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Niemann-Pick disease type B is a mild subtype of Niemann-Pick disease, an autosomal recessive lysosomal disease, and is characterized clinically by onset in childhood with hepatosplenomegaly, growth retardation, and lung disorders such as infections and dyspnea [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	Niemann-Pick disease type B	c0268243	6,300	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=77293	2021-01-23T17:57:28	{"gard": ["10729"], "mesh": ["D052537"], "omim": ["607616"], "umls": ["C0268243"], "icd-10": ["E75.2"]}
## Clinical Features In his autobiography 'Surprised by Joy', Lewis (1955) wrote as follows: 'What drove me to write was the extreme manual clumsiness from which I have always suffered. I attribute it to a physical defect which my brother and I both inherit from our father; we have only one joint in the thumb. The upper joint (that furthest (sic) from the nail) is visible, but it is a mere sham; we cannot bend it. But whatever the cause, nature laid on me from birth an utter incapacity to make anything. With pencil and pen I was handy enough, and I can still tie as good a bow as ever lay on a man's collar; but with a tool or a bat or a gun, a sleeve link or a corkscrew, I have always been unteachable. It was this that forced me to write. I longed to make things, ships, houses, engines. Many sheets of cardboard and pairs of scissors I spoiled, only to turn from my hopeless failures in tears. As a last resource, as a pis aller, I was driven to write stories instead....' Thus, we have a record of father and 2 sons with presumed synostosis involving the first metacarpophalangeal joint. If the first metacarpal is homologically a phalanx, we are justified in considering the anomaly Lewis described in himself and relatives to be a form of symphalangism. We know of no other report. Some cases of fibrodysplasia ossificans progressiva (a disorder obviously not present in Lewis) have fusion of the first metacarpophalangeal joint. Stiff thumbs, possibly of the same type, were accompanied by brachydactyly type A1 (112500) and mental retardation in females in 3 generations of the family reported by Piussan et al. (1983). This is clearly a different disorder; see 188201. Limbs \- Stiff thumbs \- First metacarpophalangeal joint synostosis 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	SYMPHALANGISM, C. S. LEWIS TYPE	c1861404	6,301	omim	https://www.omim.org/entry/185650	2019-09-22T16:34:01	{"mesh": ["C566100"], "omim": ["185650"], "synonyms": ["Alternative titles", "THUMBS, STIFF"]}
A number sign (#) is used with this entry because of evidence that fast-channel congenital myasthenic syndrome-4B (CMS4B) is caused by homozygous or compound heterozygous mutation in the CHRNE gene (100725) on chromosome 17p13. Mutation in the CHRNE gene can also cause slow-channel myasthenic syndrome (CMS4A; 605809) and CMS with acetylcholine receptor (AChR) deficiency (CMS4C; 608931). Description Fast-channel congenital myasthenic syndrome (FCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically from abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (summary by Sine et al., 2003 and Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462). Clinical Features Uchitel et al. (1993) reported a 21-year-old woman with moderately severe myasthenic symptoms since birth who responded poorly to acetylcholinesterase inhibitors. No serum antibodies to the AChR were detected. Electrophysiologic studies showed very small miniature endplate potentials (MEPPs) and currents (MEPCs), but the density and distribution of AChRs in the synapse were normal. Quantal content was also normal, and the junctional folds were intact. Channel conductance studies indicated a kinetic abnormality of the AChR, and the authors postulated a defect in the interaction of ACh with the AChR. In a follow-up study, Ohno et al. (1996) reported favorable response to treatment with 3,4-diaminopyridine, which increases the number of AChR quanta released at the presynaptic membrane by nerve impulses. Ohno et al. (1996) reported a 4-year-old boy and his younger sister who both had myasthenic symptoms from birth. Both patients had negative tests for anti-AChR antibodies and responded incompletely to anticholinesterase drugs. Electrophysiologic studies showed small MEPPs, normal AChR density, and normal endplate ultrastructure. Patch-clamp studies showed infrequent AChR channel openings, a decrease in channel-opening rate, and resistance to desensitization by ACh. The mean opening bursts of the endplate were shorter than normal, consistent with FCCMS. Shen et al. (2012) reported an 8-year-old boy, born of consanguineous parents, with fast-channel congenital myasthenic syndrome. The patient, who had severe myasthenic symptoms since birth, was wheelchair-bound. Three similarly affected sibs died in infancy, and he had 1 similarly affected brother. Inheritance The transmission pattern of CMS4B in the family reported by Shen et al. (2012) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 unrelated patients with FCCMS, 1 of whom had been reported by Uchitel et al. (1993), Ohno et al. (1996) identified compound heterozygosity for 2 mutations in the CHRNE gene: both patients had a pro121-to-leu change (P121L; 100725.0003), and each patient had a different null mutation (G8R, 100725.0017; S143L, 100725.0018). In 4 affected patients from 3 unrelated families with FCCMS, Wang et al. (2000) identified a missense mutation in the CHRNE gene (A411P; 100725.0019). The mutation was found in homozygosity in 2 patients and in compound heterozygosity with a null mutation in 2 patients. Functional expression studies showed that the A411P mutation caused an increase in the distribution rates for channel opening and closing, increasing the range of activation kinetics. In an 8-year-old boy, born of consanguineous parents, with FCCMS, Shen et al. (2012) identified a homozygous missense mutation in the CHRNE gene (W55R; 100725.0021). In vitro functional expression in HEK293 cells showed that the mutant protein was expressed, but patch-clamp recordings indicated 30-fold reduced ACh affinity and 75-fold reduced apparent gating efficiency. The mutation hindered isomerization of the receptor from the closed to the open state, slowed the apparent opening rate, speeded the apparent closing rate, and reduced open channel probability. These altered channel kinetics predicted a short duration and low amplitude of the endplate potential with an inability to activate postsynaptic sodium channels. There was also a low opening probability of the mutant receptor over a range of ACh concentrations, which explained the limited clinical response to pyridostigmine that was observed in this patient. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Facial muscle weakness Eyes \- Ptosis \- Ophthalmoplegia Neck \- Neck muscle weakness RESPIRATORY \- Respiratory insufficiency ABDOMEN Gastrointestinal \- Poor feeding MUSCLE, SOFT TISSUES \- Hypotonia, neonatal \- Muscle weakness \- Easy fatigability \- Decremental response to repetitive nerve stimulation \- Decreased amplitudes of the miniature endplate potential (MEPP) and current (MEPC) \- Shortened open AChR channel duration NEUROLOGIC Central Nervous System \- Delayed motor development due to muscle weakness MISCELLANEOUS \- Onset in infancy \- Early death may occur \- May respond to cholinesterase inhibitors of amifampridine MOLECULAR BASIS \- Caused by mutation in the cholinergic receptor, nicotinic, epsilon polypeptide gene (CHRNE, 100725.0003 ) ▲ 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	MYASTHENIC SYNDROME, CONGENITAL, 4B, FAST-CHANNEL	c0751882	6,302	omim	https://www.omim.org/entry/616324	2019-09-22T15:49:12	{"doid": ["0110677"], "mesh": ["D020294"], "omim": ["616324"], "orphanet": ["98913", "590"], "synonyms": [], "genereviews": ["NBK1168"]}
A number sign (#) is used with this entry because of evidence that microcephaly, short stature, and impaired glucose metabolism-1 (MSSGM1) is caused by homozygous mutation in the TRMT10A gene (616013) on chromosome 4q23. Another syndrome involving microcephaly, short stature, and impaired glucose metabolism (MSSGM2; 616817) is caused by mutation in the PPP1R15B gene (613257) on chromosome 1q32. In addition, Wolcott-Rallison syndrome (226980), characterized by multiple epiphyseal dysplasia as well as microcephaly, short stature, and early-onset diabetes mellitus, is caused by mutation in the EIF2AK3 gene (604032) on chromosome 2p11. Clinical Features Igoillo-Esteve et al. (2013) reported 3 sibs from a consanguineous family of Moroccan descent who had microcephaly with mental retardation, short stature, and early-onset diabetes. The female proband had a history of petit mal seizures in adolescence; brain MRI showed a small brain with no other abnormalities. She developed diabetes at age 22 years, and also had osteoporosis with no other bony abnormalities. Dysmorphic features included short neck, wide nose, low hairline, dorsocervical fat pad, retraction of the right fifth toe, scoliosis, and joint laxity. Her sister and brother, who both had short stature, microcephaly, and mental retardation, also developed diabetes at 19 and 14 years of age, respectively. None of the sibs had ketoacidosis and all were treated with insulin at diagnosis. They were negative for diabetes-associated autoantibodies and had an HLA genotype that did not confer risk for type I diabetes. Endogenous insulin secretion persisted for up to 20 years of follow-up. Their parents developed diabetes in the sixth decade of life and were treated with oral agents; family history included a paternal grandfather and 2 paternal aunts who had adult-onset diabetes, and a sister who developed gestational diabetes at 22 years of age but had a normal fasting plasma glucose at age 30. Gillis et al. (2014) described a sister and 2 brothers from a consanguineous Jewish Uzbek family who had microcephaly, short stature, and abnormalities of glucose homeostasis. All 3 had delayed psychomotor development, and all experienced recurrent seizures from 5 to 6 years of age, with normal EEG recordings and CT scans. Oral glucose tolerance testing (OGTT) was consistent with insulin resistance (high fasting insulin with low to normal fasting glucose levels) as well as inappropriately low insulin secretion in response to glucose. The 19-year-old female proband was treated with diet alone, including nocturnal feedings to prevent hypoglycemia, and reported occasional seizures following high-carbohydrate meals. She also exhibited delayed pubertal development at 16 years of age, with Tanner stage 2 breast and pubic hair development, and had primary amenorrhea at age 19. OGTT in her 2 affected brothers demonstrated inappropriate insulin secretion, with elevated insulin levels during hypoglycemia; the 14-year-old brother was treated with oral diazoxide, whereas the 13-year-old brother was withdrawn from further study by the parents and treated only by frequent feedings. Mapping In 3 sibs from a consanguineous family of Moroccan descent who had microcephaly, short stature, mental retardation, and early-onset diabetes, Igoillo-Esteve et al. (2013) performed SNP array analysis and identified a 12.4-Mb region of homozygosity, between SNPs rs4128340 and rs10516462 on chromosome 4q22-q23, that was common to all 3 affected sibs. Microsatellite analysis confirmed homozygosity and biparental inheritance of a haplotype shared by both parents, and a multipoint lod score of 3.0 was obtained. Recombination events narrowed the critical region to a 3.1-Mb segment at 4q23. Molecular Genetics In a consanguineous family of Moroccan descent in which 3 sibs had microcephaly with mental retardation, short stature, and early-onset diabetes mapping to chromosome 4q23, Igoillo-Esteve et al. (2013) sequenced 5 positional candidate genes but found no mutations. Exome sequencing in the proband revealed homozygosity for a nonsense mutation in the TRMT10A gene (R127X; 616013.0001) that was confirmed by Sanger sequencing. The mutation segregated with disease in the family and was not found in 51 in-house control exomes or in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Igoillo-Esteve et al. (2013) screened the TRMT10A gene in 20 patients with a similar phenotype of microcephaly, intellectual disability, seizures, developmental delay, and/or short stature, as well as in 26 probands with early-onset nonautoimmune diabetes who were negative for mutations in MODY (see 125850)-associated genes, but they did not detect any mutations. In the proband from a consanguineous Jewish Uzbek family with microcephaly, short stature, mental retardation, and hyperinsulinemic hypoglycemia, Gillis et al. (2014) performed whole-exome sequencing and identified homozygosity for a missense mutation (G206R; 616013.0002) in the TRMT10A gene. The mutation segregated with disease in the family and was not found in the dbSNP (build 138) database or in 6,503 exomes in the NHLBI Exome Sequencing Project Exome Variant Server database. The proband's 10-month-old brother, who had microcephaly and developmental delay and was born late in the study, was also found to be homozygous for the mutation; fasting blood glucose tested on several occasions was normal, indicating that hypoglycemia was not present in infancy. Gillis et al. (2014) noted that their patients shared the neuronal and growth failures described in association with a nonsense mutation in TRMT10A (Igoillo-Esteve et al., 2013); however, the glucose metabolism disturbances in the Uzbek family, which included ketotic and nonketotic hyperinsulinemic hypoglycemia and postprandial hyperglycemia, differed from those of the Moroccan patients, who had only nonautoimmune insulinopenic diabetes without ketoacidosis. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly Face \- Low hairline Nose \- Wide nose Neck \- Short neck CHEST Breasts \- Delayed thelarche (rare) ABDOMEN Pancreas \- Inappropriate insulin secretion (in some patients) GENITOURINARY Internal Genitalia (Female) \- Primary amenorrhea (rare) SKELETAL \- Osteoporosis (rare) Skull \- Microcephaly Spine \- Scoliosis (rare) Limbs \- Joint laxity (rare) MUSCLE, SOFT TISSUES \- Buffalo hump (rare) NEUROLOGIC Central Nervous System \- Mental retardation \- Delayed motor development \- Hypoglycemia-related seizures \- Small brain with no other malformation see on MRI ENDOCRINE FEATURES \- Hyperinsulinemic hypoglycemia (in some patients) \- Diabetes, early-onset (in some patients) \- Delayed pubertal development (rare) MOLECULAR BASIS \- Caused by mutation in the tRNA methyltransferase 10A gene (TRMT10A, 616013.0001 ) ▲ 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	MICROCEPHALY, SHORT STATURE, AND IMPAIRED GLUCOSE METABOLISM 1	c4014997	6,303	omim	https://www.omim.org/entry/616033	2019-09-22T15:50:10	{"omim": ["616033"], "orphanet": ["391408"], "synonyms": ["MSSGM", "Alternative titles"]}
Rare syndrome Johnson–Munson syndrome Other namesAphalangy-hemivertebrae-urogenital-intestinal dysgenesis syndrome Aphalangy, hemivertebrae and urogenital-intestinal dysgenesis is an extremely rare syndrome, described only in three siblings.[1] It associates hypoplasia or aplasia of phalanges of hands and feet, hemivertebrae and various urogenital and/or intestinal abnormalities. Intrafamilial variability is important as one sister had lethal abnormalities (Potter sequence and pulmonary hypoplasia), while her affected brother was in good health with normal psychomotor development at 6 months of age. Prognosis seems to depend mainly on the severity of visceral malformations. Etiology and inheritance remain unknown.[2][3] ## References[edit] 1. ^ Johnson VP, Munson DP (Nov 1990). "A new syndrome of aphalangy, hemivertebrae, and urogenital-intestinal dysgenesis". Clin. Genet. 38 (5): 346–52. doi:10.1111/j.1399-0004.1990.tb03593.x. PMID 2282714. 2. ^ Johnson Munson syndrome at NIH's Office of Rare Diseases 3. ^ Bruno Dallapiccola; Alessandro Castriota-Scanderbeg (2005). Abnormal Skeletal Phenotypes: From Simple Signs to Complex Diagnoses. Springer. p. 188. ISBN 3-540-67997-9. ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 207620 * MeSH: C535881 External resources * Orphanet: 1112 This article about a congenital malformation 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	Johnson–Munson syndrome	c1859754	6,304	wikipedia	https://en.wikipedia.org/wiki/Johnson%E2%80%93Munson_syndrome	2021-01-18T18:59:24	{"mesh": ["C535881"], "umls": ["C1859754"], "orphanet": ["1112"], "wikidata": ["Q6268578"]}
Ringtail, also known as tail necrosis,[1] is an epidermal disease that may occur in rats, mice, hamsters and other rodents.[2] In affected individuals, the tail swells as a consequence of annular constrictions along its length (hence the name "ringtail") and subsequent dehydration;[1] in the most severe cases, the process may end up in the tail becoming gangrenous and dropping off. Feet may also swell and redden.[3] Ringtail is traditionally attributed to low environmental humidity and high temperature,[1][2] although a number of other possible causes have been suggested, from dietary deficiencies (low levels of fatty acids) to genetic predisposition. For lab and pet rodents, poor bedding (i.e., overly absorbent bedding) or repeated blood draws from tail veins have also been identified as possible causes of ringtail.[1] ## Footnotes[edit] 1. ^ a b c d Ringtail at Rat Guide 2. ^ a b L.Crippa et al., Ringtail in suckling Munich Wistar Fromter rats: a histopathologic study 3. ^ Ringtail, The Free Dictionary [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	Ringtail (disease)	None	6,305	wikipedia	https://en.wikipedia.org/wiki/Ringtail_(disease)	2021-01-18T18:59:28	{"wikidata": ["Q2153528"]}
A number sign (#) is used with this entry because of evidence that hyperphosphatasia with mental retardation syndrome-2 (HPRMS2) is caused by compound heterozygous mutation in the PIGO gene (614730) on chromosome 9p13. Description Hyperphosphatasia with mental retardation syndrome-2 is an autosomal recessive disorder characterized by moderately to severely delayed psychomotor development, facial dysmorphism, brachytelephalangy, and increased serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures (summary by Krawitz et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of hyperphosphatasia with mental retardation syndrome, see HPMRS1 (239300). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). Clinical Features Krawitz et al. (2012) reported 2 sisters, born of unrelated British parents, and an unrelated girl with hyperphosphatasia with mental retardation. All 3 patients had normal birth parameters, but were born with anal stenosis or anal atresia with perineal fistula. One of the sisters had vesicoureteral reflux. The unrelated girl also had atrial septal defect, peripheral pulmonary stenosis, left coronal synostosis causing plagiocephaly, enlarged ventricles, and microcephaly (-5 SD). Two of the patients showed poor growth. Psychomotor development was moderately to severely retarded and all showed hypotonia. The unrelated girl died at age 22 months of severe generalized seizures. Common facial features in these patients included wide-set eyes with long palpebral fissures, short nose with broad nasal bridge and tip, and a tented mouth. Fingers showed nail hypoplasia, especially of the second, fourth, and fifth digits, and absent nails of the fifth digits. The halluces were broad, but the toes showed small nails or aplasia of nails, especially of the fourth and fifths digits, all findings consistent with brachytelephalangy. Serum alkaline phosphatase (ALP) activity was persistently elevated. Inheritance The transmission pattern of hyperphosphatasia with mental retardation syndrome-2 in the family reported by Krawitz et al. (2012) was consistent with autosomal recessive inheritance. Molecular Genetics By exome sequencing of 2 sisters with HPMRS, Krawitz et al. (2012) identified compound heterozygosity for 2 mutations in the PIGO gene (614730.0001 and 614730.0002). Sequencing of this gene in 11 additional patients with a similar disorder identified 1 patient who was compound heterozygous for 2 mutations (614730.0001 and 614730.0003). In vitro functional expression studies showed that the mutant proteins either lacked or had decreased functional activity. PIGO-deficient CHO cell lines had decreased cell surface placental ALP activity and increased secretion of ALP, which was rescued by transfection with wildtype PIGO. The findings indicated that hyperphosphatasia in the patients with mutations was a result of release of ALP into the serum due to a defect in glycosylphosphatidylinositol (GPI) anchoring to the cell membrane. INHERITANCE \- Autosomal recessive GROWTH Other \- Poor growth HEAD & NECK Head \- Microcephaly (in some patients) Ears \- Hearing impairment Eyes \- Hypertelorism \- Long palpebral fissures \- Upslanting palpebral fissures Nose \- Short nose \- Broad nasal bridge \- Broad nasal tip Mouth \- Tented mouth \- Cleft palate CARDIOVASCULAR Heart \- Heart defects \- Atrial septal defect ABDOMEN Gastrointestinal \- Anal stenosis \- Anal atresia \- Megacolon GENITOURINARY Bladder \- Vesicoureteral reflux (1 patient) SKELETAL Skull \- Plagiocephaly (1 patient) \- Coronal synostosis (1 patient) Hands \- Brachytelephalangy Feet \- Brachytelephalangy \- Broad halluces SKIN, NAILS, & HAIR Nails \- Hypoplastic or absent nails NEUROLOGIC Central Nervous System \- Delayed psychomotor development, moderate to severe \- Delayed speech and language development \- Hypotonia \- Seizures \- Enlarged ventricles (1 patient) LABORATORY ABNORMALITIES \- Increased serum alkaline phosphatase \- Hyperphosphatasia MISCELLANEOUS \- Onset at birth MOLECULAR BASIS \- Caused by mutation in the phosphatidylinositol glycan, class O gene (PIGO, 614730.0001 ) ▲ 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	HYPERPHOSPHATASIA WITH MENTAL RETARDATION SYNDROME 2	c1855923	6,306	omim	https://www.omim.org/entry/614749	2019-09-22T15:54:20	{"mesh": ["C565495"], "omim": ["614749"], "orphanet": ["247262"], "synonyms": ["Alternative titles", "GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 6"]}
A rare, early-onset and life-threatening, multiple carboxylase deficiency that when left untreated, is characterized by vomiting, tachypnea, irritability, lethargy, exfoliative dermatitis, and seizures that can worsen to coma and death. ## Epidemiology The exact prevalence of holocarboxylase synthertase deficiency (HCSD) is unknown, but the condition is one of the rarest inborn errors of metabolism. Prevalence at birth is estimated to be less than 1/200,000. ## Clinical description Clinical onset is usually within hours, days or weeks of birth, although it may occur during infancy or early childhood. Individuals with the disorder usually exhibit poor appetite, vomiting, lethargy, irritability, hypotonia and exfoliative dermatitis. Metabolically, they have ketolactic acidosis, organic acidemia (-uria) and hyperammonemia. Without treatment, affected infants may progress to intractable seizures, cerebral edema and coma. These children often develop growth and developmental delays. ## Etiology HCSD is caused by mutations in the HLCS gene (21q22.1) resulting in reduced holocarboxylase synthertase (HCS) activity. This enzyme is important in covalent binding of biotin to the various biotin-dependent carboxylases that require the vitamin for activity. Failure to attach the biotin results in multiple carboxylase deficiency and accumulation of various, specific abnormal organic acids. ## Diagnostic methods Some affected individuals are identified through newborn screening by demonstration of abnormal organic acids, consistent with multiple carboxyalse deficiency. Diagnosis is based on clinical signs and typical organic acid abnormalities. Diagnosis can be confirmed by enzyme activity assays in leukocytes or fibroblast extracts, or by mutation analysis. ## Differential diagnosis Based on organic acids, conditions to be considered in the differential diagnosis include biotinidase deficiency and isolated carboxyalse deficiencies. Other conditions to be consider include urea cycle defects (based on presence of hyperammonemia) and sepsis and other inborn errors of metabolism (based on neurological compromise and seizures in the neonatal period). ## Antenatal diagnosis Prenatal diagnosis can be performed by organic acid analysis by stable isotope dilution techniques in amniotic fluid, enzymatic determination of HCS activity in amniocytes, or mutation analysis on DNA from chorionic villus biopsy or amniocentesis. ## Genetic counseling Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child for each pregnancy. ## Management and treatment The primary treatment for HCSD is free biotin supplementation which can improve the clinical status of symptomatic individuals with the enzyme deficiency and prevent some or all symptoms from developing in asymptomatic individuals with the disorder. Treatment should be started as soon as possible after diagnosis and must be continued lifelong. Affected individuals should be monitored for later-onset complications and for compliance with therapy. Timely and ongoing treatment makes it possible to reduce symptoms considerably, although some patients develop complications despite appropriate treatment often requiring higher doses of biotin. ## Prognosis In the absence of early diagnosis and treatment, mortality is high. Morbidity in surviving affected individuals depends on the time of diagnosis and on the degree of damage related to metabolic crises. [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	Holocarboxylase synthetase deficiency	c0268581	6,307	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79242	2021-01-23T19:06:01	{"gard": ["2721"], "mesh": ["D028922"], "omim": ["253270"], "umls": ["C0268581"], "icd-10": ["E53.8"], "synonyms": ["Early-onset multiple carboxylase deficiency", "Neonatal multiple carboxylase deficiency"]}
A number sign (#) is used with this entry because of evidence that diffuse nonepidermolytic palmoplantar keratoderma (NEPPK) is caused by heterozygous mutation in the KRT1 gene (139350) on chromosome 12q. A focal form of NEPPK (FNEPPK; 613000) is caused by mutation in the KRT16 gene (148067) on chromosome 17q. The diffuse Bothnian type of NEPPK (PPKB; 600231) is caused by mutation in the AQP5 gene (600442) on chromosome 12q13. The diffuse Nagashima type of NEPPK (PPKN; 615598) is caused by mutation in the SERPINB7 gene (603357) on chromosome 18q21. A form of NEPPK that can be focal or diffuse (PPKNEFD; 615735) is caused by mutation in the KRT6C gene (612315) on chromosome 12q13. For discussion of phenotypic and genetic heterogeneity of palmoplantar keratoderma, see epidermolytic PPK (144200). Nomenclature Vorner (1901) provided an early description of localized epidermolytic hyperkeratosis of the palms and soles, whereas Thost (1880) and Unna (1883) reported what appeared to be a nonepidermolytic diffuse form of palmoplantar keratoderma; the designations 'Vorner' and 'Unna-Thost' thus became eponymous for the epidermolytic and nonepidermolytic forms of the disorder, respectively. However, Kuster and Becker (1992) and Kuster et al. (2002) reinvestigated the Thost kindred and found features of epidermolytic hyperkeratosis in a study of a descendant; Lind et al. (1994) stated that the designation 'Unna-Thost' is misleading and should be avoided. Clinical Features Rogaev et al. (1993) studied a large 5-generation Uzbek pedigree segregating autosomal dominant nonepidermolytic palmoplantar keratoderma. Affected individuals had thick, white, smooth skin that desquamated in large flakes on the palmar surfaces of the hands and the soles of the feet. Skin creases displayed deep fissures, nails were often stubby with numerous hangnails, and the skin over the joint surfaces of the hands and feet was thickened, red, and edematous with poor elasticity. The skin on the backs of the hands, tops of the feet, and in the interdigital spaces was reddened and wrinkled, with very fine desquamation. Blistering, either spontaneously or in response to mild mechanical or thermal stress, was not a feature of the disease in this pedigree, and skin in other parts of the body was unaffected. Skin biopsies from affected individuals lacked cytolysis and abnormal keratohyalin granules and were thus consistent with nonepidermolytic hyperkeratosis. Kimonis et al. (1994) examined 6 affected and 1 unaffected member across 3 generations of a family segregating autosomal dominant nonepidermolytic palmoplantar keratoderma. In adults the disease manifested as moderate to severe thickening of the skin on palms and soles, with extension of hyperkeratosis along the Achilles tendon of the foot and occasionally the extensor tendon of the great toe. However, involvement stopped abruptly at the wrist flexure and at the border of the dorsal aspect of the hands and feet, with an erythematous halo separating hyperkeratotic from normal-appearing skin. There were discrete hyperkeratotic pads over several knuckles of the hands, and some adult patients experienced mild limitation of extension of the digits; nails showed a slight beaking (concave) deformity. Three of the 4 adult patients examined had dermatophyte infection of the toenails and feet, and 2 had involvement of the palms. Hyperkeratosis of the umbilicus and nipple areolae were present, as well as very mild thickening and dryness of the knees and elbows. The 2 affected children who were examined had presented at birth with mild thickening of the palms and soles; both had generalized dryness with fine, powdery scale, and hyperkeratosis of the areolae and umbilicus. Biopsy of affected palms and elbow showed hyperkeratosis of the stratum corneum with no evidence of epidermolysis; on electron microscopy, cells of the granular and spinous layers did not show the aggregated tonofilaments or large keratohyalin granules characteristic of epidermolytic hyperkeratosis. Kimonis et al. (1994) stated that the NEPPK in this family was consistent with that described previously by Thost (1880) and Unna (1883). Lind et al. (1994) described an autosomal dominant form of NEPPK with a high prevalence in northern Sweden (see Bothnian-type PPK, 600231). Kelsell et al. (1999) studied 3 families from the south of England with nonepidermolytic PPK that was present at birth: affected individuals had diffuse smooth waxy thickening of the entire palmoplantar surface including the non-weight-bearing digits, and secondary fungal infection was a common clinical problem leading to desquamation of the palms and soles. Two of the families had previously been reported by Kelsell et al. (1995), and skin biopsies from 2 affected individuals from each family confirmed the nonepidermolytic pattern of PPK. Terron-Kwiatkowski et al. (2002) reported 2 families with PPK. In the first family, a single affected girl who was born to unaffected parents had symmetric diffuse PPK at birth, but no history of skin fragility or blistering even in the neonatal period. At 8 years of age, she was noted to have diffuse PPK with some superficial scale as well as fine scaling over the lateral and anterior neck, lower back, external ears, and axillae. In the second family, an affected father and daughter each had mild diffuse PPK at birth with no history of neonatal fragility or blistering. The 34-year-old father had persistent mild diffuse PPK and mild flexural-limited scaling; the daughter had similarly mild disease with involvement limited to the palms and soles, popliteal fossae, and axillae. Mapping Kimonis et al. (1994) performed linkage analysis in a 4-generation family segregating autosomal dominant nonepidermolytic PPK and excluded the chromosomal region of the type I keratins; they obtained a maximum multipoint lod score of 3.61 (theta = 0.0) in the type II keratin region on chromosome 12q11-q13 with markers D12S96, D12S103, and D12S90. In 2 unrelated families from the south of England segregating autosomal dominant diffuse NEPPK, Kelsell et al. (1995) found linkage to chromosome 12q, with a 2-point lod score of 3.83 at D12S368 (theta = 0.0). A crossover event in an affected individual from 1 of the families placed the susceptibility locus centromeric to marker D12S96. In 3 unrelated families from the south of England with diffuse NEPPK, including 2 families previously reported by Kelsell et al. (1995), Kelsell et al. (1999) performed fine mapping and further analysis of the previously identified crossover event, which placed the disease locus centromeric to D12S803, proximal to the type II keratin gene cluster. ### Heterogeneity Rogaev et al. (1993) analyzed anonymous microsatellite and VNTR markers in a large 5-generation Uzbek family with NEPPK and obtained lod scores greater than 3.00 for markers clustered in the 17q12-q22 interval over a range of assumptions concerning penetrance, disease allele frequency, and marker allele frequencies. Haplotype analysis localized the NEPPK defect to an 8-cM region between THRA1 and D17S806 containing a cluster of keratin genes as well as the retinoic acid receptor alpha gene (RARA; 180240); an informative insertion/deletion polymorphism within the coding sequence of the C-terminal domain of the KRT10 gene (148080) was shown to segregate with the disease (lod score, 8.36 at theta = 0.00). Molecular Genetics In a 4-generation family with nonepidermolytic PPK mapping to chromosome 12q11-q13, Kimonis et al. (1994) identified a missense mutation in the KRT1 gene (K73I; 139350.0004) that segregated completely with the disease and was not found in 50 unrelated controls. In 2 families with mild PPK, Terron-Kwiatkowski et al. (2002) identified a splice site mutation (139350.0010) and a deletion (139350.0011) in the KRT1 gene, respectively. ### Heterogeneity In 3 affected and 3 unaffected members of a large 5-generation Uzbek pedigree with NEPPK mapping to chromosome 17q12-q22, Rogaev et al. (1993) analyzed exon 1 of the KRT10 gene (in which mutations had been found in patients with generalized epidermolytic hyperkeratosis; see 113800) but found no mutations. Genotype/Phenotype Correlations Both epidermolytic and nonepidermolytic forms of palmoplantar keratoderma have been observed with various mutations in the KRT1 gene (139350). Kimonis et al. (1994) suggested that the specific region of the keratin protein affected by mutation might be a major determining factor in the different clinical and histologic consequences. Mutations of the KRT1 and KRT9 genes that are associated with the epidermolytic form of PPK affect the central regions of the protein that are important for filament assembly and stability, and for that reason lead to cellular degeneration or disruption. On the other hand, the mutation of the KRT1 gene that Kimonis et al. (1994) found in association with PPK was located in the amino-terminal variable end region, which may be involved in supramolecular interactions of keratin filaments rather than stability. INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Skin \- Smooth, waxy, thick skin over palms and soles, desquamating in large flakes \- Well-defined erythematous border \- Deep fissures of skin creases \- Skin over joint surfaces of hands and feet is thick, red, and edematous \- Hyperkeratosis of skin at nipples and umbilicus Skin Histology \- Hyperkeratosis of stratum corneum \- No cytolysis \- No abnormal keratohyalin granules Electron Microscopy \- No aggregated tonofilaments \- No large keratohyalin granules MOLECULAR BASIS \- Caused by mutation in the keratin 1 gene (KRT1, 139350.0004 ) ▲ 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	PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC	c1833030	6,308	omim	https://www.omim.org/entry/600962	2019-09-22T16:15:35	{"doid": ["0050428"], "mesh": ["C563422"], "omim": ["600962"], "orphanet": ["496", "530838"], "synonyms": ["TYLOSIS", "Alternative titles", "PPKNE", "NONEPIDERMOLYTIC PALMOPLANTAR KERATODERMA", "Non-epidermolytic palmoplantar keratoderma", "KRT1-related diffuse NEPPK", "KERATODERMA, NONEPIDERMOLYTIC PALMOPLANTAR"]}
Injuries in rock climbing may occur due to falls, or due to overuse (see Sports injury). Injuries due to falls are relatively uncommon; the vast majority of injuries result from overuse, most often occurring in the fingers, elbows, and shoulders.[1] Such injuries are often no worse than torn calluses, cuts, burns and bruises. However, overuse symptoms, if ignored, may lead to permanent damage (esp. to tendons, tendon sheaths, ligaments, and joint capsules). ## Contents * 1 Risk groups * 2 Overuse injuries in climbing * 2.1 Finger injuries * 2.1.1 Pulleys * 2.1.2 Knuckle * 2.2 Shoulder injuries * 2.3 Elbow injuries * 2.4 Calluses, dry skin * 3 Young/adolescent climbers * 4 See also * 5 References ## Risk groups[edit] The climbers most prone to injuries are intermediate to expert within lead climbing or bouldering.[2] ## Overuse injuries in climbing[edit] In terms of overuse injuries a British study found that:[3] * 40% occurred in the fingers * 16% in the shoulders * 12% in the elbows * 5% in the knees * 5% in the back * 4% in the wrists One injury that tend to be very common among climbers is Carpal tunnel syndrome. It is found in about 25% of climbers.[4] ### Finger injuries[edit] 604 injured rock climbers were prospectively evaluated from January 1998 to December 2001, due to the rapid growth of new complex finger trauma in the mid-1980s. Of the most frequent injuries, three out of four were related to the fingers: pulley injuries accounted for 20%, tendovaginitis for 7%, and joint capsular damage for 6.1%.[5] #### Pulleys[edit] Damage to the flexor tendon pulleys that encircle and support the tendons that cross the finger joints is the most common finger injury within the sport (see climber's finger).[4] The main culprit for pulley related injuries is the common crimp grip, especially in the closed position. The crimp grip requires a near ninety-degree flexion of the middle finger joint, which produces a tremendous force load on the A2 pulley. Injuries to the A2 pulley can range from microscopic to partial tears and, in the worst case, complete ruptures. Some climbers report hearing a pop, which might be a sign of a significant tear or complete rupture, during an extremely heavy move (e.g. tiny crimp, one- or two-finger pocket). Small partial tears, or inflammation can occur over the course of several sessions.[6] * Grade I – Sprain of the finger ligaments (collateral ligaments), pain locally at the pulley, pain when squeezing or climbing. * Grade II – Partial rupture of the pulley tendon. Pain locally at the pulley, pain when squeezing or climbing, possible pain while extending your finger. * Grade III – Complete rupture of the pulley, causing bowstringing of the tendon. Symptoms can include: Pain locally at the pulley (usually sharp), may feel/hear a 'pop' or 'crack', swelling and possible bruising, pain when squeezing or climbing, pain when extending your finger, pain with resisted flexion of the finger.[7] #### Knuckle[edit] * Stress fractures * Collateral ligament injuries ### Shoulder injuries[edit] Shoulder related injuries include rotator cuff tear, strain or tendinitis, biceps tendinitis and SLAP lesion.[8] ### Elbow injuries[edit] Tennis elbow (Lateral Epicondylitis) is a common elbow injury among climbers, as is Golfer's elbow (Medial Epicondylitis, which is similar, but occurs on the inside of the elbow). ### Calluses, dry skin[edit] Climbers often develop calluses on their fingers from regular contact with the rock and the rope. When calluses split open they expose a raw layer of skin that can be very painful. This type of injury is commonly referred to as a flapper. The use of magnesium carbonate (chalk) for better grip dries out the skin and can often lead to cracked and damaged hands [9] There are a number of skincare products available for climbers that help to treat calluses, moisturise dry hands and reduce recovery time. ## Young/adolescent climbers[edit] "Any finger injury that is sustained by a young adolescent (12–16) should be seen by a physician and have x-rays performed. These skeletally immature athletes are very susceptible to developing debilitating joint arthritis later in adulthood."[10] ## See also[edit] * Related topics * Carpal tunnel syndrome * Climber's finger * Golfer's elbow * Repetitive strain injury * Radial tunnel syndrome * Tennis elbow * Lists and glossaries * List of climbing topics * Climbing terminology * Climbing command ## References[edit] 1. ^ Hörst, Eric J. (2003). Training for Climbing: The Definitive Guide to Improving Your Climbing. Guilford, Connecticut, Helena, Montana: Falcon Publishing. p. 151. ISBN 0-7627-2313-0. 2. ^ Wright, D. M.; Royle, T. J.; Marshall, T (2001). "Indoor rock climbing: who gets injured?" (PDF). British Journal of Sports Medicine. Br J Sports Med. 35 (3): 181–5. doi:10.1136/bjsm.35.3.181. PMC 1724320. PMID 11375878. Archived from the original (PDF) on 18 February 2011. Retrieved 11 January 2011. 3. ^ article by: Doran, D. A.; Reay, M. (2000). "Injuries and associated training and performance characteristics in recreational rock climbers". The Science of Rock Climbing and Mountaineering (A collection of scientific articles). Human Kinetics Publishing. ISBN 0-7360-3106-5. 4. ^ a b Preston, Dayton. "Rock Climbing Reaching New Heights". Hughston health alert. Retrieved 11 January 2011. 5. ^ Schöffl, V.; Hochholzer, T.; Winkelmann, H.P.; Strecker, W. (Summer 2003). "Pulley injuries in rock climbers". Wilderness Environ Med. Wilderness & environmental medicine. 14 (2): 94–100. doi:10.1580/1080-6032(2003)014[0094:piirc]2.0.co;2. PMID 12825883. 6. ^ Hörst, Eric J (2008). "Finger Tendon Pulley Injury". Nicros. Archived from the original on 16 March 2009. Retrieved 11 January 2011. 7. ^ Roseborrough, Aimee; Roseborrough, Kyle (2009). "DIAGNOSIS: Pulleys". Retrieved 11 January 2011. 8. ^ Roseborrough, Aimee; Roseborrough, Kyle (2009). "Climbing Injuries: Shoulders". Retrieved 11 January 2011. 9. ^ "Hand cream for rock climbers". Kletter Retter. Archived from the original on February 6, 2015. Retrieved 5 February 2015. 10. ^ Edell, David (24 October 2009). "Finger Injuries". Retrieved 11 January 2011. [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	Climbing injuries	None	6,309	wikipedia	https://en.wikipedia.org/wiki/Climbing_injuries	2021-01-18T18:47:51	{"wikidata": ["Q5133670"]}
Nonbullous congenital ichthyosiform erythroderma (NBCIE) is a specific type of ichthyosis mainly affecting the skin. Most infants with NBCIE are born with a tight, shiny covering on their skin, called a collodion membrane, which is typically shed within a few weeks. Other signs and symptoms include redness of the skin (erythroderma); fine, white scales on the skin; and thickening of the skin on the palms and soles of feet (palmoplantar keratoderma). Some people with NBCIE also have outward turning eyelids (ectropion); outward turning lips (eclabium); and nails that do not grow normally (nail dystrophy). NBCIE may be caused by mutations in any one of at least three genes: ALOX12B, ALOXE3 or NIPAL4. In some people with NBCIE, the cause of the disorder 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	Nonbullous congenital ichthyosiform erythroderma	c0079154	6,310	gard	https://rarediseases.info.nih.gov/diseases/9736/nonbullous-congenital-ichthyosiform-erythroderma	2021-01-18T17:58:40	{"mesh": ["D017490"], "omim": ["242100"], "orphanet": ["79394"], "synonyms": ["Ichthyosiform erythroderma, congenital, nonbullous, 1", "NCIE", "Ichthyosiform erythroderma, Brocq congenital, nonbullous form", "Congenital ichthyosiform erythroderma", "CIE", "NBCIE", "Congenital non-bullous ichthyosiform erythroderma", "Erythrodermic ichthyosis", "Non-bullous congenital ichthyosiform erythroderma"]}
A number sign (#) is used with this entry because benign familial infantile seizures-2 (BFIS2) is caused by heterozygous mutation in the PRRT2 gene (614386) on chromosome 16p11. Description Benign familial infantile seizure is an autosomal dominant disorder characterized by afebrile partial complex or generalized tonic-clonic seizures occurring between 3 and 12 months of age with a good response to medication and no neurologic sequelae. Seizures usually remit by age 18 months (summary by Weber et al., 2004). For a general phenotypic description and a discussion of genetic heterogeneity of benign familial infantile seizures, see BFIS1 (601764). Benign familial infantile seizures can also occur in 2 allelic disorders: infantile convulsions and choreoathetosis (ICCA; 602066) and paroxysmal kinesigenic choreoathetosis (EKD1; 128200). Clinical Features Caraballo et al. (2001) identified and studied 7 families with autosomal dominant BFIS. In 1 family, Caraballo et al. (2001) observed a patient who was clearly homozygous for the BFIS2 gene. Infantile convulsions did not respond well to anticonvulsants, in contrast to all other affected members of his family and to classic BFIS. In addition, although the families had been selected on the basis of clinical evidence of BFIS only, this patient had atypical paroxysmal choreic/dystonic dyskinesia beginning at age 2 years. The age of onset was earlier than that of classic paroxysmal dyskinesias (which usually begins at age 5 to 16 years). Dyskinetic movements sometimes occurred a few seconds after starting exertion, which suggested a kinesigenic type. However, the patient did not respond to carbamazepine, a finding that is consistent with an exertional rather than a kinesigenic type. Weber et al. (2004) reported 14 families with BFIS2 showing linkage to chromosome 16p12-q12. Onset of seizures occurred between 2 and 7 months of age and disappeared at the latest by age 18 months. Seizure types included complex partial seizures and generalized tonic-clonic seizures. Other features included loss of consciousness, paleness, cyanosis, hypotonia, gaze deviation, and focal clonicity. Medication was effective, and could be stopped by age 4 years without seizure relapse. Most interictal EEG did not show abnormalities, but some had focal seizure activity. Schubert et al. (2012) reported 39 families with BFIS2. The phenotype was homogeneous, with an onset of seizures between 3 and 12 months of age and a benign outcome in almost all cases without long-term anticonvulsive treatment. Seizure types mainly included complex partial seizures and generalized tonic-clonic seizures. Some patients reported migraine, but none had febrile seizures, choreoathetosis, or dyskinesia. Some of the families had previously been reported by Striano et al. (2006) and Weber et al. (2004). Inheritance The transmission pattern of BFIS2 in the families reported by Schubert et al. (2012) was consistent with autosomal dominant inheritance with incomplete penetrance. Mapping Caraballo et al. (2001) performed linkage analysis in 7 families with autosomal dominant BFIS. The results excluded linkage to chromosome 19q and established linkage to chromosome 16p12-q12 (maximum 2-point lod score of 3.32). The authors suggested that BFIS2, PKC, and ICCA syndrome may be allelic disorders. Alternatively, they suggested that homologous genes may have arisen through duplication in this region of chromosome 16 which may be responsible for nonallelic disorders. In 14 families with BFIS, Weber et al. (2004) found linkage to a 22.5-Mb region on chromosome 16p12-q12 between D16S690 and D16S3136 (maximum cumulative 2-point lod score of 6.1 at D16S411). There was evidence for incomplete penetrance. Striano et al. (2006) found linkage to chromosome 16p12-q12 in 16 families with BFIS (maximum lod score of 10.18 at D16S401 under 1 model). Callenbach et al. (2005) found linkage to 16p in 2 unrelated Dutch families with pure BFIS. By haplotype analysis and combination with data from earlier studies, Callenbach et al. (2005) narrowed the disease locus to a 2.7-Mb interval on 16p12-p11 between markers D16S690 and D16S685. Penetrance in both families was approximately 60%. Two additional Dutch families with BFIS did not map to any of the known BFIS loci, indicating further genetic heterogeneity. Molecular Genetics In affected members of 14 (82%) of 17 families with benign familial infantile seizures-2, Heron et al. (2012) identified heterozygous mutations in the PRRT2 gene (see, e.g., 614386.0001 and 614386.0006). The 649insC mutation (614386.0001) was the most common mutation, found in 12 families with BFIS2. Heterozygous mutations in the PRRT2 gene were also found in 5 (83%) of 6 families with familial infantile convulsions with paroxysmal choreoathetosis (ICCA; 602066), a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (EKD1; 128200), cooccur. The 649insC mutation was found in 3 families with ICCA. The families with this mutation were of different ethnic origin, including Australasian of western European heritage, Swedish, and Israeli Sephardic-Jewish, and there was no evidence of a common haplotype among these families, indicating a mutation hotspot. These findings demonstrated that mutations in PRRT2 cause both epilepsy and a movement disorder, with obvious pleiotropy in age of expression. The mutations were identified by linkage analysis, confirming linkage to chromosome 16p, followed by sequence-capture array of coding and promoter sequences within the candidate region. Schubert et al. (2012) identified a heterozygous 649dupC mutation in the PRRT2 gene in 39 of 49 families with BFIS2 and in 1 patient with sporadic occurrence of the disorder (77% of index cases). Three additional heterozygous PRRT2 mutations (see, e.g., 614386.0013; 614386.0014) were found in 3 other families with the disorder. The patients were of German, Italian, Japanese, and Turkish origin. Some of the families had previously been reported by Striano et al. (2006) and Weber et al. (2004). The 649dupC mutation, which occurs in an unstable DNA sequence of 9 cytosines, arose independently in families of different origin. Some unaffected family members also carried the mutation, indicating incomplete penetrance. Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese families with EKD1 and in 2 Japanese families with BFIS2. The mutation was shown to occur de novo in at least 1 family, suggesting that it is a mutation hotspot. EKD1, ICCA, and BFIS2 segregated with the mutation even within the same family. The findings indicated that all 3 disorders are allelic and are likely caused by a similar mechanism. In 1 family, a Japanese mother and daughter both carried a heterozygous mutation (Q250X; 614386.0015). The mother had EKD1 and her daughter had BFIS2. Pelzer et al. (2014) reexamined a large multigenerational Dutch family segregating both BFIS and familial hemiplegic migraine. The family had previously been reported by Terwindt et al. (1997) and Vanmolkot et al. (2003) as having BFIS and familial hemiplegic migraine-2 (FHM2; 602481) associated with a heterozygous mutation in the ATP1A2 gene (R689Q; 182340.0004). Pelzer et al. (2014) identified a heterozygous truncating mutation in the PRRT2 gene (614386.0016) in 4 members of this family who had BFIS. The mutation was also found in 4 family members without a history of febrile seizures. Thus, 2 different neurologic disorders segregated in this family; the diagnosis was more complex as both disorders showed incomplete penetrance. INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Seizures, partial, afebrile \- Secondary generalization may occur \- Seizures, generalized, afebrile \- Seizures occur in clusters \- Normal psychomotor development \- Migraine (uncommon) MISCELLANEOUS \- Average onset 6 months (range 3-9) \- Dyskinesia may occur in homozygotes (1 reported case) \- Seizures easily controlled by medications \- Seizures remit in early childhood \- Incomplete penetrance MOLECULAR BASIS \- Caused by mutation in the proline-rich transmembrane protein 2 gene (PRRT2, 614386.0001) ▲ 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	SEIZURES, BENIGN FAMILIAL INFANTILE, 2	c0220669	6,311	omim	https://www.omim.org/entry/605751	2019-09-22T16:11:04	{"doid": ["0060169"], "mesh": ["D020936"], "omim": ["605751"], "orphanet": ["306"], "synonyms": ["Alternative titles", "CONVULSIONS, BENIGN FAMILIAL INFANTILE, 2"], "genereviews": ["NBK475803"]}
In an infant brother and sister born of unrelated parents, Mena et al. (1991) observed a similar and possibly unique set of congenital malformations. These included fused eyelids, craniofacial anomalies, ovarian cyst (in the female), subglottic stenosis, and specific digital abnormalities. Both infants had extension of metacarpophalangeal joints with flexion of the proximal interphalangeal joint of both index fingers with resulting overlap of the second digit over the third. Similar changes were noted in both second toes. Mena et al. (1991) concluded that the findings, although similar to those in the Fraser syndrome (219000), were sufficiently different to justify recognition as a distinct entity. HEENT \- Fused eyelids \- Craniofacial anomalies GU \- Ovarian cyst Inheritance \- Autosomal recessive Resp \- Subglottic stenosis Skel \- Index finger metacarpophalangeal joints extended \- Index finger proximal interphalangeal joints flexed \- Overlap of index finger over the third digit \- Overlap of second toe over the third ▲ 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	FRASER-LIKE SYNDROME	c1856708	6,312	omim	https://www.omim.org/entry/229230	2019-09-22T16:27:46	{"mesh": ["C565562"], "omim": ["229230"], "orphanet": ["2051"], "synonyms": ["Alternative titles", "FUSED EYELIDS, AIRWAY ANOMALIES, OVARIAN CYSTS, AND DIGITAL ANOMALIES"]}
Poor cellular differentiation, indicative of potential for cancer -plasia and -trophy * Anaplasia (structural differentiation loss within a cell or group of cells). * Aplasia (organ or part of organ missing) * Desmoplasia (connective tissue growth) * Dysplasia (change in cell or tissue phenotype) * Hyperplasia (proliferation of cells) * Hypoplasia (congenital below-average number of cells, especially when inadequate) * Metaplasia (conversion in cell type) * Neoplasia (abnormal proliferation) * Prosoplasia (development of new cell function) * Abiotrophy (loss in vitality of organ or tissue) * Atrophy (reduced functionality of an organ, with decrease in the number or volume of cells) * Hypertrophy (increase in the volume of cells or tissues) * Hypotrophy (decrease in the volume of cells or tissues) * Dystrophy (any degenerative disorder resulting from improper or faulty nutrition) * v * t * e Anaplasia (from Ancient Greek: ἀνά ana, "backward" + πλάσις plasis, "formation") is a condition of cells with poor cellular differentiation, losing the morphological characteristics of mature cells and their orientation with respect to each other and to endothelial cells. The term also refers to a group of morphological changes in a cell (nuclear pleomorphism, altered nuclear-cytoplasmic ratio, presence of nucleoli, high proliferation index) that point to a possible malignant transformation.[1] Such loss of structural differentiation is especially seen in most, but not all, malignant neoplasms.[2] Sometimes, the term also includes an increased capacity for multiplication.[3] Lack of differentiation is considered a hallmark of aggressive malignancies (for example, it differentiates leiomyosarcomas from leiomyomas). The term anaplasia literally means "to form backward". It implies dedifferentiation, or loss of structural and functional differentiation of normal cells. It is now known, however, that at least some cancers arise from stem cells in tissues; in these tumors failure of differentiation, rather than dedifferentiation of specialized cells, account for undifferentiated tumors. Anaplastic cells display marked pleomorphism (variability). The nuclei are characteristically extremely hyperchromatic (darkly stained) and large. The nuclear-cytoplasmic ratio may approach 1:1 instead of the normal 1:4 or 1:6. Giant cells that are considerably larger than their neighbors may be formed and possess either one enormous nucleus or several nuclei (syncytia). Anaplastic nuclei are variable and bizarre in size and shape. The chromatin is coarse and clumped, and nucleoli may be of astounding size. More important, mitoses are often numerous and distinctly atypical; anarchic multiple spindles may be seen and sometimes appear as tripolar or quadripolar forms. Also, anaplastic cells usually fail to develop recognizable patterns of orientation to one another (i.e., they lose normal polarity). They may grow in sheets, with total loss of communal structures, such as gland formation or stratified squamous architecture. Anaplasia is the most extreme disturbance in cell growth encountered in the spectrum of cellular proliferations.[4] ## See also[edit] * Pleomorphism * List of biological development disorders ## References[edit] 1. ^ "anaplasia" – via The Free Dictionary. 2. ^ "Anaplasia - Medical Definition from MediLexicon". 3. ^ "Anaplasia - Biology-Online Dictionary". 4. ^ Kumar, Vinay, Abul Abbas, Nelson Fausto, and Richard Mitchell. Robbins Basic Pathology. 8th ed. Philadelphia: Saunders Elsevier, 2007. 176-177. * 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 [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	Anaplasia	c0002793	6,313	wikipedia	https://en.wikipedia.org/wiki/Anaplasia	2021-01-18T18:30:08	{"mesh": ["D000708"], "umls": ["C0002793"], "wikidata": ["Q486082"]}
