any of the affected patients. Molecular Genetics To test the hypothesis that defects in the RAXL1 gene could result in retinal disease, Wang et al. (2004) screened a cohort of patients with retinopathies, including 322 with a diagnosis of CORD, 107 with Leber congenital amaurosis, 92 with age-related macular degeneration, 14 with autosomal recessive retinitis pigmentosa, and 14 with autosomal dominant retinitis pigmentosa, as well as 94 normal individuals, for mutations in RAXL1. In 2 unrelated patients with CORD, one of whom was described as having macular degeneration with ERG evidence of peripheral retinal involvement, Wang et al. (2004) identified heterozygous mutations (610362.0002 and 610362.0003). In coimmunoprecipitation analyses and transient transfection assays, these mutations resulted in decreased interaction of the protein with CRX (602225) and altered transactivation activity. In a 4-generation family exhibiting retinal dystrophy with an electronegative scotopic response to bright stimuli, Yang et al. (2015) screened 3 affected and 2 unaffected individuals for mutation in 26 genes associated with cone or cone-rod dystrophy, including CRX, GUCY2D (600179), and PRPH2 (179605), and identified a heterozygous 11-bp deletion in the RAX2 gene (610362.0004) that segregated with disease. Yang et al. (2015) noted that the ERG results in this family showed both inner-retinal and photoreceptor dysfunction, consistent with expression of the RAX2 gene in both the inner and outer layers of the retina (Wang et al., 2004). INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Decreased visual acuity, slowly progressive \- Photophobia (in some patients) \- Decreased night vision (in some patients) \- Difficulty with color discrimination (in some patients) \- Decreased pericentral vision \- Decreased peripheral visual \- Relative central scotoma on kinetic field testing, progressive \- Peripheral scotomata (late onset) \- Attenuation of retinal vessels, progressive \- Perivascular pigment accumulation \- Yellow macular deposits \- Pigment granularity of macula \- Macular atrophy, progressive \- Waxy disc pallor \- Bull's eye maculopathy \- Pigment granularity of peripheral retina \- Bone-spicule pigmentation (in some patients) \- Mixed rod and cone dysfunction on electroretinography (ERG) \- Electronegative scotopic waveform response to bright flashes on ERG \- Macular hypoautofluorescence on wide-field images \- Perimacular hyperautofluorescence \- Atrophy of macular retinal pigment epithelium on spectral-domain optical coherence tomography MISCELLANEOUS \- Based on detailed clinical description of 1 family \- Variable age at onset of symptoms, ranging from the second to seventh decades of life MOLECULAR BASIS \- Caused by mutation in the retina and anterior neural fold homeobox-2 gene (RAX2, 610362.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	CONE-ROD DYSTROPHY 11	c3489532	6,497	omim	https://www.omim.org/entry/610381	2019-09-22T16:04:37	{"doid": ["0111018"], "mesh": ["D000071700"], "omim": ["120970", "610381"], "orphanet": ["1872"], "synonyms": []}
Severe combined immunodeficiency (SCID) due to CTPS1 deficiency is a rare primary immunodeficiency disorder due to impaired capacity of activated T- and B-cells to proliferate in response to antigen receptor-mediated activation characterized by early-onset, severe, persistent and/or recurrent viral infections due to Epstein-Barr virus (EBV) and Varicella Zoster virus (VZV, including generalized varicella)), as well as recurrent sino-pulmonary bacterial infections due to encapsulated pathogens. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Severe combined immunodeficiency due to CTPS1 deficiency	c4014617	6,498	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=420573	2021-01-23T17:22:06	{"omim": ["615897"], "icd-10": ["D81.2"], "synonyms": ["SCID due to CTPS1 deficiency"]}