A rare autosomal dominant malformation syndrome characterized by hypertelorism, omphalocoele, cleft lip, ear pits, uterine malformation (bicornuate uterus), and more variably by diaphragmatic hernia and congenital heart defects. ## Epidemiology Unknown. Less than 40 patients reported with genetic confirmation. The clinical diagnostic is unreliable in older literature due to phenotypic confusion. ## Clinical description Presentation is typically with characteristic facial dysmorphism: prominent forehead, hypertelorism (>95%) and telecanthus, cleft lip/palate (25%), slightly downslanting palpebral fissures, long philtrum prominent nasal root, and a large nose with a large tip. Malformations include omphalocoele (50%), uterine malformations (>25%), congenital heart malformations (20%), ear pits (30%), dysphagia, reflux and other esophageal problems (30%) and, less commonly, diaphragmatic herniae (10%), inguinal herniae, aortic root dilation, and rarely CNS anomalies (ventriculomegaly, agenesis of the corpus callosum) and craniosynostosis. Learning disability affects 20% of patients, and intellectual disability (ID) is present in 10%. ## Etiology The disorder is due to heterozygous gain of function variants in SPECC1L (Sperm antigen with calponin homology and Coiled-Coil domains 1 Like) located in 22q11.23. The SPECC1L protein is a cytoskeletal protein that associates with both actin and microtubules to affect larger cytoskeletal function. It is involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. Of note, heterozygous loss of function of SPECC1L causes Tessier IV oblique facial cleft. ## Diagnostic methods SPECC1L syndrome is suspected on clinical findings: ocular hypertelorism and at least one other of the characterstic findings (omphalocoele or diaphragmatic hernia, bicornuate uterus, ear pits). Diagnosis is confirmed by identification of a SPECC1L variant. ## Differential diagnosis Opitz GBBB syndrome is the main differential diagnosis of SPECC1L syndrome. Opitz GBBB syndrome has strikingly overlapping craniofacial phenotype, leading to confusion in the past literature between MID1-confirmed Opitz GBBG and various overlapping conditions. Earpits, uterine malformations, omphalocoele, diaphragmatic herniae are specific to SPECC1L, whereas laryngeal and anorectal defects are specific to Optiz GBBB. ID is more common in the latter. Baraitser-Winter cerebrofrontofacial syndrome (ACTB and ACTG1), craniofrontonasal dysplasia (EFNB1), frontonasal dysplasia and Aarskog syndrome (FGD1) share marked hypertelorism. ## Antenatal diagnosis Prenatal testing is possible for at-risk pregnancies if a SPECC1L mutation has been previously identified in a family member. ## Genetic counseling The pattern of inheritance is autosomal dominant and genetic counseling is recommended for young adults who are affected. The offspring of an affect individual have a 50% risk of also being affected. ## Management and treatment Multidisciplinary medical support with pediatricians, craniofacial, ENT (ear, nose and throat) and abdominal surgeons, cardiologists, and a medical geneticist is required. Neurodevelopmental support and speech therapy may be necessary. Uterine anomalies may cause fertility issues. ## Prognosis Prognosis is variable but usually favorable, depending on the severity of malformations and associated ID. * 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	Hypertelorism, Teebi type	c0796179	6,314	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1519	2021-01-23T18:40:20	{"gard": ["957"], "mesh": ["C536951"], "omim": ["145420"], "umls": ["C1840378"], "icd-10": ["Q87.0"], "synonyms": ["Brachycephalofrontonasal dysplasia", "Craniofrontonasal dysplasia, Teebi type", "Teebi hypertelorism syndrome", "Teebi syndrome"]}
The CDG (Congenital Disorders of Glycosylation) syndromes are a group of autosomal recessive disorders affecting glycoprotein synthesis. CDG syndrome type If is characterised by psychomotor delay, seizures, failure to thrive, and cutaneous and ocular anomalies. ## Epidemiology It has been described in four children. ## Etiology The syndrome is caused by mutations in the MPDU1 gene, localised to the p13.1-p12 region of chromosome 17. [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	MPDU1-CDG	c1836669	6,315	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79323	2021-01-23T18:53:13	{"gard": ["9832"], "mesh": ["C535744"], "omim": ["609180"], "umls": ["C1836669"], "icd-10": ["E77.8"], "synonyms": ["CDG syndrome type If", "CDG-If", "CDG1F", "Carbohydrate deficient glycoprotein syndrome type If", "Congenital disorder of glycosylation type 1f", "Congenital disorder of glycosylation type If"]}
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency is a unique form of congenital adrenal hyperplasia (CAH; see this term) characterized by glucocorticoid deficiency, severe sexual ambiguity in both sexes and skeletal (especially craniofacial) malformations. ## Epidemiology It has an annual incidence of 1/100,000-200,000 live births. ## Clinical description Prenatal androgen excess is responsible for severe virilization of external genitalia in girls and undervirilization in boys manifesting as a micropenis to severe perineoscrotal hypospadias. Craniofacial malformations observed include large domed forehead, flat nose, midface hypoplasia with proptosis and dysplastic ears and other features similar to those seen in Antley-Bixler syndrome (see this term). ## Etiology This form of CAH is caused by a mutation in the POR gene located on chromosome 7 q11.2. ## Genetic counseling The disease 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	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	c1860042	6,316	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=95699	2021-01-23T17:11:24	{"gard": ["12664"], "mesh": ["D054882"], "omim": ["613571"], "icd-10": ["E25.0"], "synonyms": ["Congenital adrenal hyperplasia due to cytochrome POR deficiency", "POR deficiency", "PORD"]}
Japanese spotted fever Other namesOriental spotted fever SpecialtyInfectious disease Japanese spotted fever is a condition characterized by a rash that has early macules, and later, in some patients, petechiae.[1] It is caused by Rickettsia japonica.[2][3] ## See also[edit] * Flea-borne spotted fever * Flinders Island spotted fever * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 1130. ISBN 978-1-4160-2999-1. 2. ^ Mahara F (1997). "Japanese spotted fever: report of 31 cases and review of the literature". Emerging Infect. Dis. 3 (2): 105–11. doi:10.3201/eid0302.970203. PMC 2627607. PMID 9204291. 3. ^ Inc, GIDEON Informatics; Berger, Dr Stephen (2017). Infectious Diseases of Japan: 2017 edition. GIDEON Informatics Inc. p. 237. ISBN 9781498813846. Retrieved 11 November 2017. ## External links[edit] Classification D * ICD-10: A77.8 * 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 dermatology 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	Japanese spotted fever	c2108396	6,317	wikipedia	https://en.wikipedia.org/wiki/Japanese_spotted_fever	2021-01-18T18:51:00	{"mesh": ["D000073605"], "icd-10": ["A77.8"], "wikidata": ["Q6159042"]}
Common bile duct stone Other namesCholedocholithiasis Magnetic resonance cholangiopancreatography (MRCP) image of two gallstones in the distal common bile duct SpecialtyGastroenterology Common bile duct stone, also known as choledocholithiasis, is the presence of gallstones in the common bile duct (CBD) (thus choledocho- \+ lithiasis). This condition can cause jaundice and liver cell damage. Treatment is by choledocholithotomy and endoscopic retrograde cholangiopancreatography (ERCP). ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 References * 7 External links ## Signs and symptoms[edit] Murphy's sign is commonly negative on physical examination in choledocholithiasis, helping to distinguish it from cholecystitis. Jaundice of the skin or eyes is an important physical finding in biliary obstruction. Jaundice and/or clay-colored stool may raise suspicion of choledocholithiasis or even gallstone pancreatitis.[1] If the above symptoms coincide with fever and chills, the diagnosis of ascending cholangitis may also be considered. More than 70% of people with gallstones are asymptomatic and are diagnosed incidentally during ultrasound. Studies have shown that 10% of those with gallstones will develop symptoms within 5 years of diagnosis, and 20% within 20 years.[2] ## Causes[edit] While stones can frequently pass through the common bile duct into the duodenum, some stones may be too large to pass through the common bile duct and may cause an obstruction. One risk factor for this is duodenal diverticulum. ## Pathophysiology[edit] This obstruction may lead to jaundice, elevation in alkaline phosphatase, increase in conjugated bilirubin in the blood and increase in cholesterol in the blood. It can also cause acute pancreatitis and ascending cholangitis. ## Diagnosis[edit] Choledocholithiasis (stones in common bile duct) is one of the complications of cholelithiasis (gallstones), so the initial step is to confirm the diagnosis of cholelithiasis. Patients with cholelithiasis typically present with pain in the right-upper quadrant of the abdomen with the associated symptoms of nausea and vomiting, especially after a fatty meal. The physician can confirm the diagnosis of cholelithiasis with an abdominal ultrasound that shows the ultrasonic shadows of the stones in the gallbladder. The diagnosis of choledocholithiasis is suggested when the liver function blood test shows an elevation in bilirubin and serum transaminases. Other indicators include raised indicators of ampulla of vater (pancreatic duct obstruction) such as lipases and amylases. In prolonged cases the international normalized ratio (INR) may change due to a decrease in vitamin K absorption. (It is the decreased bile flow which reduces fat breakdown and therefore absorption of fat soluble vitamins). The diagnosis is confirmed with either a magnetic resonance cholangiopancreatography (MRCP), an endoscopic retrograde cholangiopancreatography (ERCP), or an intraoperative cholangiogram. If the patient must have the gallbladder removed for gallstones, the surgeon may choose to proceed with the surgery, and obtain a cholangiogram during the surgery. If the cholangiogram shows a stone in the bile duct, the surgeon may attempt to treat the problem by flushing the stone into the intestine or retrieve the stone back through the cystic duct. On a different pathway, the physician may choose to proceed with ERCP before surgery. The benefit of ERCP is that it can be utilized not just to diagnose, but also to treat the problem. During ERCP the endoscopist may surgically widen the opening into the bile duct and remove the stone through that opening. ERCP, however, is an invasive procedure and has its own potential complications. Thus, if the suspicion is low, the physician may choose to confirm the diagnosis with MRCP, a non-invasive imaging technique, before proceeding with ERCP or surgery. * Common bile duct stone impacted at ampulla of Vater seen at time of endoscopic retrograde cholangiopancreatography (ERCP) * Abdominal ultrasonography of a common bile duct stone * Fluoroscopic image taken during endoscopic retrograde cholangiopancreatography (ERCP). Multiple gallstones are present in the gallbladder and cystic duct. The common bile duct and pancreatic duct appear to be unobstructed. ## Treatment[edit] Treatment involves an operation called a choledocholithotomy, which is the removal of the gallstone from the bile duct using ERCP, although surgeons are now increasingly using laparoscopy with cholangiography. In this procedure, tiny incisions are made in the abdomen and then in the cystic duct that connects the gallbladder to the bile duct, and a thin tube is introduced to perform a cholangiography. If stones are identified, the surgeon inserts a tube with an inflatable balloon to widen the duct and the stones are usually removed using either a balloon or tiny basket. A laser can be used to split big stones and make it easier to solve it using laparoscopy.[3] If laparoscopy is unsuccessful, an open choledocholithotomy is performed. This procedure may be used in the case of large stones, when the duct anatomy is complex, during or after some gallbladder operations when stones are detected, or when ERCP or laparoscopic procedures are not available.[4] Typically, the gallbladder is then removed, an operation called cholecystectomy, to prevent a future occurrence of common bile duct obstruction or other complications.[5] ## References[edit] 1. ^ National Institute of Diabetes and Digestive and Kidney Diseases (2007). "Gallstones" (PDF). Bethesda, Maryland: National Digestive Diseases Information Clearinghouse, National Institutes of Health, United States Department of Health and Human Services. Archived from the original (PDF) on 2010-12-05. Retrieved 2010-11-06. 2. ^ Portincasa, P.; Moschetta, A.; Petruzzelli, M.; Palasciano, G.; Di Ciaula, A.; Pezzolla, A. (2006). "Gallstone disease: Symptoms and diagnosis of gallbladder stones". Best Pract Res Clin Gastroenterol. 20 (6): 1017–29. doi:10.1016/j.bpg.2006.05.005. PMID 17127185. 3. ^ Navarro-Sánchez, Antonio; Ashrafian, Hutan; Segura-Sampedro, Juan José; Martrinez-Isla, Alberto (29 August 2016). "LABEL procedure: Laser-Assisted Bile duct Exploration by Laparoendoscopy for choledocholithiasis: improving surgical outcomes and reducing technical failure". Surgical Endoscopy. 31 (5): 2103–2108. doi:10.1007/s00464-016-5206-1. 4. ^ "Open or Laparoscopic Common Bile Duct Exploration (Choledocholithotomy)". The New York Times Health Guide. The New York Times Company. 26 Aug 2013. Archived from the original on 17 April 2014. Retrieved 17 April 2014. 5. ^ McAlister, Vivian; Davenport, Eric; Renouf, Elizabeth (2007). "Cholecystectomy Deferral in Patients with Endoscopic Sphincterotomy". Cochrane Database of Systematic Reviews (4): CD006233. doi:10.1002/14651858.CD006233.pub2. PMID 17943900. ## External links[edit] Classification D * ICD-10: Xxx.x * ICD-9-CM: xxx * MeSH: D042883 [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	Common bile duct stone	c0701818	6,318	wikipedia	https://en.wikipedia.org/wiki/Common_bile_duct_stone	2021-01-18T19:05:49	{"mesh": ["D042883"], "umls": ["C0701818"], "wikidata": ["Q9290860"]}
A number sign (#) is used with this entry because of evidence that orofaciodigital syndrome XV (OFD15) is caused by compound heterozygous mutation in the KIAA0753 gene (617112) on chromosome 17p13. One such patient has been reported. Clinical Features Chevrier et al. (2016) studied a female infant who was born with facial dysmorphism, lobulated tongue, clefting of the alveolar ridges, left hand postaxial polydactyly, broad right hallux and left hallux duplication, and intermittent respiratory difficulty. Brain MRI showed multiple anomalies, including vermis hypoplasia with molar tooth sign (MTS), agenesis of corpus callosum, and ventricular dilation. Abdominal ultrasound revealed bilateral hydronephrosis. Because of the association of oral defects, polydactyly, and MTS, the authors designated the clinical classification of this patient as orofaciodigital syndrome type VI (OFD6; see 277170). Molecular Genetics By exome sequencing in a female infant with orofaciodigital syndrome, Chevrier et al. (2016) identified compound heterozygosity for a nonsense mutation (K631X; 617112.0001) and a splice site mutation (617112.0002) in the KIAA0753 gene. Her unaffected mother carried the nonsense mutation, but the splice mutation occurred de novo. Analysis of KIAA0753 in 32 patients diagnosed with either OFD6 or Joubert syndrome (see 213300) did not reveal any additional mutations. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Flat facial profile Ears \- Low-set left ear Eyes \- Hypertelorism \- Straight palpebral fissures Nose \- Wide nasal bridge \- Upturned nares Mouth \- Lobulated tongue \- Clefting of alveolar ridges RESPIRATORY \- Intermittent respiratory difficulties GENITOURINARY Kidneys \- Bilateral hydronephrosis SKELETAL Hands \- Postaxial polydactyly, unilateral Feet \- Broad hallux \- Duplication of hallux NEUROLOGIC Central Nervous System \- Vermis hypoplasia \- Molar tooth sign \- Agenesis of the corpus callosum \- Dilated ventricles MISCELLANEOUS \- Based on report of 1 patient (last curated September 2016) MOLECULAR BASIS \- Caused by mutation in the KIAA0753 gene (KIAA0753, 617112.0001 ) ▲ 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	OROFACIODIGITAL SYNDROME XV	c2745997	6,319	omim	https://www.omim.org/entry/617127	2019-09-22T15:46:52	{"mesh": ["C536531"], "omim": ["617127"], "orphanet": ["2754"], "synonyms": ["Alternative titles", "OFDS XV", "ORAL-FACIAL-DIGITAL SYNDROME, TYPE XV"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (June 2016) Prosopometamorphopsia is a rare visual perceptual distortion resulting in an altered perception of faces. It is distinct from prosopagnosia which is characterised by the inability to recognise faces, and is relatively more common.[1] ## Contents * 1 Presentation * 2 Causes * 3 Diagnosis * 3.1 Classification * 4 Treatment * 5 Case studies * 6 References ## Presentation[edit] Generally, faces tend to appear distorted to a person who is affected by this condition.[2] Those who suffer from this condition are able to recognise faces normally but perceive them as strangely disfigured. These facial hallucinations are usually described as ugly, and have prominent eyes and teeth.[3] Some have described the faces as having a cartoon-like quality. Faces have been known to be perceived as contorted and as having displaced features.[4] For example, one patient described a person's face as having a nose deviated to the side, the mouth laying at a diagonal and one eyebrow being higher than the other.[4] Prosopometamorphopsia may either involve perceptions of the whole face or only one side of the face (usually after right hemisphere damage).[1] ## Causes[edit] The definitive cause for prosopometamorphopsia is still relatively unknown. However, several potential theories have been expressed in the literature in this area. Generally, this condition has been associated with damage or abnormalities in various brain areas (temporal, occipital, parietal, and frontal lobes).[2] The development of prosopometamorphopsia has been recorded to be a manifestation of epilepsy in some cases.[2] Hyperactivity in the core or distributed face areas (without lesions) may be connected to causation. Functional imaging studies in humans have identified an area in the fusiform gyrus which is selectively activated by stimulation when exposed to faces called the fusiform face area (FFA).[3] Another area known to be activated by face stimuli is the superior temporal sulcus (STS). This region is particularly active when having to process facial expressions, especially the expressive features related to the eyes. Therefore, it has been suggested that the prominent eyes (which is a typical feature in the facial perceptions) in the distortions recorded is more in accordance with increased activity (which would cause an over-representation of the eyes) within the STS rather than the fusiform face area.[3] Other studies, however, have found that stimulation of the posterior and mid-fusiform face selective regions in a patient with medication-resistant epilepsy resulted in perceptions consistent with that of facial metamorphoses (patient noted that the experimenter's face started to droop).[2] This study found that the perceived distortions correlated with signal changes in the patient's FFA and not in the STS. ## Diagnosis[edit] ### Classification[edit] Prosopometamorphopsia is considered a face hallucination and is included under the umbrella of complex visual hallucinations.[5] Unlike other forms of hallucinations such as peduncular hallucinosis or Charles Bonnet syndrome, prosopometamorphopsia does not predominate at a particular time of day; it is a constant experience.[5] However, patients with Charles Bonnet syndrome have noted descriptions of prosopometamorphopsia.[4] This form of perceptual distortion along with others such as macropsia and micropsia (alteration of perceived object size) and palinopia (spatial and temporal varieties and polyopia) are classified under the category termed metamorphopsia.[6] These facial distortions can occur to either hallucinated perceptions or true (non-hallucinated) perceptions.[4] It is attributed to structural brain changes or functional disorders like epilepsy, migraine or eye diseases.[7] ## Treatment[edit] Antidepressants such as citalopram and the antipsychotic quetiapine have been recorded as unable to facilitate improvements for these symptoms.[7] Valproic acid was initially used to treat the woman who hallucinated the dragon-like faces and this alleviated her symptoms entirely, however, she went on to develop auditory hallucinations as a side effect.[7] She was subsequently prescribed rivastigmine instead which reduced the auditory hallucinations and reduced her visual symptoms. The 75-year-old woman in the previous study was treated with intravenous heparin infusion and coumadization over a period of 10 days which enabled the alleviation of her visual symptoms almost entirely.[1] The type of treatment may vary depending on the cause of the facial distortions. ## Case studies[edit] One study reported a 24-year-old woman who developed prosopometamorphopsia after a childbirth.[6] Initially she developed severe migraines and blurred vision mainly in her right visual hemifield and was in a confused state. The visual disturbances persisted long after the migraine had subsided several hours later. She described the left half of people's faces as "out of place" and would see these distortions irrespective of whether the faces were familiar or unknown. However, she was able to visualise the faces of familiar people in her mind without the distortions. She also did not report perceiving distortions in stimuli other than faces and demonstrated the same patterns a year after the first assessments. It was discovered that this woman had a left hemisphere lesion which resulted in distortions of the left half of the faces to which she was exposed. The unilateral aspect of the defect suggests that the early stages of face processing occurs in parallel mechanisms across both hemispheres and the right hemisphere then integrates the information that results in a unitary face representation.[6] Another study examined a 75-year-old woman who suffered from a sudden onset of nausea, dizziness and blurred vision.[1] The central part of faces, especially the nose and mouth, were described as being out of shape. She claimed that noses looked narrow and lengthened toward the mouth which looked small and rounded regardless of whether the faces were familiar to her or not. She was found not to have any other impairments in her visuoperceptual performances, nor did she have any cognitive or psychiatric impairments. A T2-weighted brain MRI revealed an infarction in the right medial temporooccipital lobe including the parahippocampal gyrus (complement of the FFA). A 52-year-old woman suffered from a lifelong history of seeing faces morph into dragon-like faces and reported hallucinating similar faces several times a day.[7] Initially she would recognise the actual faces but after a while they would become black, grew long pointy ears and a protruding snout, displayed reptile-like skin and had large protruding eyes in bright colours. She would see these faces coming towards her several times in a day from objects like electric sockets. She has also had these hallucinations in the dark. She had previously suffered from recurrent headaches, passage hallucinations (to see movements in the corner of the eyes) and zoopsia (she saw large ants crawling over her hands). A MRI of the brain showed minor white-matter abnormalities near the lentiform nucleus and in the semioval center. The visual perceptions she had experienced were attributed to unusual electrophysiological activity in the regions of the brain that are specialised for face and colour in the ventral occipito-temporal cortex.[7] A 44-year-old woman reported to have begun seeing facial distortions.[2] She perceived that people's faces would change to look more like caricatures of them and her perception worsened over time. She had a history of epilepsy in childhood and had suffered a concussion several years before having this condition, though no medical evidence of seizure was found during distortions. She reported that occasionally she would experience a pixelated vision, like television static and mentioned that these symptoms occurred several times a week with each event lasting from a few minutes to a few hours. ## References[edit] 1. ^ a b c d Hwang, Jung Yun; Ha, Sang Won; Cho, Eun Kyoung; Han, Jeong Ho; Lee, Seon Hwa; Lee, Seung Yeon; Kim, Doo Eung (2012). "A Case of Prosopometamorphopsia Restricted to the Nose and Mouth with Right Medial Temporooccipital Lobe Infarction That Included the Fusiform Face Area". Journal of Clinical Neurology. 8 (4): 311–313. doi:10.3988/jcn.2012.8.4.311. PMC 3540293. PMID 23323142. 2. ^ a b c d e Dalrymple, Kirsten; Davies-Thompson, Jodie; Oruc, Ipek; Barton, Jason; Duchaine, Brad (2014). "Spontaneous Perceptual Facial Distortions Correlate with Ventral Occipitotemporal Activity". Neuropsychologia. 59: 179–191. doi:10.1016/j.neuropsychologia.2014.05.005. 3. ^ a b c Santhouse, A M; Howard, R J; ffytche, D H (2000). "Visual Hallucinatory Syndromes and the Anatomy of the Visual Brain". Brain. 123 (10): 2055–2064. doi:10.1093/brain/123.10.2055. PMID 11004123. 4. ^ a b c d ffytche, D H; Howard, R J (1999). "The Perceptual Consequences of Visual Loss: 'Positive' Pathologies of Vision". Brain. 122 (7): 1257–1260. doi:10.1093/brain/122.7.1247. 5. ^ a b Mocellin, Ramon; Walterfang, Mark; Velakoulis, Dennis (2006). "Neuropsychiatry of Complex Visual Hallucinations". Australian and New Zealand Journal of Psychiatry. 40 (9): 742–751. doi:10.1080/j.1440-1614.2006.01878.x. PMID 16911748. 6. ^ a b c Trojano, Luigi; Conson, Massimiliano; Salzano, Sara; Manzo, Valentino; Grossi, Dario (2009). "Unilateral Left Prosopometamorphopsia: A Neuropsychological Case Study". Neuropsychologia. 47 (3): 942–948. doi:10.1016/j.neuropsychologia.2008.12.015. PMID 19136018. 7. ^ a b c d e Blom, Jan Dirk; Sommer, Iris; Koops, Sanne; Sacks, Oliver (2014). "Prosopometamorphopsia and Facial Hallucinations". The Lancet. 384 (9958): 1998. doi:10.1016/s0140-6736(14)61690-1. PMID 25435453. [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	Prosopometamorphopsia	None	6,320	wikipedia	https://en.wikipedia.org/wiki/Prosopometamorphopsia	2021-01-18T18:59:10	{"wikidata": ["Q24896809"]}
## Clinical Features Neuhauser et al. (1975) reported a family in which 3 sibs were affected with megalocornea, iris hypoplasia, severe mental retardation, hypotonia, seizures, and minor facial anomalies, including frontal bossing, downslanting palpebral fissures, epicanthal folds, and broad nasal base. Four sporadic cases were also reported. Neuhauser et al. (1975) suggested autosomal recessive inheritance. Schmidt and Rapin (1981) reported 2 unrelated patients with megalocornea associated with mental retardation. Both patients had hypotonia and facial features similar to those reported by Neuhauser et al. (1975). Del Giudice et al. (1987) reported 2 unrelated cases, one of which occurred in a girl whose parents were third cousins. Her parents noticed hypotonia, slow psychomotor development, and prominent eyes during her first months of life. Gronbech-Jensen (1989) described a case with short stature and mild malformation of the left auricle. Kimura et al. (1991) described a patient with Neuhauser syndrome who also had primary hypothyroidism and delayed myelination observed on brain magnetic resonance imaging (MRI). Santolaya et al. (1992) reported an affected patient. Hypotonia was noted at birth, and developmental delay was apparent soon after. Facial features included a round face, low frontal hairline, mild frontal bossing, broad nasal bridge, large corneas, mild hypertelorism, long upper lip, high palate, and small chin. She also had poor coordination. Santolaya et al. (1992) concluded that hypotonia is a major feature of this syndrome. Antinolo et al. (1994) reported an isolated case of megalocornea, mental retardation, and hypotonia. Sarkozy et al. (2002) reported a child with megalocornea-mental retardation syndrome who had also had primary hypothyroidism, osteopenia, and hypercholesterolemia. They suggested that the latter 3 features, previously described in only one case each, may be distinct features of MMR. Derbent et al. (2004) reported a male child with features of Neuhauser syndrome, including mental and motor retardation, megalocornea, and generalized hypotonia. He had characteristic facies with frontal bossing, hypertelorism, depressed and broad nasal root, long philtrum, micrognathia, and high-arched palate. Other features included bifid uvula and cerebral cortical atrophy. ### Clinical Variability Frydman et al. (1990) described 2 unrelated patients with mild mental retardation, megalocornea, and hypotonia suggestive of Neuhauser syndrome. However, they had additional features which were not consistent, including macrocephaly, swallowing difficulties, large, fleshy ears, and long fingers. One child was obese and the other had scoliosis. Verloes et al. (1993) reported 4 unrelated cases of megalocornea and mental retardation associated with anomalies that the authors considered to be distinct from Neuhauser syndrome. The authors classified the megalocornea-mental retardation syndromes into 5 types: type 1 was Neuhauser syndrome, with iris hypoplasia and minor anomalies. Type 2 was a recessive form reported by Frank et al. (1973) and Temtamy et al. (1991), with camptodactyly, scoliosis, and growth retardation (see Frank-ter Haar syndrome; 249420). Type 3, including their 4 cases, included patients with normal irides, severe hypotonia, relative or absolute macrocephaly and minor anomalies. They suggested that the patients reported by Frydman et al. (1990) might comprise a fourth form, with normal irides, megalencephaly, and obesity. Type 5 included provisionally unclassifiable cases. Nomenclature Raas-Rothschild et al. (1988) noted that the clinical findings of mental retardation and megalocornea are nonspecific and suggested the eponym 'Neuhauser syndrome' to describe this disorder. Molecular Genetics In a 10-year-old boy with megalocornea, intellectual disability, facial dysmorphism, and a history of hypotonicity and seizures, Davidson et al. (2014) sequenced the CHRDL1 gene (300350) and identified a missense mutation that was also present in his unaffected mother. However, the authors stated that it was unlikely that his extraocular features were caused by the CHRDL1 mutation because no other patients with megalocornea due to CHRDL1 mutations (see 309300) exhibited developmental delay or any of the other extraocular phenotypes associated with MMR syndrome. Furthermore, his deceased maternal grandfather was reported to have had 'large eyes,' cataracts, and glaucoma, whereas 2 paternal half sibs had seizures and intellectual disability. Whole-exome sequencing in the patient revealed several plausible variants that might have caused his extraocular phenotype, but due to lack of familial DNA samples, the potential pathogenicity of those variants could not be tested. Davidson et al. (2014) suggested that MMR syndrome may be digenic or multigenic in some cases. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly \- Macrocephaly Face \- Frontal bossing, mild \- Round facies \- Micrognathia Ears \- Abnormal auricles Eyes \- Megalocornea (diameter greater than 12 mm) \- Normal intraocular pressure \- Bulging eyes \- Iris hypoplasia \- Iridodonesis \- Myopia \- Downslanting palpebral fissures \- Hypertelorism \- Epicanthal folds Nose \- Broad nasal root/bridge \- Depressed nasal root/bridge Mouth \- Long philtrum \- High-arched palate \- Bifid uvula (reported in 3 patients) SKELETAL \- Osteopenia (reported in 2 patients) Limbs \- Genu valga \- Genu recurvatum Feet \- Pes planus \- Pes valgus SKIN, NAILS, & HAIR Hair \- Low frontal hairline MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Hypotonia \- Mental retardation \- Seizures \- Poor coordination \- Ataxia \- Cerebral cortical atrophy, diffuse \- Delayed myelination on brain MRI (reported in 1 patient) ENDOCRINE FEATURES \- Primary hypothyroidism (reported in 2 patients) LABORATORY ABNORMALITIES \- Hypercholesterolemia (reported in 2 patients) ▲ 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	MEGALOCORNEA-MENTAL RETARDATION SYNDROME	c0796086	6,321	omim	https://www.omim.org/entry/249310	2019-09-22T16:25:29	{"mesh": ["C536143"], "omim": ["249310"], "orphanet": ["2479"], "synonyms": ["Alternative titles", "MMR SYNDROME", "NEUHAUSER SYNDROME"]}
For other uses, see Mania (disambiguation). "Maniacal" redirects here. For other uses, see Maniacal (disambiguation). State of abnormally elevated or irritable mood, arousal, and/or energy levels Mania Other namesManic syndrome, manic episode Graphical representation of mania and hypomania SpecialtyPsychiatry Mania, also known as manic syndrome, is a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together with lability of affect."[1] During a manic episode, an individual will experience rapidly changing emotions and moods, highly influenced by surrounding stimuli. Although mania is often conceived as a "mirror image" to depression, the heightened mood can be either euphoric or dysphoric.[2] As the mania intensifies, irritability can be more pronounced and result in anxiety or violence. The symptoms of mania include elevated mood (either euphoric or irritable), flight of ideas and pressure of speech, increased energy, decreased need and desire for sleep, and hyperactivity. They are most plainly evident in fully developed hypomanic states. However, in full-blown mania, they undergo progressively severe exacerbations and become more and more obscured by other signs and symptoms, such as delusions and fragmentation of behavior.[3] ## Contents * 1 Causes and diagnosis * 2 Classification * 2.1 Mixed states * 2.2 Hypomania * 2.3 Associated disorders * 3 Signs and symptoms * 4 Cause * 5 Mechanism * 6 Diagnosis * 7 Treatment * 8 Society and culture * 9 Etymology * 10 See also * 11 References * 12 Further reading * 13 External links ## Causes and diagnosis[edit] Mania is a syndrome with multiple causes. Although the vast majority of cases occur in the context of bipolar disorder, it is a key component of other psychiatric disorders (such as schizoaffective disorder, bipolar type) and may also occur secondary to various general medical conditions, such as multiple sclerosis; certain medications may perpetuate a manic state, for example prednisone; or substances prone to abuse, especially stimulants, such as caffeine and cocaine. In the current DSM-5, hypomanic episodes are separated from the more severe full manic episodes, which, in turn, are characterized as either mild, moderate, or severe, with certain diagnostic criteria (e.g. catatonia, psychosis). Mania is divided into three stages: hypomania, or stage I; acute mania, or stage II; and delirious mania (delirium), or stage III. This "staging" of a manic episode is useful from a descriptive and differential diagnostic point of view [4] Mania varies in intensity, from mild mania (hypomania) to delirious mania, marked by such symptoms as disorientation, florid psychosis, incoherence, and catatonia.[5] Standardized tools such as Altman Self-Rating Mania Scale[6] and Young Mania Rating Scale[7] can be used to measure severity of manic episodes. Because mania and hypomania have also long been associated with creativity and artistic talent,[8] it is not always the case that the clearly manic/hypomanic bipolar patient needs or wants medical help; such persons often either retain sufficient self-control to function normally or are unaware that they have "gone manic" severely enough to be committed or to commit themselves.[citation needed] Manic persons often can be mistaken for being under the influence of drugs. ## Classification[edit] ### Mixed states[edit] Main article: Mixed affective state In a mixed affective state, the individual, though meeting the general criteria for a hypomanic (discussed below) or manic episode, experiences three or more concurrent depressive symptoms. This has caused some speculation, among clinicians, that mania and depression, rather than constituting "true" polar opposites, are, rather, two independent axes in a unipolar—bipolar spectrum. A mixed affective state, especially with prominent manic symptoms, places the patient at a greater risk for completed suicide. Depression on its own is a risk factor but, when coupled with an increase in energy and goal-directed activity, the patient is far more likely to act with violence on suicidal impulses. ### Hypomania[edit] Main article: Hypomania Hypomania, which means "less than mania",[9] is a lowered state of mania that does little to impair function or decrease quality of life.[10] It may, in fact, increase productivity and creativity. In hypomania, there is less need for sleep and both goal-motivated behaviour and metabolism increase. Some studies exploring brain metabolism in subjects with hypomania, however, did not find any conclusive link; while there are studies that reported abnormalities, some failed to detect differences.[11] Though the elevated mood and energy level typical of hypomania could be seen as a benefit, true mania itself generally has many undesirable consequences including suicidal tendencies, and hypomania can, if the prominent mood is irritable as opposed to euphoric, be a rather unpleasant experience. In addition, the exaggerated case of hypomania can lead to problems. For instance, trait-based positivity for a person could make him more engaging and outgoing, and cause him to have a positive outlook in life.[12] When exaggerated in hypomania, however, such a person can display excessive optimism, grandiosity, and poor decision making, often with little regard to the consequences.[12] ### Associated disorders[edit] A single manic episode, in the absence of secondary causes, (i.e., substance use disorders, pharmacologics, or general medical conditions) is often sufficient to diagnose bipolar I disorder. Hypomania may be indicative of bipolar II disorder. Manic episodes are often complicated by delusions and/or hallucinations; and if the psychotic features persist for a duration significantly longer than the episode of typical mania (two weeks or more), a diagnosis of schizoaffective disorder is more appropriate. Certain obsessive-compulsive spectrum disorders as well as impulse control disorders share the suffix "-mania," namely, kleptomania, pyromania, and trichotillomania. Despite the unfortunate association implied by the name, however, no connection exists between mania or bipolar disorder and these disorders. Furthermore, evidence indicates a B12 deficiency can also cause symptoms characteristic of mania and psychosis.[13] Hyperthyroidism can produce similar symptoms to those of mania, such as agitation, elevated mood, increased energy, hyperactivity, sleep disturbances and sometimes, especially in severe cases, psychosis.[14][15] ## Signs and symptoms[edit] A manic episode is defined in the American Psychiatric Association's diagnostic manual as a "distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least 1 week and present most of the day, nearly every day (or any duration, if hospitalization is necessary),"[16] where the mood is not caused by drugs/medication or a non-mental medical illness (e.g., hyperthyroidism), and: (a) is causing obvious difficulties at work or in social relationships and activities, or (b) requires admission to hospital to protect the person or others, or (c) the person is suffering psychosis.[17] To be classified as a manic episode, while the disturbed mood and an increase in goal directed activity or energy is present, at least three (or four, if only irritability is present) of the following must have been consistently present: 1. Inflated self-esteem or grandiosity. 2. Decreased need for sleep (e.g., feels rested after 3 hours of sleep). 3. More talkative than usual, or acts pressured to keep talking. 4. Flights of ideas or subjective experience that thoughts are racing. 5. Increase in goal directed activity, or psychomotor acceleration. 6. Distractibility (too easily drawn to unimportant or irrelevant external stimuli). 7. Excessive involvement in activities with a high likelihood of painful consequences.(e.g., extravagant shopping, improbable commercial schemes, hypersexuality).[17] Though the activities one participates in while in a manic state are not always negative, those with the potential to have negative outcomes are far more likely. If the person is concurrently depressed, they are said to be having a mixed episode.[17] The World Health Organization's classification system defines a manic episode as one where mood is higher than the person's situation warrants and may vary from relaxed high spirits to barely controllable exuberance, is accompanied by hyperactivity, a compulsion to speak, a reduced sleep requirement, difficulty sustaining attention and/or often increased distractibility. Frequently, confidence and self-esteem are excessively enlarged, and grand, extravagant ideas are expressed. Behavior that is out of character and risky, foolish or inappropriate may result from a loss of normal social restraint.[3] Some people also have physical symptoms, such as sweating, pacing, and weight loss. In full-blown mania, often the manic person will feel as though his or her goal(s) are of paramount importance, that there are no consequences or that negative consequences would be minimal, and that they need not exercise restraint in the pursuit of what they are after.[18] Hypomania is different, as it may cause little or no impairment in function. The hypomanic person's connection with the external world, and its standards of interaction, remain intact, although intensity of moods is heightened. But those who suffer from prolonged unresolved hypomania do run the risk of developing full mania, and may cross that "line" without even realizing they have done so.[19] One of the signature symptoms of mania (and to a lesser extent, hypomania) is what many have described as racing thoughts. These are usually instances in which the manic person is excessively distracted by objectively unimportant stimuli.[20] This experience creates an absent-mindedness where the manic individual's thoughts totally preoccupy him or her, making him or her unable to keep track of time, or be aware of anything besides the flow of thoughts. Racing thoughts also interfere with the ability to fall asleep. Manic states are always relative to the normal state of intensity of the afflicted individual; thus, already irritable patients may find themselves losing their tempers even more quickly, and an academically gifted person may, during the hypomanic stage, adopt seemingly "genius" characteristics and an ability to perform and articulate at a level far beyond that which they would be capable of during euthymia. A very simple indicator of a manic state would be if a heretofore clinically depressed patient suddenly becomes inordinately energetic, enthusiastic, cheerful, aggressive, or "over happy". Other, often less obvious, elements of mania include delusions (generally of either grandeur or persecution, according to whether the predominant mood is euphoric or irritable), hypersensitivity, hypervigilance, hypersexuality, hyper-religiosity, hyperactivity and impulsivity, a compulsion to over explain (typically accompanied by pressure of speech), grandiose schemes and ideas, and a decreased need for sleep (for example, feeling rested after only 3 or 4 hours of sleep). In the case of the latter, the eyes of such patients may both look and seem abnormally "wide open", rarely blinking, and may contribute to some clinicians’ erroneous belief that these patients are under the influence of a stimulant drug, when the patient, in fact, is either not on any mind-altering substances or is actually on a depressant drug. Individuals may also engage in out-of-character behavior during the episode, such as questionable business transactions, wasteful expenditures of money (e.g., spending sprees), risky sexual activity, abuse of recreational substances, excessive gambling, reckless behavior (such as extreme speeding or other daredevil activity), abnormal social interaction (e.g. over familiarity and conversing with strangers), or highly vocal arguments. These behaviours may increase stress in personal relationships, lead to problems at work, and increase the risk of altercations with law enforcement. There is a high risk of impulsively taking part in activities potentially harmful to the self and others.[21][22] Although "severely elevated mood" sounds somewhat desirable and enjoyable, the experience of mania is ultimately often quite unpleasant and sometimes disturbing, if not frightening, for the person involved and for those close to them, and it may lead to impulsive behaviour that may later be regretted. It can also often be complicated by the sufferer's lack of judgment and insight regarding periods of exacerbation of characteristic states. Manic patients are frequently grandiose, obsessive, impulsive, irritable, belligerent, and frequently deny anything is wrong with them. Because mania frequently encourages high energy and decreased perception of need or ability to sleep, within a few days of a manic cycle, sleep-deprived psychosis may appear, further complicating the ability to think clearly. Racing thoughts and misperceptions lead to frustration and decreased ability to communicate with others. Mania may also, as earlier mentioned, be divided into three “stages”. Stage I corresponds with hypomania and may feature typical hypomanic characteristics, such as gregariousness and euphoria. In stages II and III mania, however, the patient may be extraordinarily irritable, psychotic or even delirious. These latter two stages are referred to as acute and delirious (or Bell's), respectively. ## Cause[edit] Various triggers have been associated with switching from euthymic or depressed states into mania. One common trigger of mania is antidepressant therapy. Studies show that the risk of switching while on an antidepressant is between 6-69 percent. Dopaminergic drugs such as reuptake inhibitors and dopamine agonists may also increase risk of switch. Other medication possibly include glutaminergic agents and drugs that alter the HPA axis. Lifestyle triggers include irregular sleep-wake schedules and sleep deprivation, as well as extremely emotional or stressful stimuli.[23] Various genes that have been implicated in genetic studies of bipolar have been manipulated in preclinical animal models to produce syndromes reflecting different aspects of mania. CLOCK and DBP polymorphisms have been linked to bipolar in population studies, and behavioral changes induced by knockout are reversed by lithium treatment. Metabotropic glutamate receptor 6 has been genetically linked to bipolar, and found to be under-expressed in the cortex. Pituitary adenylate cyclase-activating peptide has been associated with bipolar in gene linkage studies, and knockout in mice produces mania like-behavior. Targets of various treatments such as GSK-3, and ERK1 have also demonstrated mania like behavior in preclinical models.[24] Mania may be associated with strokes, especially cerebral lesions in the right hemisphere.[25][26] Deep brain stimulation of the subthalamic nucleus in Parkinson's disease has been associated with mania, especially with electrodes placed in the ventromedial STN. A proposed mechanism involves increased excitatory input from the STN to dopaminergic nuclei.[27] Mania can also be caused by physical trauma or illness. When the causes are physical, it is called secondary mania.[28] ## Mechanism[edit] Further information: Biology of bipolar disorder The mechanism underlying mania is unknown, but the neurocognitive profile of mania is highly consistent with dysfunction in the right prefrontal cortex, a common finding in neuroimaging studies.[29][30] Various lines of evidence from post-mortem studies and the putative mechanisms of anti-manic agents point to abnormalities in GSK-3,[31] dopamine, Protein kinase C and Inositol monophosphatase.[32] Meta analysis of neuroimaging studies demonstrate increased thalamic activity, and bilaterally reduced inferior frontal gyrus activation.[33] Activity in the amygdala and other subcortical structures such as the ventral striatum tend to be increased, although results are inconsistent and likely dependent upon task characteristics such as valence. Reduced functional connectivity between the ventral prefrontal cortex and amygdala along with variable findings supports a hypothesis of general dysregulation of subcortical structures by the prefrontal cortex.[34] A bias towards positively valenced stimuli, and increased responsiveness in reward circuitry may predispose towards mania.[35] Mania tends to be associated with right hemisphere lesions, while depression tends to be associated with left hemisphere lesions.[36] Post-mortem examinations of bipolar disorder demonstrate increased expression of Protein Kinase C (PKC).[37] While limited, some studies demonstrate manipulation of PKC in animals produces behavioral changes mirroring mania, and treatment with PKC inhibitor tamoxifen (also an anti-estrogen drug) demonstrates antimanic effects. Traditional antimanic drugs also demonstrate PKC inhibiting properties, among other effects such as GSK3 inhibition.[30] Manic episodes may be triggered by dopamine receptor agonists, and this combined with tentative reports of increased VMAT2 activity, measured via PET scans of radioligand binding, suggests a role of dopamine in mania. Decreased cerebrospinal fluid levels of the serotonin metabolite 5-HIAA have been found in manic patients too, which may be explained by a failure of serotonergic regulation and dopaminergic hyperactivity.[38] Limited evidence suggests that mania is associated with behavioral reward hypersensitivity, as well as with neural reward hypersensitivity. Electrophysiological evidence supporting this comes from studies associating left frontal EEG activity with mania. As left frontal EEG activity is generally thought to be a reflection of behavioral activation system activity, this is thought to support a role for reward hypersensitivity in mania. Tentative evidence also comes from one study that reported an association between manic traits and feedback negativity during receipt of monetary reward or loss. Neuroimaging evidence during acute mania is sparse, but one study reported elevated orbitofrontal cortex activity to monetary reward, and another study reported elevated striatal activity to reward omission. The latter finding was interpreted in the context of either elevated baseline activity (resulting in a null finding of reward hypersensitivity), or reduced ability to discriminate between reward and punishment, still supporting reward hyperactivity in mania.[39] Punishment hyposensitivity, as reflected in a number of neuroimaging studies as reduced lateral orbitofrontal response to punishment, has been proposed as a mechanism of reward hypersensitivity in mania.[40] ## Diagnosis[edit] In the ICD-10 there are several disorders with the manic syndrome: organic manic disorder (F06.30), mania without psychotic symptoms (F30.1), mania with psychotic symptoms (F30.2), other manic episodes (F30.8), unspecified manic episode (F30.9), manic type of schizoaffective disorder (F25.0), bipolar affective disorder, current episode manic without psychotic symptoms (F31.1), bipolar affective disorder, current episode manic with psychotic symptoms (F31.2). ## Treatment[edit] Before beginning treatment for mania, careful differential diagnosis must be performed to rule out secondary causes. The acute treatment of a manic episode of bipolar disorder involves the utilization of either a mood stabilizer (valproate, lithium, lamotrigine, or carbamazepine) or an atypical antipsychotic (olanzapine, quetiapine, risperidone, or aripiprazole). Although hypomanic episodes may respond to a mood stabilizer alone, full-blown episodes are treated with an atypical antipsychotic (often in conjunction with a mood stabilizer, as these tend to produce the most rapid improvement).[41] When the manic behaviours have gone, long-term treatment then focuses on prophylactic treatment to try to stabilize the patient's mood, typically through a combination of pharmacotherapy and psychotherapy. The likelihood of having a relapse is very high for those who have experienced two or more episodes of mania or depression. While medication for bipolar disorder is important to manage symptoms of mania and depression, studies show relying on medications alone is not the most effective method of treatment. Medication is most effective when used in combination with other bipolar disorder treatments, including psychotherapy, self-help coping strategies, and healthy lifestyle choices.[42] Lithium is the classic mood stabilizer to prevent further manic and depressive episodes. A systematic review found that long term lithium treatment substantially reduces the risk of bipolar manic relapse, by 42%.[43] Anticonvulsants such as valproate, oxcarbazepine and carbamazepine are also used for prophylaxis. More recent drug solutions include lamotrigine and topiramate, both anticonvulsants as well. In some cases, long-acting benzodiazepines, particularly clonazepam, are used after other options are exhausted. In more urgent circumstances, such as in emergency rooms, lorazepam, combined with haloperidol, is used to promptly alleviate symptoms of agitation, aggression, and psychosis. Antidepressant monotherapy is not recommended for the treatment of depression in patients with bipolar disorders I or II, and no benefit has been demonstrated by combining antidepressants with mood stabilizers in these patients. Some atypical antidepressants, however, such as mirtazepine and trazodone have been occasionally used after other options have failed.[44] ## Society and culture[edit] In Electroboy: A Memoir of Mania by Andy Behrman, he describes his experience of mania as "the most perfect prescription glasses with which to see the world... life appears in front of you like an oversized movie screen".[45] Behrman indicates early in his memoir that he sees himself not as a person suffering from an uncontrollable disabling illness, but as a director of the movie that is his vivid and emotionally alive life. There is some evidence that people in the creative industries suffer from bipolar disorder more often than those in other occupations.[46] Winston Churchill had periods of manic symptoms that may have been both an asset and a liability.[47] English actor Stephen Fry, who suffers from bipolar disorder,[48] recounts manic behaviour during his adolescence: "When I was about 17 ... going around London on two stolen credit cards, it was a sort of fantastic reinvention of myself, an attempt to. I bought ridiculous suits with stiff collars and silk ties from the 1920s, and would go to the Savoy and Ritz and drink cocktails."[49] While he has experienced suicidal thoughts, he says the manic side of his condition has had positive contributions on his life.[48] ## Etymology[edit] The nosology of the various stages of a manic episode has changed over the decades. The word derives from the Ancient Greek μανία (manía), "madness, frenzy"[50] and the verb μαίνομαι (maínomai), "to be mad, to rage, to be furious".[51] ## See also[edit] * Abnormal psychology * Adult attention deficit hyperactivity disorder * Bipolar disorder * Cyclothymia * Hyperthymia * Hypomania * People with bipolar disorder * International Society for Bipolar Disorders * Major depressive disorder * Young Mania Rating Scale ## References[edit] 1. ^ Berrios GE (2004). "Of mania". History of Psychiatry. 15 (57 Pt 1): 105–124. doi:10.1177/0957154X04041829. PMID 15104084. 2. ^ https://www.medicalnewstoday.com/articles/315016 3. ^ a b "Manic episode". Retrieved 18 November 2016. 4. ^ Coon, Hilary; Hoff, Mark; Holik, John; Byerley, William (1995). "Search for a gene predisposing to manic-depression on chromosome 21". American Journal of Medical Genetics. 60 (3): 231–233. doi:10.1002/ajmg.1320600312. PMID 7573177. 5. ^ Semple, David. 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"Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis". Lancet. 378 (9799): 1306–15. doi:10.1016/S0140-6736(11)60873-8. PMID 21851976. 42. ^ Melinda Smith, M.A., Lawrence Robinson, Jeanne Segal, and Damon Ramsey, MD (1 March 2012). "The Bipolar Medication Guide". HelpGuide.org. Archived from the original on 10 March 2012. Retrieved 23 March 2012.CS1 maint: multiple names: authors list (link) 43. ^ Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM (February 2004). "Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials". The American Journal of Psychiatry. 161 (2): 217–22. doi:10.1176/appi.ajp.161.2.217. PMID 14754766. 44. ^ Nierenberg AA (2010). "A critical appraisal of treatments for bipolar disorder". Primary Care Companion to the Journal of Clinical Psychiatry. 12 (Suppl 1): 23–29. doi:10.4088/PCC.9064su1c.04. PMC 2902191. PMID 20628503. 45. ^ Behrman, Andy (2002). Electroboy: A Memoir of Mania. Random House Trade Paperbacks. pp. Preface: Flying High. ISBN 978-0-8129-6708-1. 46. ^ Collingwood, Jane. "The Link Between Bipolar Disorder and Creativity". Psychcentral. Retrieved 26 December 2018. 47. ^ Nolen-Hoeksema, Susan (2014). Abnormal psychology (Sixth ed.). McGraw Hill Education. p. 184. ISBN 978-0-07-803538-8. 48. ^ a b "Stephen Fry: My battle with mental illness". The Independent. Retrieved 26 December 2018. 49. ^ "Stephen Fry: my battle with manic depression". The Guardian. Retrieved 26 December 2018. 50. ^ μανία, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus Digital Library 51. ^ μαίνομαι, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus Digital Library ## Further reading[edit] * Expert Opin Pharmacother. 2001 December;2(12):1963–73. * Schizoaffective Disorder. 2007 September Mayo Clinic. Retrieved October 1, 2007. * Schizoaffective Disorder. 2004 May. All Psych Online: Virtual Psychology Classroom. Retrieved October 2, 2007. * Psychotic Disorders. 2004 May. All Psych Online: Virtual Psychology Classroom. Retrieved October 2, 2007. * Sajatovic, Martha; DiBiovanni, Sue Kim; Bastani, Bijan; Hattab, Helen; Ramirez, Luis F. (1996). "Risperidone therapy in treatment refractory acute bipolar and schizoaffective mania". Psychopharmacology Bulletin. 32 (1): 55–61. PMID 8927675. ## External links[edit] Look up mania in Wiktionary, the free dictionary. * Bipolar Mania Symptoms * Depression and Bipolar Support Alliance Classification D * ICD-10: F06.30, F30.1, F30.2, F30.8, F30.9, F31.1, F31.2 * ICD-9-CM: 296.0, 296.4, 296.6 * MeSH: D001714 * v * t * e Mood disorder History * Emil Kraepelin * Karl Leonhard * John Cade * Mogens Schou * Frederick K. Goodwin * Kay Redfield Jamison Symptoms * Hallucination * Delusion * Emotional dysregulation * Anhedonia * Dysphoria * Suicidal ideation * Mood swing * Sleep disorder * Hypersomnia * Insomnia * Psychosis * Racing thoughts * Reduced affect display * Depression (differential diagnoses) Spectrum * Bipolar disorder * Bipolar I * Bipolar II * Cyclothymia * Bipolar NOS * Depression * Major depressive disorder * Dysthymia * Seasonal affective disorder * Atypical depression * Melancholic depression * Schizoaffective disorder * Mania * Mixed affective state * Hypomania * Major depressive episode * Rapid cycling Treatment Anticonvulsants * Carbamazepine * Lamotrigine * Oxcarbazepine * Valproate * Sodium valproate * Valproate semisodium Sympathomimetics, SSRIs and similar * Dextroamphetamine * Methylphenidate * Bupropion * Sertraline * Fluoxetine * Escitalopram Other mood stabilizers * Antipsychotics * Lithium * Lithium carbonate * Lithium citrate * Lithium sulfate * Lithium toxicity * Atypical antipsychotics Non-pharmaceutical * Clinical psychology * Electroconvulsive therapy * Involuntary commitment * Light therapy * Psychotherapy * Transcranial magnetic stimulation * Cognitive behavioral therapy * Dialectical behavior therapy * v * t * e Mental and behavioral disorders Adult personality and behavior Gender dysphoria * Ego-dystonic sexual orientation * Paraphilia * Fetishism * Voyeurism * Sexual maturation disorder * Sexual relationship disorder Other * Factitious disorder * Munchausen syndrome * Intermittent explosive disorder * Dermatillomania * Kleptomania * Pyromania * Trichotillomania * Personality disorder Childhood and learning Emotional and behavioral * ADHD * Conduct disorder * ODD * Emotional and behavioral disorders * Separation anxiety disorder * Movement disorders * Stereotypic * Social functioning * DAD * RAD * Selective mutism * Speech * Stuttering * Cluttering * Tic disorder * Tourette syndrome Intellectual disability * X-linked intellectual disability * Lujan–Fryns syndrome Psychological development (developmental disabilities) * Pervasive * Specific Mood (affective) * Bipolar * Bipolar I * Bipolar II * Bipolar NOS * Cyclothymia * Depression * Atypical depression * Dysthymia * Major depressive disorder * Melancholic depression * Seasonal affective disorder * Mania Neurological and symptomatic Autism spectrum * Autism * Asperger syndrome * High-functioning autism * PDD-NOS * Savant syndrome Dementia * AIDS dementia complex * Alzheimer's disease * Creutzfeldt–Jakob disease * Frontotemporal dementia * Huntington's disease * Mild cognitive impairment * Parkinson's disease * Pick's disease * Sundowning * Vascular dementia * Wandering Other * Delirium * Organic brain syndrome * Post-concussion syndrome Neurotic, stress-related and somatoform Adjustment * Adjustment disorder with depressed mood Anxiety Phobia * Agoraphobia * Social anxiety * Social phobia * Anthropophobia * Specific social phobia * Specific phobia * Claustrophobia Other * Generalized anxiety disorder * OCD * Panic attack * Panic disorder * Stress * Acute stress reaction * PTSD Dissociative * Depersonalization disorder * Dissociative identity disorder * Fugue state * Psychogenic amnesia Somatic symptom * Body dysmorphic disorder * Conversion disorder * Ganser syndrome * Globus pharyngis * Psychogenic non-epileptic seizures * False pregnancy * Hypochondriasis * Mass psychogenic illness * Nosophobia * Psychogenic pain * Somatization disorder Physiological and physical behavior Eating * Anorexia nervosa * Bulimia nervosa * Rumination syndrome * Other specified feeding or eating disorder Nonorganic sleep * Hypersomnia * Insomnia * Parasomnia * Night terror * Nightmare * REM sleep behavior disorder Postnatal * Postpartum depression * Postpartum psychosis Sexual dysfunction Arousal * Erectile dysfunction * Female sexual arousal disorder Desire * Hypersexuality * Hypoactive sexual desire disorder Orgasm * Anorgasmia * Delayed ejaculation * Premature ejaculation * Sexual anhedonia Pain * Nonorganic dyspareunia * Nonorganic vaginismus Psychoactive substances, substance abuse and substance-related * Drug overdose * Intoxication * Physical dependence * Rebound effect * Stimulant psychosis * Substance dependence * Withdrawal Schizophrenia, schizotypal and delusional Delusional * Delusional disorder * Folie à deux Psychosis and schizophrenia-like * Brief reactive psychosis * Schizoaffective disorder * Schizophreniform disorder Schizophrenia * Childhood schizophrenia * Disorganized (hebephrenic) schizophrenia * Paranoid schizophrenia * Pseudoneurotic schizophrenia * Simple-type schizophrenia Other * Catatonia Symptoms and uncategorized * Impulse control disorder * Klüver–Bucy syndrome * Psychomotor agitation * Stereotypy [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	Mania	c0338831	6,322	wikipedia	https://en.wikipedia.org/wiki/Mania	2021-01-18T18:40:22	{"mesh": ["D001714"], "icd-9": ["296.4", "296.0", "296.6"], "icd-10": ["F30"], "wikidata": ["Q185935"]}
For a phenotypic description and a discussion of genetic heterogeneity of panic disorder, see 167870. Mapping To locate genes predisposing to anxiety disorders, Thorgeirsson et al. (2003) used the extensive genealogic records and relative homogeneity of the Icelandic population in a study in which participants were recruited in 2 stages: an initial case identification by a population screening for anxiety disorders and then by a more detailed diagnostic workup with screening for anxiety in close relatives. They used 976 microsatellite markers to genotype 62 families affected with anxiety. Affected-only linkage analysis on a subset of 25 extended families in which at least 1 affected individual had panic disorder resulted in a lod score of 4.18 at marker D9S271 on chromosome 9q31. Thorgeirsson et al. (2003) noted that the linkage results may be relevant to anxiety in general, not only to panic 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	PANIC DISORDER 2	c1842922	6,323	omim	https://www.omim.org/entry/607853	2019-09-22T16:08:33	{"omim": ["607853"], "synonyms": ["Alternative titles", "PAND2", "PANIC DISORDER SUSCEPTIBILITY LOCUS, CHROMOSOME 9q-RELATED"]}
A number sign (#) is used with this entry because neuronal lipofuscinosis-4B (CLN4B) is caused by heterozygous mutation in the DNAJC5 gene (611203) on chromosome 20q13. Description Neuronal ceroid lipofuscinosis-4B is an autosomal dominant neurodegenerative disorder characterized by onset of symptoms in adulthood. It belongs to a group of progressive neurodegenerative diseases characterized by accumulation of intracellular autofluorescent lipopigment storage material in the brain and other tissues. Several different forms have been described according to age of onset (see, e.g., CLN3, 204200). Individuals with the adult form, sometimes referred to as Kufs disease, develop psychiatric manifestations, seizures, cerebellar ataxia, and cognitive decline. Retinal degeneration is usually not present (summary by Benitez et al., 2011 and Velinov et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730). Clinical Features Boehme et al. (1971) reported a family (named Parry) in which 11 individuals over 4 generations were affected with adult-onset neuronal ceroid lipofuscinosis (NCL) in an autosomal dominant pattern of inheritance. The strikingly consistent clinical picture was onset of a cerebellar syndrome at about age 31 years, followed by seizures, myoclonic jerks, and progressive dementia. Pathologic features included neuronal loss and accumulation of lipopigment in remaining neurons. No curvilinear or fingerprint patterns were apparent on ultrastructural examination. Armstrong et al. (1974) studied 3 sibs from Boehme's family and found that all 3 had low peroxidase although only 2 were clinically affected. Brodner and Noh (1976) and Brodner et al. (1976) studied a 24-year-old man from the family reported by Boehme et al. (1971). Cortical biopsy at the time of craniotomy for removal of astrocytoma showed changes indicative of Kufs disease. Velinov et al. (2012) reported follow-up of the Parry family reported by Boehme et al. (1971). The 49-year-old female proband developed psychiatric problems, including irritability and obsessive-compulsive manifestations, in her mid-twenties. EEG showed recurrent burst of 4- to 6-Hz slow waves, and she later developed overt seizures. This was followed by progressive memory loss and gait ataxia. In her forties, she reported progressive visual disturbances, described as 'yellow blinding lights.' Electron microscopic analysis of patient lymphocytes showed no lysosomal inclusions at age 26 years, but changes consistent with granular osmiophilic deposits and curvilinear profiles were observed at age 34. Ferrer et al. (1980) reported a family with autosomal dominant Kufs disease with 6 affected individuals in 2 generations. Disease onset ranged from age 33 to 37 years and was characterized by progressive dementia and involuntary movements of the face and neck. One affected individual had seizures. Brain biopsy showed mild neuronal loss and the accumulation of a granular, membrane-bound product resembling lipofuscin with occasional dense compact rectilinear profiles, but no fingerprint or curvilinear profiles. Goebel and Braak (1989) provided a detailed review of adult-onset NCL. Psychiatric and behavioral changes, mental deterioration, seizures, extrapyramidal symptoms, and ataxia dominate the clinical picture, while ocular symptoms are conspicuously absent. Josephson et al. (2001) reported a family of English ancestry in which 10 members over 5 generations had Kufs disease. Age of onset ranged from 32 to 40 years, with the initial manifestation being new-onset seizures. Dementia developed in all affected members within 3 years of seizure onset and was characterized by impaired episodic memory, visual/spatial abilities, and executive function. Motor symptoms included myoclonus and extrapyramidal symptoms. Detailed postmortem examination of 1 patient showed cortical atrophy and autofluorescent granular accumulations in neurons of the cortex, basal ganglia, thalamus, brainstem, and cerebellum. Ultrastructural examination of the granular deposits did not show fingerprint or curvilinear profiles. Nijssen et al. (2002) reported a Dutch family with autosomal dominant Kufs disease. There were 6 affected individuals in 3 generations, with an age of onset ranging from 24 to 46 years. Clinical features were similar to previously reported cases, including seizures, myoclonus, and dementia. Parkinsonian features such as rigidity, short-stepped gait, masked face, and stooped posture were also present in later stages of the disease. Some individuals also had hearing impairment. Neuropathologic examination of some affected individuals showed ballooned cells with autofluorescent and PAS-positive intraneuronal storage material and granular osmiophilic deposits. Burneo et al. (2003) reported a family from Alabama with the disorder in which at least 4 generations were affected. In addition to seizures, dementia, and myoclonus, several affected individuals also had parkinsonism. Noskova et al. (2011) had excluded a mutation in the DNAJC5 gene in the family reported by Burneo et al. (2003), but Cadieux-Dion et al. (2013) did find a DNAJC5 mutation (611203.0001) in this family. Noskova et al. (2011) reported a 3-generation Czech family with autosomal dominant adult-onset CLN. The proband presented at age 30 with myoclonic epilepsy, generalized tonic-clonic seizures, and progressive cognitive deterioration with depression; these symptoms were followed by progressive motor neurologic symptoms leading to death at age 37 years. Neuropathologic examination of postmortem brain tissue showed characteristic neurolysosomal storage of autofluorescent material with ultrastructural appearance corresponding to granular osmiophilic deposits (GROD). Other family members showed a similar clinical course. Inheritance The transmission pattern of adult-onset NCL in the family reported by Boehme et al. (1971) was consistent with autosomal dominant inheritance. Mapping By linkage analysis of the large family with adult-onset NCL reported by Boehme et al. (1971), Cadieux-Dion et al. (2013) found linkage to a 3.8-Mb region on chromosome 20q13.33 (maximum multipoint lod score of 5.3 at SNP rs11204451). Molecular Genetics In a Czech family with autosomal dominant adult-onset ceroid neuronal lipofuscinosis-4B, Noskova et al. (2011) identified a heterozygous deletion mutation in the DNAJC5 gene (346_348del; 611203.0001). The mutation was found by a combination of linkage analysis, copy-number analysis, gene-expression analysis, and exome sequencing of candidate genes. Screening of this gene in 20 additional families identified pathogenic mutations in 4 (346_348del or L115R, 611203.0002). Two of the families had been reported by Josephson et al. (2001) and Nijssen et al. (2002). In patients with CLN4B, Benitez et al. (2011) and Velinov et al. (2012) found the same 2 heterozygous mutations in the DNCJC5 gene as those reported by Noskova et al. (2011), thus confirming the findings. Benitez et al. (2011) studied the family originally reported by Josephson et al. (2001), and Velinov et al. (2012) studied the Parry family originally reported by Boehme et al. (1971). By linkage analysis combined with exome sequencing in the large family (Parry) reported by Boehme et al. (1971), Cadieux-Dion et al. (2013) identified heterozygosity for the same deletion in the DNAJC5 gene that had previously been identified (611203.0001). The mutation was confirmed by Sanger sequencing, was not found in 380 control chromosomes, and segregated with the disorder in the family. The American patient reported by Noskova et al. (2011) who carried this mutation was found to be from the Parry family. Cadieux-Dion et al. (2013) also identified the deletion mutation in affected members of a family from Alabama reported by Burneo et al. (2003), even though the mutation in this family had not been found by Noskova et al. (2011). Haplotype analysis did not show a founder effect between the 2 families, suggesting that it is a recurrent mutation. Cadieux-Dion et al. (2013) also identified a heterozygous L115R mutation in 1 of 6 additional patients with the disorder; this patient had no family history. Overall, DNAJC5 mutations accounted for 38% of cases with unexplained adult-onset NCL in their cohort, with the mutations occurring at mutational hotspots. INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Seizures \- Dementia \- Speech deterioration \- Myoclonus \- Cerebellar signs \- Cerebellar ataxia \- Parkinsonism may occur \- Extrapyramidal signs \- Autofluorescent lipopigment in neurons Behavioral Psychiatric Manifestations \- Behavioral changes \- Depression \- Auditory and visual hallucinations LABORATORY ABNORMALITIES \- 'Fingerprint' profiles ultrastructurally \- 'Curvilinear' profiles ultrastructurally \- 'Rectilinear' profiles ultrastructurally \- Granular osmiophilic deposits (GROD) in cells MISCELLANEOUS \- Onset in adulthood (third to fourth decade) \- Rapidly progressive \- For similar autosomal recessive form, see CLN4 ( 204300 ) MOLECULAR BASIS \- Caused by mutation in the DNAJ/HSP40 homolog, subfamily C, member 5 gene (DNAJC5, 611203.0001 ) ▲ 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	CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT	c0022797	6,324	omim	https://www.omim.org/entry/162350	2019-09-22T16:37:32	{"doid": ["0110720"], "mesh": ["D009472"], "omim": ["162350"], "orphanet": ["228343", "79262"], "synonyms": ["KUFS DISEASE, AUTOSOMAL DOMINANT", "Alternative titles", "CEROID LIPOFUSCINOSIS, NEURONAL, PARRY TYPE"]}
SLC35A1-CDG is an extremely rare form of CDG syndrome (see this term) characterized clinically in the single reported case by repeated hemorrhagic incidents, including severe pulmonary hemorrhage. [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	SLC35A1-CDG	c1970344	6,325	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=238459	2021-01-23T18:53:11	{"gard": ["12409"], "mesh": ["C567040"], "omim": ["603585"], "umls": ["C1970344"], "icd-10": ["E77.8"], "synonyms": ["CDG syndrome type IIf", "CDG-IIf", "CDG2F", "CMP-sialic acid transporter deficiency", "Carbohydrate deficient glycoprotein syndrome type IIf", "Congenital disorder of glycosylation type 2f", "Congenital disorder of glycosylation type IIf"]}
Parasitic disease Toxoplasmosis T. gondii tachyzoites SpecialtyInfectious disease SymptomsOften none, during pregnancy (birth defects)[1][2] CausesToxoplasma gondii[3] Risk factorsEating poorly cooked food, exposure to infected cat feces[3] Diagnostic methodBlood test, amniotic fluid test[4] TreatmentDuring pregnancy spiramycin or pyrimethamine/sulfadiazine and folinic acid[5] FrequencyUp to 50% of people, 200,000 cases of congenital toxoplasmosis a year[6][7] Toxoplasmosis is a parasitic disease caused by Toxoplasma gondii.[3] Infections with toxoplasmosis usually cause no obvious symptoms in adults.[2] Occasionally, people may have a few weeks or months of mild, flu-like illness such as muscle aches and tender lymph nodes.[1] In a small number of people, eye problems may develop.[1] In those with a weak immune system, severe symptoms such as seizures and poor coordination may occur.[1] If infected during pregnancy, a condition known as congenital toxoplasmosis may affect the child.[1] Toxoplasmosis is usually spread by eating poorly cooked food that contains cysts, exposure to infected cat feces, and from an infected mother to her baby during pregnancy.[3] Rarely, the disease may be spread by blood transfusion.[3] It is not otherwise spread between people.[3] The parasite is known to reproduce sexually only in the cat family.[8] However, it can infect most types of warm-blooded animals, including humans.[8] Diagnosis is typically by testing blood for antibodies or by testing amniotic fluid for the parasite's DNA.[4] Prevention is by properly preparing and cooking food.[9] Pregnant women are also recommended not to clean cat litter boxes, or if they must to wear gloves and wash their hands afterwards.[9] Treatment of otherwise healthy people is usually not needed.[5] During pregnancy, spiramycin or pyrimethamine/sulfadiazine and folinic acid may be used for treatment.[5] Up to half of the world's population is infected by toxoplasmosis, but have no symptoms.[7] In the United States, approximately 11% of people are infected, while in some areas of the world this is more than 60%.[3] Approximately 200,000 cases of congenital toxoplasmosis occur a year.[6] Charles Nicolle and Louis Manceaux first described the organism in 1908.[10] In 1941, transmission during pregnancy from a mother to a baby was confirmed.[10] There is tentative evidence that infection may affect people's behavior.[11] ## Contents * 1 Signs and symptoms * 1.1 Acute * 1.2 Latent * 1.3 Skin * 2 Cause * 2.1 Parasitology * 2.2 Transmission * 2.3 Pregnancy precautions * 3 Diagnosis * 3.1 Congenital * 4 Treatment * 4.1 Acute * 4.2 Latent * 4.3 Congenital * 5 Epidemiology * 6 History * 7 Society and culture * 7.1 "Crazy cat-lady" * 7.2 Notable cases * 8 Other animals * 8.1 Livestock * 8.2 Domestic cats * 8.3 Rodents * 8.4 Marine mammals * 8.5 Giant panda * 9 Research * 9.1 Mental health * 9.2 Neurological disorders * 9.3 Traffic accidents * 9.4 Climate change * 10 See also * 11 References * 12 Bibliography * 13 External links ## Signs and symptoms[edit] Infection has three stages: ### Acute[edit] Acute toxoplasmosis is often asymptomatic in healthy adults.[12][13] However, symptoms may manifest and are often influenza-like: swollen lymph nodes, headaches, fever, and fatigue,[14] or muscle aches and pains that last for a month or more. It is rare for a human with a fully functioning immune system to develop severe symptoms following infection. People with weakened immune systems are likely to experience headache, confusion, poor coordination, seizures, lung problems that may resemble tuberculosis or Pneumocystis jiroveci pneumonia (a common opportunistic infection that occurs in people with AIDS), or blurred vision caused by severe inflammation of the retina (ocular toxoplasmosis).[14] Young children and immunocompromised people, such as those with HIV/AIDS, those taking certain types of chemotherapy, or those who have recently received an organ transplant, may develop severe toxoplasmosis. This can cause damage to the brain (encephalitis) or the eyes (necrotizing retinochoroiditis).[15] Infants infected via placental transmission may be born with either of these problems, or with nasal malformations, although these complications are rare in newborns. The toxoplasmic trophozoites causing acute toxoplasmosis are referred to as tachyzoites, and are typically found in various tissues and body fluids, but rarely in blood or cerebrospinal fluid.[16] Swollen lymph nodes are commonly found in the neck or under the chin, followed by the armpits and the groin. Swelling may occur at different times after the initial infection, persist, and recur for various times independently of antiparasitic treatment.[17] It is usually found at single sites in adults, but in children, multiple sites may be more common. Enlarged lymph nodes will resolve within 1–2 months in 60% of cases. However, a quarter of those affected take 2–4 months to return to normal, and 8% take 4–6 months. A substantial number (6%) do not return to normal until much later.[18] ### Latent[edit] Due to the absence of obvious symptoms,[12][13] hosts easily become infected with T. gondii and develop toxoplasmosis without knowing it. Although mild, flu-like symptoms occasionally occur during the first few weeks following exposure, infection with T. gondii produces no readily observable symptoms in healthy human adults.[7][19] In most immunocompetent people, the infection enters a latent phase, during which only bradyzoites (in tissue cysts) are present;[20] these tissue cysts and even lesions can occur in the retinas, alveolar lining of the lungs (where an acute infection may mimic a Pneumocystis jirovecii infection), heart, skeletal muscle, and the central nervous system (CNS), including the brain.[21] Cysts form in the CNS (brain tissue) upon infection with T. gondii and persist for the lifetime of the host.[22] Most infants who are infected while in the womb have no symptoms at birth, but may develop symptoms later in life.[23] Reviews of serological studies have estimated that 30–50% of the global population has been exposed to and may be chronically infected with latent toxoplasmosis, although infection rates differ significantly from country to country.[7][24][25] This latent state of infection has recently been associated with numerous disease burdens,[7] neural alterations,[22][24] and subtle gender-dependent[dubious – discuss] behavioral changes in immunocompetent humans,[26][27] as well as a increased risk of motor vehicle collisions.[28] ### Skin[edit] While rare, skin lesions may occur in the acquired form of the disease, including roseola and erythema multiforme-like eruptions, prurigo-like nodules, urticaria, and maculopapular lesions. Newborns may have punctate macules, ecchymoses, or "blueberry muffin" lesions. Diagnosis of cutaneous toxoplasmosis is based on the tachyzoite form of T. gondii being found in the epidermis.[29] It is found in all levels of the epidermis, is about 6 by 2 μm and bow-shaped, with the nucleus being one-third of its size. It can be identified by electron microscopy or by Giemsa staining tissue where the cytoplasm shows blue, the nucleus red.[30] ## Cause[edit] Lifecycle of Toxoplasma gondii ### Parasitology[edit] In its lifecycle, T. gondii adopts several forms.[31] Tachyzoites are responsible for acute infection; they divide rapidly and spread through the tissues of the body. Tachyzoites are also known as "tachyzoic merozoites", a descriptive term that conveys more precisely the parasitological nature of this stage.[32] After proliferating, tachyzoites convert into bradyzoites, which are inside latent intracellular tissue cysts that form mainly in the muscles and brain. The formation of cysts is in part triggered by the pressure of the host immune system.[33] The bradyzoites (also called "bradyzoic merozoites") are not responsive to antibiotics. Bradyzoites, once formed, can remain in the tissues for the lifespan of the host. In a healthy host, if some bradyzoites convert back into active tachyzoites, the immune system will quickly destroy them. However, in immunocompromised individuals, or in fetuses, which lack a developed immune system, the tachyzoites can run rampant and cause significant neurological damage.[31] The parasite's survival is dependent on a balance between host survival and parasite proliferation.[33] T. gondii achieves this balance by manipulating the host's immune response, reducing the host's immune response, and enhancing the parasite's reproductive advantage.[33] Once it infects a normal host cell, it resists damage caused by the host's immune system, and changes the host's immune processes.[citation needed] As it forces its way into the host cell, the parasite forms a parasitophorous vacuole (PV) membrane from the membrane of the host cell.[2][34] The PV encapsulates the parasite, and is both resistant to the activity of the endolysosomal system, and can take control of the host's mitochondria and endoplasmic reticulum.[2][34] When first invading the cell, the parasite releases ROP proteins from the bulb of the rhoptry organelle.[2] These proteins translocate to the nucleus and the surface of the PV membrane where they can activate STAT pathways to modulate the expression of cytokines at the transcriptional level, bind and inactivate PV membrane destroying IRG proteins, among other possible effects.[2][34][35] Additionally, certain strains of T. gondii can secrete a protein known as GRA15, activating the NF-κB pathway, which upregulates the pro-inflammatory cytokine IL-12 in the early immune response, possibly leading to the parasite's latent phase.[2] The parasite's ability to secrete these proteins depends on its genotype and affects its virulence.[2][35] The parasite also influences an anti-apoptotic mechanism, allowing the infected host cells to persist and replicate. One method of apoptosis resistance is by disrupting pro-apoptosis effector proteins, such as BAX and BAK.[36] To disrupt these proteins, T. gondii causes conformational changes to the proteins, which prevent the proteins from being transported to various cellular compartments where they initiate apoptosis events. T. gondii does not, however, cause downregulation of the pro-apoptosis effector proteins.[36] T. gondii also has the ability to initiate autophagy of the host's cells.[37] This leads to a decrease in healthy, uninfected cells, and consequently fewer host cells to attack the infected cells. Research by Wang et al finds that infected cells lead to higher levels of autophagosomes in normal and infected cells.[37] Their research reveals that T. gondii causes host cell autophagy using a calcium-dependent pathway.[37] Another study suggests that the parasite can directly affect calcium being released from calcium stores, which are important for the signalling processes of cells.[36] The mechanisms above allow T. gondii to persist in a host. Some limiting factors for the toxoplasma is that its influence on the host cells is stronger in a weak immune system and is quantity-dependent, so a large number of T. gondii per host cell cause a more severe effect.[38] The effect on the host also depends on the strength of the host immune system. Immunocompetent individuals do not normally show severe symptoms or any at all, while fatality or severe complications can result in immunocompromised individuals.[38] Since the parasite can change the host's immune response, it may also have an effect, positive or negative, on the immune response to other pathogenic threats.[33] This includes, but is not limited to, the responses to infections by Helicobacter felis, Leishmania major, or other parasites, such as Nippostrongylus brasiliensis.[33] ### Transmission[edit] Toxoplasmosis is generally transmitted through the mouth when Toxoplasma gondii oocysts or tissue cysts are accidentally eaten.[39] Congenital transmittance from mother to fetus can also occur.[40] Transmission may also occur during the solid organ transplant process[41] or hematogenous stem cell transplants.[42] Oral transmission may occur through: * Ingestion of raw or partly cooked meat, especially pork, lamb, or venison containing Toxoplasma cysts: Infection prevalence in countries where undercooked meat is traditionally eaten has been related to this transmission method. Tissue cysts may also be ingested during hand-to-mouth contact after handling undercooked meat, or from using knives, utensils, or cutting boards contaminated by raw meat.[43] * Ingestion of unwashed fruit or vegetables that have been in contact with contaminated soil containing infected cat feces.[44] * Ingestion of cat feces containing oocysts: This can occur through hand-to-mouth contact following gardening, cleaning a cat's litter box, contact with children's sandpits; the parasite can survive in the environment for months.[45] * Ingestion of untreated, unfiltered water through direct consumption or utilization of water for food preparation.[46] * Ingestion of unpasteurized milk and milk products, particularly goat's milk. * Ingestion of raw seafood. Cats excrete the pathogen in their feces for a number of weeks after contracting the disease, generally by eating an infected intermediate host that could include mammals (like rodents) or birds. Oocyst shedding usually starts from the third day after ingestion of infected intermediate hosts, and may continue for weeks. The oocysts are not infective when excreted. After about a day, the oocyst undergoes a process called sporulation and becomes potentially pathogenic.[47] In addition to cats, birds and mammals including human beings are also intermediate hosts of the parasite and are involved in the transmission process. However the pathogenicity varies with the age and species involved in infection and the mode of transmission of T. gondii.[48] Toxoplasmosis may also be transmitted through solid organ transplants. Toxoplasma-seronegative recipients who receive organs from recently infected Toxoplasma-seropositive donors are at risk. Organ recipients who have latent toxoplasmosis are at risk of the disease reactivating in their system due to the immunosuppression occurring during solid organ transplant.[41] Recipients of hematogenous stem cell transplants may experience higher risk of infection due to longer periods of immunosuppression.[42] Heart and lung transplants provide the highest risk for toxoplasmosis infection due to the striated muscle making up the heart,[41] which can contain cysts, and risks for other organs and tissues vary widely.[49] Risk of transmission can be reduced by screening donors and recipients prior to the transplant procedure and providing treatment.[49] ### Pregnancy precautions[edit] Congenital toxoplasmosis is a specific form of toxoplasmosis in which an unborn fetus is infected via the placenta.[50] Congenital toxoplasmosis is associated with fetal death and miscarriage, and in infants, it is associated with neurologic deficits, neurocognitive deficits, and chorioretinitis.[6] A positive antibody titer indicates previous exposure and immunity, and largely ensures the unborn fetus' safety. A simple blood draw at the first prenatal doctor visit can determine whether or not a woman has had previous exposure and therefore whether or not she is at risk. If a woman receives her first exposure to T. gondii while pregnant, the fetus is at particular risk.[6] Not much evidence exists around the effect of education before pregnancy to prevent congenital toxoplasmosis.[51] However educating parents before the baby is born has been suggested to be effective because it may improve food, personal and pet hygiene.[51] More research is needed to find whether antenatal education can reduce congenital toxoplasmosis.[51] For pregnant women with negative antibody titers, indicating no previous exposure to T. gondii, serology testing as frequent as monthly is advisable as treatment during pregnancy for those women exposed to T. gondii for the first time dramatically decreases the risk of passing the parasite to the fetus. Since a baby's immune system does not develop fully for the first year of life, and the resilient cysts that form throughout the body are very difficult to eradicate with antiprotozoans, an infection can be very serious in the young.[citation needed] Despite these risks, pregnant women are not routinely screened for toxoplasmosis in most countries, for reasons of cost-effectiveness and the high number of false positives generated; Portugal,[52] France,[53] Austria,[53] Uruguay,[54] and Italy[55] are notable exceptions, and some regional screening programmes operate in Germany, Switzerland and Belgium.[55] As invasive prenatal testing incurs some risk to the fetus (18.5 pregnancy losses per toxoplasmosis case prevented),[53] postnatal or neonatal screening is preferred. The exceptions are cases where fetal abnormalities are noted, and thus screening can be targeted.[53] Pregnant women should avoid handling raw meat, drinking raw milk (especially goat milk) and be advised to not eat raw or undercooked meat regardless of type.[56] Because of the obvious relationship between Toxoplasma and cats it is also often advised to avoid exposure to cat feces, and refrain from gardening (cat feces are common in garden soil) or at least wear gloves when so engaged.[56] Most cats are not actively shedding oocysts, since they get infected in the first six months of their life, when they shed oocysts for a short period of time (1–2 weeks.)[57] However, these oocysts get buried in the soil, sporulate and remain infectious for periods ranging from several months to more than a year.[56] Numerous studies have shown living in a household with a cat is not a significant risk factor for T. gondii infection,[56][58][59] though living with several kittens has some significance.[60] In 2006, a Czech research team[61] discovered women with high levels of toxoplasmosis antibodies were significantly more likely to have baby boys than baby girls. In most populations, the birth rate is around 51% boys, but women infected with T. gondii had up to a 72% chance of a boy.[62] ## Diagnosis[edit] Diagnosis of toxoplasmosis in humans is made by biological, serological, histological, or molecular methods, or by some combination of the above.[57] Toxoplasmosis can be difficult to distinguish from primary central nervous system lymphoma. It mimics several other infectious diseases so clinical signs are non-specific and are not sufficiently characteristic for a definite diagnosis. As a result, the diagnosis is made by a trial of therapy (pyrimethamine, sulfadiazine, and folinic acid (USAN: leucovorin)), if the drugs produce no effect clinically and no improvement on repeat imaging. T. gondii may also be detected in blood, amniotic fluid, or cerebrospinal fluid by using polymerase chain reaction.[63] T. gondii may exist in a host as an inactive cyst that would likely evade detection.[citation needed] Serological testing can detect T. gondii antibodies in blood serum, using methods including the Sabin–Feldman dye test (DT), the indirect hemagglutination assay, the indirect fluorescent antibody assay (IFA), the direct agglutination test, the latex agglutination test (LAT), the enzyme-linked immunosorbent assay (ELISA), and the immunosorbent agglutination assay test (IAAT).[57] The most commonly used tests to measure IgG antibody are the DT, the ELISA, the IFA, and the modified direct agglutination test.[64] IgG antibodies usually appear within a week or two of infection, peak within one to two months, then decline at various rates.[64] Toxoplasma IgG antibodies generally persist for life, and therefore may be present in the bloodstream as a result of either current or previous infection.[65] To some extent, acute toxoplasmosis infections can be differentiated from chronic infections using an IgG avidity test, which is a variation on the ELISA. In the first response to infection, toxoplasma-specific IgG has a low affinity for the toxoplasma antigen; in the following weeks and month, IgG affinity for the antigen increases. Based on the IgG avidity test, if the IgG in the infected individual has a high affinity, it means that the infection began three to five months before testing. This is particularly useful in congenital infection, where pregnancy status and gestational age at time of infection determines treatment.[66] In contrast to IgG, IgM antibodies can be used to detect acute infection but generally not chronic infection.[65] The IgM antibodies appear sooner after infection than the IgG antibodies and disappear faster than IgG antibodies after recovery.[57] In most cases, T. gondii-specific IgM antibodies can first be detected approximately a week after acquiring primary infection and decrease within one to six months; 25% of those infected are negative for T. gondii-specific IgM within seven months.[65] However, IgM may be detectable months or years after infection, during the chronic phase, and false positives for acute infection are possible.[64] The most commonly used tests for the measurement of IgM antibody are double-sandwich IgM-ELISA, the IFA test, and the immunosorbent agglutination assay (IgM-ISAGA). Commercial test kits often have low specificity, and the reported results are frequently misinterpreted.[64] ### Congenital[edit] Recommendations for the diagnosis of congenital toxoplasmosis include: prenatal diagnosis based on testing of amniotic fluid and ultrasound examinations; neonatal diagnosis based on molecular testing of placenta and cord blood and comparative mother-child serologic tests and a clinical examination at birth; and early childhood diagnosis based on neurologic and ophthalmologic examinations and a serologic survey during the first year of life.[50] During pregnancy, serological testing is recommended at three week intervals.[67] Even though diagnosis of toxoplasmosis heavily relies on serological detection of specific anti-Toxoplasma immunoglobulin, serological testing has limitations. For example, it may fail to detect the active phase of T. gondii infection because the specific anti-Toxoplasma IgG or IgM may not be produced until after several weeks of infection. As a result, a pregnant woman might test negative during the active phase of T. gondii infection leading to undetected and therefore untreated congenital toxoplasmosis.[68] Also, the test may not detect T. gondii infections in immunocompromised patients because the titers of specific anti-Toxoplasma IgG or IgM may not rise in this type of patient.[citation needed] Many PCR-based techniques have been developed to diagnose toxoplasmosis using clinical specimens that include amniotic fluid, blood, cerebrospinal fluid, and tissue biopsy. The most sensitive PCR-based technique is nested PCR, followed by hybridization of PCR products.[68] The major downside to these techniques is that they are time-consuming and do not provide quantitative data.[68] Real-time PCR is useful in pathogen detection, gene expression and regulation, and allelic discrimination. This PCR technique utilizes the 5' nuclease activity of Taq DNA polymerase to cleave a nonextendible, fluorescence-labeled hybridization probe during the extension phase of PCR.[68] A second fluorescent dye, e.g., 6-carboxy-tetramethyl-rhodamine, quenches the fluorescence of the intact probe.[68] The nuclease cleavage of the hybridization probe during the PCR releases the effect of quenching resulting in an increase of fluorescence proportional to the amount of PCR product, which can be monitored by a sequence detector.[68] Toxoplasmosis cannot be detected with immunostaining. Lymph nodes affected by Toxoplasma have characteristic changes, including poorly demarcated reactive germinal centers, clusters of monocytoid B cells, and scattered epithelioid histiocytes. The classic triad of congenital toxoplasmosis includes: chorioretinitis, hydrocephalus, and intracranial arteriosclerosis.[69] Other consequences include sensorineural deafness, seizures, and intellectual disability.[70] Congenital toxoplasmosis may also impact a child's hearing. Up to 30% of newborns have some degree of sensorineural hearing loss.[71] The child's communication skills may also be affected. A study published in 2010 looked at 106 patients, all of whom received toxoplasmosis treatment prior to 2.5 months. Of this group, 26.4% presented with language disorders.[72] ## Treatment[edit] Treatment is often only recommended for people with serious health problems, such as people with HIV whose CD4 counts are under 200 cells/mm3, because the disease is most serious when one's immune system is weak. Trimethoprim/sulfamethoxazole is the drug of choice to prevent toxoplasmosis, but not for treating active disease. A 2012 study shows a promising new way to treat the active and latent form of this disease using two endochin-like quinolones.[73] ### Acute[edit] The medications prescribed for acute toxoplasmosis are the following: * Pyrimethamine — an antimalarial medication * Sulfadiazine — an antibiotic used in combination with pyrimethamine to treat toxoplasmosis * Combination therapy is usually given with folic acid supplements to reduce incidence of thrombocytopaenia. * Combination therapy is most useful in the setting of HIV. * Clindamycin[74] * Spiramycin — an antibiotic used most often for pregnant women to prevent the infection of their children. (other antibiotics, such as minocycline, have seen some use as a salvage therapy). If infected during pregnancy, spiramycin is recommended in the first and early second trimesters while pyrimethamine/sulfadiazine and leucovorin is recommended in the late second and third trimesters.[75] ### Latent[edit] In people with latent toxoplasmosis, the cysts are immune to these treatments, as the antibiotics do not reach the bradyzoites in sufficient concentration. The medications prescribed for latent toxoplasmosis are: * Atovaquone — an antibiotic that has been used to kill Toxoplasma cysts inside AIDS patients[76] * Clindamycin — an antibiotic that, in combination with atovaquone, seemed to optimally kill cysts in mice[77] ### Congenital[edit] When a pregnant woman is diagnosed with acute toxoplasmosis, amniocentesis can be used to determine whether the fetus has been infected or not. When a pregnant woman develops acute toxoplasmosis, the tachyzoites have approximately a 30% chance of entering the placental tissue, and from there entering and infecting the fetus. As gestational age at the time of infection increases, the chance of fetal infection also increases.[31] If the parasite has not yet reached the fetus, spiramycin can help to prevent placental transmission. If the fetus has been infected, the pregnant woman can be treated with pyrimethamine and sulfadiazine, with folinic acid, after the first trimester. They are treated after the first trimester because pyrimethamine has an antifolate effect, and lack of folic acid can interfere with fetal brain formation and cause thrombocytopaenia.[78] Infection in earlier gestational stages correlates with poorer fetal and neonatal outcomes, particularly when the infection is untreated.[79] Newborns who undergo 12 months of postnatal anti-toxoplasmosis treatment have a low chance of sensorineural hearing loss.[80] Information regarding treatment milestones for children with congenital toxoplasmosis have been created for this group.[81] ## Epidemiology[edit] T. gondii infections occur throughout the world, although infection rates differ significantly by country.[25] For women of childbearing age, a survey of 99 studies within 44 countries found the areas of highest prevalence are within Latin America (about 50–80%), parts of Eastern and Central Europe (about 20–60%), the Middle East (about 30–50%), parts of Southeast Asia (about 20–60%), and parts of Africa (about 20–55%).[25] In the United States, data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004 found 9.0% of US-born persons 12–49 years of age were seropositive for IgG antibodies against T. gondii, down from 14.1% as measured in the NHANES 1988–1994.[82] In the 1999–2004 survey, 7.7% of US-born and 28.1% of foreign-born women 15–44 years of age were T. gondii seropositive.[82] A trend of decreasing seroprevalence has been observed by numerous studies in the United States and many European countries.[25] Toxoplasma gondii is considered the second leading cause of foodborne-related deaths and the fourth leading cause of foodborne-related hospitalizations in the United States.[83] The protist responsible for toxoplasmosis is T. gondii. There are three major types of T. gondii responsible for the patterns of Toxoplasmosis throughout the world. There are types I, II, and III. These three types of T. gondii have differing effects on certain hosts, mainly mice and humans due to their variation in genotypes.[84] * Type I: virulent in mice and humans, seen in people with AIDS. * Type II: non-virulent in mice, virulent in humans (mostly Europe and North America), seen in people with AIDS. * Type III: non-virulent in mice, virulent mainly in animals but seen to a lesser degree in humans as well. Current serotyping techniques can only separate type I or III from type II parasites.[85] Because the parasite poses a particular threat to fetuses when it is contracted during pregnancy,[86] much of the global epidemiological data regarding T. gondii comes from seropositivity tests in women of childbearing age. Seropositivity tests look for the presence of antibodies against T. gondii in blood, so while seropositivity guarantees one has been exposed to the parasite, it does not necessarily guarantee one is chronically infected.[87] ## History[edit] Toxoplasma gondii was first described in 1908 by Nicolle and Manceaux in Tunisia, and independently by Splendore in Brazil.[10] Splendore reported the protozoan in a rabbit, while Nicolle and Manceaux identified it in a North African rodent, the gundi (Ctenodactylus gundi).[39] In 1909 Nicolle and Manceaux differentiated the protozoan from Leishmania.[10] Nicolle and Manceaux then named it Toxoplasma gondii after the curved shape of its infectious stage (Greek root 'toxon'= bow).[10] The first recorded case of congenital toxoplasmosis was in 1923, but it was not identified as caused by T. gondii.[39] Janků (1923) described in detail the autopsy results of an 11-month-old boy who had presented to hospital with hydrocephalus. The boy had classic marks of toxoplasmosis including chorioretinitis (inflammation of the choroid and retina of the eye).[39] Histology revealed a number of "sporocytes", though Janků did not identify these as T. gondii.[39] It was not until 1937 that the first detailed scientific analysis of T. gondii took place using techniques previously developed for analyzing viruses.[10] In 1937 Sabin and Olitsky analyzed T. gondii in laboratory monkeys and mice. Sabin and Olitsky showed that T. gondii was an obligate intracellular parasite and that mice fed T. gondii-contaminated tissue also contracted the infection.[10] Thus Sabin and Olitsky demonstrated T. gondii as a pathogen transmissible between animals. T. gondii was first described as a human pathogen in 1939 at Babies Hospital in New York City.[10][88] Wolf, Cowen and Paige identified T. gondii infection in an infant girl delivered full-term by Caesarean section.[39] The infant developed seizures and had chorioretinitis in both eyes at three days. The infant then developed encephalomyelitis and died at one month of age. Wolf, Cowen and Paige isolated T. gondii from brain tissue lesions. Intracranial injection of brain and spinal cord samples into mice, rabbits and rats produced encephalitis in the animals.[10] Wolf, Cowen and Page reviewed additional cases and concluded that T. gondii produced recognizable symptoms and could be transmitted from mother to child.[39] The first adult case of toxoplasmosis was reported in 1940 with no neurological signs. Pinkerton and Weinman reported the presence of Toxoplasma in a 22-year-old man from Peru who died from a subsequent bacterial infection and fever.[39] In 1948, a serological dye test was created by Sabin and Feldman based on the ability of the patient's antibodies to alter staining of Toxoplasma.[10][89] The Sabin Feldman Dye Test is now the gold standard for identifying Toxoplasma infection.[10] Transmission of Toxoplasma by eating raw or undercooked meat was demonstrated by Desmonts et al. in 1965 Paris.[10] Desmonts observed that the therapeutic consumption of raw beef or horse meat in a tuberculosis hospital was associated with a 50% per year increase in Toxoplasma antibodies.[10] This means that more T. gondii was being transmitted through the raw meat. In 1974, Desmonts and Couvreur showed that infection during the first two trimesters produces most harm to the fetus, that transmission depended on when mothers were infected during pregnancy, that mothers with antibodies before pregnancy did not transmit the infection to the fetus, and that spiramycin lowered the transmission to the fetus.[39] Toxoplasma gained more attention in the 1970s with the rise of immune-suppressant treatment given after organ or bone marrow transplants and the AIDS epidemic of the 1980s.[10] Patients with lowered immune system function are much more susceptible to disease. ## Society and culture[edit] ### "Crazy cat-lady"[edit] "Crazy cat-lady syndrome" is a term coined by news organizations to describe scientific findings that link the parasite Toxoplasma gondii to several mental disorders and behavioral problems.[90][91] The suspected correlation between cat ownership in childhood and later development of schizophrenia suggested that further studies were needed to determine a risk factor for children;[92] however, later studies showed that T. gondii was not a causative factor in later psychoses.[93] Researchers also found that cat ownership does not strongly increase the risk of a T. gondii infection in pregnant women.[56][94] The term crazy cat-lady syndrome draws on both stereotype and popular cultural reference. It was originated as instances of the aforementioned afflictions were noted amongst the populace. A cat lady is a cultural stereotype of a woman, often a spinster, who compulsively hoards and dotes upon cats. The biologist Jaroslav Flegr is a proponent of the theory that toxoplasmosis affects human behaviour.[95][96] ### Notable cases[edit] * Tennis player Arthur Ashe developed neurological problems from toxoplasmosis (and was later found to be HIV-positive).[97] * Actor Merritt Butrick was HIV-positive and died from toxoplasmosis as a result of his already-weakened immune system.[98] * Pedro Zamora, reality television personality and HIV/AIDS activist, was diagnosed with toxoplasmosis as a result of his immune system being weakened by HIV.[99][100] * Prince François, Count of Clermont, pretender to the throne of France had congenital toxoplasmosis; his disability caused him to be overlooked in the line of succession. * Actress Leslie Ash contracted toxoplasmosis in the second month of pregnancy.