Pallister-Killian syndrome Other namesTetrasomy 12p mosaicism, Pallister mosaic aneuploidy syndrome Pallister–Killian syndrome (also tetrasomy 12p mosaicism or Pallister mosaic aneuploidy syndrome) is an extremely rare genetic disorder occurring in humans. Pallister–Killian occurs due to the presence of the anomalous extra isochromosome 12p, the short arm of the twelfth chromosome. This leads to the development of tetrasomy 12p.[1] Because not all cells have the extra isochromosome, Pallister–Killian is a mosaic condition (more readily detected in skin fibroblasts). It was first described by Philip Pallister in 1977 and further researched by Maria Teschler-Nicola and Wolfgang Killian in 1981.[2] ## Contents * 1 Presentation * 2 Causes * 3 Diagnosis * 4 See also * 5 References * 6 External links ## Presentation[edit] This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (August 2013) (Learn how and when to remove this template message) Characteristics include varying degrees of developmental disability, epilepsy, hypotonia and both hypopigmentation and hyperpigmentation. Patients also exhibit a distinctive facial structure, characterized by high foreheads, sparse hair on the temple, a wide space between the eyes, epicanthal folds and a flat nose. Vision and hearing impairments may occur. Patients may also exhibit congenital heart defects, gastroesophageal reflux, cataracts and supernumerary nipples. Diaphragm problems are also possible. * As patients pass into adolescence, the syndrome is characterized by a coarse and flat face, macroglossia, prognathism, inverted lower lip and psychomotor retardation with muscular hypertonia and contractures. ## Causes[edit] Pallister–Killian does not appear to be hereditary. Some research has suggested that the presence of the extra chromosome may be linked to premeiotic mitotic errors, both maternally and paternally. Several theories regarding the mechanism of this formation have been introduced.[3][4] ## Diagnosis[edit] The isochromosome i(12p) can be primarily detected in samples of skin fibroblasts, as well as in chorionic villus and amniotic fluid cell samples.[2] Very rarely, it can also be detected in blood lymphocytes.[5] It is also possible to detect the isochromosome in circulating lymphocytes, as well as other amniotic and placental samples. There is no strict limit as to where the isochromosome can be found. However, it is often unlikely that these samples will be tested when the blood karyotype is normal.[6] Using an ultrasound, Pallister–Killian may be diagnosed through observation of hypertelorism, broad neck, shorts limbs, abnormal hands or feet, diaphragmatic hernia, and hydramnios. Once born, a child may be diagnosed by observation of the syndrome's distinct facial features.[citation needed] ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ Peltomaki, P., S. Knuutila, A. Ritvanen; et al. (1987). "Pallister-Killian syndrome: cytogenetic and molecular studies". Clin Genet. 31 (6): 399–405. doi:10.1111/j.1399-0004.1987.tb02832.x. PMID 2887316.CS1 maint: multiple names: authors list (link) 2. ^ a b Polityko, A.D., E. Goncharova, L. Shamgina; et al. (2005). "Pallister-Killian Syndrome : Rapid Decrease of Isochromosome 12p Frequency during Amniocyte Subculturing. Conclusion for Strategy of Prenatal Cytogenetic Diagnostics". Journal of Histochemistry and Cytochemistry. 53 (3): 361–364. doi:10.1369/jhc.4A6402.2005. PMID 15750020.CS1 maint: multiple names: authors list (link) 3. ^ Hunter, A.G., B. Clifford, D.M. Cox (1985). "The characteristic physiognomy and tissue specific karyotype distribution in the Pallister-Killian syndrome". Clin Genet. 28 (1): 47–53. doi:10.1111/j.1399-0004.1985.tb01217.x. PMID 4028501.CS1 maint: multiple names: authors list (link) 4. ^ Van Dyke, D.L., V.R. Babu, L. Weiss (1987). "Parental age, and how extra isochromosomes (secondary trisomy) arise". Clin Genet. 32 (1): 75–9. doi:10.1111/j.1399-0004.1987.tb03328.x. PMID 3621657.CS1 maint: multiple names: authors list (link) 5. ^ Schubert, R., R. Viersbach, T. Eggermann (1997). "Report of two new cases of Pallister-Killian syndrome confirmed by FISH: tissue-specific mosaicism and loss of i(12p) by in vitro selection". Am J Med Genet. 72 (1): 106–110. doi:10.1002/(SICI)1096-8628(19971003)72:1<106::AID-AJMG21>3.0.CO;2-U. PMID 9295085.CS1 maint: multiple names: authors list (link) 6. ^ Zambon, Francesco (2001-05-22). "Pallister-Killian syndrome". Medline Current Contents. Archived from the original on 2006-05-09. Retrieved 2006-05-31. ## External links[edit] Classification D * ICD-10: Q99.8 * ICD-9-CM: 758.5 * OMIM: 601803 * MeSH: C538105 * SNOMED CT: 9527009 External resources * Orphanet: 884 * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Pallister–Killian syndrome	c0265449	6,499	wikipedia	https://en.wikipedia.org/wiki/Pallister%E2%80%93Killian_syndrome	2021-01-18T19:04:08	{"mesh": ["C538105"], "umls": ["C0265449"], "icd-9": ["758.5"], "icd-10": ["Q99.8"], "orphanet": ["884"], "wikidata": ["Q1425018"]}

Subsets and Splits

No community queries yet

The top public SQL queries from the community will appear here once available.