[101] * British middle-distance runner Sebastian Coe contracted toxoplasmosis in 1983, which was probably transmitted by a cat while he trained in Italy.[102][103] * Tennis player Martina Navratilova suffered from toxoplasmosis during the 1982 US Open.[104] ## Other animals[edit] Toxoplasma gondii infects virtually all warm-blooded animals; these tachyzoites were found in a bird[105] Toxoplasma gondii in the lung of a Giant panda.[106] Arrow: macrophages containing tachyzoites Although T. gondii has the capability of infecting virtually all warm-blooded animals, susceptibility and rates of infection vary widely between different genera and species.[107][108] Rates of infection in populations of the same species can also vary widely due to differences in location, diet, and other factors. Although infection with T. gondii has been noted in several species of Asian primates, seroprevalence of T. gondii antibodies were found for the first time in toque macaques (Macaca sinica) that are endemic to the island of Sri Lanka.[109] Australian marsupials are particularly susceptible to toxoplasmosis.[110] Wallabies, koalas, wombats, pademelons and small dasyurids can be killed by it, with eastern barred bandicoots typically dying within about 3 weeks of infection.[111] It is estimated that 23% of wild swine worldwide are seropositive for T. gondii.[112] Seroprevalence varies across the globe with the highest seroprevalence in North America (32%) and Europe (26%) and the lowest in Asia (13%) and South America (5%).[112] Geographical regions located at higher latitudes and regions that experience warmer, humid climates are associated with increased seroprevalence of T. gondii among wild boar.[112] Wild boar infected with T. gondii pose a potential health risk for humans who consume their meat.[112] ### Livestock[edit] Among livestock, pigs, sheep[113] and goats have the highest rates of chronic T. gondii infection.[114] The prevalence of T. gondii in meat-producing animals varies widely both within and among countries,[114] and rates of infection have been shown to be dramatically influenced by varying farming and management practices.[13] For instance, animals kept outdoors or in free-ranging environments are more at risk of infection than animals raised indoors or in commercial confinement operations.[13][44] In the United States, the percentage of pigs harboring viable parasites has been measured (via bioassay in mice or cats) to be as high as 92.7% and as low as 0%, depending on the farm or herd.[44] Surveys of seroprevalence (T. gondii antibodies in blood) are more common, and such measurements are indicative of the high relative seroprevalence in pigs across the world.[115] Along with pigs, sheep and goats are among the most commonly infected livestock of epidemiological significance for human infection.[114] Prevalence of viable T. gondii in sheep tissue has been measured (via bioassay) to be as high as 78% in the United States,[116] and a 2011 survey of goats intended for consumption in the United States found a seroprevalence of 53.4%.[117] Due to a lack of exposure to the outdoors, chickens raised in large-scale indoor confinement operations are not commonly infected with T. gondii.[13] Free-ranging or backyard-raised chickens are much more commonly infected.[13] A survey of free-ranging chickens in the United States found its prevalence to be 17–100%, depending on the farm.[118] Because chicken meat is generally cooked thoroughly before consumption, poultry is not generally considered to be a significant risk factor for human T. gondii infection.[119] Although cattle and buffalo can be infected with T. gondii, the parasite is generally eliminated or reduced to undetectable levels within a few weeks following exposure.[13] Tissue cysts are rarely present in buffalo meat or beef, and meat from these animals is considered to be low-risk for harboring viable parasites.[114][44] Horses are considered resistant to chronic T. gondii infection.[13] However, viable cells have been isolated from US horses slaughtered for export, and severe human toxoplasmosis in France has been epidemiologically linked to the consumption of horse meat.[44][120] ### Domestic cats[edit] In 1942, the first case of feline toxoplasmosis was diagnosed and reported in a domestic cat in Middletown, NY.[121] The investigators isolated oocysts from feline feces and found that the oocysts could be infectious for up to 12 months in the environment.[122] The seroprevalence of T. gondii in domestic cats, worldwide has been estimated to be around 30–40%[123] and exhibits significant geographical variation. In the United States, no official national estimate has been made, but local surveys have shown levels varying between 16% and 80%.[123] A 2012 survey of 445 purebred pet cats and 45 shelter cats in Finland found an overall seroprevalence of 48.4%,[124] while a 2010 survey of feral cats from Giza, Egypt found a seroprevalence rate of 97.4%.[125] Another survey from Colombia recorded seroprevalence of 89.3%, whereas a Chinese study found just a 2.1% prevalence.[107] T. gondii infection rates in domestic cats vary widely depending on the cats' diets and lifestyles.[126] Feral cats that hunt for their food are more likely to be infected than domestic cats, and naturally also depends on the prevalence of T. gondii-infected prey such as birds and small mammals.[127] Most infected cats will shed oocysts only once in their lifetimes, for a period of about one to two weeks.[123] This shedding can release millions of oocysts, each capable of spreading and surviving for months.[123] An estimated 1% of cats at any given time are actively shedding oocysts.[13] It is difficult to control the cat population with the infected oocysts due to lack of an effective vaccine. This remains a challenge in most cases and the programs that are readily available are questionable in efficacy.[128] ### Rodents[edit] Infection with T. gondii has been shown to alter the behavior of mice and rats in ways thought to increase the rodents' chances of being preyed upon by cats.[129][130][131] Infected rodents show a reduction in their innate aversion to cat odors; while uninfected mice and rats will generally avoid areas marked with cat urine or with cat body odor, this avoidance is reduced or eliminated in infected animals.[129][131][132] Moreover, some evidence suggests this loss of aversion may be specific to feline odors: when given a choice between two predator odors (cat or mink), infected rodents show a significantly stronger preference to cat odors than do uninfected controls.[133][134] In rodents, T. gondii–induced behavioral changes occur through epigenetic remodeling in neurons associated with observed behaviors;[135][136] for example, it modifies epigenetic methylation to induce hypomethylation of arginine vasopressin-related genes in the medial amygdala to greatly decrease predator aversion.[135][136] Similar epigenetically-induced behavioral changes have also been observed in mouse models of addiction, where changes in the expression of histone-modifying enzymes via gene knockout or enzyme inhibition in specific neurons produced alterations in drug-related behaviors.[137][138][139] Widespread histone–lysine acetylation in cortical astrocytes appears to be another epigenetic mechanism employed by T. gondii.[140][141] T. gondii-infected rodents show a number of behavioral changes beyond altered responses to cat odors. Rats infected with the parasite show increased levels of activity and decreased neophobic behavior.[142] Similarly, infected mice show alterations in patterns of locomotion and exploratory behavior during experimental tests. These patterns include traveling greater distances, moving at higher speeds, accelerating for longer periods of time, and showing a decreased pause-time when placed in new arenas.[143] Infected rodents have also been shown to have lower anxiety, using traditional models such as elevated plus mazes, open field arenas, and social interaction tests.[143][144] ### Marine mammals[edit] A University of California, Davis study of dead sea otters collected from 1998 to 2004 found toxoplasmosis was the cause of death for 13% of the animals.[145] Proximity to freshwater outflows into the ocean was a major risk factor. Ingestion of oocysts from cat feces is considered to be the most likely ultimate source.[146] Surface runoff containing wild cat feces and litter from domestic cats flushed down toilets are possible sources of oocysts.[147][148] These same sources may have also introduced the toxoplasmosis infection to the endangered Hawaiian monk seal.[149] Infection with the parasite has contributed to the death of at least four Hawaiian monk seals.[149] A Hawaiian monk seal's infection with T. gondii was first noted in 2004.[150] The parasite's spread threatens the recovery of this highly endangered pinniped. The parasites have been found in dolphins and whales.[151][152] Researchers Black and Massie believe anchovies, which travel from estuaries into the open ocean, may be helping to spread the disease.[153] ### Giant panda[edit] Toxoplasma gondii has been reported as the cause of death of a giant panda kept in a zoo in China, who died in 2014 of acute gastroenteritis and respiratory disease.[106] Although seemingly anecdotal, this report emphasizes that all warm-blooded species are likely to be infected by T. gondii, including endangered species such as the giant panda. ## Research[edit] Micrograph of a lymph node showing the characteristic changes of toxoplasmosis (scattered epithelioid histiocytes (pale cells), monocytoid cells (top-center of image), large germinal centers (left of image)) H&E stain Chronic infection with T. gondii has traditionally been considered asymptomatic in people with normal immune function.[154] Some evidence suggests latent infection may subtly influence a range of human behaviors and tendencies, and infection may alter the susceptibility to or intensity of a number of psychiatric or neurological disorders.[155][154] In most of the current studies where positive correlations have been found between T. gondii antibody titers and certain behavioral traits or neurological disorders, T. gondii seropositivity tests are conducted after the onset of the examined disease or behavioral trait; that is, it is often unclear whether infection with the parasite increases the chances of having a certain trait or disorder, or if having a certain trait or disorder increases the chances of becoming infected with the parasite.[156] Groups of individuals with certain behavioral traits or neurological disorders may share certain behavioral tendencies that increase the likelihood of exposure to and infection with T. gondii; as a result, it is difficult to confirm causal relationships between T. gondii infections and associated neurological disorders or behavioral traits.[156] ### Mental health[edit] Some evidence links T. gondii to schizophrenia.[154] Two 2012 meta-analyses found that the rates of antibodies to T. gondii in people with schizophrenia were 2.7 times higher than in controls.[157][158] T. gondii antibody positivity was therefore considered an intermediate risk factor in relation to other known risk factors.[157] Cautions noted include that the antibody tests do not detect toxoplasmosis directly, most people with schizophrenia do not have antibodies for toxoplasmosis, and publication bias might exist.[158] While the majority of these studies tested people already diagnosed with schizophrenia for T. gondii antibodies, associations between T. gondii and schizophrenia have been found prior to the onset of schizophrenia symptoms.[129] Sex differences in schizophrenia onset may be explained by a second peak of T. gondii infection incidence during ages 25–30 in females only.[159] Although a mechanism supporting the association between schizophrenia and T. gondii infection is unclear, studies have investigated a molecular basis of this correlation.[159] Antipsychotic drugs used in schizophrenia appear to inhibit the replication of T. gondii tachyzoites in cell culture.[129] Supposing a causal link exists between T. gondii and schizophrenia, studies have yet to determine why only some individuals with latent toxoplasmosis develop schizophrenia; some plausible explanations include differing genetic susceptibility, parasite strain differences, and differences in the route of the acquired T. gondii infection.[160] Correlations have also been found between antibody titers to T. gondii and OCD, suicide in people with mood disorders including bipolar disorder.[155][161] Positive antibody titers to T. gondii appear to be uncorrelated with major depression or dysthymia.[162] Although there is a correlation between T. gondii and many psychological disorders, the underlying mechanism is unclear. A 2016 study of 236 persons with high levels of Toxoplasmosis antibodies found that "there was little evidence that T. gondii was related to increased risk of psychiatric disorder, poor impulse control, personality aberrations or neurocognitive impairment".[163] ### Neurological disorders[edit] Latent infection has been linked to Parkinson's disease and Alzheimer's disease.[155] There is a negative association between an infection with the parasite T. gondii and multiple sclerosis; researchers have concluded that toxoplasmosis infection may be a protective factor.[164] ### Traffic accidents[edit] Latent T. gondii infection in humans has been associated with a higher risk of automobile accidents, potentially due to impaired psychomotor performance or enhanced risk-taking personality profiles.[155] ### Climate change[edit] Climate change has been reported to affect the occurrence, survival, distribution and transmission of T. gondii.[165] T. gondii has been identified in the Canadian arctic, a location that was once too cold for its survival.[166] Higher temperatures increase the survival time of T. gondii.[165] More snowmelt and precipitation can increase the amount of T. gondii oocysts that are transported via river flow.[165] Shifts in bird, rodent, and insect populations and migration patterns can impact the distribution of T. gondii due to their role as reservoir and vector.[165] Urbanization and natural environmental degradation are also suggested to affect T. gondii transmission and increase risk of infection.[165] ## See also[edit] * Toxoplasmic chorioretinitis * TORCH infection * Pyrimethamine ## References[edit] 1. ^ a b c d e "Parasites – Toxoplasmosis (Toxoplasma infection) Disease". 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"Impact of environmental factors on the emergence, transmission and distribution of Toxoplasma gondii". Parasites & Vectors. 9 (137): 137. doi:10.1186/s13071-016-1432-6. PMC 4785633. PMID 26965989. 166. ^ Dolgin, Elie (March 30, 2017). "Climate change: As the ice melts". Nature. 543 (7647): S54–S55. Bibcode:2017Natur.543S..54D. doi:10.1038/543S54a. PMID 28355191. S2CID 4448339. * Parts of this article are taken from the public domain CDC factsheet: Toxoplasmosis ## Bibliography[edit] * Weiss, L. M.; Kim, K. (28 April 2011). Toxoplasma gondii: The Model Apicomplexan. Perspectives and Methods. Academic Press. ISBN 978-0-08-047501-1. Retrieved 12 March 2013. * Dubey, J. P. (2016). Toxoplasmosis of Animals and Humans (2nd ed.). CRC Press. ISBN 978-1-4200-9237-0. * Dubey JP, Lindsay DS, Speer CA (April 1998). "Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts". Clinical Microbiology Reviews. 11 (2): 267–299. doi:10.1128/CMR.11.2.267. PMC 106833. PMID 9564564. * Jaroslav Flegr (2011). Pozor, Toxo!. Academia, Prague, Czech Republic. ISBN 978-80-200-2022-2. ## External links[edit] * How a cat-borne parasite infects humans (National Geographic) * Toxoplasmosis at Merck Manual of Diagnosis and Therapy Professional Edition * Toxoplasmosis at Health Protection Agency (HPA), United Kingdom * Pictures of Toxoplasmosis Medical Image Database * Video-Interview with Professor Robert Sapolsky on Toxoplasmosis and its effect on human behavior (24:27 min) * "Toxoplasmosis". MedlinePlus. U.S. National Library of Medicine. Classification D * ICD-10: B58 * ICD-9-CM: 130 * MeSH: D014123 * DiseasesDB: 13208 External resources * MedlinePlus: 000637 * eMedicine: med/2294 * Patient UK: Toxoplasmosis * v * t * e Protozoan infection: SAR and Archaeplastida SAR Alveolate Apicomplexa Conoidasida/ Coccidia * Coccidia: Cryptosporidium hominis/Cryptosporidium parvum * Cryptosporidiosis * Cystoisospora belli * Isosporiasis * Cyclospora cayetanensis * Cyclosporiasis * Toxoplasma gondii * Toxoplasmosis Aconoidasida * Plasmodium falciparum/vivax/ovale/malariae/knowlesi * Malaria * Blackwater fever * Babesia * Babesiosis Ciliophora * Balantidium coli * Balantidiasis Heterokont * Blastocystis * Blastocystosis * Pythium insidiosum * Pythiosis Archaeplastida * Algaemia: Prototheca wickerhamii * Protothecosis Authority control * NDL: 00573190 [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	Toxoplasmosis	c0040558	6,326	wikipedia	https://en.wikipedia.org/wiki/Toxoplasmosis	2021-01-18T18:41:05	{"mesh": ["D014123"], "umls": ["C0040558"], "wikidata": ["Q154878"]}
## Summary ### Clinical characteristics. Hypophosphatasia is characterized by defective mineralization of bone and/or teeth in the presence of low activity of serum and bone alkaline phosphatase. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. Although the disease spectrum is a continuum, six clinical forms are usually recognized based on age at diagnosis and severity of features: * Perinatal (severe) hypophosphatasia characterized by respiratory insufficiency and hypercalcemia * Perinatal (benign) hypophosphatasia with prenatal skeletal manifestations that slowly resolve into one of the milder forms * Infantile hypophosphatasia with onset between birth and age six months of rickets without elevated serum alkaline phosphatase activity * Childhood (juvenile) hypophosphatasia that ranges from low bone mineral density for age with unexplained fractures to rickets, and premature loss of primary teeth with intact roots * Adult hypophosphatasia characterized by stress fractures and pseudofractures of the lower extremities in middle age, sometimes associated with early loss of adult dentition * Odontohypophosphatasia characterized by premature exfoliation of primary teeth and/or severe dental caries without skeletal manifestations ### Diagnosis/testing. Although formal diagnostic criteria are not established, all forms of hypophosphatasia (except pseudohypophosphatasia) share in common reduced activity of unfractionated serum alkaline phosphatase (ALP) and presence of either one or two pathogenic variants in ALPL, the gene encoding alkaline phosphatase, tissue-nonspecific isozyme (TNSALP). ### Management. Treatment of manifestations: Perinatal (severe) type: limited experience with enzyme replacement therapy (ERT); expectant management and family support. Infantile and early childhood (juvenile) types: enzyme replacement therapy (asfotase alfa), respiratory support, treatment of hypercalcemia/hypercalciuria, treatment of seizures with vitamin B6, routine treatment of craniosynostosis. All other types: routine dental care starting at age one year; nonsteroidal anti-inflammatory drugs (NSAID) for osteoarthritis, bone pain, and osteomalacia; internal fixation for pseudofractures and stress fractures. Surveillance: Dental visits twice yearly starting at age one year; monitoring children with infantile type for increased intracranial pressure secondary to craniosynostosis. Agents/circumstances to avoid: Bisphosphonates, excess vitamin D. ### Genetic counseling. Perinatal and most infantile cases of hypophosphatasia are inherited in an autosomal recessive manner. The milder forms, especially adult and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner depending on the effect that the ALPL pathogenic variant has on TNSALP activity. * Autosomal recessive hypophosphatasia. Heterozygotes (carriers) either are asymptomatic (manifesting biochemical but not clinical abnormality) or may manifest milder symptoms, depending on the variant. Although de novo pathogenic variants have been reported, in most instances each 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. * Autosomal dominant hypophosphatasia. To date, all probands have inherited a pathogenic variant from a parent; de novo pathogenic variants have not been reported. Each child of an individual with the autosomal dominant form of hypophosphatasia has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant(s) have been identified in an affected family member. Recurrence of perinatal and infantile hypophosphatasia may reliably be identified by prenatal ultrasound examination. ## Diagnosis ### Suggestive Findings Hypophosphatasia should be suspected in individuals with: * Defective mineralization of bone and/or teeth; * Premature loss of teeth with intact roots; * Reduced serum alkaline phosphatase (ALP) activity. At least six clinical forms are currently recognized based on age at diagnosis and severity of features (see Table 1). Clinical features include the following: * Prenatal long-bone bowing with osteochondral spurs and pretibial dimpling * Infantile rickets without elevated serum alkaline phosphatase activity. Features can include growth failure, craniotabes, craniosynostosis, blue sclerae, costochondral enlargement ("rachitic rosary"), scoliosis, thickening of wrists and ankles, bowing of long bones, lax ligaments, and hypotonia. * Hypercalcemia and hypercalciuria particularly during the first year of life * Pathologic fractures and bone pain. Growing children may have a predilection to metaphyseal fractures; however, epiphyseal and diaphyseal fractures are also seen. In adults, metatarsal stress fractures and femoral pseudofractures prevail. * Premature loss of deciduous teeth beginning with the incisors. Unusually and characteristically, the dental root remains attached to the lost tooth. Dental caries and early loss or extraction of adult teeth is also seen. * Family history of any of the forms of hypophosphatasia consistent with autosomal recessive inheritance or autosomal dominant inheritance with variable expressivity The radiographic signs of hypophosphatasia vary with age and type, and may be quite distinctive. Perinatal lethal hypophosphatasia is radiographically distinct. In milder cases, the combination of clinical, laboratory, and radiographic findings are required for diagnosis because the radiographic signs are not pathognomonic. * Osteopenia, osteoporosis, or low bone mineral content for age detected by dual-energy x-ray absorptiometry (DEXA). Bone mineral content increases with age, and there may be improvement during adolescence with recurrence in middle age. * Infantile rickets. Findings include undermineralized bones, widened-appearing sutures, brachycephaly, flail chest, rachitic costochondral rib changes (see Figure 1A), flared metaphyses (resulting in enlarged wrists, knees, and ankles), poorly ossified epiphyses, and bowed legs. * Alveolar bone loss resulting in premature loss of deciduous teeth. This most typically involves the anterior mandible, with the central incisors lost first. However, any tooth may be affected (see Figure 1B). * Focal bony defects of the metaphyses resembling radiolucent "tongues" (see Figure 1C). This feature is fairly specific for childhood (juvenile) hypophosphatasia. * Metatarsal stress fractures in childhood (juvenile) and adult hypophosphatasia * Osteomalacia with lateral pseudofractures (Looser zones) in adult hypophosphatasia (see Figure 1D) #### Figure 1. Radiographic signs of hypophosphatasia A. Rachitic rib changes, flail chest, and metaphyseal dysplasia (proximal humerus) in infantile hypophosphatasia ### Table 1. Clinical Features of Hypophosphatasia by Type View in own window TypeInheritanceCardinal FeaturesDental FeaturesClinical Diagnosis Perinatal (severe)ARHypomineralization, osteochondral spurs± 1Radiographs, prenatal ultrasound examination Perinatal (benign)AR or ADLong-bone bowing, benign postnatal course±Prenatal ultrasound examination, clinical course Infantile 2Mostly ARCraniosynostosis, Hypomineralization, rachitic ribs, hypercalciuriaPremature loss, deciduous teethClinical course, radiographs, laboratory findings Childhood (juvenile)AR or ADShort stature, skeletal deformity, bone pain/fracturesPremature loss, deciduous teeth (incisors)Clinical course, radiographs, laboratory findings Adult 3AR or ADStress fractures: metatarsal, tibia; chondrocalcinosis±Clinical course, radiographs, laboratory findings Odontohypo- phosphatasiaAR or ADAlveolar bone lossExfoliation (incisors), dental cariesClinical course, dental panorex, laboratory findings AD = autosomal dominant; AR = autosomal recessive 1\. In the past individuals with severe phenotypes have typically died before teeth erupted and could be lost. In the new "treated perinatal (severe) and infantile" category, the dental features are not precisely known but emerging data suggests the possibility of such features. 2\. Rare reported cases of infantile hypophosphatasia that have normal serum alkaline phosphatase activity (in vitro) have been designated "pseudohypophosphatasia." The biochemical and molecular basis of pseudohypophosphasia remains unclear. 3\. Persons with adult hypophosphatasia may give a history of features typically reported in childhood (juvenile), infantile, and even prenatal hypophosphatasia. ### Laboratory Testing Total serum alkaline phosphatase (ALP) activity: low. In all the types of hypophosphatasia, serum ALP activity is low. * Laboratories both within and across countries use different methods and thus have very different reference ranges; the gender- and age-specific reference range determined by each reference laboratory should be used. See Table 2 (pdf) for typical lowest normal reference values. * Transient increases in serum ALP activity in affected individuals invariably occur during pregnancy. Small increases in serum ALP activity may be seen with liver disease and acute fracture or surgery. Thus, serial measurement of serum ALP activity may be necessary when the diagnosis is suspected in toddlers with unexplained fractures. * Quantitation of the activity of the bone isoform of ALP in serum is generally unnecessary; however, in the setting of liver disease, the serum activity of ALP may be "falsely" normal. The bone isoform is heat labile; the liver isoform heat stable. Urine concentration of phosphoethanolamine (PEA): elevated * This is the most commonly obtained secondary screen for hypophosphatasia. It may be obtained as part of a urine amino acid chromatogram. * An elevated urine concentration of PEA supports the diagnosis of hypophosphatasia; however, the concentration in urine may be elevated with other metabolic bone disease and may be normal in affected individuals. Note: Finding an elevated urine concentration of proline adds specificity in interpretation of test results. * Asymptomatic heterozygotes may have reduced serum ALP activity and increased urine PEA concentration. Serum concentration of pyridoxal 5'-phosphate (PLP): elevated * This biologically active metabolite of vitamin B6 may be the most sensitive indicator of hypophosphatasia [Cole et al 1986]. * Many reference laboratories measuring vitamin B6 either (1) measure PLP and report as "vitamin B6" or (2) report the PLP level; thus, ordering "vitamin B6" may suffice if PLP is not an option. * Use of vitamin supplements within a week of assaying serum concentration of PLP may lead to false positive results. Serum concentration of calcium, ionized calcium, and inorganic phosphate: normal * Normal levels distinguish hypophosphatasia from other forms of rickets. * Hypercalciuria may be present with or without elevated serum concentration of calcium. * Although inorganic phosphate concentration in serum or urine is most typically normal, it may be elevated and thus is too variable to be used in diagnosis. Serum concentration of vitamin D (25-hydroxy and 1,25-dihydroxy) and parathyroid hormone (nPTH): normal Urine inorganic pyrophosphate (PPi): elevated * This is a sensitive marker in affected individuals and asymptomatic heterozygotes. ### Establishing the Diagnosis Except in prenatal context where genetic diagnosis is essential, hypophosphatasia can be often diagnosed by routine clinical, biochemical, and radiographic means. The diagnosis is confirmed in a proband with identification of biallelic pathogenic variants or a heterozygous pathogenic variant in ALPL on molecular genetic testing (see Table 1). Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing: * Single-gene testing. Sequence analysis of ALPL is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. * A multigene panel that includes ALPL 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 single-gene testing (and/or use of a multigene panel that includes ALPL) fails to confirm a diagnosis in an individual with features of hypophosphatasia. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in 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 3. Molecular Genetic Testing Used in Hypophosphatasia View in own window Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method ALPLSequence analysis 3≈95% 4, 5 Gene-targeted deletion/duplication analysis 6Unknown 7 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. 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 individuals with severe (perinatal and infantile) hypophosphatasia, two ALPL pathogenic variants are identified in approximately 95% of individuals of European ancestry. In other forms, one or two ALPL pathogenic variants are detected, depending on the mode of inheritance. 5\. In more moderate forms in which one pathogenic variant allele is believed sufficient to cause disease, the rate of detection of pathogenic variants is more difficult to estimate. Overall, about 50% have two ALPL pathogenic variants (compound heterozygote or homozygote); about 40%-45% only one identified pathogenic variant. The milder the disease, the higher the proportion in which only one ALPL pathogenic variant is detected. 6\. 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. 7\. No data on detection rate of gene-targeted deletion/duplication analysis are available. A few deletions have been reported [Spentchian et al 2006, Mornet 2015] (see www.sesep.uvsq.fr). ## Clinical Characteristics ### Clinical Description The clinical features of hypophosphatasia represent a spectrum ranging from stillbirth without mineralized bone to pathologic fractures of the lower extremities in later adulthood [Whyte 1994]. General features of hypophosphatasia. Clinical features of rickets or osteomalacia, of varying severity, are seen at all ages. Within families, several forms may be seen in family members with heterozygous or homozygous variants. Stillbirth without mineralized bone defines the most severe phenotype. "Paradoxical" rickets, in which the serum alkaline phosphatase is not elevated (as it would be in nutritional or renal rickets) is typical. Pathologic stress fractures of the lower extremities (femoral head, tibia, and metatarsals) in older adults define the mild end. All cases are characterized by: * Defective mineralization of bone and/or teeth; * Reduced serum alkaline phosphatase (ALP) activity. Histologic evaluation * Bone histology reveals rachitic abnormalities of the growth plate. Histochemical testing of osteoclasts reveals lack of membrane-associated ALP activity. Osteoclasts and osteoblasts otherwise appear normal. * Tooth histology reveals a decrease in cementum, which varies with the severity of the disease. Specific phenotypes include the following: * Perinatal (severe) hypophosphatasia is typically identified by prenatal ultrasound examination. Pregnancies may end in stillbirth. Small thoracic cavity and short, bowed limbs are seen in both liveborn and stillborn infants. A flail chest may be present (Figure 1A). Infants with perinatal hypophosphatasia may experience pulmonary insufficiency; restrictive lung disease is the most frequent cause of death. Hypercalcemia is common and may be associated with apnea or seizures. * Perinatal (benign) hypophosphatasia is typically identified by prenatal ultrasound examination showing short and bowed long bones but normal or slightly decreased mineralization. Postnatally, skeletal manifestations slowly resolve with a less severe hypophosphatasia phenotype [Pauli et al 1999, Wenkert et al 2011]. * Infantile hypophosphatasia cases may be normal at birth. Clinical signs may be recognized between birth and age six months and resemble rickets (Figure 1A). Open fontanels and wide sutures may be deceptive, in that the hypomineralized bone causing this radiographic appearance is prone to premature fusion. Craniosynostosis and intracranial hypertension are potential complications. Clinical severity depends on the degree of pulmonary insufficiency; the infantile phenotype has high mortality, with 50% of individuals succumbing to respiratory failure caused by undermineralization of the ribs. Other complications include hypercalcemia, irritability, poor feeding, failure to thrive, hypotonia, and more rarely vitamin B6-dependent seizures (see Management). Older children may have renal damage. * Childhood (juvenile) hypophosphatasia displays wide variability in clinical presentation, ranging from low bone mineral density for age with unexplained fractures to rickets. Children may have premature loss of deciduous teeth (age <5 years), usually beginning with incisors, with the dental root characteristically remaining attached to the lost tooth. More severely affected toddlers have short stature and delay in walking, and develop a waddling myopathic gait. Bone and joint pain are typical. Diaphyseal and metaphyseal fractures may occur. * Adult hypophosphatasia is sometimes associated with a history of transient rickets in childhood ("juvenile onset") and/or premature loss of deciduous teeth. Early loss of adult dentition is common. Other dental problems in adolescents and adults with hypophosphatasia are more poorly characterized, although enamel hypoplasia and tooth mobility have been described. Adult hypophosphatasia is usually recognized in middle age, the cardinal features being stress fractures and pseudofractures of the lower extremities. Foot pain and slow-to-heal stress fractures of the metatarsals are common. Thigh and hip pain may reflect pseudofractures ("Looser zones") in the lateral cortex of the femoral diaphysis (Figure 1C). Chondrocalcinosis and osteoarthropathy may develop with age. Osteomalacia distinguishes adult hypophosphatasia from odontohypophosphatasia. * Odontohypophosphatasia can be seen as an isolated finding without additional abnormalities of the skeletal system or can be variably seen in the above forms of hypophosphatasia. Premature exfoliation of primary teeth and/or severe dental caries may be seen, with the incisors most frequently lost. ### Genotype-Phenotype Correlations Most patients with hypophosphatasia have unique genotypes, making genotype-phenotype correlation difficult. However site-directed mutagenesis experiments identified alleles producing significant residual enzymatic activity and alleles showing a dominant negative effect (see Molecular Genetics). Less severe phenotypes are correlated with alleles allowing residual enzymatic activity in recessive hypophosphatasia, and with alleles exhibiting a dominant negative effect in dominant hypophosphatasia [Fauvert et al 2009]. Clinical features of patients with reported variants, as well as residual enzyme activity for some of those variants, can be found at www.sesep.uvsq.fr. ### Nomenclature Hypophosphatasia takes its name from low activity of the enzyme alkaline phosphatase, rather than reflecting serum concentration of phosphorus. In classifications of genetic conditions, hypophosphatasia may be considered a metabolic bone disease, a skeletal dysplasia, a metaphyseal dysplasia, a dental disorder, or a disorder of membrane-bound ectoenzyme activity in the extracellular matrix. ### Prevalence Based on pediatric hospital records in Ontario, Canada, the birth prevalence of (autosomal recessive) perinatal and infantile hypophosphatasia was estimated at 1:100,000 [Fraser 1957]. Applying the Hardy-Weinberg equation to this estimate, the frequency of heterozygotes for ALPL pathogenic variants in Ontario, Canada is about 1:150. In the Canadian Mennonite population, the prevalence of the perinatal (severe) form is 1:2500, for a carrier frequency of 1:25. On the basis of molecular diagnosis in France and in Europe, the prevalence of severe forms has been estimated at 1:300,000 [Mornet et al 2011]. For mild forms (prenatal benign, childhood [juvenile], adult and odontohypophosphatasia), the prevalence is expected to be as high as 1:6300 [Mornet et al 2011] because heterozygotes may express the disease with low selective pressure. Applying the Hardy-Weinberg equation to this estimate for severe forms, the frequency of heterozygotes for ALPL pathogenic variants in France is about 1:275. In Japan, the birth prevalence of severe hypophosphatasia may be estimated at 1:150,000 on the basis on the frequency of individuals homozygous for the pathogenic variant c.1559delT (1:900,000 [Watanabe et al 2011]) and on the proportion of this allele in Japanese patients (40.9% [Michigami et al 2005]) In China, some pathogenic variants have been reported [Wei et al 2010, Zhang et al 2012, Yang et al 2013] but the birth prevalence is unknown. In Africa, no individuals with hypophosphatasia have been reported outside of North Africa; however, clinical ascertainment bias is likely significant. African American individuals with hypophosphatasia are rare; it is assumed that pathogenic variants in this population represent European admixture. ## Differential Diagnosis The differential diagnosis of hypophosphatasia depends on the age at which the diagnosis is considered. Clinical features that help differentiate hypophosphatasia from other conditions include bone hypomineralization prenatally and immediately postnatally; elevated serum concentrations of calcium and phosphorus postnatally; and of course, persistently low serum alkaline phosphatase enzyme activity. In utero. Early prenatal ultrasound examination may lead to a consideration of osteogenesis imperfecta (OI) type II, campomelic dysplasia, and chondrodysplasias with defects in bone mineralization, as well as hypophosphatasia. Experienced sonographers usually have little difficulty in distinguishing among these disorders. Fetal x-rays are sometimes helpful in recognizing the undermineralization of bone that is more typical of perinatal hypophosphatasia than the other disorders considered in the differential diagnosis. At birth. Outwardly difficult to distinguish, OI type II, thanatophoric dysplasia, campomelic dysplasia, and chondrodysplasias with bone mineralization defects are readily distinguished from hypophosphatasia by radiograph. In cases in which the diagnosis is in doubt, serum alkaline phosphatase activity and specialized biochemical testing (serum concentration of PLP or vitamin B6, urine concentration of PEA) can suggest the diagnosis pending confirmation with molecular genetic testing. Infancy and childhood. Irritability, poor feeding, failure to thrive, hypotonia, and seizures place the infantile type in a broad differential diagnosis that includes inborn errors of energy metabolism, organic acidemia, primary and secondary rickets, neglect, and non-accidental trauma. Providing that appropriate pediatric normative reference values are used, infantile hypophosphatasia is suspected with low serum alkaline phosphatase enzyme activity, making the argument for routine screening of serum alkaline phosphatase enzyme activity in cases of failure to thrive, unexplained seizures, and suspected non-accidental skeletal injury. * Intractable seizures may present prior to biochemical or radiographic manifestations of rickets in early hypophosphatasia. * Rickets defines the physical and radiographic features of early hypophosphatasia. However, whether caused by nutritional and/or vitamin D deficiency, vitamin D resistance, or renal osteodystrophy, rickets is readily distinguished from hypophosphatasia by laboratory findings. In rickets, the following are characteristic: * Elevated serum alkaline phosphatase activity * Low serum concentrations of calcium and phosphorus * Low serum concentrations of vitamin D * Elevated serum concentration of parathyroid hormone * Osteogenesis imperfecta (OI) with deformation (typically type III in infancy or type IV later on) may resemble hypophosphatasia clinically. * Dentinogenesis imperfecta (DI), whether part of OI or an isolated finding, is distinguishable from the dental presentation of hypophosphatasia. * Cleidocranial dysostosis is characterized by late closure of fontanels and cranial sutures, aplastic clavicles, delayed mineralization of the pubic rami, and delayed eruption of deciduous and permanent teeth. The skeletal dysplasia is distinguishable from hypophosphatasia on clinical examination and skeletal survey. The dental dysplasia does not result in early tooth loss, and the enamel hypoplasia is readily distinguishable from odontohypophosphatasia. * Stuve-Wiedemann syndrome (OMIM 601559) presents with temperature dysregulation, diminished reflexes, and contractures, but the severe perinatal presentation shares several features with hypophosphatasia: respiratory insufficiency, bowing of long bones, metaphyseal dysplasia, low bone density for age, and fracture predilection. * Cole-Carpenter syndrome (OMIM 112240, 616294) is characterized by bone deformities, multiple fractures, proptosis, shallow orbits, orbital craniosynostosis, frontal bossing, and hydrocephalus. * Hadju-Cheney syndrome (OMIM 102500) is characterized by failure to thrive, dysmorphic facial features, early tooth loss, genitourinary anomalies, osteopenia, pathologic fractures, Wormian bones, failure of suture ossification, basilar impression, vertebral abnormalities, joint laxity, bowed fibulae, short distal digits, acroosteolysis, and hirsutism. * Idiopathic juvenile osteoporosis (IJO) (OMIM 259750) typically presents in preadolescents with fractures and osteoporosis. The fracture susceptibility and osteoporosis usually resolve spontaneously with puberty. The etiology remains unknown. * Renal osteodystrophy may be confused with late presentation of the childhood (juvenile) type associated with renal damage; however, characteristic biochemical findings distinguish the two disorders. * Non-accidental trauma (child abuse). Like osteogenesis imperfecta, patient history, family history, physical examination, routine laboratories, radiographic imaging, and the clinical course all contribute to distinguishing hypophosphatasia from child abuse. Multiple fractures are less typical of hypophosphatasia. The family history may be particularly instructive in that the perinatal (severe) type is an autosomal recessive disorder, and the childhood (juvenile), adult, and odontohypophosphatasia types are autosomal dominant disorders; all have been reported in a single family ascertained by unexplained fracture in a child [Lia-Baldini et al 2001]. Serial measurement of serum alkaline phosphatase activity is usually sufficient to identify hypophosphatasia in this circumstance. * Pseudohypophosphatasia is characterized by clinical, biochemical, and radiographic findings reminiscent of infantile hypophosphatasia, with the exception that clinical laboratory assays of serum alkaline phosphatase activity are in the normal range. Adult and odontohypophosphatasia * Osteoarthritis and pseudogout (secondary to calcium pyrophosphate dehydrate deposition) are presentations of adult hypophosphatasia, distinguished from the more common disorders by clinical history and laboratory findings. * Osteopenia/osteoporosis needs to be distinguished from adult hypophosphatasia, in that bisphosphonates may be contraindicated (see Management, Agents/Circumstances to Avoid). * Periodontal disease may be difficult to distinguish from hypophosphatasia, in that alveolar bone loss can be seen with severe gingivitis. However, gingival inflammation is unusual with odontohypophosphatasia. Familial periodontal disease can be inherited in an autosomal dominant manner (OMIM 170650) or as part of a connective tissue disorder (e.g., Ehlers-Danlos syndrome, vascular type or Ehlers-Danlos syndrome, periodontal type VIII [OMIM 130080]) or associated with neutropenia (e.g., ELANE-related neutropenia). Ehlers-Danlos syndrome type VIII may present with root-intact tooth loss, the distinction being the low serum alkaline phosphatase of odontohypophosphatasia. Rarer autosomal recessive disorders associated with premature tooth loss and periodontal disease include Papillon-Lefevre syndrome (OMIM 245000) and Haim-Munk syndrome (HMS) (OMIM 245010), caused by pathogenic variants in CTSC, the gene encoding dipeptidyl peptidase 1. The periodontal disease is usually earlier in onset and more severe than that seen with odontohypophosphatasia. Both Papillon-Lefevre syndrome and HMS are usually associated with palmar keratosis, further distinguishing them from odontohypophosphatasia. Measurement of serum alkaline phosphatase enzyme activity is reasonable when either disorder is considered. * Dentinogenesis imperfecta (DI). Whether associated with osteogenesis imperfecta or as an isolated condition resulting from pathogenic variants in DSPP (OMIM 125420) [Rajpar et al 2002], DI is readily distinguishable from odontohypophosphatasia on biochemical findings. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hypophosphatasia, the following evaluations are recommended: * Blood urea nitrogen and serum creatinine concentration to assess renal function * Serum concentration of calcium, phosphorus, magnesium * Serum concentration of 25(OH) and 1,25(OH)2 vitamin D, nPTH (parathyroid hormone, N-terminal part) to assess rickets * Assessment of pulmonary function in infants with the perinatal type to assist in prognosis and distinguishing between the perinatal (severe) type and the perinatal (benign) type * Radiographs of the skull to assess for craniosynostosis in young children with the infantile form of hypophosphatasia * Baseline dental evaluation * Baseline orthopedic evaluation * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Management at all ages focuses on supportive therapy to minimize disease-related complications. Multidisciplinary management at various ages may include: * Endocrinology to optimize bone homeostasis and avoid exacerbating treatments * Nephrology to monitor calcium homeostasis and examine for nephrocalcinosis * Neurology to prophylactically or prospectively treat seizures and manage myopathy * Neurosurgery or craniofacial team to manage pseudocraniosynostosis * Orthopedics to manage primary and secondary skeletal manifestations * Physical medicine and rehabilitation (PM&R), physical therapy, and occupational therapy to optimize mobility and autonomy * Pain management * Psychological support * Pediatric and adult dentistry to manage tooth loss The involvement of multiple specialists treating complex interrelated medical issues mandates case management and social work support. #### Enzyme Replacement Therapy The emergence of tissue-nonspecific alkaline phosphatase (TNSALP) enzyme replacement therapy (ERT) with asfotase alfa (Strensiq™) has altered the natural history of severe perinatal and infantile HPP cases; the long-term effects of treatment are not fully known. A new phenotype of "treated perinatal and infantile HPP" is emerging, and the prior designation of "perinatal lethal HPP" may no longer universally apply in the developed world. In October 2015, the FDA approved asfotase alfa for treatment of patients with perinatal, infantile, and juvenile onset HPP [Alexion –10-23-2015]. * Perinatal/infantile HPP study outcomes. In two prospective, single-arm studies (with historical controls used for survival analysis), 68 individuals with severe, perinatal/infantile-onset HPP (age at treatment onset: 1 day – 78 months) completed at least 24-weeks of TNSALP ERT (≤9 mg/kg weekly, administered subcutaneously) [Whyte et al 2016] (final data). * Survival. Of those requiring respiratory support (n = 26), 21 (81%) survived through the last date of assessment (median age 3.2 years), in comparison to 1:20 (5%) in historical controls. * In the mixed cohort of 68 patients with perinatal/infantile onset HPP receiving asfotase alfa ERT, 54 required mechanical ventilation and of these, 91% survived and 85% were ventilator free at last contact, in comparison to 27% overall survival and 25% ventilator free in the 48 historical controls [Whyte et al 2016] (final data). Clinical trials with ERT have shown improvement in developmental milestones and pulmonary function [Whyte et al 2012]. * Bone findings. Radiographs from 64 of these individuals, and four from a third prospective open-label study of juvenile-onset HPP, were evaluated for HPP-related rickets using the 7-point Radiographic Global Impression of Change (RGI-C) scale. Radiographic change of at least +2 (defined as "responders") were seen in 50/68 (74%) of those treated (see Figure 2), at last assessment (historical comparative data does not exist). Eighteen individuals with perinatal/infantile-onset HPP experienced fractures during the course of treatment; the effect of asfotase alfa on fractures remains unclear [Whyte et al 2016] (final data). * Juvenile-onset HPP study outcomes. One prospective open-label, single arm study included eight patients with juvenile-onset HPP and five patients with perinatal/infantile-onset HPP; age at treatment onset was six to 12 years. The patients with juvenile-onset HPP completed at least 48 months of TNSALP ERT (6 mg/kg weekly, administered subcutaneously). The eight juvenile-onset patients were compared with 32 historical controls. By the RGI-C rating of radiographs, all eight patients were deemed responders; two (6%) of the historical controls were rated responders with an improvement of +2 or more at month 54. Gait, assessed using a modified Performance Oriented Mobility Assessment Gait (MPOMA-G), six-minute walk test (6MWT), and step length improved in patients treated with asfotase alfa. 6MWT improved to the normal range in six of six patients assessed by month 48, from none at baseline. The data are at present insufficient to assess the effect of asfotase alfa on fractures in juvenile-onset HPP [Whyte et al 2016] (final data). #### Figure 2. Radiograph of treated hypophosphatasia A. Patient from Figure 1A after 12 months asfotase alfa enzyme replacement therapy #### When Enzyme Replacement Therapy is Not Available or Not Typically Used Perinatal types. Limited experience exists for asfotase alfa ERT treatment of perinatal HPP in the immediate newborn period, and this therapy may not be readily available. In the immediate perinatal period, if multidisciplinary assessment identifies the perinatal severe type, comfort care and supportive management of infant and family remain an option. Infantile type. The infantile phenotype has high mortality, with 50% of individuals succumbing to respiratory failure caused by undermineralization of the ribs. In the absence of ERT, supportive management remains. * Calcium homeostasis. Management can further be complicated by recalcitrant hypercalcemia/hypercalciuria, and optimal management of this issue remains unclear: hypercalcemia/hypercalciuria is typically resistant to hydration and furosemide treatment, and bisphosphonates would be contraindicated (see Agents/Circumstances to Avoid). In the absence of ERT, calcitonin and steroids could be attempted short term, with limited efficacy [Deeb et al 2000]. * Seizures. When present, seizures may respond to treatment with vitamin B6 (pyridoxine). Pyridoxal phosphate (PLP), one of the natural substrates of alkaline phosphatase, is the active compound by which pyridoxine mediates essential enzyme activity; PLP deficiency in the central nervous system may reduce seizure threshold by reducing neurotransmitter (GABA) synthesis. * Craniosynostosis in those with the infantile phenotype is variable. When identified, involvement of a neurosurgeon to monitor for complications is prudent. Increased intracranial pressure secondary to craniosynostosis is an indication for surgical release. * Dental care beginning at age one year is important to preserve primary dentition (to support nutrition) and to preserve or replace secondary dentition. Childhood (juvenile) and adult hypophosphatasia * Osteoarthritis may respond to NSAIDs. * Bone pain and osteomalacia are managed supportively: NSAIDs appear beneficial [Girschick et al 2006]. Hypophosphatasia is a relative contraindication to treatment with bisphosphonates (see Agents/Circumstances to Avoid). * Pseudofractures and stress fractures are difficult to manage; internal fixation has been suggested as the optimal orthopedic management. Foot orthotics may help in management of tarsal fractures and pseudofractures in adults. ### Prevention of Primary Manifestations Low-impact physical activity and exercise may improve general bone health. Supervision by a physician specialist familiar with hypophosphatasia is suggested. ### Prevention of Secondary Complications Calcium supplementation and vitamin D therapy may prevent secondary hyperparathyroidism in adults. This should only be pursued with close monitoring by a physician specialist familiar with hypophosphatasia. ### Surveillance Children with hypophosphatasia should be seen by a pediatric dentist twice yearly, beginning at age one year. Children with the infantile type of hypophosphatasia are at elevated risk for increased intracranial pressure secondary to craniosynostosis, and should be monitored for this complication. ### Agents/Circumstances to Avoid Biphosphonates are relatively contraindicated in hypophosphatasia. Although adverse outcomes have not been identified in children with the severe infantile type [Deeb et al 2000], theoretic concern has long been raised based on the structure of bisphosphonates. The phosphate motifs in bisphosphonates have a similar conformation to inorganic pyrophosphate (PPi), the natural substrate of TNSALP; thus, treatment with bisphosphonates is thought to be analogous to "adding fuel to the fire." In adults with hypophosphatasia and osteomalacia treated with bisphosphonates, lateral subtrochanteric femoral pseudofractures have been described [Whyte 2009]. As the prevalence of adult hypophosphatasia is not known and many undiagnosed adult patients undoubtedly are treated with bisphosphonates, the frequency of this unusual complication is not known. Excess vitamin D can exacerbate hypercalcemia/hypercalciuria in children with infantile hypophosphatasia who have hypercalcemia. Teriparatide (recombinant human parathyroid hormone fragment, amino acids 1-34) at high doses induces osteosarcoma in rats, and may increase the risk of radiation-induced osteosarcoma (a pediatric growth plate tumor) in humans. It is contraindicated in children with hypophosphatasia. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Enzyme replacement therapy (ERT). Autosomal recessive hypophosphatasia remains an extremely rare and severe condition. The treatment duration and long-term effects of ERT with asfotase alfa remain unknown for perinatal and infantile HPP. Clinical trials are in Phase IV, with patients treated up to 78 months at the time of FDA approval. For milder autosomal recessive and autosomal dominant childhood (juvenile) and adult-onset HPP, limited information about asfotase alfa exists; clinical trials are underway in children, adolescents, and adults. Bone marrow transplantation (hematopoietic cell transplantation) was used to treat an eight-month-old girl with severe hypophosphatasia with prolonged, significant clinical and radiologic improvement [Whyte et al 2003]. Seven years after transplantation, the patient was reported to be active and growing, and to have the clinical phenotype of the more mild childhood (juvenile) form of hypophosphatasia [Cahill et al 2007]. In another trial, both bone marrow and allogenic mesenchymal stem cells were implanted in an eight-month old patient, resulting in improvement of respiratory conditions [Tadokoro et al 2009]. However,the patient developed therapy-related leukemia [Taketani et al 2013]. Transplantation of ex vivo expanded mesenchymal stem cells for patients who had previously undergone bone marrow transplantation improved bone mineralization, muscle mass, respiratory function, intellectual development, and survival [Taketani et al 2015]. 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. 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A number sign (#) is used with this entry because of evidence that hereditary neuralgic amyotrophy (HNA) is caused by heterozygous mutation in the SEPT9 gene (604061) on chromosome 17q25. Description Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant form of recurrent focal neuropathy characterized clinically by acute, recurrent episodes of brachial plexus neuropathy with muscle weakness and atrophy preceded by severe pain in the affected arm. Clinical Features Taylor (1960) studied a family in which 5 generations were affected by single or recurrent attacks of mononeuritis with a particular predilection for proximal brachial localization. The trait behaved as an autosomal dominant with high penetrance. Clinically, the picture closely resembled serum neuritis, suggesting that the fundamental defect might be a genetic susceptibility to 'hyperergic reactions.' The authors noted that episodes may be triggered by periods of physical or emotional stress and pregnancy. In 7 patients from 2 unrelated families, Jacob et al. (1961) observed 14 similar episodes of recurrent brachial neuritis or mononeuritis multiplex. Attacks were featured by incapacitating pain, weakness, wasting, depression of reflexes, and sensory loss. The legs were involved only in instances of severe arm involvement. Narrow face with close-set eyes was a feature. Gardner and Maloney (1968) emphasized ocular hypotelorism and reported associated syndactyly in this disorder. Guillozet and Mercer (1973) described 4 cases of recurrent brachial neuropathy in 3 generations of a family. These patients showed recurrent attacks of pain, weakness, and sometimes muscle-wasting in the arms and hands. These attacks generally were known to remit gradually, sometimes leaving residual weakness or muscular atrophy. Although the brachial plexus is primarily involved in this condition, the lower cranial nerves and the sympathetic nervous system may also be affected. Airaksinen et al. (1985) reported a Finnish pedigree in which 13 members in 3 generations were affected with recurrent brachial plexus neuropathy. The first episode usually occurred in childhood after a mild infection. Affected patients had hypotelorism, small palpebral fissures, and a small mouth. Despite limitation of symptoms to the upper limbs, sural nerve biopsy in 1 patient showed tomaculous neuropathy. The authors interpreted this finding as indicating a generalized abnormality of Schwann cells predisposing the patients to recurrent palsies precipitated by exogenous factors. Phillips (1986) pointed out that isolated long thoracic nerve palsy causing weakness of the serratus anterior muscle and winging of the scapula, while usually traumatic in origin, can be a major manifestation of familial brachial plexus neuropathy. He studied the disorder in 4 persons in 3 generations of a family. There was male-to-male transmission. In 1 person, facial paresis was also present. Thomas and Ormerod (1993) described a family in which 4 members over 2 generations were affected by neuralgic amyotrophy. A brother and sister were described in detail; another brother and the father were described briefly and not examined. At 19 years of age, the sister had developed pain around her right shoulder which lasted for about 2 days and was followed by difficulty in elevating the right arm and winging of the right scapula. This resolved over the following 5 months. At the age of 20 years, she began to suffer from episodes of pain, usually in the limbs, which lasted for a few days and were followed by areas of sensory loss. At the age of 31, toward the end of a pregnancy, she developed severe pain over the outer aspect of the right upper thigh which she maintained was worse than her subsequent labor pains. This was followed by cutaneous sensory loss in the same area. A brother developed painful winged scapula at age 25 with subsequent recovery. The father of the 3 sibs experienced a painful winged scapula which developed 2 weeks after an injection of antitetanus serum. Although the pain subsided, muscle strength was recovered only partially. There were no dysmorphic features in the family. Thomas and Ormerod (1993) pointed out similarities to the migrant sensory neuritis of Wartenberg (Matthews and Esiri, 1983). Stogbauer et al. (1997) noted that the disorder is characterized clinically by episodes of brachial plexus neuropathy with muscle weakness and atrophy, as well as sensory disturbances. In almost all cases, the onset of muscle weakness is preceded by severe pain in the affected arm. The age of onset of the disease is in the second and third decade of life, although children in the first decade may be affected. Recovery is usually complete and begins weeks to months after the onset of symptoms. Recurrent episodes affect the same as well as the opposite arm. From electrophysiologic studies there is no evidence for a generalized neuropathy in HNA. Histologically, minor signs of axonal degeneration distal to the affected brachial plexus have been described. Several minor dysmorphic features are associated with HNA, including short stature, hypotelorism, epicanthal folds, and cleft palate, but clear segregation of the dysmorphism with the neuropathy has not been proved. In the hereditary form, as in the sporadic form, individual episodes of symptoms may be preceded by infections or immunization (Jacob et al., 1961; Taylor, 1960; Tsairis et al., 1972). Orstavik et al. (1997) described a mother and son with recurrent episodes of brachial plexus neuropathy. They suggested that the hereditary form of this disorder is usually associated with dysmorphic features (Airaksinen et al., 1985), such as hypotelorism, small palpebral fissures, and a small mouth. Although their patients had only very slight dysmorphic features, they concluded that they represented the inherited form. Pellegrino et al. (1997) noted that dysmorphic features, including hypotelorism, long nasal bridge, and facial asymmetry, are frequently associated with this disorder. Meuleman et al. (2001) reviewed the topic of hereditary neuralgic amyotrophy. They pointed out that 2 different clinical courses had been discerned: the classic relapsing-remitting course and a chronic undulating course, consistent with the evidence of genetic heterogeneity. Jeannet et al. (2001) cited 27 patients with hereditary neuralgic amyotrophy from 7 families. Twenty-five patients had an average of 3 attacks of brachial neuritis. The right arm was involved more frequently. Cleft palate was present in 4 individuals. Facial measurements showed significant hypotelorism in patients versus controls. Unusual skin folds and creases were observed on the necks of several individuals, as well as on the scalp of 1 man (cutis verticis gyrata). In 3 families, deep skin creases were present on the limbs of infants and toddlers who were subsequently affected by hereditary neuralgic amyotrophy. Thus, the phenotypic spectrum is wider than previously appreciated and involves nonneural tissues. Kuhlenbaumer et al. (2005) summarized the clinical features of hereditary neuralgic amyotrophy, also called neuralgic amyotrophy with predilection for brachial plexus. The disorder, an autosomal dominant recurrent neuropathy affecting the brachial plexus, is triggered by environmental factors such as infection or parturition. The clinical hallmarks are recurrent painful brachial plexus neuropathies with weakness and atrophy of arm muscles and sensory loss. Full or partial recovery occurs in most affected individuals within weeks to months. A more common sporadic form of painful brachial plexus neuropathy, called Parsonage-Turner syndrome, is clinically indistinguishable from HNA. Attacks of brachial plexus neuritis are often triggered by infections, immunizations, and strenuous use of the affected limb. Inflammatory changes in the blood and brachial plexus have been shown, suggesting involvement of the immune system. Dysmorphic features such as hypotelorism, epicanthal folds, and, rarely, cleft palate had been found in many but not all individuals with the disorder (Pellegrino et al., 1997). Laccone et al. (2008) reported a brother and sister, aged 2.5 years and 6.5 years, respectively, with HNA and dysmorphic features. Dysmorphic features included hypotelorism, upslanting palpebral fissures, very thin, downslanting eyebrows, deep-set eyes, and blepharophimosis. Both sibs also had slight ptosis, epicanthal folds, depressed nasal root, microstomia, and low-set dorsally rotated ears with very broad upper helices. The boy had cleft palate. Developmental milestones for both were normal. On history, the father and paternal grandmother reported painful episodes of brachial muscle weakness with residual wasting and paralysis, consistent with HNA. Photographs of the father and grandmother as children showed similar dysmorphic features as in the 2 sibs. Genetic analysis identified a heterozygous mutation in the SEPT9 gene (R88W; 604061.0001) in all 4 individuals. The boy was originally thought to have BPES (110100), but that was excluded by genetic analysis. His sister had experienced a painful attack in her elbow at age 2.5 years and was incorrectly diagnosed with radial head subluxation at that time. Laccone et al. (2008) emphasized that wider recognition of the characteristic dysmorphic features of HNA can facilitate clinical diagnosis of this syndrome. Diagnosis Kuhlenbaumer et al. (2000) presented diagnostic guidelines for HNA, as reported on behalf of the European CMT Consortium. Pertinent exclusion criteria are absence of pain before or during attacks, signs of a generalized neuropathy, and presence of mutations in the PMP22 gene. Mapping ### Distinction from HNPP Although hereditary neuralgic amyotrophy with predilection for the brachial plexus has some similarities to hereditary neuropathy with liability to pressure palsies (HNPP; 162500), several studies have confirmed that they are distinct disorders. HNPP is associated with deletion or abnormal structure of the PMP22 gene (601097) on 17p12-p11.2, the same gene that is duplicated or the site of point mutations in Charcot-Marie-Tooth disease type Ia (CMT1A; 118220). In affected members from 3 pedigrees with neuralgic amyotrophy, Chance et al. (1994) did not find the deletion associated with HNPP or any abnormality in the PMP22 structure. Gouider et al. (1994) showed that in affected members of 2 families with neuralgic amyotrophy, the PMP22 gene is not deleted, duplicated, or mutated and that the disease is not linked to any other gene in the HNPP region. Thus, the genetic evidence supported the conclusion that from clinical, electrophysiologic, and pathologic studies, the 2 disorders are distinct. Windebank et al. (1995) reported the same findings from a larger study involving fluorescence in situ hybridization using a DNA probe that hybridizes to 17p11.2 in the area deleted in HNPP. Their study involved 14 persons from 4 unrelated families with HNPP and 7 members from 3 unrelated families with inherited brachial plexus neuropathy. While all of the HNPP patients showed deletion, Windebank et al. (1995) found that all 10 control subjects and the 7 patients with inherited brachial plexus neuropathy showed normal fluorescent signals on both chromosomes 17. ### Linkage to Chromosome 17q Pellegrino et al. (1996) analyzed 2 pedigrees to demonstrate linkage of HNA to markers from the distal part of 17q. In a large Turkish pedigree with 14 affected members, Stogbauer et al. (1997) confirmed the presence of the mutant locus on 17q, and by defining flanking markers, refined the localization of the locus to a 16-cM region on 17q24-q25. Stogbauer et al. (1997) commented that genes coding for connective tissue proteins may be critical for hereditary neuralgic neuropathy through both direct pressure and diminished blood supply. As triggers, strenuous use of the affected arm and parturition have been observed. Possible immunologic mechanisms as a trigger were suggested by Geiger et al. (1974). Pellegrino et al. (1997) assessed genetic homogeneity in 6 pedigrees with HNA and found linkage of the NAPB locus to chromosome 17; combined lod score = 10.94, theta = 0.05 with marker D17S939. Analysis of crossovers placed the locus within an approximately 4.0-cM interval flanked by D17S1603 and D17S802. Analysis of DNA from a human/mouse somatic cell hybrid using these linked markers suggested that band 17q25 harbors the NAPB locus. Meuleman et al. (2001) excluded several genes that map to the 17q25 region as candidates involved in the causation of HNA: MLL septin-like fusion gene (MSF; 604061), the thymidine kinase-1 gene (TK1; 188300), and the SEC14-like 1 gene (SEC14L1; 601504). These genes mapped on the clone contigs of the hereditary neuralgic amyotrophy region. With a high-density set of DNA markers from 17q25, Watts et al. (2002) narrowed the locus for hereditary neuralgic amyotrophy to an interval of approximately 1 Mb flanked by markers D17S722 and D17S802. They compared genotypes of 12 markers from 7 pedigrees from the U.S. that showed linkage to 17q25. The haplotypes identified a founder effect in 6 of the 7 pedigrees with a minimal shared haplotype that further refined the locus to an interval of approximately 500 kb. The findings suggested that, for the pedigrees from the U.S., there are at least 2 different mutations in the responsible gene. Heterogeneity Klein et al. (2009) identified a common conserved 17q25 sequence in affected members of 5 North American kindreds with HNA, consistent with a founder effect. However, no mutations were identified in the SEPT9 gene in these families, and SEPT9 mRNA levels were similar to controls. Molecular Genetics Kuhlenbaumer et al. (2005) performed linkage analysis in 10 previously reported multigeneration families with the classical phenotype of what they referred to as hereditary neuralgic amyotrophy (HNA). The families were derived from different geographic areas. Segregation analysis of short tandem repeat (STR) markers in informative recombinants of these families allowed further reduction of the HNA locus to a 600-kb interval containing only 2 known genes, SEC14L1 and SEPT9 (604061). Kuhlenbaumer et al. (2005) sequenced the coding region of SEPT9 including its untranslated regions (UTRs), multiple splice variants, and alternative first exons. In 4 families with HNA, they found a sequence variation (262C-T) in exon 2 of the SEPT9 gene. This transition caused the amino acid change R88W (604061.0001). These 4 families did not share a common disease-associated haplotype, suggestive of a mutation hotspot rather than a founder mutation. The genomic variation occurred at a potential hypermutable CG dinucleotide. In one family they detected an S93F missense mutation (604061.0002). In another family a variation was found in the 5-prime UTR of the SEPT9 alpha transcript (604061.0003). In 8 of 42 unrelated pedigrees with HNA, Hannibal et al. (2009) identified mutations in the SEPT9 gene. The R88W mutation was consistent with a founder effect. Landsverk et al. (2009) identified an intragenic 38-kb tandem duplication in the SEPT9 gene (604061.0004) that was linked to HNA in 12 North American families that shared a common founder haplotype. The duplication was identical in all pedigrees and included the 645-bp exon in which 2 previous HNA mutations had been found. Collie et al. (2010) identified heterozygous tandem duplications affecting the SEPT9 gene in affected individuals from 6 unrelated families with HNA. All of the duplications were of different sizes with unique breakpoints and ranged size from 30 to 330 kb. The smallest common region shared by all duplications encompassed the proline-rich 645-bp exon in which HNA-linked mutations had previously been identified, suggesting that this region is involved in the pathogenesis of the disorder. Five of the duplications generated larger protein products compared to the wildtype protein. The largest 330-kb duplication spanned the entire SEPT9 gene and included a portion of the adjacent gene SEC14L1 (601504); this duplication did not generate aberrant transcripts or proteins, suggesting that increased dosage of SEPT9 alone may be responsible for the disorder. There was no single mechanism responsible for the generation of these duplications. The HNA phenotype was the same as that observed for other mutations in the SEPT9 gene. History Meuleman et al. (2001) suggested that Dreschfeld (1886) may have published the first report of hereditary neuralgic amyotrophy, that of a 43-year-old woman who had suffered 3 episodes of painful upper limb weakness and whose sister had suffered 7 similar attacks. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature (in some cases) HEAD & NECK Face \- Facial asymmetry Ears \- Low-set ears \- Dorsally rotated ears Eyes \- Hypotelorism \- Epicanthal folds \- Upslanting palpebral fissures \- Downslanting eyebrows \- Deep-set eyes \- Blepharophimosis \- Ptosis Nose \- Long nasal bridge \- Depressed nasal root Mouth \- Cleft palate \- Microstomia Neck \- Skin folds or creases SKIN, NAILS, & HAIR Skin \- Skin folds or creases (neck or forearm) NEUROLOGIC Peripheral Nervous System \- Acute, recurrent episodes of brachial plexus (lumbosacral and phrenic nerve in some cases) neuropathy \- Muscle weakness usually following neuropathy \- Muscle atrophy usually following neuropathy \- Sensory deficits (in some patients) \- Focal paresis \- Hyporeflexia (in some patients) \- Axonal degeneration \- EMG of affected limb shows denervation MISCELLANEOUS \- Onset usually in first to third decade of life \- Number of episodes varies from 1 to many (up to 20) \- Symptoms resolve over weeks to months with usually no residual symptoms between attacks \- Episodes are triggered by infection, immunization, surgery, strenuous exercise, cold, pregnancy \- Facial dysmorphic features may not be present and may become less apparent in adulthood \- Distinct disorder from hereditary neuropathy with liability to pressure palsies (HNPP, 162500 ) MOLECULAR BASIS \- Caused by mutation in the septin 9 gene (SEPT9, 604061.0001 ) ▲ 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	AMYOTROPHY, HEREDITARY NEURALGIC	c0221759	6,328	omim	https://www.omim.org/entry/162100	2019-09-22T16:37:34	{"doid": ["10383"], "mesh": ["D020968"], "omim": ["162100"], "orphanet": ["2901"], "synonyms": ["Alternative titles", "NEURITIS WITH BRACHIAL PREDILECTION", "BRACHIAL PLEXUS NEUROPATHY, HEREDITARY", "AMYOTROPHY, HEREDITARY NEURALGIC, WITH PREDILECTION FOR BRACHIAL PLEXUS"], "genereviews": ["NBK1395"]}
"B-cell CLL" redirects here. For the gene family, see B-cell CLL/lymphoma. Chronic lymphocytic leukemia Other namesB-cell chronic lymphocytic leukemia (B-CLL)[1] Peripheral blood smear showing CLL cells SpecialtyHematology and oncology SymptomsEarly: None[2] Later: Non-painful lymph nodes swelling, feeling tired, fever, weight loss[2] Usual onsetOlder than 50[3] Risk factorsFamily history, Agent Orange, certain insecticides[2][4] Diagnostic methodBlood tests[5] Differential diagnosisMononucleosis, hairy cell leukemia, acute lymphocytic leukemia, persistent polyclonal B-cell lymphocytosis[5] TreatmentWatchful waiting, chemotherapy, immunotherapy[4][5] PrognosisFive-year survival ~83% (US)[3] Frequency904,000 (2015)[6] Deaths60,700 (2015)[7] Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).[2][8] Early on there are typically no symptoms.[2] Later non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur.[2][9] Enlargement of the spleen and low red blood cells (anemia) may also occur.[2][4] It typically worsens gradually over years.[2] Risk factors include having a family history of the disease.[2] Exposure to Agent Orange and certain insecticides might also be a risk.[4] CLL results in the buildup of B cell lymphocytes in the bone marrow, lymph nodes, and blood.[4] These cells do not function well and crowd out healthy blood cells.[2] CLL is divided into two main types: those with a mutated IGHV gene and those without.[4] Diagnosis is typically based on blood tests finding high numbers of mature lymphocytes and smudge cells.[5] Early-stage CLL in asymptomatic cases responds better to careful observation, as there is no evidence that early intervention treatment can alter the course of the disease.[10] Immune defects occur early in the course of CLL and these increase the risk of developing serious infection, which should be treated appropriately with antibiotics.[10] In those with significant symptoms, chemotherapy or immunotherapy may be used.[4] As of 2019 ibrutinib is often the initial medication recommended.[11] The medications fludarabine, cyclophosphamide, and rituximab were previously the initial treatment in those who are otherwise healthy.[12] CLL affected about 904,000 people globally in 2015 and resulted in 60,700 deaths.[6][7] The disease most commonly occurs in people over the age of 50.[3] Men are diagnosed around twice as often as women (6.8 to 3.5 ratio).[13] It is much less common in people from Asia.[4] Five-year survival following diagnosis is approximately 83% in the United States.[3] It represents less than 1% of deaths from cancer.[7] ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Cause * 3 Diagnosis * 3.1 Clinical staging * 3.1.1 Array-based karyotyping * 3.2 Related diseases * 3.3 Differential diagnosis * 4 Treatment * 4.1 Decision to treat * 4.2 Chemotherapy * 4.3 Targeted therapy * 4.4 Stem cell transplantation * 4.5 Refractory CLL * 4.6 During pregnancy * 5 Prognosis * 6 Epidemiology * 7 Research directions * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] A diagram showing the cells affected by CLL Most people are diagnosed as having CLL based on the result of a routine blood test that shows a high white blood cell count, specifically a large increase in the number of circulating lymphocytes.[9] These people generally have no symptoms.[9] Less commonly, CLL may present with enlarged lymph nodes.[9] This is referred to as small lymphocytic lymphoma. Less commonly the disease comes to light only after the cancerous cells overwhelm the bone marrow resulting in low red blood cells, neutrophils, or platelets.[9] Or there is fever, night sweats, weight loss, and the person feels tired.[9] CLL can be grouped with Small lymphocytic lymphoma (SLL) as one disease with two clinical presentations.[14] Wherein, with CLL, diseased cells propagate from within the bone marrow, in SLL they propagate from within the lymphatic tissue.[14] CLLs are, in virtually all cases, preceded by a particular subtype of monoclonal B-cell lymphocytosis (MBL). This subtype, termed chronic lymphocytic leukemia-type MBL (CLL-type MBL) is an asymptomatic, indolent, and chronic disorder in which individuals exhibit a mild increase in the number of circulating B-cell lymphocytes. These B-cells are abnormal: they are monoclonal, i.e. produced by a single ancestral B-cell, and have some of the same cell marker proteins, chromosome abnormalities, and gene mutations found in CLL.[15][16] CLL/SLL MBL consist of two groups: low-count CLL/SLL MBL has monoclonal B-cell blood counts of <0.5x9 cells/liter (i.e. 0.5x9/L) while high-count CLL/SLL MBL has blood monoclonal B-cell counts ≥0.5x9/L but <5x109/L.[17] Individuals with blood counts of these monoclonal B-cells >5x9/L are diagnosed as having CLL. Low-count CLL/SLL MBL rarely if ever progresses to CLL while high-count CLL/SLL MBL does so at a rate of 1-2% per year. Thus, CLL may present in individuals with a long history of having high-count CLL/SLL MBL. There is no established treatment for these individuals except monitoring for development of the disorder's various complications (see treatment of MBL complications) and for their progression to CLL.[18][19] ### Complications[edit] Complications include a low level of antibodies in the bloodstream (hypogammaglobulinemia) leading to recurrent infection, warm autoimmune hemolytic anemia in 10–15% of patients, and bone marrow failure. Chronic lymphocytic leukemia may also transform into Richter's syndrome, the development of fast-growing diffuse large B cell lymphoma, prolymphocytic leukemia, Hodgkin's lymphoma, or acute leukemia in some patients. Its incidence is estimated to be around 5% in patients with CLL.[20] Gastrointestinal (GI) involvement can rarely occur with chronic lymphocytic leukemia. Some of the reported manifestations include intussusception, small intestinal bacterial contamination, colitis, and others. Usually, GI complications with CLL occur after Richter transformation. Two cases to date have been reported of GI involvement in chronic lymphocytic leukemia without Richter's transformation.[21] ## Cause[edit] CLL can be caused by many different genetic mutations, the most common being deletions in the 13q14.3 region, (seen in 50% of CLL cases), as well as trisomy in chromosome 12 (seen in 20% of cases), other deletions (i.e., in 11q22-23, 17p13, or 16q21 regions), and less commonly, translocations (for example, involving the 13q14 region).[22] CLL can also be caused by a number of epigenetic changes, which can be classified into 3 different methylation subgroups (naïve B-cell-like, memory B-cell-like, and intermediate).[22] Some relevant genetic mutations may be inherited. Since there is no one single mutation that causes CLL in all cases, an individual’s susceptibility may be impacted when multiple mutations that increase the risk of CLL are co-inherited.[23] Up until 2014, very few of these mutations or significant “risk alleles” had been identified.[23] Men are about twice as likely to get CLL as women, and risk increases with age.[24] It is relatively rare among Asians. Exposure to Agent Orange increases the risk of CLL, and exposure to hepatitis C virus may increase the risk.[24] There is no clear association between ionizing radiation exposure and the risk of developing CLL.[24] Blood transfusions have been ruled out as a risk factor.[4] ## Diagnosis[edit] Micrograph of a lymph node affected by B-CLL showing a characteristic proliferation center (right of image), composed of larger, lighter-staining, cells, H&E stain CLL is usually first suspected by a diagnosis of lymphocytosis, an increase in a type of white blood cell, on a complete blood count test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 5000 cells per microliter (µl) of blood, but can be much higher.[12] The presence of lymphocytosis in an elderly individual should raise strong suspicion for CLL, and a confirmatory diagnostic test, in particular flow cytometry, should be performed unless clinically unnecessary.[citation needed] A peripheral blood smear showing an abundance of damaged cells known as "smudge cells" or "basket cells" can also indicate the presence of the disease (smudge cells are due to cancer cells lacking in vimentin, a cytoskeletal protein).[25]:1899 The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. This atypical molecular pattern includes the coexpression of cell surface markers clusters of differentiation 5 (CD5) and 23. In addition, all the CLL cells within one individual are clonal, that is, genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive antibody light chains, kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody-producing cells, resulting in a mixture of both kappa- and lambda-expressing cells. The lack of the normal distribution of these B cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any B cell malignancy (B cell non-Hodgkin lymphoma). The combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by flow cytometry to confirm clonality and marker molecule expression is needed to establish the diagnosis of CLL. Both are easily accomplished on a small amount of blood. A flow cytometer instrument can examine the expression of molecules on individual cells in fluids. This requires the use of specific antibodies to marker molecules with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (expressing marker molecules clusters of differentiation 19 and 20), and characteristically express the marker molecules CD5 and CD23. These B cells resemble normal lymphocytes under the microscope, although slightly smaller, and are fragile when smeared onto a glass slide, giving rise to many broken cells, which are called "smudge" or "smear" cells.[26] Smudge cells in peripheral blood The Matutes's CLL score allows the identification of a homogeneous subgroup of classical CLL, that differs from atypical/mixed CLL for the five markers' expression (CD5, CD23, FMC7, CD22, and immunoglobulin light chain) Matutes's CLL scoring system is very helpful for the differential diagnosis between classical CLL and the other B cell chronic lymphoproliferative disorders, but not for the immunological distinction between mixed/atypical CLL and mantle cell lymphoma (MCL malignant B cells).[27] Discrimination between CLL and MCL can be improved by adding non-routine markers such as CD54[28] and CD200.[29] Among routine markers, the most discriminating feature is the CD20/CD23 mean fluorescence intensity ratio. In contrast, FMC7 expression can surprisingly be misleading for borderline cases.[30] ### Clinical staging[edit] Staging, determining the extent of the disease, is done with the Rai staging system or the Binet classification (see details[31]) and is based primarily on the presence of a low platelet or red cell count. Early-stage disease does not need to be treated. CLL and SLL are considered the same underlying disease, just with different appearances.[32]:1441 Rai staging system[33][34] * Stage 0: characterized by absolute lymphocytosis (>15,000/mm3) without lymphadenopathy, hepatosplenomegaly, anemia, or thrombocytopenia * Stage I: characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia * Stage II: characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy * Stage III: characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly * Stage IV: characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia Binet classification[35] * Clinical stage A: characterized by no anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai stages 0, I, and II) * Clinical stage B: characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai stages I and II) * Clinical stage C: characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV) #### Array-based karyotyping[edit] Main article: Virtual karyotype Array-based karyotyping is a cost-effective alternative to FISH for detecting chromosomal abnormalities in CLL. Several clinical validation studies have shown >95% concordance with the standard CLL FISH panel.[36][37][38][39][40] ### Related diseases[edit] In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, these are now recognized as a separate disease group and are currently classified as T-cell prolymphocytic leukemias.[41][42] CLL should not be confused with acute lymphoblastic leukemia, a highly aggressive leukemia most commonly diagnosed in children, and highly treatable in the pediatric setting. ### Differential diagnosis[edit] Lymphoid disorders that can present as chronic leukemia and can be confused with typical B-cell chronic lymphoid leukemia[43] Follicular lymphoma Splenic marginal zone lymphoma Nodal marginal zone B cell lymphoma Mantle cell lymphoma Hairy cell leukemia Prolymphocytic leukemia (B cell or T cell) Lymphoplasmacytic lymphoma Sézary syndrome Smoldering adult T cell leukemia/lymphoma Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma. * B cell prolymphocytic leukemia, a related, but more aggressive disorder, has cells with similar phenotype, but are significantly larger than normal lymphocytes and have a prominent nucleolus. The distinction is important as the prognosis and therapy differ from CLL. * Hairy cell leukemia is also a neoplasm of B lymphocytes, but the neoplastic cells have a distinct morphology under the microscope (hairy cell leukemia cells have delicate, hair-like projections on their surfaces) and unique marker molecule expression. All the B cell malignancies of the blood and bone marrow can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow, and occasionally lymph node cells by a pathologist with specific training in blood disorders. A flow cytometer is necessary for cell marker analysis, and the detection of genetic problems in the cells may require visualizing the DNA changes with fluorescent probes by FISH. ## Treatment[edit] CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. In those without or only minimal symptoms watchful waiting is generally appropriate.[11] CLL is treated by chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy – removal of enlarged spleen) or by radiation therapy ("de-bulking" swollen lymph nodes). Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. Any of dozens of agents may be used for CLL therapy.[44] ### Decision to treat[edit] While it is generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years—in some cases for decades. Because of its slow onset, early-stage CLL is, in general, not treated since it is believed that early CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time to detect any change in the disease pattern.[11][45] The decision to start CLL treatment is taken when the person's symptoms or blood counts indicate that the disease has progressed to a point where it may affect quality of life. Clinical "staging systems" such as the Rai four-stage system and the Binet classification can help to determine when and how to treat the patient.[31] Determining when to start treatment and by what means is often difficult; no survival advantage is seen in treating the disease very early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.[46] ### Chemotherapy[edit] Combination chemotherapy regimens are effective in both newly diagnosed and relapsed CLL. Combinations of fludarabine with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents: * FC (fludarabine with cyclophosphamide)[47] * FR (fludarabine with rituximab)[48] * FCR (fludarabine, cyclophosphamide, and rituximab)[49] * CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) Although the purine analogue fludarabine was shown to give superior response rates to chlorambucil as primary therapy,[50][51] no evidence shows early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease. Chemoimmunotherapy with FCR has shown to improve response rates, progression-free survival, and overall survival in a large randomized trial in CLL patients selected for good physical fitness.[52] This has been the first clinical trial demonstrating that the choice of a first-line therapy can improve the overall survival of patients with CLL. Alkylating agents approved for CLL include bendamustine and cyclophosphamide. ### Targeted therapy[edit] Targeted therapy attacks cancer cells at a specific target, with the aim of not harming normal cells. Targeted drugs used in CLL include venetoclax (a Bcl-2 inhibitor), ibrutinib (a Bruton's tyrosine kinase inhibitor), idelalisib and duvelisib (inhibitors of some forms of the enzyme phosphoinositide 3-kinase), as well as monoclonal antibodies against CD20 (rituximab, ofatumumab and obinutuzumab) and CD52 (alemtuzumab).[11][53] ### Stem cell transplantation[edit] Autologous stem cell transplantation, using the recipient's own cells, is not curative.[32]:1458 Younger individuals, if at high risk for dying from CLL, may consider allogeneic hematopoietic stem cell transplantation (HSCT). Myeloablative (bone marrow killing) forms of allogeneic stem cell transplantation, a high-risk treatment using blood cells from a healthy donor, may be curative, but treatment-related toxicity is significant.[32]:1458 An intermediate level, called reduced-intensity conditioning allogeneic stem cell transplantation, may be better tolerated by older or frail patients.[54][55] ### Refractory CLL[edit] "Refractory" CLL is a disease that no longer responds favorably to treatment. In this case, more aggressive therapies, including lenalidomide, flavopiridol, and bone marrow (stem cell) transplantation, are considered.[56] The monoclonal antibody alemtuzumab (directed against CD52) may be used in patients with refractory, bone marrow-based disease.[57] ### During pregnancy[edit] Leukemia is rarely associated with pregnancy, affecting only about one in 10,000 pregnant women.[58] Treatment for chronic lymphocytic leukemias can often be postponed until after the end of the pregnancy. If treatment is necessary, then giving chemotherapy during the second or third trimesters is less likely to result in pregnancy loss or birth defects than treatment during the first trimester.[58] ## Prognosis[edit] Prognosis can be affected by the type of genetic mutation that the person with CLL has.[59] Some examples of genetic mutations and their prognoses are: mutations in the IGHV region are associated with a median overall survival (OS) of more than 20–25 years, while no mutations in this region is associated with a median OS of 8–10 years; deletion of chromosome 13q is associated with a median OS of 17 years; and trisomy of chromosome 12, as well as deletion of chromosome 11q, is associated with a median OS of 9–11 years.[60] While prognosis is highly variable and dependent on various factors including these mutations, the average 5-year relative survival is 86.1%.[61] Telomere length has been suggested to be a valuable prognostic indicator of survival.[62] ## Epidemiology[edit] CLL is primarily a disease of older adults, with a median age of 70 years at the time of diagnosis.[63] Though less common, CLL sometimes affects people between 30 and 39 years of age.[medical citation needed] The incidence of CLL increases very quickly with increasing age.[medical citation needed] In the United States during 2014, about 15,720 new cases are expected to be diagnosed, and 4,600 patients are expected to die from CLL.[64] Because of the prolonged survival, which was typically about 10 years in past decades, but which can extend to a normal life expectancy,[31] the prevalence (number of people living with the disease) is much higher than the incidence (new diagnoses). CLL is the most common type of leukemia in the UK, accounting for 38% of all leukemia cases. Approximately 3,200 people were diagnosed with the disease in 2011.[65] In Western populations, subclinical "disease" can be identified in 3.5% of normal adults,[66] and in up to 8% of individuals over the age of 70.[citation needed] That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown. In contrast, CLL is rare in Asian countries, such as Japan, China, and Korea, accounting for less than 10% of all leukemias in those regions.[32]:1432[63] A low incidence is seen in Japanese immigrants to the US, and in African and Asian immigrants to Israel.[32] Of all cancers involving the same class of blood cell, 7% of cases are CLL/SLL.[67] Rates of CLL are somewhat elevated in people exposed to certain chemicals. Under U.S. Department of Veterans' Affairs regulations, Vietnam veterans who served in-country or in the inland waterways of Vietnam and who later develop CLL are presumed to have contracted it from exposure to Agent Orange and may be entitled to compensation. ## Research directions[edit] Research in 2008 is comparing different forms of bone marrow transplants to determine which patients are the best candidates and which approach is best in different situations.[54] Wikinews has related news: * Scientists use gene therapy, patients' own immune systems to fight leukemia Researchers at the Abramson Cancer Center of the University of Pennsylvania School of Medicine reported preliminary success in the use of gene therapy, through genetically modified T cells, to treat CLL.[68] The findings, which were published in August 2011,[69][70] were based on data from three patients who had modified T cells injected into their blood. The T cells had been modified to express genes that would allow the cells to proliferate in the body and destroy B cells including those causing the leukemia. Two patients went into remission, while the presence of leukemia in the third patient reduced by 70%.[71][72] One of the patients had been diagnosed with CLL for 13 years, and his treatment was failing before he participated in the clinical trial. One week after the T cells were injected, the leukemia cells in his blood had disappeared.[73] The T cells were still found in the bloodstream of the patients six months after the procedure, meaning they would be able to fight the disease should leukemia cells return.[71] This was the first time scientists "have used gene therapy to successfully destroy cancer tumors in patients with advanced disease".[74] Research is also investigating therapies targeting B cell receptor signalling. Syk inhibitor fostamatinib is in trials.[75] The trial of a combination of ibrutinib and venetoclax had encouraging results in a small number of people.[76] ## See also[edit] * Monoclonal B-cell lymphocytosis * Virtual karyotype * B-cell CLL/lymphoma ## References[edit] 1. ^ O'Brien S, Gribben JG (2008). Chronic Lymphocytic Leukemia. CRC Press. p. 19. ISBN 9781420068962. 2. ^ a b c d e f g h i j "Chronic Lymphocytic Leukemia Treatment". National Cancer Institute. 26 October 2017. Retrieved 19 December 2017. 3. ^ a b c d "Chronic Lymphocytic Leukemia - Cancer Stat Facts". seer.cancer.gov. Retrieved 20 December 2017. 4. ^ a b c d e f g h i Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G, Wierda WG, et al. (January 2017). "Chronic lymphocytic leukaemia". Nature Reviews. Disease Primers. 3: 16096. doi:10.1038/nrdp.2016.96. PMC 5336551. PMID 28102226. 5. ^ a b c d Ferri FF (2017). Ferri's Clinical Advisor 2018 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 750. 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Blood. 130 (Suppl 1): 428. ## External links[edit] * Chronic Lymphocytic Leukemia at American Cancer Society * General information about CLL from the US National Cancer Institute * Cancer.Net: Chronic Lymphocytic Leukemia Classification D * ICD-10: C91.1 * ICD-9-CM: V10.60 204.1 V10.60 * ICD-O: M9823/3 (CLL) 9670/3 (SCL) * MeSH: D015451 * DiseasesDB: 2641 External resources * MedlinePlus: 000532 * eMedicine: med/370 * NCI: Chronic lymphocytic leukemia * v * t * e Leukaemias, lymphomas and related disease B cell (lymphoma, leukemia) (most CD19 * CD20) By development/ marker TdT+ * ALL (Precursor B acute lymphoblastic leukemia/lymphoma) CD5+ * naive B cell (CLL/SLL) * mantle zone (Mantle cell) CD22+ * Prolymphocytic * CD11c+ (Hairy cell leukemia) CD79a+ * germinal center/follicular B cell (Follicular * Burkitt's * GCB DLBCL * Primary cutaneous follicle center lymphoma) * marginal zone/marginal zone B-cell (Splenic marginal zone * MALT * Nodal marginal zone * Primary cutaneous marginal zone lymphoma) RS (CD15+, CD30+) * Classic Hodgkin lymphoma (Nodular sclerosis) * CD20+ (Nodular lymphocyte predominant Hodgkin lymphoma) PCDs/PP (CD38+/CD138+) * see immunoproliferative immunoglobulin disorders By infection * KSHV (Primary effusion) * EBV * Lymphomatoid granulomatosis * Post-transplant lymphoproliferative disorder * Classic Hodgkin lymphoma * Burkitt's lymphoma * HCV * Splenic marginal zone lymphoma * HIV (AIDS-related lymphoma) * Helicobacter pylori (MALT lymphoma) Cutaneous * Diffuse large B-cell lymphoma * Intravascular large B-cell lymphoma * Primary cutaneous marginal zone lymphoma * Primary cutaneous immunocytoma * Plasmacytoma * Plasmacytosis * Primary cutaneous follicle center lymphoma T/NK T cell (lymphoma, leukemia) (most CD3 * CD4 * CD8) By development/ marker * TdT+: ALL (Precursor T acute lymphoblastic leukemia/lymphoma) * prolymphocyte (Prolymphocytic) * CD30+ (Anaplastic large-cell lymphoma * Lymphomatoid papulosis type A) Cutaneous MF+variants * indolent: Mycosis fungoides * Pagetoid reticulosis * Granulomatous slack skin aggressive: Sézary disease * Adult T-cell leukemia/lymphoma Non-MF * CD30-: Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma * Pleomorphic T-cell lymphoma * Lymphomatoid papulosis type B * CD30+: CD30+ cutaneous T-cell lymphoma * Secondary cutaneous CD30+ large-cell lymphoma * Lymphomatoid papulosis type A Other peripheral * Hepatosplenic * Angioimmunoblastic * Enteropathy-associated T-cell lymphoma * Peripheral T-cell lymphoma not otherwise specified (Lennert lymphoma) * Subcutaneous T-cell lymphoma By infection * HTLV-1 (Adult T-cell leukemia/lymphoma) NK cell/ (most CD56) * Aggressive NK-cell leukemia * Blastic NK cell lymphoma T or NK * EBV (Extranodal NK-T-cell lymphoma/Angiocentric lymphoma) * Large granular lymphocytic leukemia Lymphoid+ myeloid * Acute biphenotypic leukaemia Lymphocytosis * Lymphoproliferative disorders (X-linked lymphoproliferative disease * Autoimmune lymphoproliferative syndrome) * Leukemoid reaction * Diffuse infiltrative lymphocytosis syndrome Cutaneous lymphoid hyperplasia * Cutaneous lymphoid hyperplasia * with bandlike and perivascular patterns * with nodular pattern * Jessner lymphocytic infiltrate of the skin General * Hematological malignancy * leukemia * Lymphoproliferative disorders * Lymphoid leukemias [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	Chronic lymphocytic leukemia	c1868683	6,329	wikipedia	https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia	2021-01-18T19:10:44	{"gard": ["6104", "8227"], "mesh": ["D015451"], "umls": ["C1868683", "C0855095"], "icd-10": ["C91.1"], "orphanet": ["67038"], "wikidata": ["Q1088156"]}
Biliary reflux, bile reflux (gastritis), duodenogastroesophageal reflux (DGER) or duodenogastric reflux is a condition that occurs when bile and/or other contents like bicarbonate, and pancreatic enzymes flow upward (refluxes) from the duodenum into the stomach and esophagus.[1][2] Biliary reflux can be confused with acid reflux, also known as gastroesophageal reflux disease (GERD). While bile reflux involves fluid from the small intestine flowing into the stomach and esophagus, acid reflux is backflow of stomach acid into the esophagus. These conditions are often related, and differentiating between the two can be difficult. Bile is a digestive fluid made by the liver, stored in the gallbladder, and discharged into duodenum after food is ingested to aid in the digestion of fat. Normally, the pyloric sphincter prevents bile from entering the stomach. When the pyloric sphincter is damaged or fails to work correctly, bile can enter the stomach and then be transported into the esophagus as in gastric reflux. The presence of small amounts of bile in the stomach is relatively common and usually asymptomatic, but excessive refluxed bile causes irritation and inflammation.[3] Bile reflux has been associated with gastric cancer, chemical gastritis and the development of ulcers.[4] ## Contents * 1 Symptoms * 2 Epidemiology * 3 Diagnosis * 4 Management * 4.1 Surgery * 5 References * 6 External links ## Symptoms[edit] * Frequent heartburn[1] * Pain in the upper part of the abdomen[4] * Vomiting bile and or Regurgitation (digestion)[1][4] * Hypersalivation[1] Bile reflux can be asymptomatic when laying down or after eating, as bile reflux occurs physiologically.[4] ## Epidemiology[edit] Obesity is an independent risk factor for development of bile reflux.[1] Bile reflux is very infrequent in healthy individuals.[5] ## Diagnosis[edit] Bile reflux is usually associated with: * Erosive esophagitis[1] * Barrett's esophagus[1] ## Management[edit] Ursodeoxycholic acid is an adequate treatment of bile reflux gastritis. The dosage is usually of 1000 mg/day and for a 4 weeks treatment.[6] Medications used in managing biliary reflux include bile acid sequestrants, particularly cholestyramine, which disrupt the circulation of bile in the digestive tract and sequester bile that would otherwise cause symptoms when refluxed; and prokinetic agents, to move material from the stomach to the small bowel more rapidly and prevent reflux. ### Surgery[edit] Biliary reflux may also be treated surgically, if medications are ineffective or if precancerous tissue is present in the esophagus.[7] ## References[edit] 1. ^ a b c d e f g Eldredge TA, Myers JC, Kiroff GK, Shenfine J (2018). "Detecting Bile Reflux-the Enigma of Bariatric Surgery". Obes Surg. 28 (2): 559–566. PMID 29230622.CS1 maint: uses authors parameter (link) 2. ^ Cheifetz, Adam S.; Brown, Alphonso; Curry, Michael; Alan C. Moss (2011-03-10). Oxford American Handbook of Gastroenterology and Hepatology. Oxford University Press US. pp. 239–. ISBN 978-0-19-538318-8. Retrieved 2 August 2011. 3. ^ Distinguishing Between Bile Reflux and Acid Reflux can be Difficult 4. ^ a b c d Mabrut JY, Collard JM, Baulieux J. (2006). "[Duodenogastric and gastroesophageal bile reflux]". Journal de chirurgie. 143 (6): 355–65. PMID 17285081.CS1 maint: uses authors parameter (link) 5. ^ Sifrim D (2013). "Management of bile reflux". Gastroenterol Hepatol (N Y). 9 (3): 179–80. PMC 3745208. PMID 23961269. 6. ^ McCabe ME 4th, Dilly CK (2018). "New Causes for the Old Problem of Bile Reflux Gastritis". Clin Gastroenterol Hepatol. 16 (9): 1389–1392. PMID 29505908.CS1 maint: uses authors parameter (link) 7. ^ http://www.mayoclinic.org/diseases-conditions/bile-reflux/basics/definition/con-20025548 ## External links[edit] * The damage of reflux * Bile Reflux page at CNN Health:symptoms, causes, diagnosis, treatment, prevention [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	Biliary reflux	c0013299	6,330	wikipedia	https://en.wikipedia.org/wiki/Biliary_reflux	2021-01-18T18:41:34	{"mesh": ["D004383"], "umls": ["C0013299"], "wikidata": ["Q4170873"]}
Southeast Asian ovalocytosis (SAO) is a rare hereditary red cell membrane defect characterized by the presence of oval-shaped erythrocytes and with most patients being asymptomatic or occasionally manifesting with mild symptoms such as pallor, jaundice, anemia and gallstones. ## Epidemiology SAO is common in Southeast Asian and Western Pacific countries (i.e. Thailand, Malaysia, Indonesia, Philippines and Papua New Guinea). SAO is very common in malaria-endemic areas (prevalence 1/20-1/4) but in Europe it is very rare. ## Clinical description SAO can occur at any age. Newborns with SAO might be symptomatic with hemolysis at birth that leads to anemia, pallor or jaundice. Anemia and hyperbilirubinemia in neonates is common together with mild splenomegaly and gallstones. Hemolysis usually disappears in the first three years of life. Adults are asymptomatic or have only minimal hemolytic anemia. Resistance to malaria (see this term) is also noted. ## Etiology SAO results from a 27 bp deletion in the SLC4A1 gene, localized on chromosome 17q21.31 (SLC4A1del27 mutation). This gene codes for a band 3 anion transport protein which is the bicarbonate/chloride exchanger in red blood cell membranes and defects in this protein cause membrane rigidity. Heterozygous mutations for the deletion are found in almost all cases, as homozygosity is thought to be lethal to the developing embryo. A homozygous mutation was recently reported in one case of SAO as the primary cause of extremely severe dyserythropoietic anemia associated with distal renal tubular acidosis (see this term), and that which would have been lethal if the fetus had not been transfused in utero. The association of mutation SLC4A1del27 with other mutations in the SLC4A1 gene may result in distal renal tubular acidosis associated with SAO in some cases. ## Diagnostic methods Diagnosis is based on the presence on a peripheral blood smear of macro-ovalocytes, some of them stomatocytic with more than one stoma, in the absence of hemolysis. Genetic assays can also be used to identify the mutation in the SLC4A1 gene. ## Differential diagnosis Differential diagnosis includes all forms of hereditary elliptocytosis and hereditary spherocytosis, and dehydrated hereditary stomatocytosis (see these terms). ## Antenatal diagnosis Antenatal diagnosis is possible but not undertaken because of the benign nature of the disease. ## Genetic counseling SAO follows an autosomal dominant pattern of inheritance. Genetic counseling is possible. ## Management and treatment Most cases of SAO are asymptomatic and treatment is not necessary. ## Prognosis SAO is not life threatening. [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	Southeast Asian ovalocytosis	c1862322	6,331	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98868	2021-01-23T17:52:49	{"mesh": ["C566230"], "omim": ["166900"], "icd-10": ["D58.1"], "synonyms": ["Hereditary ovalocytosis", "Melanesian elliptocytosis", "Melanesian ovalocytosis", "SAO", "Stomatocytic elliptocytosis"]}
Rare endometriosis is a rare, non-malformative gynecologic disease characterized by the presence of functional endometrial glands and stroma in extrapelvic locations, such as lungs, pleura, kidneys, bladder, abdominal wall, umbilicus, and cesarean section scar among others. Clinical manifestations are menstrually-related and depend on the location of the ectopic tissue, but in general include pain, mass/nodule, swelling and/or bleeding in the involved area. [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	Extrapelvic endometriosis	c0014175	6,332	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=137820	2021-01-23T18:47:23	{"mesh": ["D004715"], "umls": ["C0014175"], "icd-10": ["N80.0", "N80.1", "N80.2", "N80.3", "N80.4", "N80.5", "N80.6", "N80.8", "N80.9"], "synonyms": ["Endometriosis outside pelvis"]}
Esophageal web SpecialtyGastroenterology Esophageal webs are thin membranes occurring anywhere along the esophagus.[1] ## Contents * 1 Presentation * 2 Causes * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Presentation[edit] Its main symptoms are pain and difficulty in swallowing (dysphagia).[citation needed] Esophageal webs are thin 2–3 mm (0.08–0.12 in) membranes of normal esophageal tissue consisting of mucosa and submucosa that can partially protrude/obstruct the esophagus. They can be congenital or acquired. Congenital webs commonly appear in the middle and inferior third of the esophagus, and they are more likely to be circumferential with a central or eccentric orifice. Acquired webs are much more common than congenital webs and typically appear in the cervical area (postcricoid).[citation needed] Clinical symptoms of this condition are selective (solid more than liquids) dysphagia, thoracic pain, nasopharyngeal reflux, aspiration, perforation and food impaction (the last two are very rare).[citation needed] * Esophageal web stenosis in barium swallow examination lateral view. * Web with "jet-phenomenon". Arrowhead on incomplete opening of the upper esophageal sphincter. * Esophageal web stenosis in barium swallow examination frontal view. ## Causes[edit] They are mainly observed in the Plummer–Vinson syndrome,[2] which is associated with chronic iron deficiency anemia. One in 10 patients with Plummer-Vinson syndrome will eventually develop squamous cell carcinoma of the esophagus,[3] but it is unclear if esophageal webs in and of themselves are a risk factor. Esophageal webs are associated with bullous diseases (such as epidermolysis bullosa, pemphigus, and bullous pemphigoid), with graft versus host disease involving the esophagus, and with celiac disease.[citation needed] Esophageal webs are more common in white individuals and in women (with a ratio 2:1). The literature describes relations between these webs and Plummer-Vinson Syndrome, bullous dermatologic disorders, inlet patch, graft-versus-host disease and celiac disease. The postulated mechanisms are sideropenic anemia (mechanism unknown) or some interference of the immune system. Esophageal webs can be ruptured during upper endoscopy.[citation needed] ## Diagnosis[edit] The diagnostic test of choice is a barium swallow.[citation needed] ## Treatment[edit] Esophageal webs and rings can be treated with endoscopic dilation.[citation needed] ## References[edit] 1. ^ Medscape "Esophageal Webs and Rings" Retrieved on 27 March 2017 2. ^ Okamura H, Tsutsumi S, Inaki S, Mori T (September 1988). "Esophageal web in Plummer-Vinson syndrome". The Laryngoscope. 98 (9): 994–8. doi:10.1288/00005537-198809000-00014. PMID 3412097. 3. ^ "What are the risk factors for cancer of the esophagus?". Esophagus Cancer. American Cancer Society. Retrieved 15 April 2012. ## External links[edit] Classification D * ICD-10: Q39.4 * DiseasesDB: 31503 External resources * eMedicine: med/3413 * v * t * e Congenital malformations and deformations of digestive system Upper GI tract Tongue, mouth and pharynx * Cleft lip and palate * Van der Woude syndrome * tongue * Ankyloglossia * Macroglossia * Hypoglossia Esophagus * EA/TEF * Esophageal atresia: types A, B, C, and D * Tracheoesophageal fistula: types B, C, D and E * esophageal rings * Esophageal web (upper) * Schatzki ring (lower) Stomach * Pyloric stenosis * Hiatus hernia Lower GI tract Intestines * Intestinal atresia * Duodenal atresia * Meckel's diverticulum * Hirschsprung's disease * Intestinal malrotation * Dolichocolon * Enteric duplication cyst Rectum/anal canal * Imperforate anus * Rectovestibular fistula * Persistent cloaca * Rectal atresia Accessory Pancreas * Annular pancreas * Accessory pancreas * Johanson–Blizzard syndrome * Pancreas divisum Bile duct * Choledochal cysts * Caroli disease * Biliary atresia Liver * Alagille syndrome * Polycystic liver 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	Esophageal web	c0267080	6,333	wikipedia	https://en.wikipedia.org/wiki/Esophageal_web	2021-01-18T18:54:47	{"icd-10": ["Q39.4"], "wikidata": ["Q1496010"]}
Scrub typhus is a rare dust mite-borne infectious disease caused by the Orientia tsutsugamushi bacterium and characterized clinically by an eruptive fever which is potentially serious. ## Epidemiology Precise prevalence and incidence rates of scrub typhus are not known. An estimated 1 billion people worldwide are at risk for scrub typhus, and an estimated 1 million cases occur each year. The disease is widespread in rural South and South-East Asia and the Western Pacific (Korea to Australia) as well as from Japan to India and Pakistan. In these regions its annual incidence is approximately 1/4,000. Scrub typhus occurs preferentially in spring and autumn in rural areas and has frequently been reported in individuals who traveled to endemic regions. ## Clinical description After a silent incubation period of 10 days or more, onset is sudden with constant high fever, headache, obtundation, cough, myalgia and nausea. A pale macular rash is common and an inoculation eschar at the site of the mite bite is found in many cases, often with painful satellite lymph nodes. Splenomegaly is observed in 1/3 of cases. Most cases are mild, but pneumonitis, meningoencephalitis, multiorgan failure, bleeding and even death may occur, especially in untreated patients. Relapses after recovery may occur but are usually less severe than the inaugural episode. ## Etiology Scrub typhus is caused by Orientia tsutsugamushi, an obligate intracellular Gram-negative rod bacteria belonging to the genus Orentia, which is transmitted to humans by the bites of larval thrombiculid mites (chiggers). ## Diagnostic methods Diagnosis is based on clinical signs (fever, headache, eschar at the bite site, rash) in an endemic rural zone. Non-specific laboratory test results include increased transaminase levels, thrombocytopenia, leucopenia and CD4/CD8 lymphocyte ratio inversion. A definitive diagnosis can be made by culture of O. tsutsugamushi in a shell vial or molecular biology analysis of sampling (skin, lymph nodes, EDTA blood) using PCR amplification. The organisms stain poorly with the Gimenez method but easily with Giemsa staining. Immunohistochemistry of skin lesions may reveal an O. tsutsugamushi infection. Later serological confirmation is possible by indirect immunofluorescence. ## Differential diagnosis Differential diagnosis includes typhoid fever, leptospirosis, malaria, and dengue (see these terms), as well as HIV seroconversion and rickettsial diseases (see this term). ## Management and treatment Treatment usually involves drug therapy with doxycycline and chloramphenicol. Doxycycline is administered for a short time (3-7 days) in adults (200 mg/day) and children (2.2 mg/kg, twice daily). All patients with a suspected infection should be treated. Patients with poor response to doxycycline and chloramphenicol, as well as pregnant women, can be treated with rifampicin (600-900 mg/day) or azithromycin (500 mg on the first day, then 250 mg/day). ## Prognosis The disease course may be severe. However, the mortality rate depends on the geographic areas and varies from 3% in Taiwan up to 30% in Northern Japan. The exact reasons for the variable mortality in these regions are not known, but it is likely that different serotypes may account for the varying manifestations 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	Scrub typhus	c0036472	6,334	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=83317	2021-01-23T17:19:38	{"mesh": ["D012612"], "umls": ["C0036472"], "icd-10": ["A75.3"], "synonyms": ["Tsutsugamushi disease", "Tsutsugamushi fever"]}
A number sign (#) is used with this entry because autoimmune lymphoproliferative syndrome type III (ALPS3) is caused by homozygous mutation in the PRKCD gene (176977) on chromosome 3p21. Description Autoimmune lymphoproliferative syndrome type III is an autosomal recessive disorder of immune dysregulation. The phenotype is variable, but most patients have significant lymphadenopathy associated with variable autoimmune manifestations. Some patients may have recurrent infections. Lymphocyte accumulation results from a combination of impaired apoptosis and excessive proliferation (summary by Oliveira, 2013). For a general description and a discussion of genetic heterogeneity of ALPS, see 601859. Clinical Features Salzer et al. (2013) reported a 12-year-old boy, born of consanguineous Turkish parents, with a primary immune deficiency syndrome characterized by B-cell deficiency and severe autoimmunity. He had recurrent infections involving most systems (respiratory, urinary, gastrointestinal) beginning in the first year of life. At age 15 months, he developed autoimmune nephrotic syndrome; renal biopsy showed membranous glomerulonephritis with IgG and complement component deposits. By age 3 years, he had hepatosplenomegaly and generalized lymphadenopathy associated with low-grade herpes viremia. Additional autoimmune features included polychondritis and antiphospholipid syndrome, with antinuclear, anti-dsDNA, and anticardiolipin IgG antibodies. He was treated with IV IgG at age 4 years, which resulted in a decrease in infections, and with anti-CD20 therapy, but autoantibodies persisted. Initial immunologic workup showed low IgG with increased IgA and IgM. The formal criteria of CVID, which includes decreased levels of at least 2 classes of Ig were not met, but the phenotype was consistent with a CVID-like disorder. B-cell studies showed a reduction of CD19+ B cells, decreased memory B cells, and increased CD21(low) B cells. T-cell studies showed mildly decreased proliferative responses. The patient's father had Behcet disease and mild autoimmune thyroiditis at age 40 years, whereas his mother was asymptomatic. Oliveira (2013) noted that the patient reported by Salzer et al. (2013) had an autoimmune lymphoproliferative disorder that resembled ALPS without meeting the formal diagnostic criteria for it. Treatment with low-dose steroids and the immunosuppressive agent mycophenolate mofetil resulted in good disease control in this patient. Andre et al. (2007) reported 3 sibs, born of consanguineous parents of European descent, with a childhood-onset autoinflammatory disorder. The most severely affected child presented at age 3 years with a lymphoproliferative syndrome with lymphadenopathy and hepatosplenomegaly. She had severe hemolytic anemia and later developed idiopathic thrombocytopenia purpura. She also had manifestations reminiscent of systemic lupus erythematosus (SLE; 152700), such as cutaneous erythema and glomerulonephritis arthralgias. Laboratory studies showed increased erythrocyte sedimentation rate, hypergammaglobulinemia, and autoantibodies. B cells were increased, but alpha/beta, CD4-/CD8- T cells were not detectable. The condition required vigorous immunosuppressive treatment. The patient's sister and brother presented at ages 10 and 6 years, respectively, with features of SLE, including rash, arthritis, and glomerulonephritis, but without a frank lymphoproliferative disorder. In vitro assays of patient lymphocytes showed impaired activation-induced apoptosis associated with increased levels of the antiapoptotic factor BCL2A1 (601056). In a follow-up of the patients reported by Andre et al. (2007), Belot et al. (2013) noted that none of them presented with features of early-onset immunodeficiency, although 1 died at age 13 years of septic shock. The patients had increased numbers of immature B cells and decreased numbers of memory B cells. B cells from 1 patient showed a hyperproliferative response to stimulation, and mutant lymphocytes were resistant to calcium-dependent apoptosis. Kuehn et al. (2013) reported a Hispanic boy who had recurrent sinusitis and otitis in early childhood associated with generalized lymphadenopathy, hepatosplenomegaly, and recurrent fevers. He also had a facial rash and erythematous macules, but no renal disease. Laboratory studies showed several nonspecific autoantibodies, hypergammaglobulinemia, increased erythrocyte sedimentation rate and C-reactive protein, and B-cell lymphocytosis with the majority of cells expressing the immature marker CD5 (153340); class-switched memory B cells were decreased. Cultured B cells showed increased secretion of IL10 (124092). NK cells showed impaired function. The patient responded well to immunosuppressive therapy. Patient B cells were increased in number and showed hyperproliferation in response to stimulus; T cells did not show an increased rate of proliferation. Inheritance The transmission pattern of immune dysregulation in the families reported by Salzer et al. (2013) and Andre et al. (2007) was consistent with autosomal recessive inheritance. Molecular Genetics In a patient with ALPS3, Salzer et al. (2013) identified a homozygous splice site mutation in the PRKCD gene (176977.0001). The mutation was found by homozygosity mapping and exome sequencing and segregated with the disorder in the family. Western blot analysis showed absent expression of the PRKCD protein in patient cells and decreased expression in cells from the heterozygous father. Patient cells showed defective phosphorylation of MARCKS (177061), a downstream target of PRKCD, as well as increased IL6 (147620) production after stimulation. Genetic analysis also revealed a heterozygous variant (rs231775) in the CTLA4 gene (123890.0001) in the patient and his father, which may have acted as a disease modifier given its association with autoimmune disorders. In 3 sibs with ALPS3, originally reported by Andre et al. (2007), Belot et al. (2013) identified a homozygous missense mutation in the PRKCD gene (G510S; 176977.0002). The mutation was found by a combination of linkage analysis and whole-exome sequencing. In a Hispanic boy with ALPS3, Kuehn et al. (2013) identified a homozygous missense mutation in the PRKCD gene (R614W; 176977.0003). Western blot analysis showed low levels of mutant protein expression in patient cells, and immunohistochemical studies showed absent protein expression in the patient's lymph node. Knockdown of PRKCD by siRNA in control B cells caused an increase in B-cell proliferation without an increase in T-cell proliferation. Animal Model PRKCD is involved in B-cell signaling and in the regulation of growth, apoptosis, and differentiation of a variety of cell types. Prkcd is most abundant in B and T lymphocytes of lymphoid organs, cerebrum, and intestine of normal mice. By generating mice with a disruption in the Prkcd gene, Miyamoto et al. (2002) observed that the mice are viable up to 1 year but prone to autoimmune disease, with enlarged lymph nodes and spleens containing numerous germinal centers. Flow cytometric analysis showed increased numbers of bone marrow-derived B cells, but no change in CD5+ B cells or T cells. Transfer of B cells into Rag1 (179615) -/- mice resulted in greater numbers of splenic B cells and germinal centers in mice receiving Prkcd -/- cells. Prkcd-deficient B cells also mounted a stronger proliferative response than those from wildtype mice. RT-PCR analysis detected higher levels of IL6 (147620), but not other cytokines, in mutant than in wildtype B cells. EMSA analysis showed increased DNA-binding activity of NFIL6 (CEBPB; 189965) but not NFKB. Serum IgG1 and IgA, but not other isotype, concentrations were greater in Prkcd-deficient mice. Although Miyamoto et al. (2002) did not detect antinuclear antibodies, they did observe high levels of primarily IgG antibodies to chromatin in older mutant mice. Histologic analysis revealed evidence of glomerulonephritis with deposition of IgG and complement component C3. Miyamoto et al. (2002) noted that crosslinking of B-cell receptors leads to activation of both Prkcb (176970) and Prkcd, but that proliferation in mice deficient in these enzymes is reduced and enhanced, respectively, possibly allowing for fine regulation of the immune response. INHERITANCE \- Autosomal recessive ABDOMEN Liver \- Hepatomegaly Spleen \- Splenomegaly GENITOURINARY Kidneys \- Nephrotic syndrome (in some patients) \- Membranous glomerulonephritis (in some patients) \- Deposition of IgG and complement seen on renal biopsy (in some patients) SKELETAL \- Polychondritis, autoimmune \- Arthralgia SKIN, NAILS, & HAIR Skin \- Erythematous rash (in some patients) HEMATOLOGY \- Antiphospholipid syndrome Hemolytic anemia \- Autoimmune thrombocytopenia IMMUNOLOGY \- Recurrent infections \- Decreased CD19+ B cells \- Decreased memory B cells \- Increased CD21+ (low) B cells \- Decreased IgG \- Increased Ig \- B-cell lymphocytosis \- Autoantibodies (anti-nuclear, anti-dsDNA, anti-cardiolipin) \- Lymphadenopathy \- Autoimmune disorders \- Mildly decreased proliferative responses of T cells \- Impaired lymphocyte apoptosis MISCELLANEOUS \- Onset in infancy or childhood \- Variable manifestations MOLECULAR BASIS \- Caused by mutation in the protein kinase C, delta gene (PRKCD, 176977.0001 ) ▲ 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	AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE III	c1328840	6,335	omim	https://www.omim.org/entry/615559	2019-09-22T15:51:37	{"doid": ["0110119"], "mesh": ["D056735"], "omim": ["615559"], "orphanet": ["3261"], "synonyms": ["Alternative titles", "IMMUNODEFICIENCY, COMMON VARIABLE, 9, FORMERLY"]}
## Summary ### Clinical characteristics. DCX-related disorders include the neuronal migration disorders: * Classic thick lissencephaly (more severe anteriorly), usually in males * Subcortical band heterotopia (SBH), primarily in females Males with classic DCX-related lissencephaly typically have early and profound cognitive and language impairment, cerebral palsy, and epileptic seizures. The clinical phenotype in females with SBH varies widely with cognitive abilities that range from average or mild cognitive impairment to severe intellectual disability and language impairment. Seizures, which frequently are refractory to antiepileptic medication, may be either focal or generalized and behavioral problems may also be observed. In DCX-related lissencephaly and SBH the severity of the clinical manifestation correlates roughly with the degree of the underlying brain malformation as observed in cerebral imaging. ### Diagnosis/testing. The diagnosis of a DCX-related disorder is established in a proband by identification of a DCX pathogenic variant on molecular genetic testing. ### Management. Treatment of manifestations: Antiepileptic drugs for epileptic seizures; deep brain stimulation may improve the seizure disorder in individuals with SBH; special feeding strategies in newborns with poor suck; physical therapy to promote mobility and prevent contractures; special adaptive chairs or positioners as needed; occupational therapy to improve fine motor skills and oral-motor control; participation in speech therapy, educational training, and enrichment programs. Surveillance: Regular neurologic examination and monitoring of seizure activity, EEG, and antiepileptic drug levels; regular measurement of height, weight, and head circumference; evaluation of feeding and nutrition status; assessment of psychomotor, speech, and cognitive development; prompt consultation in the event of novel neurologic findings or deterioration, aspiration, or infections; monitoring for orthopedic complications such as foot deformity or scoliosis. ### Genetic counseling. DCX-related disorders are inherited in an X-linked manner. Up to10% of unaffected mothers of children with a DCX pathogenic variant are presumed to have germline mosaicism with or without somatic mosaicism. A woman who is heterozygous for a DCX pathogenic variant has a 50% chance of transmitting the pathogenic variant in each pregnancy. Hemizygous male offspring usually manifest DCX-related classic lissencephaly, while heterozygous female offspring may be asymptomatic or more frequently manifest a wide phenotypic spectrum of SBH. If the pathogenic variant has been identified in the family, testing to determine the genetic status of at-risk family members and prenatal testing for pregnancies at increased risk are possible. ## Diagnosis DCX-related disorders are X-linked conditions involving abnormal neuronal migration; they include: * Classic lissencephaly, usually in males * Subcortical band heterotopia (SBH), primarily in females ### Suggestive Findings A DCX-related disorder should be suspected in individuals with characteristic findings in brain magnetic resonance imaging (MRI) in combination with epileptic seizures and/or developmental delay or behavioral problems. A family history consistent with X-linked inheritance is an additional supportive finding. #### Brain MRI Findings Classic thick lissencephaly, usually in males: * Is typically characterized by agyria (sulci >30 mm apart) or pachygyria (abnormally wide gyri with sulci 15-30 mm apart) with thickened cortex of ~10-20 mm (normal: ~4 mm) (Figure 1B-C) [Mutch et al 2016, DiDonato et al 2017]; * Is more severe anteriorly, referred to as an anterior-to-posterior (A>P) gradient; * May be accompanied by: * Prominent perivascular (Virchow Robin) spaces * Delayed myelination * Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles * Normal or diffusely thin corpus callosum * No obvious cerebellar or brain stem abnormalities * Enlarged caudate head * Mildly to moderately diminished cerebral white matter. #### Figure 1. Cerebral MRI of three patients with DCX-related disorders A. Characteristic bilateral subcortical band heterotopia () in a female patient with heterozygous DCX exon deletion Subcortical band heterotopia (SBH), usually in females, is characterized by one or more of the following: Symmetric, usually bilateral bands of gray matter within the white matter between and parallel to the cortex and the lateral ventricles appearing as an isointense second cortical structure beneath the cortex (double cortex) and separated from the cortex by a thin layer of normal-appearing white matter. The heterotopic band is more often thick (~70%) than thin (1-7 mm) (Figure 1A) [Bahi-Buisson et al 2013, Di Donato et al 2017]. * Normal-appearing and/or thickened cerebral cortex with or without simplified gyration * Predominant location in the frontoparietal lobe region #### Clinical Features Findings may include: * Intellectual disability * Language impairment * Psychomotor delay * Behavioral disturbances * Seizures * Microcephaly #### Family History Evidence for X-linked inheritance obtained from a detailed family history. Special attention should be paid to epilepsy, miscarriages, stillbirths, children, who died at a young age without conclusive diagnosis, and cognitive impairment or developmental delay. ### Establishing the Diagnosis The diagnosis of a DCX-related disorder is established in a proband by identification of one of the following on molecular genetic testing (see Table 1): * A hemizygous DCX pathogenic variant in a male proband * A heterozygous DCX pathogenic variant in a female proband Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of DCX-related disorders is broad, individuals with the distinctive brain MRI findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with insufficient clinical and imaging datain whom the diagnosis of aDCX-related disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of a DCX-related disorder molecular genetic testing approaches can include single-gene testing or use of a multigene panel: * Single-gene testing. Sequence analysis of DCX detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. Typically exon or whole-gene deletions/duplications in females are not detected; however, a deletion may result in PCR failure in a male. Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. * A multigene panel that includes DCX and other genes of interest (see Differential Diagnosis) 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. 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 Due to phenotypic overlap with other inherited neuronal migration disorders, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option especially in the absence of sufficient clinical and imaging data. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. Note: Somatic mosaicism is a common finding in DCX-related disorders [D'Agostino et al 2002, Aigner et al 2003, Quélin et al 2012, Jamuar et al 2014, Tsai et al 2016, González-Morón et al 2017]. Sequence analysis methods, such as Sanger or next-generation sequencing, vary in their ability to detect mosaicism and should be evaluated for their detection rate. Due to assay sensitivity, the proportion of somatic mosaicism in both affected individuals and parents may be underestimated. Analysis of DNA from different tissues (e.g., hair roots, buccal swabs) can be useful in the detection or confirmation of somatic mosaicism. ### Table 1. Molecular Genetic Testing Used in DCX-Related Disorders View in own window Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method DCXSequence analysis 3, 496% 5 Gene-targeted deletion/duplication analysis 64% 5 KaryotypeSingle case 7 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\. Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. 5\. Matsumoto et al [2001]; Hoischen et al [2009]; Bahi-Buisson et al [2013]; Authors, unpublished data 6\. 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. 7\. Gleeson et al [1998] reported a balanced X:2 translocation in a female which disrupted DCX between the first two coding exons. ## Clinical Characteristics ### Clinical Description An individual with a DCX-related disorder usually presents with epileptic seizures and/or developmental delay and behavioral disturbances [Matsumoto et al 2001, Bahi-Buisson et al 2013] and with the characteristic findings on brain MRI noted during clinical evaluation. #### Males DCX-related classic lissencephaly usually manifests with early and profound cognitive and language impairment, cerebral palsy, and epileptic seizures. Development. Severity of symptoms usually correlates with the degree of the underlying brain malformation observed in cerebral imaging. Motor development is compromised, but overall better than in patients with PAFAH1B1-associated classic lissencephaly. Leger et al [2008] reported on the development of 33 males with DCX-related lissencephaly: * At a median age of 7.5 years (range 1.5-37 years) almost half were reported to walk independently, the remaining individuals showed moderate to severe motor impairment. * Almost half of the individuals in the study did not develop any speech. Behavioral disturbances may include agitation and irritability or autistic features. Epileptic seizures occur in more than 80% of affected males and commonly start within the first year. The observed seizure pattern may include multiple seizure types, frequently with infantile spasms with or without characteristic hypsarrhythmia [Leger et al 2008, Dobyns 2010]. Seizure control remains insufficient in more than half of the affected individuals [Bahi-Buisson et al 2013]. Other findings * Disturbed muscle tone and immobility may result in contractures and scoliosis. * More severe clinical manifestations may also affect feeding and swallowing, thus resulting in insufficient nutrition or aspiration. * Head circumference may decline postnatally and result in postnatal microcephaly. Life span. Individuals with severe classic lissencephaly may survive into adulthood. However, life span overall is shortened due to complications either directly related to the seizure disorder (including sudden unexplained death in epilepsy or in the course of a developing epileptic encephalopathy), or resulting from disturbed cerebral regulation of vital functions (e.g., breathing abnormalities) or aspiration during respiratory infections or associated with food intake. The rare male with the milder cerebral manifestation of subcortical band heterotopia (SBH) has findings similar to those in females with SBH [D'Agostino et al 2002, Aigner et al 2003]. #### Females The SBH clinical phenotype in heterozygous females is markedly milder than the classic lissencephaly clinical phenotype in males, very variable, and roughly correlated with the extent and thickness of the subcortical band as observed in cerebral imaging. Bahi-Buisson et al [2013] proposed two distinct subgroups among females with DCX pathogenic variants: a more severe clinical phenotype usually observed in sporadic cases and a milder phenotype mainly observed in heterozygous asymptomatic females with normal cerebral MRI or only thin frontal subcortical bands. Severe phenotype associated with thicker SBH typically includes: * Developmental delay * Moderate-to-severe intellectual disability * Severe language impairment * Behavioral problems * Seizures (frequently refractory to antiepileptic medication) that may be either focal or generalized (~50% each) and in more severe cases eventually progress to Lennox-Gastaut syndrome [Dobyns 2010] Mild phenotype associated with thin frontal band heterotopia or normal-appearing cerebral MRI may include: * Average or mildly impaired cognitive skills [Guerrini et al 2003] * No additional symptoms * Recognition only after prenatal or postnatal diagnosis of a DCX-related disorder in an offspring or other family member As in other X-linked disorders, X-chromosome inactivation has been postulated to contribute to inter- and intrafamilial phenotypic variability in females heterozygous for a DCX pathogenic variant. As an example, such variability has been observed in monozygous female twins heterozygous for a recurrent DCX nonsense variant [Martin et al 2004]. Both twins had thick generalized SBH, clearly delineated from the cortex by a small band of white matter. However, one twin had a broader heterotopic band than the other including frontal pachygyria associated with more profound cognitive and psychomotor impairment and a more abnormal EEG than observed in her twin sister. #### Somatic Mosaicism Somatic mosaicism for DCX pathogenic variants has been repeatedly documented in both females and males with milder manifestations [D'Agostino et al 2002, Aigner et al 2003, Bahi-Buisson et al 2013, Jamuar et al 2014]. #### Pathophysiology In hemizygous males all neurons express the pathogenic variant and are disturbed in their migratory properties, leading to the smoothened and disorganized thickened cortex observed in classic lissencephaly. In females heterozygous for a DCX pathogenic variant, inactivation of one of the two X chromosomes in neural/somatic cells is thought to result in two neuronal populations [Forman et al 2005, Marcorelles et al 2010, Wynshaw-Boris et al 2010]: * Cells expressing the wild type allele that continue and complete their migratory process to form the normal cortex * Cells expressing the pathogenic variant that accumulate in the white matter between the cortex and lateral ventricles as a heterotopic band of neurons ### Genotype-Phenotype Correlations About one third of all DCX pathogenic variants are recurrent, resulting in rather similar pathogenic variant-specific cortical phenotypes in and between families [Bahi-Buisson et al 2013]. A slight effect of the type and location of the DCX pathogenic variant on the resulting severity of the brain malformation for both SBH and classic lissencephaly has been suggested [Leventer 2005, Bahi-Buisson et al 2013]. * DCX pathogenic nonsense variants in males are very rare and have mainly been observed as postzygotic mosaic events. * Loss-of-function variants are more likely to occur in simplex cases (i.e., a single occurrence in a family); missense variants are more likely to be observed in familial cases [Gleeson et al 1999, Leger et al 2008, Bahi-Buisson et al 2013]. * Hemizygous DCX missense variants within the N-terminal DC tandem repeat domain tend to result in more severe forms of lissencephaly than missense variants in the C-DC domain. * Truncating variants were more frequently associated with generalized subcortical bands; missense variants were more commonly associated with frontal band heterotopia only [Matsumoto et al 2001, Leventer 2005, Leger et al 2008, Haverfield et al 2009]. * DCX-related SBH in males appears to result predominantly from either mosaicism for a DCX pathogenic variant or specific missense variants with residual function [Leger et al 2008]. For further information on postulated functional consequences of various DCX pathogenic missense variants and the observed clinical manifestations in male and female patients see Bahi-Buisson et al [2013]. ### Penetrance Males * No instances of asymptomatic males with germline hemizygous DCX pathogenic variants have been reported, thus suggesting full penetrance of germline DCX pathogenic variants in males. * Males with postzygotic mosaic pathogenic variants may have milder clinical manifestations or, in rare cases, be asymptomatic (see Clinical Description, Somatic Mosaicism). Females * Heterozygous females with germline missense or nonsense DCX variants may have no obvious brain malformation or seizures [Aigner et al 2003, Guerrini et al 2003]. * Penetrance was reported to be less than 50% in the mothers with a heterozygous or mosaic pathogenic variant in DCX whose children presented with DCX-related disorders [Bahi-Buisson et al 2013]. ### Nomenclature Classic lissencephaly may also be called lissencephaly type 1. In the absence of associated intra- or extracranial malformations it is also termed isolated lissencephaly sequence. Classic lissencephaly that occurs in combination with cerebellar hypoplasia is classified as lissencephaly with cerebellar hypoplasia. Classic lissencephaly is morphologically and etiologically distinct from lissencephaly type 2, which is also called cobblestone lissencephaly, and from thin lissencephaly. To emphasize their X-linked inheritance, DCX-related lissencephaly and SBH have variably been termed and abbreviated: * X-linked lissencephaly (XLIS) * Lissencephaly, X-linked (LISX) * Isolated lissencephaly, X-linked (ILSX) * Subcortical laminar heterotopia, X-linked (X-SCLH) * Subcortical band heterotopia, X-linked (SBHX) DCX-related lissencephaly and SBH have also been referred to as double cortex syndrome. ### Prevalence The incidence of all forms of type 1 lissencephaly has been estimated at 1:100,000 births [Orphanet], with the majority resulting from heterozygous pathogenic variants of PAFAH1B1 (LIS1). No specific data on the prevalence of lissencephaly due to pathogenic variants in DCX are available. DCX-related disorders account for: * Virtually all families with X-linked inheritance of classic lissencephaly and/or SBH; * About 10% of all persons with classic lissencephaly (38% of all males, but only rare females); * About 53%-85% of all SBH, about 80% of sporadic SBH, and about 29% of SBH in males [Pilz et al 1998, Gleeson et al 1999, Matsumoto et al 2001, Guerrini & Filippi 2005]. ## Differential Diagnosis See Tables 2a, 2b, and 2c for disorders to consider in the differential diagnosis of DCX-related disorders. ### Table 2a. Disorders with Lissencephaly-Pachygyria with Classic or Thick Lissencephaly (cortex 10-20 mm) to Consider in the Differential Diagnosis View in own window DisorderGene(s)MOIClinical Features Differentiating This Disorder from DCX Disorders PAFAH1B1- associated lissencephalyPAFAH1B1AD * Most frequent cause of classic or thick lissencephaly * More prominent in the posterior regions of the brain, w/a P>A gradient (DCX-related lissencephaly presents w/an A>P gradient.) 1 Miller-Dieker syndromeMicrodeletion of 17p13.3 2AD * Distinctive facial features (i.e., prominent forehead, bitemporal hollowing, short nose w/upturned tip & anteverted nostrils, & protuberant upper lip w/thin vermilion border) * Cardiac malformations & omphalocele also reported as rare associated extracerebral manifestations 3 TUBA1A- related lissencephaly (see Tubulinopathies Overview)TUBA1AAD * Tubulinopathy-related dysgyria as more complex cortical phenotype including areas w/polymicrogyria-like appearance or simplified gyral pattern * Small brain stem, cerebellar vermis &/or cerebellar hemispheres, dysmorphic or absent corpus callosum, anterior limb of the capsula interna not delineated, large tectum 4 DYNC1H1- related pachygyria (OMIM 614563)DYNC1H1ADPosterior or anterior predominant pachygyria or dysgyria 5 KIF5C-related pachygyria (OMIM 615282)KIF5CAD * Posterior or anterior predominant pachygyria * Severe intrauterine growth retardation * Arthrogryposis * Microcephaly 5 Baraitser- Winter syndrome (OMIM PS243310)ACTB ACTG1AD * Thick cortex anterior or central predominant or SBH * Dysmorphic features * Iris or retinal coloboma * Sensoneurinal deafness * Congenital cardiac or renal malformations * Abnormal corpus callosum (short, thick or absent) 6 CDK5-related lissencephaly (OMIM 616342)CDK5AR * Agyria * Agenesis of the corpus callosum * Severe cerebellar & pontine hypoplasia * Dilated subarachnoidal spaces * Dysmorphic facial features, lymphedema, arthrogryposis multiplex * Early lethal 7 A = anterior; AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; P = posterior; SBH = subcortical band heterotopia 1\. Uyanik et al [2007] 2\. Miller-Dieker syndrome is caused by either small cytogenetically visible deletions or FISH-detectable microdeletions of 17p13.3 that include LIS1 (officially designated as PAFAH1B1) and YWHAE, and intervening genes. 3\. Bruno et al [2010] 4\. Bahi-Buisson et al [2014] 5\. Poirier et al [2013] 6\. Di Donato et al [2016a], Di Donato et al [2016b] 7\. Magen et al [2015] ### Table 2b. Disorders with Lissencephaly-Pachygyria with Thin Lissencephaly (cortex 5-10 mm) to Consider in the Differential Diagnosis View in own window DisorderGene(s)MOIClinical Features Differentiating This Disorder from DCX Disorders X-linked lissencephaly w/ambiguous genitalia (OMIM 300215)ARXXL * Temporal predominant thin lissencephaly (6-10 mm) * Agenesis of the corpus callosum * Perinatal encephalopathy w/intractable seizures * Brain stem & cerebellum appear normal * Ambiguous or underdeveloped genitalia * Chronic diarrhea * High lethality in 1st 3 mos of life 1 RELN-related lissencephaly (OMIM 257320)RELNAR * Thin lissencephaly w/A>P gradient * Severe cerebellar hypoplasia 2 VLDLR- associated cerebellar hypoplasiaVLDLRAR * Thin lissencephaly w/A>P gradient * Severe cerebellar hypoplasia 2 CRADD related lissencephaly (OMIM 614499)CRADDAR * Anterior predominant thin lissencephaly * Megalencephaly * Normal cerebellum 3 A = anterior; AR = autosomal recessive; MOI = mode of inheritance; P = posterior; XL = X-linked 1\. Uyanik et al [2003], Coman et al [2017] 2\. Valence et al [2016] 3\. Di Donato et al [2016a], Di Donato et al [2016b] ### Table 2c. Disorders with Subcortical Band Heterotopia to Consider in the Differential Diagnosis View in own window DisorderGene(s)MOIClinical Features Differentiating This Disorder from DCX Disorders PAFAH1B1- associated subcortical band heterotopiaPAFAH1B1ADMore prominent in the posterior regions of the brain, w/a P>A gradient (DCX-related SBH presents w/an A>P gradient.) 1 Baraitser- Winter syndrome (OMIM 243310, 614583)ACTB ACTG1AD * Short central regions of SBH adjacent to frontal pachygyria * Dysmorphic features * Iris or retinal coloboma * Sensoneurinal deafness * Congenital cardiac or renal malformations * Abnormal corpus callosum (short; thick or absent) 2 A = anterior; AD = autosomal dominant; MOI = mode of inheritance; P = posterior; SBH = subcortical band heterotopia 1\. Uyanik et al [2007] 2\. Di Donato et al [2016a], Di Donato et al [2016b] Other disorders to consider include those with cobblestone lissencephaly (i.e., Walker-Warburg syndrome, muscle eye brain disease [see OMIM PS236670], and Fukuyama congenital muscular dystrophy) as well as tubulinopathies (see Tubulinopathies Overview), disorders with polymicrogyria, and disorders with periventricular nodular heterotopia (see FLNA-Related Periventricular Nodular Heterotopia). ## Management ### Evaluations Following Initial Diagnosis To establish the individual clinical manifestation of a DCX-related disorder, the following evaluations are recommended if they have not already been completed: * Neurologic evaluation, including EEG and cerebral MRI. This is best performed by a pediatric neurologist or neurologist with special expertise in the diagnosis, treatment, and surveillance of individuals with multiple disabilities and difficult-to-treat seizures * Developmental evaluation including motor skills, cognition, and speech * Growth and head circumference * Nutrition and feeding evaluation (including a swallowing assessment in individuals lacking head control or the ability to sit unsupported) to enable early recognition of malnutrition or risk constellations for aspiration that would require special medical surveillance or measures (e.g., tube feeding) * Ophthalmologic evaluation for impaired vision, potentially correctable by glasses * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Epileptic seizures require antiepileptic medication. Individual treatment strategies should be based on the type and frequency of seizures, EEG results, and responsiveness. Surgical resection of heterotopic brain tissue has been tried in only a few individuals with SBH; overall it has not been effective in reducing seizure activity and thus is not recommended [Bernasconi et al 2001]. More recently, deep brain stimulation has been suggested to improve the seizure disorder in individuals with SBH based on first results in small treated cohorts [Franco et al 2016]. In addition, appropriate interdisciplinary management should start at the time of diagnosis and can prolong survival and improve quality of life for individuals with a DCX-related disorder: * Feeding problems in newborns may require special strategies including placement of a percutaneous endoscopic gastrostomy tube to deal with weak or uncoordinated sucking. * Physical therapy helps to maintain and promote mobility and prevent contractures. Special adaptive chairs or positioners or other measures may support sitting and mobility. * Occupational therapy may help improve fine motor skills and oral motor control. * Speech therapy may improve communication * A full range of educational training and enrichment programs should be available. * Parents should be informed early and repeatedly on the common presentation and appropriate management of seizures. For parents of individuals with a severe manifestation of a DCX-related disorder this should also include appropriate discussion of the level of care in sudden critical situations. * For information on non-medical interventions and coping strategies for parents or caregivers of children with seizure disorders see Epilepsy & My Child Toolkit. ### Prevention of Secondary Complications Adequate antiepileptic treatment is important to reduce the number of seizures, which may be associated with irreversible and life-threatening complications. ### Surveillance The following are appropriate: * Regular neuropediatric or neurologic examination including monitoring of seizure activity, EEG, and antiepileptic drug (AED) levels * Regular measurement of height, weight, and head circumference; evaluation of feeding and nutrition status; assessment of psychomotor, speech, and cognitive development * Prompt neuropediatric, neurologic, or pediatric consultation in the event of novel neurologic findings or deterioration, aspiration, or infections * Monitoring of orthopedic complications including foot deformity and scoliosis ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management For pregnant women with DCX-related SBH and known history of seizures or current epileptic seizures, close medical surveillance by a neurologist familiar with the treatment of seizures (preferably at an epilepsy center) is recommended. Counseling should include discussion of the teratogenic risks associated with the currently used antiepileptic medication. For some antiepileptic medications or their combination, a substantially increased risk for fetal malformations may prompt reconsideration of the dosage or drug combination. Pregnant women should, however, be encouraged to continue medical seizure control under close surveillance and be informed about the risks associated with discontinuation of treatment. Counseling should also cover the preferred mode of delivery based on the current neurologic findings as well as any recommended postnatal measures for the newborn related to fetal medication exposure and its postnatal drop. Whenever possible, women should discuss the current antiepileptic medication or any recommended replacement of medication with higher teratogenic potential prior to any planned pregnancy. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for 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	DCX-Related Disorders	None	6,336	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1185/	2021-01-18T21:32:17	{"synonyms": []}
A number sign (#) is used with this entry because pontocerebellar hypoplasia type 6 (PCH6) is caused by homozygous or compound heterozygous mutation in the gene encoding mitochondrial arginyl-tRNA synthetase (RARS2; 611524) on chromosome 6q15. Description Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596). Clinical Features Edvardson et al. (2007) investigated 3 patients, the products of a consanguineous Sephardic Jewish marriage, who had infantile encephalopathy and a putative defect in mitochondrial translation. The eldest of the 3 affected children showed generalized hypotonia and poor sucking at several hours of age, and brain magnetic imaging (MRI) at age 3 days showed cerebellar and vermian hypoplasia but normal brain volume. Recurrent apnea from age 1 week was controlled by phenobarbital, but intractable seizures starting at age 2 months were resistant to multidrug therapy. Microcephaly became evident at age 1 year. No developmental milestones were attained, and muscle tone became spastic. The results of funduscopic observations were normal. Serial brain MRI revealed progressive atrophy of the cerebellum, pons, cerebral cortex, and white matter. The patient died at age 16 months. Activities of mitochondrial complexes I, III, and IV in muscle from this patient were markedly reduced, but activity of complex II was relatively preserved. The fourth child in the family and the second to be affected was a boy who was markedly hypotonic and lethargic from birth. He was found dead in his crib at age 7 weeks. The fifth child in the family and the third to be affected was normal on neurologic examination on the first day of life, but an apneic episode occurred on the second day. At age 3 weeks, poor feeding, lethargy, and generalized hypotonia became evident. At 4 months, she developed generalized seizures, and head growth was arrested. Brain MRI at age 3 months revealed general atrophy, with most marked changes in the pons and cerebellum. Rankin et al. (2010) reported a girl, born of unrelated British parents, with PCH6. After a normal birth, she was admitted after 19 hours with poor feeding and high respiratory rate. Laboratory studies showed increased serum lactate, which resolved with treatment. She later developed severe hypotonia, myoclonic seizures, profound developmental delay with absence of social smiling and poor head control, and poor feeding requiring gastrostomy. Brain MRI at age 14 months showed generalized cerebral atrophy, thinning of the pons, and atrophy of the cerebellar hemispheres. Examination at age 2 and 3 years showed severe progressive microcephaly and dysmorphic features, such as bitemporal narrowing, deep-set eyes with prominent nasal bridge, full cheeks, and narrow palate. She also had edematous hands and feet, and required a tracheostomy for upper airway obstruction due to hypotonia. Muscle biopsy showed normal respiratory chain activity. Rankin et al. (2010) noted some phenotypic overlap with PEHO syndrome (260565), but their patient lacked optic atrophy. Li et al. (2015) reported 2 Hispanic sibs with PCH6. Both presented in the first year of life with hypotonia and delayed psychomotor development after normal early development in the first months of life. Variable features included head lag or poor head control, weak reflexes that progressed to increased reflexes, and dysconjugate eye movements. The brother developed seizures at age 9 months. At age 4.5 years, he had microcephaly, progressive visual loss, no functional speech, refractory seizures, clinodactyly, and adducted thumb, and he required tube feeding. Brain imaging showed small posterior fossa, cerebellar vermis hypoplasia, small pons, cerebellar atrophy, and increased subarachnoid space over the frontotemporal regions. The sister was less severely affected: at age 18 months, she was able to sit with support and had started to babble; brain imaging showed cerebellar hypoplasia. She did not have seizures or visual loss. Inheritance The transmission pattern of PCH6 in the family reported by Li et al. (2015) was consistent with autosomal recessive inheritance. Mapping In a consanguineous Sephardic Jewish family with pontocerebellar hypoplasia, Edvardson et al. (2007) identified an identical haplotype in a region of chromosome 6 within a 22.46-Mb region between markers D6S1546 and D6S268 in all 3 affected patients by homozygosity mapping. Molecular Genetics In a consanguineous Sephardic Jewish family with infantile encephalopathy mapping to chromosome 6q16.1 and a putative defect in mitochondrial translation, Edvardson et al. (2007) sequenced the RARS2 gene and identified a homozygous intronic mutation (611524.0001) that segregated with the disorder in the family. In a British girl, born of unrelated British parents, with PCH6, Rankin et al. (2010) identified compound heterozygous mutations in the RARS2 gene (611524.0002 and 611524.0003). Each unaffected parent was heterozygous for 1 of the mutations. In 2 Hispanic sibs with PCH6, Li et al. (2015) identified a homozygous mutation in the promoter of the RARS2 gene (611524.0004). Patient cells showed decreased expression of RARS2 compared to controls, and luciferase studies in HEK293 cells transfected with the mutation showed a 40% reduction of promoter activity compared to wildtype. INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Head \- Microcephaly, progressive Face \- Dysmorphic features described in 1 patient \- Bitemporal narrowing Eyes \- Deep-set eyes \- Dysconjugate eye movements Nose \- Prominent nasal bridge Mouth \- Narrow palate RESPIRATORY \- Apneic episodes ABDOMEN Gastrointestinal \- Poor sucking \- Feeding difficulties MUSCLE, SOFT TISSUES \- Hypotonia \- Edematous hands and feet (1 patient) \- Reduced activity of mitochondrial respiratory chains (1 family) NEUROLOGIC Central Nervous System \- Developmental delay, profound \- Lack of speech \- Poor head control \- Seizures \- Limb spasticity \- Hyperreflexia \- Cerebral atrophy \- Cerebellar atrophy \- Brainstem atrophy LABORATORY ABNORMALITIES \- Increased serum lactate \- Increased CSF lactate MISCELLANEOUS \- Onset at birth or in first days or life \- Progressive disorder \- Variable severity \- Death in childhood may occur MOLECULAR BASIS \- Caused by mutation in the mitochondrial arginyl-tRNA synthetase gene (RARS2, 611524.0001 ) ▲ 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	PONTOCEREBELLAR HYPOPLASIA, TYPE 6	c1969084	6,337	omim	https://www.omim.org/entry/611523	2019-09-22T16:03:10	{"doid": ["0060275"], "mesh": ["C548074"], "omim": ["611523"], "orphanet": ["166073"], "synonyms": ["Alternative titles", "ENCEPHALOPATHY, FATAL INFANTILE, WITH MITOCHONDRIAL RESPIRATORY CHAIN DEFECTS"]}
## Summary ### Clinical characteristics. Spinocerebellar ataxia type 11 (SCA11) is characterized by progressive cerebellar ataxia and abnormal eye signs (jerky pursuit, horizontal and vertical nystagmus). Pyramidal features are seen on occasion. Peripheral neuropathy and dystonia are rare. Six families have been reported to date, one each from the UK, Pakistan, France, Germany, Denmark, and China. Age of onset ranged from early childhood to the mid-40s. Life span is thought to be normal. ### Diagnosis/testing. The diagnosis of spinocerebellar ataxia type 11 (SCA11) is established in a proband with a heterozygous pathogenic variant in TTBK2 identified by molecular genetic testing. ### Management. Treatment of manifestations: Management is supportive; there are no known disease-modifying treatments to date. Physiotherapy and assessment for assistive devices for ambulation; occupational therapy, including home adaptations; speech and language therapy for dysarthria and dysphagia; ankle-foot orthotics if required and good foot care for those with neuropathy; treatment per ophthalmologist for vision issues; prism glasses may be helpful for diplopia. Surveillance: Annual neurologic evaluation; evaluations with physiotherapist, occupational therapist, speech and language therapist, and ophthalmologist as indicated. ### Genetic counseling. SCA11 is inherited in an autosomal dominant manner. The proportion of SCA11 caused by de novo mutation is unknown. Each child of an individual with SCA11 has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for at-risk pregnancies is possible if the diagnosis has been established by molecular genetic testing in an affected family member. ## Diagnosis ### Suggestive Findings Spinocerebellar ataxia type 11 (SCA11) should be considered in individuals with the following clinical features: * Progressive cerebellar ataxia * Abnormal eye signs (jerky pursuit, horizontal and vertical nystagmus) * Dysarthria * Pyramidal features (mild-to-moderate lower-extremity hyperreflexia; in very rare cases, a positive Babinski sign or other pyramidal features) * Swallowing difficulties Rare findings in SCA11: * Peripheral neuropathy * Dystonia ### Establishing the Diagnosis The diagnosis of spinocerebellar ataxia type 11 (SCA11) is established in a proband with a heterozygous pathogenic variant in TTBK2 identified by molecular genetic testing (see Table 1). Because the phenotype of SCA11 is indistinguishable from many other inherited disorders with ataxia, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing. Note: Single-gene testing (sequence analysis of TTBK2, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. * An ataxia multigene panel that includes TTBK2 and other genes of interest (see Differential Diagnosis) 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. 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. Of note, given the rarity of SCA11, some panels for ataxia may not include this gene. (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. * Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible. 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 Spinocerebellar Ataxia Type 11 View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method TTBK2Sequence analysis 36/6 families 4 Gene-targeted deletion/duplication analysis 5Unknown 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\. Houlden et al [2007], Bauer et al [2010], Lindquist et al [2017], Deng et al [2019] 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 data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics ### Clinical Description To date, 28 individuals from six families have been identified with a pathogenic variant in TTBK2 [Houlden et al 2007, Bauer et al 2010, Lindquist et al 2017, Deng et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports. ### Table 2. Clinical Features of Spinocerebellar Ataxia Type 11 View in own window FeatureNumber of Persons w/FeatureComment Cerebellar ataxia28/28Variable truncal &/or gait ataxia Limb ataxia21/28 Dysarthria22/28 Jerky pursuit18/28 Nystagmus20/28 Ophthalmoplegia2/28 Diplopia4/28 Hyperreflexia18/28 * Most prominent in the British family * Lower > upper limbs Extrapyramidal features1/28 * Laterocollis * "No-no" head tremor Onset. In the six families described with spinocerebellar ataxia type 11 (SCA11), age of onset ranged from age nine years in the family of Danish origin to age 40-50 years in the families from France, Germany, and China. Most individuals present with a pure ataxia phenotype, with few additional features. Abnormal eye findings were identified in a third of individuals, a small proportion of whom presented with diplopia at onset. Ataxia. The cerebellar ataxia was clinically similar in all six families. All individuals presented with an ataxia-predominant disorder and difficulty walking due to unsteadiness and maintaining balance. In approximately a third of individuals, limb ataxia was also present. Ataxia was usually slowly progressive. For example, in the British family described, the mean disease duration was 26.8 years [Houlden et al 2007]. Abnormal eye findings include jerky pursuit and horizontal and vertical nystagmus. All of the individuals with SCA11 from Devon had abnormal eye movements at presentation, with jerky pursuit and vertical nystagmus more prevalent than horizontal nystagmus [Houlden et al 2007]. Half of the individuals with vertical nystagmus had an upbeat nystagmus [Giunti et al 2012]. Only a very small proportion were found to be symptomatic with ophthalmoplegia and diplopia. No members of the French family had abnormal eye findings. One individual in the German family had oculomotor disturbances with jerky pursuit, gaze-evoked nystagmus, dysmetric saccades, and impaired optokinetic nystagmus on presentation, nine years after symptom onset [Bauer et al 2010]. In the Danish family, one individual presented with diplopia and nystagmus at age nine years [Lindquist et al 2017]. A sib presented at age four years with ataxia and was found to have nystagmus at age nine years [Lindquist et al 2017]. Three individuals of Chinese descent had nystagmus at the time of presentation [Deng et al 2019]. It is unclear if abnormal eye findings progress, but ocular symptoms were the only presenting feature for one individual out of 28 affected. Although abnormal eye findings may be seen at the time of presentation, they are rarely symptomatic. Pyramidal features exist in varying degrees across the different families. In the British family, mild limb hyperreflexia more prevalent in the upper than the lower limbs (with negative Babinski sign) was found in all but one affected individual [Houlden et al 2007]. In the family from Pakistan, mild-to-moderate hyperreflexia was observed in only two of five affected individuals [Houlden et al 2007]. Only one of the three individuals affected from the Danish family had hyperreflexia [Lindquist et al 2017]. Two of the five individuals of Chinese descent had hyperreflexia [Deng et al 2019]. Reflexes and tone were, however, normal in the German and French families described [Bauer et al 2010]. No other pyramidal signs apart from hyperreflexia were observed in the 28 individuals apart from one individual with upgoing plantar reflexes. This individual from Devon presented with both extrapyramidal and pyramidal signs including spastic gait, hyperreflexia with upgoing plantar reflexes, "no-no" head tremor, and upper-limb tremor with laterocollis [Giunti et al 2012]. No extrapyramidal signs have been described in other individuals. Bulbar symptoms. Dysarthria and swallowing difficulties are common in individuals with SCA11. Dysarthria as a result of cerebellar dysfunction was moderate to severe in almost all individuals in the families of British and Pakistani origin but was not present at diagnosis [Houlden et al 2007]. In the French family, dysarthria was an early feature [Bauer et al 2010]. Dysarthria was reported to be progressive in individuals in the family of Chinese origin [Deng et al 2019]. Liquid dysphagia was also noted in individuals with SCA11, especially in the families from Devon and China, but was not common at presentation. Peripheral neuropathy is not a common feature of SCA11. In the British cohort, nerve conduction studies (NCS) and electromyography (EMG) were normal in eight affected subjects [Houlden et al 2007]. One other affected subject had slightly small sensory nerve action potentials at the age of 61 (disease duration 43 years) but without clinically manifesting neuropathy. In the Pakistani, Danish, French, and German families, neuropathy was not seen. In the Chinese family, EMG of the proband showed extensive neurogenic damage. Somatosensory evoked potentials of the lower limbs were abnormal. Generalized neurogenic damage was seen on NCS and EMG of two other affected Chinese individuals, but it is not apparent whether these individuals also presented with neuropathy symptoms clinically. Other. One individual from Devon presented with laterocollis [Giunti et al 2012]. Dystonia has not been described in other individuals. Prognosis. SCA11 is slowly progressive with severity ranging from very mild balance problems at disease onset, to severe speech and swallowing problems and ataxia requiring the use of a wheelchair. In affected individuals from the British and Pakistani families, eight of 17 persons required a wheelchair 20 to 30 years after onset. The same was reported in the French and German families, where progression of disease is slow; individuals remained active many years and required a wheelchair decades after onset [Bauer et al 2010]. Life span in individuals with SCA11 is normal; many affected individuals live beyond age 75 years. In nine individuals from the British and Pakistani families, death occurred between ages 55 and 88 years. Neuroimaging. Brain MRI examination shows mild-to-severe atrophy in both cerebellar hemispheres and the vermis. The brain stem and cerebrum were normal in most individuals [Giunti et al 2012]. Occasionally, atrophy has also been described in the medulla but this was not associated with disease severity [Giunti et al 2012, Deng et al 2019]. In a Danish proband, an 18Ffluorodeoxyglucose positron emission tomography scan showed reduced metabolic activity in the cerebellum and pons, and repeat brain MRI four years later showed worsening cerebellar atrophy with olivopontine atrophy [Lindquist et al 2017]. Neuropathology. Neuropathologic examination of the brain of one affected individual showed marked cerebellar and brain stem loss with Purkinje cell degeneration and abnormal tau deposition in the brain stem and cortex [Houlden et al 2007]. ### Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ### Penetrance The TTBK2 pathogenic variants in the six families described to date appear to be fully penetrant, although a number of at-risk relatives are younger than the typical age of onset. To date, no non-penetrant pathogenic variants have been identified in older individuals. ### Prevalence Prevalence is unknown but SCA11 is a rare cause of pure spinocerebellar ataxia. It accounts for less than 1% of autosomal dominant ataxia in Europe [Bauer et al 2010]. Pathogenic variants in TTBK2 were identified in six of 238 families with spinocerebellar ataxia [Houlden et al 2007; Bauer et al 2010; Author, personal observation]. A study in Germany of 49 individuals with a family history of ataxia did not identify pathogenic variants in TTBK2 [Edener et al 2009]. A study in China of 68 unrelated probands with autosomal dominant ataxia also did not identify pathogenic variants in TTBK2 [Xu et al 2010]. The six families described with SCA11 are from Devon (UK), Pakistan, France, Germany, Denmark, and China. ## Differential Diagnosis According to AE Harding's classification, spinocerebellar ataxia type 11 (SCA11) is included in the pure autosomal dominant cerebellar ataxias (ADCA III) [Worth et al 1999], the most common group of inherited ataxias. SCA11 accounts for approximately 2% of ADCA III. Significant overlap is observed between SCA11 and SCA5, SCA6, SCA15, and SCA20, all of which may be distinguished by molecular genetic testing (see Table 3). ### Table 3. Hereditary Ataxia Disorders of Interest in the Differential Diagnosis of Spinocerebellar Ataxia Type 11 View in own window GeneDisorderMOIKey Clinical Features CACNA1ASCA6ADPure cerebellar ataxia w/slow progression. Some described w/downbeat nystagmus, whereas 50% of British individuals w/SCA11 had an upbeat nystagmus. ITPR1SCA15ADSlowly progressive pure cerebellar ataxia w/mild tremor & mild hyperreflexia SPTBN2SCA5 (OMIM 600224)ADSlowly progressive pure cerebellar ataxia Unknown 1SCA20ADSlowly progressive cerebellar ataxia w/abnormal phonation & dysarthria, & palatal tremor in two thirds of individuals. Minor pyramidal signs may also be seen. AD = autosomal dominant; MOI = mode of inheritance; SCA = spinocerebellar ataxia 1\. The locus for SCA20 lies within the pericentromeric region of chromosome 11; the gene is unknown. A 260-kb duplication of 11q12.2-11q12.3 has been proposed as the probable cause of SCA20 in the index family. See the Hereditary Ataxia Overview for information on other types of inherited (genetic) ataxia. ## Management Management is supportive; a multidisciplinary approach is recommended. ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 11 (SCA11), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 11 View in own window System/ConcernEvaluationComment NeurologicNeurologic evaluationUse SARA 1 to establish baseline Head MRIInitial imaging to establish extent of cerebellar atrophy at disease presentation Feeding evaluationTo evaluate for bulbar involvement that may require intervention, e.g., adjustment to dietary consistency to improve safe swallow Speech & language therapy evaluationIf dysarthria is atypical or severe enough to cause communication problems Physiotherapy & occupational therapy evaluationTo evaluate mobility, activities of daily living, & need for adaptive devices Peripheral nervous systemNerve conduction studiesNerve conduction studies are recommended to exclude a coexisting neuropathy that may require further monitoring. OphthalmologicOphthalmologic evaluationTo evaluate eye movement & for diplopia OtherConsultation w/clinical geneticist &/or genetic counselor 1\. SARA = Scale for the Assessment and Rating of Ataxia ### Treatment of Manifestations Management is supportive; no disease-modifying treatments are known to date. ### Table 5. Treatment of Manifestations in Individuals with SCA11 View in own window Manifestation ConcernTreatmentConsiderations/Other Ataxia * PT evaluation/treatment * OT evaluation/treatment Consider adaptive devices (cane &/or wheelchair) & home adaptations to maintain/improve independent mobility. Weight controlTo facilitate ambulation Dysarthria & dysphagiaSpeech & language therapy evaluation/treatmentTo teach strategies to improve articulation & avoid aspiration Modify food consistency to reduce aspiration riskVideo esophagram may help define best consistency. Peripheral neuropathyAnkle-foot orthoticsEnsure good foot care & foot health w/regular review by podiatrist. DiplopiaOphthalmologic consultationPrism glasses can be helpful. OT = occupational therapy; PT = physical therapy ### Surveillance ### Table 6. Recommended Surveillance for Individuals with SCA11 View in own window System/ConcernEvaluationFrequency AtaxiaNeurologic evaluationAnnually PT & OTIdeally, in the context of a multidisciplinary setting w/more intensive follow up if needed Dysarthria & dysphagiaEvaluation w/speech & language therapistFollow up dependent on severity & requirements Ophthalmoplegia & diplopiaOphthalmologyFollow up dependent on severity & requirements OT = occupational therapy; PT = physical therapy ### Evaluation of Relatives at Risk 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 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. [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 11	c1858351	6,338	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1757/	2021-01-18T20:54:48	{"mesh": ["C565772"], "synonyms": ["SCA11"]}
For other uses, see Angina (disambiguation). Chest discomfort due to not enough blood flow to heart muscle Angina Other namesAngina pectoris Diagram of discomfort caused by coronary artery disease. Pressure, fullness, squeezing or pain in the center of the chest. Can also feel discomfort in the neck, jaw, shoulders, back or arms Pronunciation * /ænˈdʒaɪnə, ˈændʒɪnə/ ann-JY-nə, AN-jin-ə[1] SpecialtyCardiology Angina, also known as angina pectoris, is chest pain or pressure, usually due to not enough blood flow to the heart muscle. Angina is usually due to obstruction or spasm of the arteries that supply blood to the heart muscle.[2] Other causes include anemia, abnormal heart rhythms and heart failure. The main mechanism of coronary artery obstruction is atherosclerosis as part of coronary artery disease. The term derives from the Latin angere ("to strangle") and pectus ("chest"), and can therefore be translated as "a strangling feeling in the chest". There is a weak relationship between severity of pain and degree of oxygen deprivation in the heart muscle, where there can be severe pain with little or no risk of a myocardial infarction (heart attack) and a heart attack can occur without pain. In some cases, angina can be quite severe. In the early 20th century this was a known sign of impending death.[3] However, given current medical therapies, the outlook has improved substantially. People with an average age of 62 years, who have moderate to severe degrees of angina (grading by classes II, III, and IV) have a 5-year survival rate of approximately 92%.[4] Worsening angina attacks, sudden-onset angina at rest, and angina lasting more than 15 minutes are symptoms of unstable angina (usually grouped with similar conditions as the acute coronary syndrome). As these may precede a heart attack, they require urgent medical attention and are, in general, treated in similar fashion to myocardial infarction. ## Contents * 1 Classification * 1.1 Stable angina * 1.2 Unstable angina * 1.3 Cardiac syndrome X * 2 Signs and symptoms * 3 Cause * 3.1 Major risk factors * 3.2 Other medical problems * 3.3 Other cardiac problems * 4 Pathophysiology * 5 Diagnosis * 6 Treatment * 6.1 Microvascular angina in women * 6.2 Suspected angina * 7 Epidemiology * 8 History * 9 References * 10 External links ## Classification[edit] Illustration depicting angina ### Stable angina[edit] Also known as 'effort angina', this refers to the classic type of angina related to myocardial ischemia. A typical presentation of stable angina is that of chest discomfort and associated symptoms precipitated by some activity (running, walking, etc.) with minimal or non-existent symptoms at rest or after administration of sublingual nitroglycerin.[5] Symptoms typically abate several minutes after activity and recur when activity resumes. In this way, stable angina may be thought of as being similar to intermittent claudication symptoms. Other recognized precipitants of stable angina include cold weather, heavy meals, and emotional stress. ### Unstable angina[edit] Unstable angina (UA) (also "crescendo angina"; this is a form of acute coronary syndrome) is defined as angina pectoris that changes or worsens.[6] It has at least one of these three features: 1. it occurs at rest (or with minimal exertion), usually lasting more than 10 minutes 2. it is severe and of new onset (i.e., within the prior 4–6 weeks) 3. it occurs with a crescendo pattern (i.e., distinctly more severe, prolonged, or frequent than before). UA may occur unpredictably at rest, which may be a serious indicator of an impending heart attack. What differentiates stable angina from unstable angina (other than symptoms) is the pathophysiology of the atherosclerosis. The pathophysiology of unstable angina is the reduction of coronary flow due to transient platelet aggregation on apparently normal endothelium, coronary artery spasms, or coronary thrombosis.[7][8] The process starts with atherosclerosis, progresses through inflammation to yield an active unstable plaque, which undergoes thrombosis and results in acute myocardial ischemia, which, if not reversed, results in cell necrosis (infarction).[8] Studies show that 64% of all unstable anginas occur between 22:00 and 08:00 when patients are at rest.[8][9] In stable angina, the developing atheroma is protected with a fibrous cap. This cap may rupture in unstable angina, allowing blood clots to precipitate and further decrease the area of the coronary vessel's lumen. This explains why, in many cases, unstable angina develops independently of activity.[8] See also: variant angina ### Cardiac syndrome X[edit] Main article: Cardiac syndrome X Cardiac syndrome X, sometimes known as microvascular angina is characterized by angina-like chest pain, in the context of normal epicardial coronary arteries (the largest vessels on the surface of the heart, prior to significant branching) on angiography. The original definition of cardiac syndrome X also mandated that ischemic changes on exercise (despite normal coronary arteries) were displayed, as shown on cardiac stress tests.[10] The primary cause of cardiac syndrome X is unknown, but factors apparently involved are endothelial dysfunction and reduced flow (perhaps due to spasm) in the tiny "resistance" blood vessels of the heart.[11] Since microvascular angina is not characterized by major arterial blockages, it is harder to recognize and diagnose.[12][13][14] Microvascular angina was previously considered a rather benign condition, but more recent data has changed this attitude. Studies, including the Women's Ischemia Syndrome Evaluation (WISE), suggest that microvascular angina is part of the pathophysiology of ischemic heart disease, perhaps explaining the higher rates of angina in women than in men, as well as their predilection towards ischemia and acute coronary syndromes in the absence of obstructive coronary artery disease.[15] ## Signs and symptoms[edit] This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (June 2013) (Learn how and when to remove this template message) Angina pectoris can be quite painful, but many patients with angina complain of chest discomfort rather than actual pain: the discomfort is usually described as a pressure, heaviness, tightness, squeezing, burning, or choking sensation. Apart from chest discomfort, anginal pains may also be experienced in the epigastrium (upper central abdomen), back, neck area, jaw, or shoulders. This is explained by the concept of referred pain, and is due to the fact that the spinal level that receives visceral sensation from the heart simultaneously receives cutaneous sensation from parts of the skin specified by that spinal nerve's dermatome, without an ability to discriminate the two. Typical locations for referred pain are arms (often inner left arm), shoulders, and neck into the jaw. Angina is typically precipitated by exertion or emotional stress. It is exacerbated by having a full stomach and by cold temperatures. Pain may be accompanied by breathlessness, sweating, and nausea in some cases. In this case, the pulse rate and the blood pressure increases. Chest pain lasting only a few seconds is normally not angina (such as precordial catch syndrome). Myocardial ischemia comes about when the myocardium (the heart muscle) receives insufficient blood and oxygen to function normally either because of increased oxygen demand by the myocardium or because of decreased supply to the myocardium. This inadequate perfusion of blood and the resulting reduced delivery of oxygen and nutrients are directly correlated to blocked or narrowed blood vessels. Some experience "autonomic symptoms" (related to increased activity of the autonomic nervous system) such as nausea, vomiting, and pallor. Major risk factors for angina include cigarette smoking, diabetes, high cholesterol, high blood pressure, sedentary lifestyle, and family history of premature heart disease. A variant form of angina—Prinzmetal's angina—occurs in patients with normal coronary arteries or insignificant atherosclerosis. It is believed caused by spasms of the artery. It occurs more in younger women.[16] Coital angina, also known as angina d'amour, is angina subsequent to sexual intercourse.[17] It is generally rare, except in patients with severe coronary artery disease.[17] ## Cause[edit] ### Major risk factors[edit] [citation needed] * Age (≥ 45 years for men, ≥ 55 for women) * Smoking * Diabetes mellitus * Dyslipidemia * Family history of premature cardiovascular disease (men <55 years, female <65 years old) * Hypertension * Kidney disease (microalbuminuria or GFR<60 mL/min) * Obesity (BMI ≥ 30 kg/m2) * Physical inactivity * Prolonged psychosocial stress[18] Routine counselling of adults to advise them to improve their diet and increase their physical activity has not been found to significantly alter behaviour, and thus is not recommended.[19] Conditions that exacerbate or provoke angina [20] * Medications * Vasodilators * Excessive thyroid hormone replacement * Vasoconstrictors * Polycythemia, which thickens the blood, slowing its flow through the heart muscle * Hypothermia * Hypervolemia * Hypovolemia One study found that smokers with coronary artery disease had a significantly increased level of sympathetic nerve activity when compared to those without. This is in addition to increases in blood pressure, heart rate, and peripheral vascular resistance associated with nicotine, which may lead to recurrent angina attacks. In addition, the Centers for Disease Control and Prevention (CDC) reports that the risk of CHD (Coronary heart disease), stroke, and PVD (Peripheral vascular disease) is reduced within 1–2 years of smoking cessation. In another study, it was found that, after one year, the prevalence of angina in smoking men under 60 after an initial attack was 40% less in those having quit smoking compared to those that continued. Studies have found that there are short-term and long-term benefits to smoking cessation.[21][22][23][24] ### Other medical problems[edit] * Esophageal disorders * Gastroesophageal reflux disease (GERD) * Hyperthyroidism * Hypoxemia * Profound anemia * Uncontrolled hypertension ### Other cardiac problems[edit] * Bradyarrhythmia * Hypertrophic cardiomyopathy * Tachyarrhythmia * Valvular heart disease[25][26] Myocardial ischemia can result from: 1. a reduction of blood flow to the heart that can be caused by stenosis, spasm, or acute occlusion (by an embolus) of the heart's arteries. 2. resistance of the blood vessels. This can be caused by narrowing of the blood vessels; a decrease in radius.[27] Blood flow is proportional to the radius of the artery to the fourth power.[28] 3. reduced oxygen-carrying capacity of the blood, due to several factors such as a decrease in oxygen tension and hemoglobin concentration.[29] This decreases the ability of hemoglobin to carry oxygen to myocardial tissue.[30] Atherosclerosis is the most common cause of stenosis (narrowing of the blood vessels) of the heart's arteries and, hence, angina pectoris. Some people with chest pain have normal or minimal narrowing of heart arteries; in these patients, vasospasm is a more likely cause for the pain, sometimes in the context of Prinzmetal's angina and syndrome X. Myocardial ischemia also can be the result of factors affecting blood composition, such as reduced oxygen-carrying capacity of blood, as seen with severe anemia (low number of red blood cells), or long-term smoking. ## Pathophysiology[edit] Angina results when there is an imbalance between the heart's oxygen demand and supply. This imbalance can result from an increase in demand (e.g., during exercise) without a proportional increase in supply (e.g., due to obstruction or atherosclerosis of the coronary arteries). However, the pathophysiology of angina in females varies significantly as compared to males.[31] Non-obstructive coronary disease is more common in females.[32][33] ## Diagnosis[edit] Angina should be suspected in people presenting tight, dull, or heavy chest discomfort that is:[34] 1. Retrosternal or left-sided, radiating to the left arm, neck, jaw, or back. 2. Associated with exertion or emotional stress and relieved within several minutes by rest. 3. Precipitated by cold weather or a meal. Some people present with atypical symptoms, including breathlessness, nausea, or epigastric discomfort or burning. These atypical symptoms are particularly likely in older people, women, and those with diabetes.[34] Anginal pain is not usually sharp or stabbing or influenced by respiration. Antacids and simple analgesics do not usually relieve the pain. If chest discomfort (of whatever site) is precipitated by exertion, relieved by rest, and relieved by glyceryl trinitrate, the likelihood of angina is increased.[34] In angina patients momentarily not feeling any chest pain, an electrocardiogram (ECG) is typically normal unless there have been other cardiac problems in the past. During periods of pain, depression, or elevation of the ST segment may be observed. To elicit these changes, an exercise ECG test ("treadmill test") may be performed, during which the patient exercises to his/her maximum ability before fatigue, breathlessness, or pain intervenes; if characteristic ECG changes are documented (typically more than 1 mm of flat or downsloping ST depression), the test is considered diagnostic for angina. Even constant monitoring of the blood pressure and the pulse rate can lead to some conclusion regarding angina. The exercise test is also useful in looking for other markers of myocardial ischemia: blood pressure response (or lack thereof, in particular, a drop in systolic blood pressure), dysrhythmia and chronotropic response. Other alternatives to a standard exercise test include a thallium scintigram or sestamibi scintigram (in patients unable to exercise enough for the purposes of the treadmill tests, e.g., due to asthma or arthritis or in whom the ECG is too abnormal at rest) or stress echocardiography. In patients in whom such noninvasive testing is diagnostic, a coronary angiogram is typically performed to identify the nature of the coronary lesion, and whether this would be a candidate for angioplasty, coronary artery bypass graft (CABG), treatment only with medication, or other treatments. In hospitalized patients with unstable angina (or the newer term of "high-risk acute coronary syndromes"), those with resting ischaemic ECG changes or those with raised cardiac enzymes such as troponin may undergo coronary angiography directly. ## Treatment[edit] Further information: Antianginal The most specific medicine to treat angina is antianginal where nitroglycerin is a potent vasodilator that decreases myocardial oxygen demand by decreasing the heart's workload. Beta blockers and calcium channel blockers act to decrease the heart's workload, and thus its requirement for oxygen. Nitroglycerin should not be given if certain inhibitors such as sildenafil, tadalafil, or vardenafil have been taken within the previous 12 hours as the combination of the two could cause a serious drop in blood pressure. Treatments for angina are balloon angioplasty, in which the balloon is inserted at the end of a catheter and inflated to widen the arterial lumen. Stents to maintain the arterial widening are often used at the same time. Coronary bypass surgery involves bypassing constricted arteries with venous grafts. This is much more invasive than angioplasty. The main goals of treatment in angina pectoris are relief of symptoms, slowing progression of the disease, and reduction of future events, especially heart attacks and death. Beta blockers (e.g., carvedilol, metoprolol, propranolol) have a large body of evidence in morbidity and mortality benefits (fewer symptoms, less disability and longer life) and short-acting nitroglycerin medications have been used since 1879 for symptomatic relief of angina.[35] Calcium channel blockers (such as nifedipine (Adalat) and amlodipine), isosorbide mononitrate and nicorandil are vasodilators commonly used in chronic stable angina.[citation needed] A new therapeutic class, called If inhibitor, has recently been made available: Ivabradine provides heart rate reduction without affecting contractility[36] leading to major anti-ischemic and antianginal efficacy. ACE inhibitors are also vasodilators with both symptomatic and prognostic benefit. Statins are the most frequently used lipid/cholesterol modifiers, which probably also stabilize existing atheromatous plaque.[37] Low-dose aspirin decreases the risk of heart attack in patients with chronic stable angina, and was part of standard treatment. However, in patients without established cardiovascular disease, the increase in hemorrhagic stroke and gastrointestinal bleeding offsets any benefits and it is no longer advised unless the risk of myocardial infarction is very high.[38] Exercise is also a very good long-term treatment for the angina (but only particular regimens – gentle and sustained exercise rather than intense short bursts),[39] probably working by complex mechanisms such as improving blood pressure and promoting coronary artery collateralisation. Though sometimes used by patients, evidence does not support the use of traditional Chinese herbal products (THCP) for angina.[40] Identifying and treating risk factors for further coronary heart disease is a priority in patients with angina. This means testing for elevated cholesterol and other fats in the blood, diabetes and hypertension (high blood pressure), and encouraging smoking cessation and weight optimization. The calcium channel blocker nifedipine prolongs cardiovascular event- and procedure-free survival in patients with coronary artery disease. New overt heart failures were reduced by 29% compared to placebo; however, the mortality rate difference between the two groups was statistically insignificant.[41] ### Microvascular angina in women[edit] Women with myocardial ischemia often have either no or atypical symptoms, such as palpitations, anxiety, weakness, and fatigue. Additionally, many women with angina are found to have cardiac ischemia, yet no evidence of obstructive coronary artery disease on cardiac catheterization. Evidence is accumulating that nearly half of women with myocardial ischemia suffer from coronary microvascular disease, a condition often called microvascular angina (MVA). Small intramyocardial arterioles constrict in MVA causing ischemic pain that is less predictable than with typical epicardial coronary artery disease (CAD). The pathophysiology is complex and still being elucidated, but there is strong evidence that endothelial dysfunction, decreased endogenous vasodilators, inflammation, changes in adipokines, and platelet activation are contributing factors. The diagnosis of MVA may require catheterization during which there is assessment of the microcirculatory response to adenoside or acetylcholine and measurement of coronary and fractional flow reserve. New techniques include positron emission tomography (PET) scanning, cardiac magnetic resonance imaging (MRI), and transthoracic Doppler echocardiography. Managing MVA can be challenging, for example, women with this condition have less coronary microvascular dilation in response to nitrates than do those without MVA. Women with MVA often have traditional risk factors for CAD such as obesity, dyslipidemia, diabetes, and hypertension. Aggressive interventions to reduce modifiable risk factors are an important component of management, especially smoking cessation, exercise, and diabetes management. The combination of nonnitrate vasodilators, such as calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors along with HMG-CoA reductase inhibitors (statins), also has been shown to be effective in many women, and new drugs, such as Ranolazine and Ivabradine, have shown promise in the treatment of MVA. Other approaches include spinal cord stimulators, adenosine receptor blockade, and psychiatric intervention.[42][43][44][45][46][47] ### Suspected angina[edit] Hospital admission for people with the following symptoms is recommended, as they may have unstable angina: pain at rest (which may occur at night), pain on minimal exertion, angina that seems to progress rapidly despite increasing medical treatment. All people with suspected angina should be urgently referred to a chest pain evaluation service, for confirmation of the diagnosis and assessment of the severity of coronary heart disease.[48] ## Epidemiology[edit] As of 2010, angina due to ischemic heart disease affects approximately 112 million people (1.6% of the population) being slightly more common in men than women (1.7% to 1.5%).[49] In the United States, 10.2 million are estimated to experience angina with approximately 500,000 new cases occurring each year.[5][50] Angina is more often the presenting symptom of coronary artery disease in women than in men. The prevalence of angina rises with increasing age, with a mean age of onset of 62.3 years.[51] After five years post-onset, 4.8% of individuals with angina subsequently died from coronary heart disease. Men with angina were found to have an increased risk of subsequent acute myocardial infarction and coronary heart disease related death than women. Similar figures apply in the remainder of the Western world. All forms of coronary heart disease are much less-common in the Third World, as its risk factors are much more common in Western and Westernized countries; it could, therefore, be termed a disease of affluence. ## History[edit] This section needs expansion. You can help by adding to it. (November 2020) The condition was named "hritshoola" in ancient India and was described by Sushruta (6th century BC).[52] ## References[edit] 1. ^ "The definition of angina". 2. ^ "MerckMedicus: Dorland's Medical Dictionary". Retrieved 2009-01-09. 3. ^ White, PD (1931). Heart Disease (1st ed.). Macmillan. 4. ^ COURAGE Trial Research Group (2007). "Optimal Medical Therapy with or without PCI for Stable Coronary Disease". N Engl J Med. 356 (15): 1503–1516. doi:10.1056/NEJMoa070829. PMID 17387127. 5. ^ a b Tobin, Kenneth J. (2010). "Stable Angina Pectoris: What Does the Current Clinical Evidence Tell Us?". The Journal of the American Osteopathic Association. 110 (7): 364–70. PMID 20693568. 6. ^ "MerckMedicus: Dorland's Medical Dictionary". Retrieved 2009-01-09. 7. ^ Hombach, V.; Höher, M.; Kochs, M.; Eggeling, T.; Schmidt, A.; Höpp, H. W.; Hilger, H. H. (1988). "Pathophysiology of unstable angina pectoris—correlations with coronary angioscopic imaging". European Heart Journal. 9: 40–5. doi:10.1093/eurheartj/9.suppl_N.40. PMID 3246255. 8. ^ a b c d Simons, Michael (March 8, 2000). "Pathophysiology of unstable angina". Archived from the original on March 30, 2010. Retrieved April 28, 2010. 9. ^ "What Is Angina?". National Heart Lung and Blood Institute. Retrieved April 28, 2010. 10. ^ Kaski (editor), Juan Carlos (1999). Chest pain with normal coronary angiograms: pathogenesis, diagnosis and management. Boston: Kluwer. pp. 5–6. ISBN 978-0792384212.CS1 maint: extra text: authors list (link) 11. ^ Guyton, Arthur. "Textbook of Medical Physiology" 11th edition. Philadelphia; Elsevier, 2006.[page needed] 12. ^ "Cardiac Syndrome X". HeartHealthyWomen.org.[unreliable medical source?] 13. ^ "Heart Attack and Angina Statistics". Archived from the original on 2010-04-13. Retrieved 2010-04-13.[failed verification]. 14. ^ "Angina". Texas Heart Institute. October 2012. Archived from the original on 2014-08-17. Retrieved 2010-05-04. 15. ^ Gulati, M; Shaw, LJ; Bairey Merz, C. Noel (2012). "Myocardial ischemia in women: lessons from the NHLBI WISE study". Clinical Cardiology. 35 (3): 141–148. doi:10.1002/clc.21966. PMC 3297966. PMID 22389117. 16. ^ Sun, Hongtao; Mohri, Masahiro; Shimokawa, Hiroaki; Usui, Makoto; Urakami, Lemmy; Takeshita, Akira (28 February 2002). "Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina". Journal of the American College of Cardiology. 39 (5): 847–851. doi:10.1016/S0735-1097(02)01690-X. PMID 11869851. 17. ^ a b Levine, Glenn N.; Steinke, Elaine E.; Bakaeen, Faisal G.; Bozkurt, Biykem; Cheitlin, Melvin D.; Conti, Jamie Beth; Foster, Elyse; Jaarsma, Tiny; Kloner, Robert A. (2012-02-28). "Sexual Activity and Cardiovascular Disease A Scientific Statement From the American Heart Association". Circulation. 125 (8): 1058–1072. doi:10.1161/CIR.0b013e3182447787. ISSN 0009-7322. PMID 22267844. 18. ^ Linden, Wolfgang; Stossel, Carmen; Maurice, Jeffrey (1996). "Psychosocial Interventions for Patients with Coronary Artery Disease: A Meta-analysis". Archives of Internal Medicine. 156 (7): 745–52. doi:10.1001/archinte.1996.00440070065008. PMID 8615707. 19. ^ Moyer, Virginia A.; U.S. Preventive Services Task Force (2012). "Behavioral Counseling Interventions to Promote a Healthful Diet and Physical Activity for Cardiovascular Disease Prevention in Adults: U.S. Preventive Services Task Force Recommendation Statement". Annals of Internal Medicine. 157 (5): 367–71. doi:10.7326/0003-4819-157-5-201209040-00486. PMID 22733153. 20. ^ Wells, Barbara; DiPiro, Joseph; Schwinghammer, Terry; DiPiro, Cecily (2008). Pharmacotherapy Handbook (7th ed.). New York: McGraw-Hill. p. 140. ISBN 978-0-07-148501-2. 21. ^ "Health Benefits of Cessation". Centers for Disease Control and Prevention. January 3, 2013. 22. ^ Daly, L E; Graham, I M; Hickey, N; Mulcahy, R (1985). "Does stopping smoking delay onset of angina after infarction?". BMJ. 291 (6500): 935–7. doi:10.1136/bmj.291.6500.935. PMC 1417185. PMID 3929970. 23. ^ Daly, L E; Mulcahy, R; Graham, I M; Hickey, N (1983). "Long term effect on mortality of stopping smoking after unstable angina and myocardial infarction". BMJ. 287 (6388): 324–6. doi:10.1136/bmj.287.6388.324. PMC 1548591. PMID 6409291. 24. ^ Shinozaki, Norihiko; Yuasa, Toyoshi; Takata, Shigeo (2008). "Cigarette Smoking Augments Sympathetic Nerve Activity in Patients with Coronary Heart Disease". International Heart Journal. 49 (3): 261–72. doi:10.1536/ihj.49.261. PMID 18612184. 25. ^ Gibbons, Raymond J; Abrams, Jonathan; Chatterjee, Kanu; Daley, Jennifer; Deedwania, Prakash C; Douglas, John S; Ferguson Jr, T.Bruce; Fihn, Stephan D; Fraker Jr, Theodore D; Gardin, Julius M; O'Rourke, Robert A; Pasternak, Richard C; Williams, Sankey V; American College Of, Raymond J; Alpert, Joseph S; Antman, Elliott M; Hiratzka, Loren F; Fuster, Valentin; Faxon, David P; Gregoratos, Gabriel; Jacobs, Alice K; Smith, Sidney C (2003). "ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article". Journal of the American College of Cardiology. 41 (1): 159–68. doi:10.1016/S0735-1097(02)02848-6. PMID 12570960. 26. ^ Fraker, Theodore D.; Fihn, Stephan D.; 2002 Chronic Stable Angina Writing Committee; American College Of, Cardiology; American Heart, Association; Gibbons, RJ; Abrams, J; Chatterjee, K; Daley, J; Deedwania, PC; Douglas, JS; Ferguson Jr, TB; Gardin; O'Rourke, RA; Williams, SV; Smith Jr, SC; Jacobs, AK; Adams, CD; Anderson, JL; Buller, CE; Creager, MA; Ettinger, SM; Halperin; Hunt, SA; Krumholz, HM; Kushner, FG; Lytle, BW; Nishimura, R; Page, RL; Riegel, B (2007). "2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients with Chronic Stable Angina". Journal of the American College of Cardiology. 50 (23): 2264–74. doi:10.1016/j.jacc.2007.08.002. PMID 18061078. 27. ^ Kusumoto, Fred M (2009-10-20). "Chapter 10: Cardiovascular Disorders: Heart Disease". In McPhee, SJ; Hammer, GD (eds.). Pathophysiology of Disease: An Introduction to Clinical Medicine (6th ed.). p. 276. ISBN 978-0-07-162167-0. 28. ^ Thomas, Michel (2005-09-13). "Treatment of Myocardial Ischemia". In Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutic (11th ed.). p. 823. ISBN 978-0071422802. 29. ^ Podrid, Philip J (November 28, 2012). "Pathophysiology and clinical presentation of ischemic chest pain". UpToDate. Wolters Kluwer.(registration required) 30. ^ The Crucial Role of Iron in the Body 31. ^ Vaccarino, V. (16 February 2010). "Ischemic Heart Disease in Women: Many Questions, Few Facts". Circulation: Cardiovascular Quality and Outcomes. 3 (2): 111–115. doi:10.1161/CIRCOUTCOMES.109.925313. PMC 3012351. PMID 20160161. 32. ^ Shaw, LJ; Merz, CN; Pepine, CJ; Reis, SE; Bittner, V; Kip, KE; Kelsey, SF; Olson, M; Johnson, BD; Mankad, S; Sharaf, BL; Rogers, WJ; Pohost, GM; Sopko, G (Aug 29, 2006). Women's Ischemia Syndrome Evaluation (WISE), Investigators. "The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health--National Heart, Lung, and Blood Institute--sponsored Women's Ischemia Syndrome Evaluation". Circulation. 114 (9): 894–904. doi:10.1161/CIRCULATIONAHA.105.609990. PMID 16923752. 33. ^ Banks, Kamakki; Lo, Monica; Khera, Amit (1 February 2010). "Angina in Women without Obstructive Coronary Artery Disease". Current Cardiology Reviews. 6 (1): 71–81. doi:10.2174/157340310790231608. PMC 2845797. PMID 21286281. 34. ^ a b c NHS Clinical Knowledge Summaries (2009) Angina - stable. "Archived copy". Archived from the original on 2010-03-10. Retrieved 2010-01-04.CS1 maint: archived copy as title (link) Date site accessed: 04/01/2009 35. ^ Sneader, Walter (2005). Drug discovery: a history. ISBN 978-0-471-89980-8.[page needed] 36. ^ Sulfi, S.; Timmis, A. D. (2006). "Ivabradine – the first selective sinus node if channel inhibitor in the treatment of stable angina". International Journal of Clinical Practice. 60 (2): 222–8. doi:10.1111/j.1742-1241.2006.00817.x. PMC 1448693. PMID 16451297. 37. ^ Nissen SE; Nicholls SJ; Sipahi I; et al. (2006). "Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: The asteroid trial". JAMA. 295 (13): 1556–1565. doi:10.1001/jama.295.13.jpc60002. PMID 16533939. 38. ^ Barnett, H.; Burrill, P.; Iheanacho, I. (2010). "Don't use aspirin for primary prevention of cardiovascular disease". BMJ. 340: c1805. doi:10.1136/bmj.c1805. PMID 20410163. S2CID 3137720. 39. ^ Ades, P. A.; Waldmann, M. L.; Poehlman, E. T.; Gray, P.; Horton, E. D.; Horton, E. S.; Lewinter, M. M. (1993). "Exercise conditioning in older coronary patients. Submaximal lactate response and endurance capacity". Circulation. 88 (2): 572–7. doi:10.1161/01.CIR.88.2.572. PMID 8339420. 40. ^ Zhuo, Qi; Yuan, Zhengyong; Chen, Hengxi; Wu, Taixiang (2010-05-12). "Traditional Chinese herbal products for stable angina". Cochrane Database of Systematic Reviews (5): CD004468. doi:10.1002/14651858.cd004468.pub2. PMC 6718232. PMID 20464731. 41. ^ Poole-Wilson, Philip A; Lubsen, Jacobus; Kirwan, Bridget-Anne; Van Dalen, Fred J; Wagener, Gilbert; Danchin, Nicolas; Just, Hanjörg; Fox, Keith AA; Pocock, Stuart J; Clayton, Tim C; Motro, Michael; Parker, John D; Bourassa, Martial G; Dart, Anthony M; Hildebrandt, Per; Hjalmarson, Åke; Kragten, Johannes A; Molhoek, G Peter; Otterstad, Jan-Erik; Seabra-Gomes, Ricardo; Soler-Soler, Jordi; Weber, Simon; Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system investigators (2004). "Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): Randomised controlled trial". The Lancet. 364 (9437): 849–57. doi:10.1016/S0140-6736(04)16980-8. PMID 15351192. S2CID 12795811. 42. ^ Celik T et al: Int J Cardiol 218:233-234, 2016 43. ^ Cattaneo M et al: Int J Cardiol 181:376-381, 2015 44. ^ Lanza GA et al: Circ J 2016 May 27 45. ^ Marinescu MA et al: JACC Cardiovasc Imaging 8(2): 210-220, 2015 46. ^ Selthofer-Relatic K, Boxnjak I, Kibel A: Cardiol Res Pract 2016: 8173816, 2016 47. ^ Titterington JS, Hung OY, Wenger N: Future Cardiol 11(2): 229-242, 2015 48. ^ NHS Clinical Knowledge Summaries (2009): "Suspected angina" Archived December 14, 2010, at the Wayback Machine 49. ^ Vos, T; Flaxman, AD; Naghavi, M; Lozano, R; Michaud, C; Ezzati, M; Shibuya, K; Salomon, JA; et al. (Dec 15, 2012). "Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet. 380 (9859): 2163–96. doi:10.1016/S0140-6736(12)61729-2. PMC 6350784. PMID 23245607. 50. ^ Rosamond, W.; Flegal, K.; Furie, K.; Go, A.; Greenlund, K.; Haase, N.; Hailpern, S. M.; Ho, M.; Howard, V.; Kissela, B.; Kittner, S.; Lloyd-Jones, D.; McDermott, M.; Meigs, J.; Moy, C.; Nichol, G.; O'Donnell, C.; Roger, V.; Sorlie, P.; Steinberger, J.; Thom, T.; Wilson, M.; Hong, Y. (17 December 2007). "Heart Disease and Stroke Statistics – 2008 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee". Circulation. 117 (4): e25–e146. doi:10.1161/CIRCULATIONAHA.107.187998. PMID 18086926. 51. ^ Buckley, B. S; Simpson, C. R; McLernon, D. J; Murphy, A. W; Hannaford, P. C (2009). "Five year prognosis in patients with angina identified in primary care: Incident cohort study". BMJ. 339: b3058. doi:10.1136/bmj.b3058. PMC 2722695. PMID 19661139. 52. ^ Dwivedi, Girish; Dwivedi, Shridhar (2007). "Sushruta – the Clinician – Teacher par Excellence" (PDF). The Indian Journal of Chest Diseases and Allied Sciences. 49: 243–4. Archived from the original (PDF) on 2008-10-10. ## External links[edit] * Treatment of stable angina recommendations for patients in layman terms * British Heart Foundation - Angina * Angina Pectoris Animation Video 3D * Guidelines on the management of stable angina pectoris - European Society of Cardiology * Heart Attack and Angina Statistics by American Heart Association : Final 2006 statistics for the United States Classification D * ICD-10: I20 * ICD-9-CM: 413 * MeSH: D000787 * DiseasesDB: 8695 External resources * MedlinePlus: 000198 * eMedicine: med/133 * v * t * e Symptoms and signs relating to the circulatory system Chest pain * Referred pain * Angina * Levine's sign Auscultation * Heart sounds * Split S2 * S3 * S4 * Gallop rhythm * Heart murmur * Systolic * Functional murmur * Still's murmur * Diastolic * Pulmonary insufficiency * Graham Steell murmur * Continuous * Carey Coombs murmur * Mitral insufficiency * Presystolic murmur * Pericardial friction rub * Heart click * Bruit * carotid Pulse * Tachycardia * Bradycardia * Pulsus paradoxus * doubled * Pulsus bisferiens * Pulsus bigeminus * Pulsus alternans Other * Palpitations * Apex beat * Cœur en sabot * Jugular venous pressure * Cannon A waves * Hyperaemia * Shock * Cardiogenic * Obstructive * Hypovolemic * Distributive * See further Template:Shock Cardiovascular disease Aortic insufficiency * Collapsing pulse * De Musset's sign * Duroziez's sign * Müller's sign * Austin Flint murmur * Mayne's sign Other endocardium * endocarditis: Roth's spot * Janeway lesion/Osler's node * Bracht–Wachter bodies Pericardium * Cardiac tamponade/Pericardial effusion: Beck's triad * Ewart's sign Other * rheumatic fever: * Anitschkow cell * Aschoff body * EKG * J wave * Gallavardin phenomenon Vascular disease Arterial * aortic aneurysm * Cardarelli's sign * Oliver's sign * pulmonary embolism * Right heart strain * radial artery sufficiency * Allen's test * pseudohypertension * thrombus * Lines of Zahn * Adson's sign * arteriovenous fistula * Nicoladoni sign Venous * Friedreich's sign * Caput medusae * Kussmaul's sign * Trendelenburg test * superior vena cava syndrome * Pemberton's sign * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever Authority control * NDL: 00567282 [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	Angina	c0002962	6,339	wikipedia	https://en.wikipedia.org/wiki/Angina	2021-01-18T18:40:01	{"mesh": ["D000787"], "umls": ["C0002962"], "icd-9": ["413"], "icd-10": ["I20"], "wikidata": ["Q180762"]}
Hematocolpos SpecialtyGynaecology Hematocolpos is a medical condition in which the vagina is pooled with menstrual blood due to multiple factors leading to the blockage of menstrual blood flow. The medical definition of hematocolpos is 'an accumulation of blood within the vagina'. It is often caused by the combination of menstruation with an imperforate hymen.[1][2] It is sometimes seen in Robinow syndrome, uterus didelphys, or other vaginal anomalies. A related disorder is hematometra, where the uterus fills with menstrual blood.[3] It presents after puberty as primary amenorrhoea, recurrent pelvic pain with a pelvic mass. This can be caused by a congenital stenosis of the cervix, or by a complication of a surgical treatment.[4] Mucometrocolpos is the accumulation of mucous secretions behind an imperforate hymen.[5][6] Mucometrocolpos can sometimes cause abdominal distention.[7][8][9][10] ## Contents * 1 Symptoms * 2 Causes * 3 Treatment * 4 References * 5 External links ## Symptoms[edit] * On and off lower abdominal pain lasting more than a week [11] * Pain with cramping, with episodes of worse pain in between[11] * Vomiting without blood or bile [11] * Abdominal bloating and distention [11] * Constipation and changes in urine output [11] * Tender breasts [11] * Vaginal bleeding or discharge [11] * Severe cyclic pelvic pain * Urinary retention ## Causes[edit] There can be four possible causes of hematocolpos[12] * Imperforate hymen: An imperforate hymen is a medical condition where the girls are born with a hymen which covers the whole opening of the vagina. An imperforate hymen may be diagnosed at any age. However, when a girl hits puberty, this type of hymen blocks the blood from flowing out and the bloods pools in the vagina. this condition is called Hematocolpos. As the blood backs up in the vagina, it causes: -Mass or fullness in the lower abdomen -Stomach ache -Back pain -Problems in urinating and bowel movements,[13] * Cervical atresia: Cervical Atresia is a relatively rare Mullerian duct anomaly of the female reproductive tract. It is associated with acute or chronic pain in the abdomen or pelvic pain along with other reproductive problems. A significant share of the women with cervical atresia have it since birth, that is, they congenital cervical atresia. However, Cervical Atresia is distinct from other Mullerian duct anomalies.[14] * Vaginal atresia: Vaginal atresia is another congenital defect which results in the uterovaginal outflow tract obstruction. it occurs when the caudal portion of the vagina fails to form and is rather replaced with fibrous tissues only. Vaginal Atresia has three basic categories of anomalies- Vaginal Agenesis, ambiguous genitalia, and imperforate anus and urogenital sinus variants. The different features associated with an ambiguous genitalia which might eventually lead to a blockage of menstrual blood flow are: i) Rugal folds over the labia ii) Mass in an apparent labium iii) Excess clitoral tissue. [15] Due to these anomalies, there are chances that the menstrual blood would not be able to flow out of the vagina, eventually leading to Hematocolpos. * Transverse vaginal septum: A transverse vaginal septum is another medical condition whereby an extra horizontal wall of tissue that has formed during embryological development creates a blockage in the vagina. Transverse vaginal septa are relatively rare anomalies, occurring in about 1 in 70,000 girls. The diagnosis can be made at various ages, from neonates presenting with hydrocolpos to young women presenting with primary amenorrhea and pelvic pain due to the development of hematocolpos. Often, women might have a normal hymeneal opening but this wall of tissue might be blocking the access to the vaginal canal. A small opening in the septum called the fenestration allows the menstrual blood to flow out of the vagina. However, it takes longer than the usual menstrual cycle. For the women who do not have a fenestration, blood will pool in the upper vagina and this would lead to serious abdominal pain. This also results in infertility.[16] ## Treatment[edit] As the causes for Hematocolpos are diverse, there are different surgical treatments which needs to be undertaken to cure it. Surgical interventions for congenital cervical atresia range from complete hysterectomy with canalization to conservative options, such as uterine cavity catheterization.[17] For the women who have an imperforate hymen, a minor surgery is required incising the extra hymen membrane. It is generally treated surgically, with a hymenotomy or other surgery to remove any tissue that blocks the menstrual flow. Also, post surgery, the patient is required to insert dilators into the vagina for a few minutes each day for a few days post the surgery to avoid the incision being closed on its own. Once the patient has recovered from the surgery- that is, there are no burning sensation around the vaginal, they can have regular periods, normal sexual intercourse. Unlike an imperforate hymen which can be easily corrected, surgical correction of a transverse septum can be difficult if the surgery is not carefully planned. Postoperative complications, such as vaginal stenosis and re-obstruction can occur, especially when the septum is thick. The thickness and location of the septum is most commonly evaluated by transperineal ultrasound or MRI before attempting its resection.[1] ## References[edit] 1. ^ Kloss, Brian T.; Nacca, Nicholas E.; Cantor, Richard M. (6 May 2010). "Hematocolpos secondary to imperforate hymen". International Journal of Emergency Medicine. 3 (4): 481–482. doi:10.1007/s12245-010-0171-2. PMC 3047835. PMID 21373333. 2. ^ TOMPKINS, PENDLETON (2 September 1939). "The Treatment of Imperforate Hymen with Hematocolpos". Journal of the American Medical Association. 113 (10): 913–916. doi:10.1001/jama.1939.02800350023007. 3. ^ Smith, Roger Perry (2008-01-01). Netter's Obstetrics and Gynecology. Elsevier Health Sciences. ISBN 978-1416056829. 4. ^ Verma, SK; Baltarowich, OH; Lev-Toaff, AS; Mitchell, DG; Verma, M; Batzer, F (Jul 2009). "Hematocolpos secondary to acquired vaginal scarring after radiation therapy for colorectal carcinoma" (PDF). Journal of Ultrasound in Medicine. 28 (7): 949–53. doi:10.7863/jum.2009.28.7.949. PMID 19546336. S2CID 11759668. 5. ^ Yapar, E. G.; Ekici, E.; Aydogdu, T.; Senses, E.; Gökmen, O. (1996-12-18). "Diagnostic problems in a case with mucometrocolpos, polydactyly, congenital heart disease, and skeletal dysplasia". American Journal of Medical Genetics. 66 (3): 343–346. doi:10.1002/(SICI)1096-8628(19961218)66:3<343::AID-AJMG19>3.0.CO;2-M. ISSN 0148-7299. PMID 8985498. 6. ^ Babcock, Diane S. (January 1989). Neonatal and pediatric ultrasonography. Churchill Livingstone. ISBN 9780443086069. 7. ^ Saclarides, Theodore J.; Myers, Jonathan A.; Millikan, Keith W. (2015-01-02). Common Surgical Diseases: An Algorithmic Approach to Problem Solving. Springer. ISBN 9781493915651. 8. ^ Kaiser, Georges L. (2012-12-13). Symptoms and Signs in Pediatric Surgery. Springer Science & Business Media. ISBN 9783642311611. 9. ^ Stevenson, Roger E. (2015-10-27). Human Malformations and Related Anomalies. Oxford University Press. ISBN 9780199386031. 10. ^ Dosedla, Erik; Kacerovsky, Marian; Calda, Pavel (2011-03-01). "Prenatal diagnosis of hydrometrocolpos in a down syndrome fetus". Journal of Clinical Ultrasound. 39 (3): 169–171. doi:10.1002/jcu.20785. ISSN 1097-0096. PMID 21387330. S2CID 11211408. 11. ^ a b c d e f g Kotter, Haleigh; Weingrow, Daniel; Canders, Caleb (2017-07-28). "Hematometrocolpos in a Pubescent Girl with Abdominal Pain". Clinical Practice and Cases in Emergency Medicine. 1 (3): 218–220. doi:10.5811/cpcem.2017.3.33369. ISSN 2474-252X. PMC 5965174. PMID 29849312. 12. ^ "Most common cause of hematocolpos (LQ)A cervical atresiaB vaginal atresiaC transverse vaginal septumD imperforate hymen - Flash cards Miscellaneous - Dr. Bhatia Medical Coaching Institute Pvt. Ltd. - Dr Bhatia Medical Coaching Institute". GradeStack Courses. Retrieved 2018-10-27. 13. ^ "Imperforate hymen: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2019-09-21. 14. ^ Xie, Zhihong; Zhang, Xiaoping; Liu, Jiandong; Zhang, Ningzhi; Xiao, Hong; Liu, Yongying; Li, Liang; Liu, Xiaoying (2014-02-21). "Clinical characteristics of congenital cervical atresia based on anatomy and ultrasound: a retrospective study of 32 cases". European Journal of Medical Research. 19 (1): 10. doi:10.1186/2047-783X-19-10. ISSN 0949-2321. PMC 3996070. PMID 24555664. 15. ^ "Vaginal Atresia: Background, Anatomy, Pathophysiology". 2019-07-03. Cite journal requires `\|journal=` (help) 16. ^ "Transverse Vaginal Septum \| Boston Children's Hospital". www.childrenshospital.org. Retrieved 2019-09-21. 17. ^ Xie, Zhihong; Zhang, Xiaoping; Liu, Jiandong; Zhang, Ningzhi; Xiao, Hong; Liu, Yongying; Li, Liang; Liu, Xiaoying (2014-02-21). "Clinical characteristics of congenital cervical atresia based on anatomy and ultrasound: a retrospective study of 32 cases". European Journal of Medical Research. 19 (1): 10. doi:10.1186/2047-783X-19-10. ISSN 0949-2321. PMC 3996070. PMID 24555664. ## External links[edit] Classification D * ICD-10: N89.7 * ICD-9-CM: 626.8 * MeSH: D006399 Look up hematocolpos in Wiktionary, the free dictionary. * v * t * e Female diseases of the pelvis and genitals Internal Adnexa Ovary * Endometriosis of ovary * Female infertility * Anovulation * Poor ovarian reserve * Mittelschmerz * Oophoritis * Ovarian apoplexy * Ovarian cyst * Corpus luteum cyst * Follicular cyst of ovary * Theca lutein cyst * Ovarian hyperstimulation syndrome * Ovarian torsion Fallopian tube * Female infertility * Fallopian tube obstruction * Hematosalpinx * Hydrosalpinx * Salpingitis Uterus Endometrium * Asherman's syndrome * Dysfunctional uterine bleeding * Endometrial hyperplasia * Endometrial polyp * Endometriosis * Endometritis Menstruation * Flow * Amenorrhoea * Hypomenorrhea * Oligomenorrhea * Pain * Dysmenorrhea * PMS * Timing * Menometrorrhagia * Menorrhagia * Metrorrhagia * Female infertility * Recurrent miscarriage Myometrium * Adenomyosis Parametrium * Parametritis Cervix * Cervical dysplasia * Cervical incompetence * Cervical polyp * Cervicitis * Female infertility * Cervical stenosis * Nabothian cyst General * Hematometra / Pyometra * Retroverted uterus Vagina * Hematocolpos / Hydrocolpos * Leukorrhea / Vaginal discharge * Vaginitis * Atrophic vaginitis * Bacterial vaginosis * Candidal vulvovaginitis * Hydrocolpos Sexual dysfunction * Dyspareunia * Hypoactive sexual desire disorder * Sexual arousal disorder * Vaginismus * Urogenital fistulas * Ureterovaginal * Vesicovaginal * Obstetric fistula * Rectovaginal fistula * Prolapse * Cystocele * Enterocele * Rectocele * Sigmoidocele * Urethrocele * Vaginal bleeding * Postcoital bleeding Other / general * Pelvic congestion syndrome * Pelvic inflammatory disease External Vulva * Bartholin's cyst * Kraurosis vulvae * Vestibular papillomatosis * Vulvitis * Vulvodynia Clitoral hood or clitoris * Persistent genital arousal 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	Hematocolpos	c0018934	6,340	wikipedia	https://en.wikipedia.org/wiki/Hematocolpos	2021-01-18T19:05:07	{"mesh": ["D006399"], "icd-9": ["626.8"], "icd-10": ["N89.7"], "wikidata": ["Q5711155"]}
Lymphangioleiomyomatosis (lim-FAN-je-o-LI-o-MI-o-ma-TO-sis), or LAM, is a rare cystic lung disease that mostly affects women in their mid-forties. In LAM, an unusual type of cell begins to grow out of control throughout the body, including in the lungs, lymph nodes and vessels, and kidneys. Over time, these LAM cells form cysts and clusters of cells, which grow throughout the lungs and slowly block the airways. They also destroy the normal lung tissue and replace it with cysts. As a result, air cannot move freely in and out of the lungs, and the lungs cannot supply enough oxygen to the body’s other organs. Some people also develop growths called angiomyolipomas (AMLs) in the kidneys. There are two forms of LAM - a sporadic form, which occurs for unknown reasons, and a form that occurs in people with a rare, inherited disease called tuberous sclerosis complex. LAM may be difficult to diagnosis in the early stages because symptoms may be similar to other lung diseases. A high resolution CT scan is the most accurate imaging test for diagnosing LAM. Additional testing may include an abdominal CT scan or ultrasound, a VEGF-D blood test (measuring the VEGF-D hormone, which would typically be high), and a lung biopsy. There are several management options for LAM, but the best course of treatment may vary from person to person. Treatment options may include therapy with an mTOR inhibitor (such as sirolimus), and supportive measures such as oxygen therapy or the use of bronchodilators. Some people may need a lung transplant when lung function is considerably impaired. [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	Lymphangioleiomyomatosis	c0751674	6,341	gard	https://rarediseases.info.nih.gov/diseases/3319/lymphangioleiomyomatosis	2021-01-18T17:59:19	{"mesh": ["D018192"], "omim": ["606690"], "orphanet": ["538"], "synonyms": ["LAM", "Lymphangio-myomatosis"]}
A number sign (#) is used with this entry because this form of limb-girdle muscular dystrophy-dystroglycanopathy (type C5; MDDGC5), also designated LGMDR9 and LGMD2I, is caused by homozygous or compound heterozygous mutation in the gene encoding fukutin-related protein (FKRP; 606596) on chromosome 19q13. Mutation in the FKRP gene can also cause a severe congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A5; MDDGA5; 613153) and a congenital muscular dystrophy-dystroglycanopathy with or without mental retardation (type B5; MDDGB5; 606612). Description MDGDC5 is an autosomal recessive muscular dystrophy characterized by variable age at onset, normal cognition, and no structural brain changes (Brockington et al., 2001). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2006). For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308). Clinical Features Bushby et al. (1998) described 7 patients, including 2 sib pairs, with late-onset limb-girdle muscular dystrophy. Apart from 1 patient, whose muscle problems began in childhood, the age at onset ranged from 17 to 40 years. The pattern of muscle involvement was similar from patient to patient, with hypertrophy of at least the calf muscles, absence of scapular winging, and predominant involvement of hip flexors and hamstrings more than quadriceps. Serum creatine kinase in all patients was at least 10 times normal, and muscle biopsies showed nonspecific dystrophic features. Six of the 7 patients were female. Linkage analysis excluded the merosin locus on chromosome 6q (156225). No abnormalities were detected on immunostaining for several proteins known to be involved in the limb-girdle muscular dystrophies, such as sarcoglycans alpha (SGCA; 600119), beta (SGCB; 600900), gamma (SGCG; 608896), and delta (SGCD; 601411), and calpain-3 (CAPN3; 114240). Brockington et al. (2001) reported 17 families with FKRP-related limb-girdle muscular dystrophy, which they called LGMD2I. Age at onset ranged from 6 months to 40 years. The disorder presented as hypotonia, waddling gait, or difficulty in climbing stairs. There was weakness in the hip and shoulder girdle muscles, calf hypertrophy, and elevated serum creatine kinase. Histologic changes were characteristic of a muscular dystrophy in all patients. A variable reduction of alpha-dystroglycan expression was observed in the skeletal muscle biopsy of all individuals studied. In addition, several cases showed a deficiency of laminin-2 (LAMA2; 156225) either by immunocytochemistry or Western blotting. Cognition was normal. Mercuri et al. (2003) described in detail the clinical phenotypes of 18 patients with limb-girdle muscular dystrophy, some of whom had previously been described by Brockington et al. (2001). Eleven of the 18 patients showed early age at onset (less than 5 years), lost ambulation in their teens, and resembled boys with Duchenne muscular dystrophy (DMD; 310300). The other 7 patients had onset between 7 and 23 years, retained ambulation, and had a milder phenotype. In general, all patients with LGMD2I had proximal weakness, calf hypertrophy, tightness of the Achilles tendon, and elevated creatine kinase. Nine patients developed scoliosis, 6 required nocturnal ventilation, and 10 had signs of dilated cardiomyopathy on echocardiography. Muscle biopsy showed a slight reduction in laminin alpha-2 and variable expression of alpha-dystroglycan. Another detailed analysis of the LGMD2I phenotype was provided by Poppe et al. (2003). Harel et al. (2004) reported a large consanguineous Bedouin family from northern Israel with LGMD2I. Nine of 11 affected patients were available for detailed study. Age at onset ranged from birth to 15 years; some patients had delayed motor milestones and minor symptoms during childhood, including difficulty in running or climbing stairs and frequent falls. The proximal lower limb muscles were the most severely affected, and 6 patients required wheelchairs by the second or third decades. All patients had hyperlordosis, kyphoscoliosis, or spinal fusion. One severely affected patient had involvement of the facial muscles. Some patients had restrictive lung disease, but none had primary cardiac involvement. Poppe et al. (2004) reported 38 LGMD2I patients with the L276I mutation (606596.0004): 23 were homozygous, and 15 were compound heterozygous with another FKRP mutation. Twenty-one (55%) patients had cardiac involvement, defined as left ventricular wall motion abnormalities. Patients who were L276I heterozygotes had earlier onset of cardiomyopathy compared to homozygotes. Forty-four percent of patients had a decreased forced vital capacity less than 75%, and 39% of patients had diaphragmatic weakness. There was no absolute correlation between skeletal muscle weakness and cardiomyopathy or respiratory insufficiency; respiratory failure was observed in some patients who were still ambulatory. Schwartz et al. (2005) found that 13 of 102 sporadic patients with a phenotype resembling Duchenne or Becker (300376) muscular dystrophy, but without mutations in the dystrophin gene (DMD; 300377), had mutations in the FKRP gene, consistent with a diagnosis of LGMD2I. Four of 7 patients showed reduced or irregular immunostaining for dystrophin on muscle biopsy. In 2 cases, a diagnosis of Becker muscular dystrophy had been made based on muscle biopsy and clinical findings, and prenatal diagnoses had been performed in their families based on that erroneous assumption. Other Features In a retrospective analysis of 26 patients with LGMD2I, Mathews et al. (2011) found that 7 (27%) had at least 1 episode of myoglobinuria following physical exertion. In 3 cases, myoglobinuria was the presenting symptom of the disorder. Another common reported feature in this group was myalgia with pain or cramps, occurring in 16 (61%) of 26 patients. Clinical Management Sveen et al. (2007) found that moderate-intensity endurance training was a safe and effective method to increase exercise performance and daily function in patients with FKRP-related limb-girdle muscular dystrophy. Nine patients, all ambulatory and homozygous for an FKRP L276I mutation (606596.0004), completed a 12-week cycling program consisting of 30-minute sessions at 65% maximal oxygen uptake. Creatine kinase levels did not increase significantly, and muscle morphology was unaffected. Sveen et al. (2007) noted that patients with the L276I mutation tend to have a mild phenotype. Mapping In a large consanguineous Tunisian family with an autosomal recessive form of limb-girdle muscular dystrophy, Driss et al. (2000) found linkage of the disorder to a locus on chromosome 19q13.3. Molecular Genetics In 17 families with LGMD2I, Brockington et al. (2001) identified several mutations in the FKRP gene. Affected individuals from 15 of the 17 families had an identical L276I (606596.0004) mutation; individuals in 5 families were homozygous for this recurrent mutation. Patients with the L276I change had a clinically less severe LGMD2I phenotype, suggesting that this is a less disruptive FKRP mutation than those found in MDC1C (MDDGB5; 606612). Four of the families had previously been described by Bushby et al. (1998). In the consanguineous Tunisian family originally reported by Driss et al. (2000) in which 13 members had LGMD2I, Driss et al. (2003) identified a homozygous mutation in the FKRP gene (606596.0006). The patients had symmetric proximal muscle weakness and wasting in all 4 limbs. No heart involvement was found. Immunohistochemical and immunoblot analysis showed abnormal expression of alpha-dystroglycan and alpha-2 laminin, supporting the hypothesis that FKRP has a role in the interaction between components of the extracellular matrix. In 16 patients with LGMD2I from 13 Brazilian families, de Paula et al. (2003) identified 10 distinct mutations, including 9 novel mutations, in the FKRP gene (see, e.g., 606596.0012-606596.0015). The most common mutation, L276I (606596.0004), was identified in 9 of 26 alleles. In 8 affected members of a large consanguineous Bedouin family with LGMD2I, Harel et al. (2004) identified a homozygous mutation in the FKRP gene (R45W; 606596.0011). In affected members of 5 Hutterite families with LGMD, Frosk et al. (2005) identified homozygosity for the L276I mutation in the FKRP gene (606596.0004). The same mutation occurs in non-Hutterite patients with LGMD from Europe, Canada, and Brazil, and appears to be a founder mutation dispersed among populations of European origin. LGMD2H (254110), due to mutation in the TRIM32 gene (D487N; 602290.0001), is a more common form of LGMD among Hutterites and may be limited to the Hutterite population. Frosk et al. (2005) found that Hutterite LGMD2I patients with the FKRP mutation had an earlier age at diagnosis, a more severe course, and higher serum creatine kinase than LGMD2H patients with the TRIM32 mutation. In addition, some of the LGMD2I patients showed calf hypertrophy, cardiac symptoms, and severe reactions to general anesthesia; none of these features were present among LGMD2H patients. Frosk et al. (2005) reported a Hutterite family in which 2 boys, aged 7 and 10 years, were homozygous for both the LGMD2H-related TRIM32 mutation, D487N, and the LGMD2I-related FKRP mutation, L276I. Although they presented at an early age with exercise intolerance and increased serum creatine kinase, the clinical phenotype was not significantly more severe than that of patients with isolated LGMD2H or LGMD2I. Both parents and 3 other sibs were homozygous for the D487N mutation, with highly variable phenotypic expression. Genotype/Phenotype Correlations Sveen et al. (2006) identified FKRP mutations in 38 of 99 Danish individuals with a clinical diagnosis of LGMD2, making LGMD2I the most common LGMD subtype in this country. Of the 38 individuals, 27 were homozygous for L276I, and 11 were compound heterozygous for L276I and another pathogenic FKRP mutation. The homozygous patients had later onset, milder clinical progression, and less muscle weakness compared to compound heterozygous patients, all of whom were wheelchair-bound by their mid-twenties. Cardiac and respiratory involvement was found in both groups. Nine L276I homozygous, but no compound heterozygous, patients had initial symptoms of exertional myoglobinuria. The L276I mutation was identified in 1 of 200 control alleles. INHERITANCE \- Autosomal recessive HEAD & NECK Mouth \- Tongue hypertrophy CARDIOVASCULAR Heart \- Dilated cardiomyopathy \- Left ventricular impairment RESPIRATORY Lung \- Restrictive respiratory insufficiency \- Decreased forced vital capacity \- Nocturnal hypoventilation SKELETAL Spine \- Scoliosis \- Spinal fusion \- Lordosis \- Kyphosis Feet \- Achilles tendon contractures MUSCLE, SOFT TISSUES \- Proximal muscle weakness \- Waddling gait \- Toe-walking \- Difficulty walking \- Difficulty climbing stairs \- Frequent falls \- Shoulder girdle weakness \- Hip girdle weakness \- Muscle cramps \- Myalgia \- Calf hypertrophy \- Thigh hypertrophy \- Tongue hypertrophy \- Muscle MRI shows fatty infiltration \- Muscle biopsy shows dystrophic changes \- Mildly decreased laminin alpha-2 expression (LAMA2, 156225 ) \- Variably decreased alpha-dystroglycan expression (DAG, 128239 ) LABORATORY ABNORMALITIES \- Increased serum creatine kinase \- Myoglobinuria, particularly after physical exertion (25% of patients) MISCELLANEOUS \- Variable age of onset (range 1-40 years) \- Variable severity \- Some patients become wheelchair-bound \- Most common mutation is LEU276ILE ( 606596.0004 ) MOLECULAR BASIS \- Caused by mutation in the fukutin-related protein gene (FKRP, 606596.0004 ) ▲ 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-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 5	c1846672	6,342	omim	https://www.omim.org/entry/607155	2019-09-22T16:09:34	{"doid": ["0110299"], "mesh": ["C564612"], "omim": ["607155"], "orphanet": ["34515"], "synonyms": ["Alternative titles", "MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 9", "MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2I", "MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY, LIMB-GIRDLE, FRKP-RELATED"]}
Sutherland (1982) found 1 example of a 9q32 fragile site in a population study. [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	FRAGILE SITE 9q32	c1850978	6,343	omim	https://www.omim.org/entry/136640	2019-09-22T16:40:56	{"omim": ["136640"]}
Hirschsprung disease (HSCR) is a congenital intestinal motility disorder that is characterized by signs of intestinal obstruction due to the presence of an aganglionic segment of variable extent in the terminal part of the colon. ## Epidemiology HSCR has an estimated annual incidence of 1/5,000 births. Short segment HSCR is more frequent in males. ## Clinical description HSCR generally manifests shortly after birth with symptoms of lower intestinal obstruction such as failure to pass meconium within the first 48 hours of life, abdominal pain, constipation, progressive abdominal distention, vomiting, and occasionally diarrhea. Rarely, it presents later in childhood with symptoms of severe constipation and failure to thrive. HSCR can also be associated with additional anomalies such as sensorineural hearing loss (neurologic Waardenburg-Shah syndrome), limb anomalies (Bardet-Biedl syndrome), intellectual deficit (Mowat-Wilson syndrome), central alveolar hypoventilation (Haddad syndrome), or medullary thyroid carcinoma (multiple endocrine neoplasia syndrome type 2B). HSCR is also associated with chromosomal abnormalities, mainly Down syndrome (see these terms). ## Etiology HSCR is a neurocristopathy and is due to a defect in the development of the enteric nervous system. It is characterized by the absence of neuronal ganglion cells (Cajal cells) (aganglionosis) in the terminal part of the intestine. The affected bowel segment maintains a state of tonic contraction, resulting in a functional bowel obstruction. 4 forms of the disease are recognized on the basis of the extent of aganglionosis: in the classic form (short segment HSCR; 80% of cases), aganglionosis is restricted to the rectosigmoid. In long-segment HSCR (15%), aganglionosis extends near the sigmoid colon, while in total colonic aganglionosis (5%) aganglionosis involves the entire large intestine. Total intestinal aganglionosis is the most severe form and is extremely rare. Genetic and environmental factors play a role in its pathogenesis. Several genes are associated with HSCR, particularly: the Ret proto-oncogene (RET), the glial cell derived neutrotrophic factor gene (GDNF), the neurturin gene (NRTN), the endothelin B receptor gene (EDNRB), the endothelin-3 gene (EDN3), the endothelin-converting enzyme 1 gene ECE1, and the L1 cell adhesion molecule gene L1CAM. ## Diagnostic methods Diagnosis is based on suction rectal biopsy of rectal mucosa and submucosa that shows aganglionosis, thickened extrinsic nerve fibres and overexpression of acetylcholinesterase. Assessment for associated anomalies allows the detection of syndromic HSCR. Plain abdominal radiography, lower gastrointestinal contrast studies, and ultrasound are useful in excluding alternative diagnoses. ## Differential diagnosis Differential diagnosis includes gastrointestinal malformations such as anorectal atresia, chronic intestinal pseudoobstruction, meconium ileus (see these terms), anorectal stenosis and pelvic tumors. ## Antenatal diagnosis No prenatal diagnosis is currently available. Abdominal distension is rarely seen on prenatal ultrasound in children with HSCR and is thus non-predictive. ## Genetic counseling Genetic counseling is difficult because HSCR is a polygenic disorder with incomplete penetrance and variable expressivity. ## Management and treatment Treatment is surgical. It consists in resection of the aganglionic segment followed by anastomosis of the proximal bowel to the anal margin (''pullthrough''). In case of total intestinal aganglionosis, intestinal transplantation may be required. ## Prognosis Overall prognosis is good in most cases, despite issues with constipation and continence even following surgical correction. The prognosis for children with total intestinal aganglionosis is poor although intestinal transplantation may offer long term survival. Hirschsprung enterocolitis, an inflammatory condition of the bowel which can be life-threatening, may also occur. [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	Hirschsprung disease	c0019569	6,344	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=388	2021-01-23T18:05:07	{"gard": ["6660"], "mesh": ["D006627"], "omim": ["142623", "600155", "600156", "606874", "606875", "608462", "611644", "613711", "613712"], "umls": ["C0019569", "C3661523"], "icd-10": ["Q43.1"], "synonyms": ["Aganglionic megacolon", "Congenital intestinal aganglionosis", "HSCR"]}
A number sign (#) is used with this entry because immunoglobulin A (IgA) deficiency-2 (IGAD2) is caused by heterozygous, homozygous, or compound heterozygous mutation in the TNFRSF13B gene (604907), which encodes the transmembrane activator and CAML interactor (TACI), on chromosome 17p11.2. Mutation in the TNFRSF13B gene can also cause common variable immunodeficiency-2 (CVID2; 240500). For a phenotypic description and a discussion of genetic heterogeneity of selective IgA deficiency, see 137100. Clinical Features Selective deficiency of immunoglobulin A (IGAD) is the most common form of primary immunodeficiency, with an incidence of approximately 1 in 600 individuals in the western world (Cunningham-Rundles, 2001). The umbrella term 'common variable immunodeficiency' (CVID; see 607594) refers to a group of disorders characterized by a deficiency in all Ig isotypes. Individuals with symptomatic IGAD and individuals with CVID suffer from recurrent sinopulmonary and gastrointestinal infections and have an increased incidence of autoimmune disorders and of lymphoid and nonlymphoid malignancies. IGAD and CVID can coexist in families, and some individuals initially present with IGAD and then develop CVID. These observations suggested that some cases of IGAD and CVID may have a common etiology (Castigli et al., 2005). Molecular Genetics By studying cohorts of immunodeficient individuals from Europe (162 individuals with CVID) and the US (19 individuals with CVID and 16 with IGAD), Salzer et al. (2005) and Castigli et al. (2005) found that mutations in the TNFRSF13B gene (604907), encoding transmembrane activator and CAML interactor (TACI), were associated with both familial and sporadic forms of the disease. Martin and Dixit (2005) noted that 3 of the 6 mutations were found in both cohorts and were seen in both familial and sporadic cases, suggesting that a small number of common mutations could account for most TACI-associated immunodeficiency cases. [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	IMMUNOGLOBULIN A DEFICIENCY 2	c1836032	6,345	omim	https://www.omim.org/entry/609529	2019-09-22T16:05:56	{"mesh": ["C536291"], "omim": ["609529"], "synonyms": ["Alternative titles", "IMMUNOGLOBULIN A, SELECTIVE DEFICIENCY OF, TACI-RELATED", "IgA, SELECTIVE DEFICIENCY OF, TACI-RELATED"]}
## Summary ### Clinical characteristics. THOC6 intellectual disability syndrome is associated with moderate-to-severe developmental delay or intellectual disability; nonspecific dysmorphic facial features (tall forehead, deep-set eyes, short and upslanted palpebral fissures, epicanthal folds, and long nose with low-hanging columella); microcephaly (typically 2-3 SD below the mean); teeth anomalies (dental caries, malocclusion, and supernumerary teeth); cardiac anomalies (most typically atrial and/or ventricular septal defects); prenatal ventriculomegaly and hydrocephalus; cryptorchidism in males; and renal malformations (most commonly unilateral renal agenesis). More rarely, affected individuals may have hypergonadotropic hypogonadism (in females), seizures, poor growth, feeding difficulties, hearing loss, refractive errors and/or other eye abnormalities, vertebral anomalies, micro/retrognathia, and imperforate / anteriorly placed anus. ### Diagnosis/testing. The diagnosis of THOC6 intellectual disability syndrome is established in a proband with biallelic pathogenic variants in THOC6 identified by molecular genetic testing. For individuals from the Hutterite population suspected of having THOC6 intellectual disability syndrome, molecular genetic testing for the specific c.136G>A (p.Gly46Arg) founder variant can be considered. ### Management. Treatment of manifestations: For those with poor weight gain, feeding therapy and consideration of a gastrostomy tube; for those with hearing loss, hearing aids may be considered; standard treatment for seizures, vision issues, dental caries/malocclusion, cardiac malformations, genital anomalies, hypergonadotropic hypogonadism, renal malformations, skeletal anomalies, and developmental delay / intellectual disability. Surveillance: At each visit: monitor developmental progress, mobility, self-help skills, and behavior; assess for signs and symptoms of hydrocephalus or for new neurologic manifestations; measurement of growth parameters and evaluation of nutritional status; assessment of vision and eye alignment; assessment for dental caries and malocclusion. Evaluate renal function (BUN, creatinine, and urinalysis) at each visit or annually for those with anomalies of the kidney and urinary tract; annual audiology evaluation; evaluation of secondary sexual characteristics and menstrual cycles at each visit in females older than age 12 years. ### Genetic counseling. THOC6 intellectual disability syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member. ## Diagnosis Formal diagnostic criteria for THOC6 intellectual disability syndrome have not been established. ### Suggestive Findings THOC6 intellectual disability syndrome should be considered in individuals with the following clinical and imaging findings: * Moderate-to-severe developmental delay (DD) or intellectual disability (ID) AND * One or more of the following features presenting in infancy or childhood: * Microcephaly * Multiple dental caries and/or dental malocclusion * Nonspecific dysmorphic features, including tall forehead, deep set eyes, short and upslanted palpebral fissures, epicanthal folds and long nose with low hanging columella * Cryptorchidism in males * Structural cardiac anomalies * Structural renal anomalies * Ventriculomegaly on brain imaging ### Establishing the Diagnosis The diagnosis of THOC6 intellectual disability syndrome is established in a proband with biallelic pathogenic variants in THOC6 identified by molecular genetic testing (see Table 1). #### Molecular Genetic Testing Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). CMA uses oligonucleotide and/or SNP arrays to detect genome-wide large deletions/duplications (including THOC6) that cannot be detected by sequence analysis. If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing. * For individuals from the Hutterite population suspected of having THOC6 intellectual disability syndrome, molecular genetic testing for the specific c.136G>A (p.Gly46Arg) founder variant can be considered first (see Molecular Genetics). * For individuals who do not originate from the Hutterite population, single-gene testing (sequence analysis of THOC6, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (CMA, exome sequencing, exome array, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of THOC6 intellectual disability syndrome is somewhat nonspecific, the majority of affected individuals have a phenotype indistinguishable from many other inherited disorders with intellectual disability. Therefore, targeted genomic testing (Option 1) or comprehensive genomic testing (Option 2) are the most reasonable methods to detect this condition. #### Option 1 An intellectual disability or microcephaly multigene panel that includes THOC6 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA 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. Of note, given the rarity of THOC6 Intellectual disability syndrome, some panels for intellectual disability may not include this gene. (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. #### Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability and other malformations, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. 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 THOC6 Intellectual Disability Syndrome View in own window Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method THOC6Sequence analysis 315/15 (100%) 4 Gene-targeted deletion/duplication analysis 5Unknown 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. 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\. Boycott et al [2010], Beaulieu et al [2013], Anazi et al [2016], Casey et al [2016], Amos et al [2017], Accogli et al [2018], Nair et al [2018], Bruel et al [2019], Elmas et al [2019], Mattioli et al [2019], Gupta et al [2020], Zhang et al [2020] 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. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. 6\. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics ### Clinical Description THOC6 intellectual disability syndrome is associated with intellectual disability, distinctive facial features, microcephaly, teeth anomalies, and cardiac and renal malformations. To date, 19 individuals from 15 families with pathogenic variants in THOC6 have been identified [Boycott et al 2010, Beaulieu et al 2013, Anazi et al 2016, Casey et al 2016, Amos et al 2017, Accogli et al 2018, Nair et al 2018, Bruel et al 2019, Elmas et al 2019, Mattioli et al 2019, Gupta et al 2020, Zhang et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports. ### Table 2. Features of THOC6 Intellectual Disability Syndrome View in own window FeatureProportion of Persons w/FeatureComment Intellectual disability19/19Moderate to severe Facial dysmorphisms17/19 Microcephaly13/19 Teeth anomalies10/19Dental caries & dental malocclusion Congenital heart defects9/19Atrial &/or ventricular septal defects Short stature8/19 Cryptorchidism in males7/19 Renal malformations6/19Mainly unilateral renal agenesis Ventriculomegaly 1Observed in at least 6 persons 1\. Ventriculomegaly may not have been assessed in all 19 reported cases in the literature so this may underestimate the actual incidence. #### Developmental Delay (DD) / Intellectual Disability (ID) Moderate-to-severe intellectual disability has been noted in all reported individuals. Most of these individuals were able to walk independently, but remained nonverbal or had very limited speech (<10 words). The oldest reported individuals are young adults. Behavior problems. Autism spectrum disorder and motor stereotypies were described in four individuals [Accogli et al 2018, Elmas et al 2019, Mattioli et al 2019]. Obsessive compulsive behavior was observed in one individual [Amos et al 2017]. #### Neurologic Most reported individuals had congenital microcephaly, predominantly 2-3 SD below the mean; 5 SD below the mean was observed in one child [Accogli et al 2018]. Epilepsy. Two affected individuals were reported to have seizures; seizure type and severity was not specified [Elmas et al 2019, Mattioli et al 2019]. Neuroimaging. Ventriculomegaly was reported prenatally in four individuals [Casey et al 2016, Accogli et al 2018, Elmas et al 2019, Mattioli et al 2019] and in six affected individuals in total [Amos et al 2017, Nair et al 2018]. * One child had postnatal hydrocephalus that required ventriculoperitoneal shunt placement [Mattioli et al 2019]. * One individual had compensated supratentorial hydrocephalus due to aqueductal stenosis and was also reported to have cerebellar hypoplasia with severe vermian dysgenesis, small pons, hippocampal dysgenesis, and partial agenesis of the septum pellucidum [Accogli et al 2018]. Corpus callosum dysgenesis was identified in five reported individuals [Amos et al 2017, Mattioli et al 2019, Bruel et al 2019, Elmas et al 2019]. #### Growth Low birth weight was present in most reported individuals, and intrauterine growth restriction was documented in four [Casey et al 2016, Amos et al 2017, Accogli et al 2018, Mattioli et al 2019]. Five individuals had failure to thrive in childhood [Anazi et al 2016, Accogli et al 2018, Gupta et al 2020, Zhang et al 2020]. Eight reported individuals were of short stature, in the range of 2-3 SD below the mean. #### Gastrointestinal Problems Three individuals presented with feeding difficulties, two requiring feeding through a gastrotomy tube because of inadequate caloric intake by mouth [Casey et al 2016, Mattioli et al 2019]. Three individuals had anal anomalies, including anal atresia, anteriorly positioned anus, and a rectoperineal fistula [Anazi et al 2016, Amos et al 2017, Accogli et al 2018]. One affected child was reported to have had a mesenteric cyst that required surgical correction [Zhang et al 2020]. #### Facial Features Dysmorphic facial features were present in most reported individuals and included the following: tall forehead, deep-set eyes, short and upslanted palpebral fissures, epicanthal folds, and long nose with low-hanging columella (Figure 1). Facial features are typically not striking enough to allow a clinician to recognize the condition on this basis alone; however, the features are often recognized as consistent with this diagnosis after the diagnosis has been suggested or confirmed. #### Figure 1. Photographs of individuals with THOC6 intellectual disability syndrome showing the following facial dysmorphisms: tall forehead, high anterior hairline, deep-set eyes with short and upslanted palpebral fissures, long nose, low-hanging columella, and thick (more...) #### Sensory Impairment Hearing loss was reported in three affected individuals, and was specified to be of sensorineural origin in one [Amos et al 2017, Mattioli et al 2019]. Eyes. Myopia was noted in three individuals [Boycott et al 2010, Gupta et al 2020]. Other reported ocular anomalies include bilateral optic disc hypoplasia [Accogli et al 2018] and alternating exotropia, nystagmus, and hyperopia [Mattioli et al 2019]. #### ENT/Mouth Micro-/retrognathia, reported in five individuals, was not significant enough to cause respiratory impairment [Boycott et al 2010, Amos et al 2017, Mattioli et al 2019]. Palatal anomalies. A cleft palate and a submucous cleft palate were seen in two individuals; one of them also had choanal atresia [Amos et al 2017, Mattioli et al 2019]. A bifid uvula and velopharyngeal insufficiency were reported in one individual each [Boycott et al 2010, Accogli et al 2018]. Teeth anomalies. Multiple dental caries and/or dental malocclusion were observed in ten affected individuals. Supernumerary teeth were also reported in one child [Accogli et al 2018]. #### Cardiovascular Anomalies Atrial septal defect, ventricular septal defect, and patent ductus arteriosus were present in eight reported individuals. A dysmorphic and mildly insufficient mitral valve was also seen in one individual [Accogli et al 2018], and pulmonary hypertension in another [Mattioli et al 2019]. #### Genital Anomalies / Puberty Males * Cryptorchidism, bilateral or unilateral, was present in seven affected males. * Two males presented with a micropenis [Nair et al 2018, Mattioli et al 2019], and one of them also had a hypospadias [Mattioli et al 2019]. Females * Premature ovarian failure was identified in one teenage girl [Boycott et al 2010]. * Hypergonadotropic hypogonadism with primary amenorrhea requiring hormone replacement therapy was reported in another girl [Accogli et al 2018]. * Endometriosis was reported in one female [Boycott et al 2010]. #### Renal Anomalies Unilateral renal agenesis was identified in four individuals [Beaulieu et al 2013, Casey et al 2016, Gupta et al 2020]. One of the individuals with unilateral renal agenesis also had a contralateral echogenic and atrophic kidney. She developed renal failure requiring dialysis at age 13 years and underwent kidney transplantation at age 15 years [Beaulieu et al 2013]. An ectopic kidney located in the pelvis or a horseshoe kidney was reported in three individuals [Beaulieu et al 2013, Accogli et al 2018, Gupta et al 2020]. Recurrent urinary tract infections were seen in three individuals [Boycott et al 2010, Amos et al 2017]. #### Skeletal Features Cervical hemivertebrae and multilevel vertebral segmentation defects causing a scoliosis were reported in two different individuals [Accogli et al 2018, Gupta et al 2020]. Two individuals presented with camptodactyly [Anazi et al 2016, Accogli et al 2018]. Other reported anomalies include pes planus, trigger thumb, calcaneovalgus and equinovarus deformities, cubitus valgus, congenital hip dislocation, radioulnar joint dysostosis, cervical rib, and Sprengel deformity. #### Prognosis It is unknown whether life span in THOC6 intellectual disability syndrome is shortened. The original four affected individuals are now young adults, with the oldest in their early 40s [Author, personal communication], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported. ### Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ### Prevalence As of early 2020, seven years after this syndrome was first described and molecularly explained, 19 affected individuals have been reported in the literature. Initially reported in the Hutterite population [Boycott et al 2010], THOC6 intellectual disability syndrome has now been identified in individuals worldwide. This disorder was more prevalent in two Hutterite leuts, with a specific founder variant (c.136G>A;p.Gly46Arg) frequency of 3% in Dariusleut controls and of 2% in Lehrerleut controls (see Molecular Genetics) [Beaulieu et al 2013]. ## Differential Diagnosis Several intellectual disability disorders are associated with additional features that overlap those observed in THOC6 intellectual disability syndrome (see Table 3). However, because the phenotypic features associated with THOC6 intellectual disability syndrome can be nonspecific, all disorders with intellectual disability (ID) without other distinctive findings should be considered in the differential diagnosis. To date more than 180 such disorders have been identified. See OMIM Phenotypic Series: Autosomal dominant ID; Autosomal recessive ID; Nonsyndromic X-linked ID; and Syndromic X-linked ID. ### Table 3. Genes of Interest in the Differential Diagnosis of THOC6 Intellectual Disability Syndrome View in own window Gene(s)DisorderMOIClinical Features of Differential Diagnosis Disorder Overlapping w/THOC6 ID syndromeDistinguishing from THOC6 ID syndrome ATR CENPJ CEP152 CEP63 DNA2 NIN NSMCE2 RBBP8 TRAIPSeckel syndrome (OMIM PS210600)ARID; microcephaly; dental malocclusionSevere growth restriction; characteristic facies CREBBP EP300Rubinstein-Taybi syndromeAD 1ID; microcephaly; genitourinary anomalies; low-hanging columellaBroad angulated thumbs & halluces; downslanting palpebral fissures & grimacing smile EMG1Bowen-Conradi syndrome (OMIM 211180)ARSevere ID, microcephaly, & micrognathia; founder effect in Hutterite populationMultiple joint contractures; severe growth restriction; early mortality KIF7Acrocallosal syndrome (OMIM 200990)ARSevere ID; corpus callosum dysgenesis; genital anomaliesDistal anomalies of limbs; macrocephaly w/protruding forehead & occiput ZEB2Mowat-Wilson syndromeAD 1Severe ID; microcephaly; corpus callosum dysgenesis; genitourinary anomalies; congenital heart defectsHirschsprung disease or chronic constipation; distinctive facial features (uplifted earlobes, widely spaced eyes, prominent & pointed chin) AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance 1\. Typically the result of a de novo dominant pathogenic variant ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with THOC6 intellectual disability syndrome, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with THOC6 Intellectual Disability Syndrome View in own window System/ConcernEvaluationComment DevelopmentDevelopmental assessment * Incl motor, adaptive, cognitive, & speech/language eval * Eval for early intervention / special education Psychiatric/ BehavioralNeuropsychiatric evalFor persons age >12 mos: screening for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD NeurologicNeurologic eval * Incl brain MRI to assess for hydrocephalus or other cerebral anomalies * Consider EEG if seizures are a concern. Gastrointestinal/ FeedingGastroenterology / nutrition / feeding team eval * Incl eval of aspiration risk & nutritional status * Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. Assess for anal anomalies.Consider referral to a gastroenterology specialist or surgeon, as appropriate. HearingAudiologic evalAssess for hearing loss. EyesOphthalmologic evalAssess for reduced vision, abnormal ocular movement, & strabismus. ENT/MouthTeeth & palate evalAssess for dental caries, dental malocclusion, & cleft palate / velopharyngeal insufficiency. CardiovascularEchocardiogramAssess for congenital heart defects. GenitalExternal genitalia exam, esp in malesAssess for cryptorchidism, hypospadias, or other genital anomalies. EndocrineEval of secondary sexual characteristics & menstruation cycles in adolescent & adult femalesAssess for primary amenorrhea or signs of premature ovarian failure. RenalRenal ultrasound * Assess for unilateral renal agenesis, ectopic kidney, or horseshoe kidney. * Assess renal function 1 & consider referral to nephrologist if an anomaly of kidney & urinary tract is present. MusculoskeletalOrthopedics / physical medicine & rehab / PT/OT evalIncl assessment of: * Gross motor & fine motor skills * Contractures, vertebral defects, & kyphoscoliosis * Mobility, ADLs, & need for adaptive devices * Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Miscellaneous/ OtherConsultation w/clinical geneticist &/or genetic counselorIncl genetic counseling Family support/resourcesAssess: * Use of community or online resources such as Parent to Parent; * Need for social work involvement for parental support; * Need for home nursing referral. ADLs = activities of daily living; OT = occupational therapy; PT = physical therapy 1\. Such as blood urea nitrogen (BUN), creatinine, and urinalysis ### Treatment of Manifestations ### Table 5. Treatment of Manifestations in Individuals with THOC6 Intellectual Disability Syndrome View in own window Manifestation/ConcernTreatmentConsiderations/Other Developmental delay / Intellectual disabilitySee Developmental Delay / Intellectual Disability Management Issues. Hydrocephalus / Cerebral malformationsStandard treatment(s) as recommended by neurologist/neurosurgeon EpilepsyStandardized treatment w/AEDs by experienced neurologist * Many AEDs may be effective; none has been demonstrated effective specifically for this disorder. * Education of parents/caregivers 1 Poor weight gain / Failure to thrive * Feeding therapy * Gastrostomy tube placement may be required for persistent feeding issues. Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia Anal anomalies / AtresiaStandard treatment per gastroenterologist &/or surgeon HearingHearing aids may be helpful per otolaryngologist.Community hearing services through early intervention or school district Abnormal vision / StrabismusStandard treatment(s) per ophthalmologistCommunity vision services through early intervention or school district Dental caries / malocclusionStandard treatment(s) per dentist Cardiac malformationsStandard treatment(s) per cardiologist Genital anomaliesStandard treatment(s) per urologist Hypergonadotropic hypogonadismHRT if indicated Renal malformationsStandard treatment(s) per nephrologist Musculoskeletal anomalies 2Standard treatment(s) per orthopedist Family/ Community * Ensure appropriate social work involvement to connect families w/local resources, respite, & support. * Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. * Ongoing assessment of need for palliative care involvement &/or home nursing * Consider involvement in adaptive sports or Special Olympics. AED = antiepileptic drug; HRT = hormone replacement therapy 1\. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. 2\. Pes planus, trigger thumb, equinovarus deformity, & congenital hip dislocation #### Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies, and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided. All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider: * IEP services: * An IEP provides specially designed instruction and related services to children who qualify. * IEP services will be reviewed annually to determine whether any changes are needed. * As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. * Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. * PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. * As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. * A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. * Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. * Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. #### Motor Dysfunction Gross motor dysfunction * Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). * Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). * For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, antiparkinsonian medications, or orthopedic procedures. Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing. Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses ,or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary. Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech and in many cases, can improve it. #### Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ### Surveillance ### Table 6. Recommended Surveillance for Individuals with THOC6 Intellectual Disability Syndrome View in own window System/ConcernEvaluationFrequency DevelopmentMonitor developmental progress & educational needs.At each visit Psychiatric/ BehavioralBehavioral assessment for signs of autism spectrum disorder Neurologic * Assess for signs & symptoms of hydrocephalus. * Monitor those w/seizures as clinically indicated. * Assess for new manifestations incl seizures, changes in tone, & movement disorders. Feeding * Measurement of growth parameters * Eval of nutritional status & safety of oral intake EyesAssess for ↓ vision, abnormal ocular movement, & strabismus. TeethAssess for dental caries & dental malocclusion. MusculoskeletalPhysical medicine, OT/PT assessment of mobility, self-help skills RenalEval of renal function 1 in individuals w/anomaly of kidney & urinary tractAt each visit or annually HearingAudiologic evalAnnually or as clinically indicated EndocrineEval of secondary sexual characteristics & menstruation cycles in femalesAt each visit for females age >12 yrs Miscellaneous/ OtherAssess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination.At each visit OT = occupational therapy; PT = physical therapy 1\. Such as blood urea nitrogen (BUN), creatinine, and urinalysis ### Evaluation of Relatives at Risk 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 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. [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	THOC6 Intellectual Disability Syndrome	c3150939	6,346	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK560442/	2021-01-18T20:53:21	{"synonyms": ["Beaulieu-Boycott-Innes Syndrome"]}
Gonadal dysgenesis with multiple anomalies is an association syndrome described only once in two sisters aged 1 1/2 and 8 1/2 years. They had a 46,XY karyotype, cleft lip and palate, preauricular pits, and a 'squashed down' appearance because of a short columella and small nares. Other anomalies included broad hands and feet, and a hypermuscular appearance. Cardiac, renal, musculoskeletal, and ectodermal anomalies were also present. Ectodermal defects included 'punched out scalp defects' and unusual positioning of hair whorls. They also had short stature, streak gonads, and mild developmental delay. The mode of 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	XY type gonadal dysgenesis-associated anomalies syndrome	c1856272	6,347	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1770	2021-01-23T19:10:57	{"mesh": ["C565536"], "omim": ["233430"], "umls": ["C1856272"], "icd-10": ["Q99.1"]}
Hepatic lipase deficiency is a disorder that affects the body's ability to break down fats (lipids). People with this disorder have increased amounts of certain fats, known as triglycerides and cholesterol, in the blood. These individuals also have increased amounts of molecules known as high-density lipoproteins (HDLs) and decreased amounts of molecules called low-density lipoproteins (LDL). These molecules transport triglycerides and cholesterol throughout the body. In people with hepatic lipase deficiency, the LDL molecules are often abnormally large. Normally, high levels of HDL (known as "good cholesterol") and low levels of LDL (known as "bad cholesterol") are protective against an accumulation of fatty deposits on the artery walls (atherosclerosis) and heart disease. However, some individuals with hepatic lipase deficiency, who have this imbalance of HDL and LDL, develop atherosclerosis and heart disease in mid-adulthood, while others do not. It is unknown whether people with hepatic lipase deficiency have a greater risk of developing atherosclerosis or heart disease than individuals in the general population. Similarly, it is unclear how increased blood triglycerides and cholesterol levels affect the risk of atherosclerosis and heart disease in people with hepatic lipase deficiency. ## Frequency Hepatic lipase deficiency is likely a rare disorder; only a few affected families have been reported in the scientific literature. ## Causes Hepatic lipase deficiency is caused by mutations in the LIPC gene. This gene provides instructions for making an enzyme called hepatic lipase. This enzyme is produced by liver cells and released into the bloodstream where it helps convert very low-density lipoproteins (VLDLs) and intermediate-density lipoproteins (IDLs) to LDLs. The enzyme also assists in transporting HDLs that carry cholesterol and triglycerides from the blood to the liver, where the HDLs deposit these fats so they can be redistributed to other tissues or removed from the body. LIPC gene mutations prevent the release of hepatic lipase from the liver or decrease the enzyme's activity in the bloodstream. As a result, VLDLs and IDLs are not efficiently converted into LDLs, and HDLs carrying cholesterol and triglycerides remain in the bloodstream. It is unclear what effect this change in lipid levels has on people with hepatic lipase deficiency. ### Learn more about the gene associated with Hepatic lipase deficiency * LIPC ## 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	Hepatic lipase deficiency	c3151466	6,348	medlineplus	https://medlineplus.gov/genetics/condition/hepatic-lipase-deficiency/	2021-01-27T08:25:11	{"gard": ["12864"], "omim": ["614025"], "synonyms": []}
A testicular nubbin is the residual tissue of the human testis after a supposed perinatal vascular accident involving the testicular blood supply. The blood supply of the testis twists (called torsion) thereby cutting off the blood supply to the testis and results in testicular atrophy (shrinking). The nubbin is usually identified in childhood by the absence of a palpable testis in the scrotal sac. The tissue remnant usually includes fibrous tissue and signs of old infarction with hemosiderin deposition identified histologically. There is some disagreement as to whether these should be removed and whether there is a risk of future malignancy. They are typically removed surgically by pediatric urologists or pediatric general surgeons through either a scrotal or inguinal (or both) incision.[1] ## References[edit] 1. ^ Cendron, Marc; Schned, Alan R.; Ellsworth, Pamela I. (1998). "Histological evaluation of the testicular nubbin in the vanishing testis syndrome". The Journal of Urology. 160 (3, part 2): 1161–1163. doi:10.1016/S0022-5347(01)62726-5. [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	Testicular nubbin	None	6,349	wikipedia	https://en.wikipedia.org/wiki/Testicular_nubbin	2021-01-18T18:43:54	{"wikidata": ["Q7705857"]}
Medical condition of the ear Pseudocyst of the auricle Other namesAuricular endochondrial pseudocyst,[1] Cystic chondromalacia,[1] Endochondral pseudocyst,[2] and Intracartilaginous cyst[1] SpecialtyDermatology Pseudocyst of the auricle is a cutaneous condition characterized by a fluctuant, tense, noninflammatory swelling on the upper half of the ear.[1][2]:681[3][4][5] ## See also[edit] * Verrucous cyst * Cutaneous columnar cyst * List of cutaneous conditions ## References[edit] 1. ^ a b c d Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ a b James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: Clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 3. ^ Glamb, Roman; Kim, Robert (1984). "Pseudocyst of the auricle". Journal of the American Academy of Dermatology. 11 (1): 58–63. doi:10.1016/S0190-9622(84)70135-6. ISSN 0190-9622. PMID 6736353. 4. ^ Lim, C. M.; Goh, Y. H.; Chao, S. S.; Lynne, Lim (2002). "Pseudocyst of the Auricle". The Laryngoscope. 112 (11): 2033–2036. doi:10.1097/00005537-200211000-00022. ISSN 0023-852X. PMID 12439175. S2CID 26489593. 5. ^ Vishwakarma, S.K.; Deepak Gupta; S. K. Verma (1987). "Pseudocyst of the Auricle". Indian Journal of Otolaryngology and Head & Neck Surgery. 39 (4). doi:10.1007/BF03024762 (inactive 2021-01-15).CS1 maint: DOI inactive as of January 2021 (link) ## Further reading[edit] * Hoffmann TJ, Richardson TF, Jacobs RJ, Torres A (March 1993). "Pseudocyst of the auricle". The Journal of Dermatologic Surgery and Oncology. 19 (3): 259–62. doi:10.1111/j.1524-4725.1993.tb00345.x. PMID 8445110. * Crusat Braña S, Nogués Orpí J, García Rodríguez MR, et al. (1996). "[Pseudocyst of the auricle]". Anales Otorrinolaringológicos Ibero-americanos (in Spanish). 23 (3): 309–18. PMID 8712315. This Epidermal nevi, neoplasms, cysts 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	Pseudocyst of the auricle	None	6,350	wikipedia	https://en.wikipedia.org/wiki/Pseudocyst_of_the_auricle	2021-01-18T18:58:00	{"wikidata": ["Q7254720"]}
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-27 (SCA27) is caused by heterozygous mutation in the gene encoding fibroblast growth factor-14 (FGF14; 601515) on chromosome 13q33. For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). Clinical Features Van Swieten et al. (2003) reported a large 3-generation Dutch family in which 14 members had cerebellar ataxia inherited in an autosomal dominant pattern. Since childhood, all patients had trembling of both hands, which was exacerbated by emotional stress and physical exercise. Mild unsteadiness and ataxia of the upper limbs, especially under unusual circumstances, began at age 15 to 20 years. Six patients did not complete primary education, and only 4 of the 14 attended secondary school. Aggressive outbursts were mentioned in 5 patients and depression in 3. Neurologic examination showed dysmetric saccades, disrupted ocular pursuit movements, gaze-evoked nystagmus, cerebellar dysarthria, and a high-frequency, small-amplitude tremor in both hands in most of the patients. Six patients showed head tremor, and subtle orofacial dyskinesias were seen in 8. Severe limb and gait ataxia were present in the 3 eldest patients. Two patients showed cerebellar atrophy on MRI. The inability to complete primary education, low cognitive performances, and aggressive outbursts in several of the patients may reflect changes in the development and survival of neuronal populations in the cerebral cortex, amygdala, and basal ganglia. Dalski et al. (2005) reported an ataxia patient with mild mental retardation (IQ of 70), inborn strabismus, and red-green colorblindness. His motor development was normal until age 12 years, when he developed a slowly progressive gait disturbance, memory loss, and depressed mood. Clinical examination at age 13 years showed truncal and gait ataxia, small-amplitude tremor in both hands, gaze-evoked nystagmus, and pes cavus. Nerve conduction studies revealed mild axonal sensory neuropathy. The patient's father, who was deceased, reportedly had gait disturbance, memory loss, and pes cavus. Cytogenetics Misceo et al. (2009) reported a mother and daughter with SCA27 resulting from a translocation, t(5;13)(q31.2;q33.1), that disrupted the FGF14 gene. Both patients showed signs of SCA, although the 5.5-year-old daughter was more severely affected with early onset cerebellar ataxia, microcephaly, and severe mental retardation. In the first year of life, the daughter showed truncal unsteadiness, which progressed to gait ataxia, axial tremor with titubation of head and neck, action and intention tremor, and dysarthria. She occasionally displayed dyskinetic jerky movements in the neck and arms. Other features included a short neck, fifth finger clinodactyly, and high-arched feet. Both mother and daughter also showed upper neuron involvement, with hyperreflexia and possible extensor plantar responses. The translocation breakpoint on der(13) was located between exons 1 and 2, encoding isoform 1b of FGF14. Isoform 1a of FGF14 was unaffected. The findings indicated that haploinsufficiency of FGF14 can cause SCA27. Molecular Genetics In affected members of a large Dutch family with early-onset tremor, dyskinesia, and slowly progressive cerebellar ataxia, van Swieten et al. (2003) identified a heterozygous mutation in the FGF14 gene (601515.0001). Other SCA loci were excluded, including that for SCA8 (608768), which maps to chromosome 13q21. The disorder was consistent with the occurrence of ataxia and paroxysmal dyskinesia in Fgf14 knockout mice (Wang et al., 2002). In an 18-year-old man with early-onset ataxia and mild mental retardation, Dalski et al. (2005) identified a truncating mutation in the FGF14 gene (601515.0002). INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Orofacial dyskinesias Eyes \- Gaze-evoked nystagmus \- Dysmetric saccades \- Disrupted ocular pursuit movements \- Strabismus \- Red-blind color blindness (reported in 1 patient) SKELETAL Feet \- Pes cavus NEUROLOGIC Central Nervous System \- Cerebellar ataxia \- Gait ataxia \- Limb ataxia \- Truncal ataxia \- Tremor, small-amplitude, high-frequency, restricted to the hands \- Head tremor, mild \- Tremor is exacerbated by stress and exercise \- Gaze-evoked nystagmus \- Dysarthria \- Memory loss \- Poor cognition \- Mental retardation, mild \- Cerebellar atrophy \- Basal ganglia degeneration Peripheral Nervous System \- Sensory axonal neuropathy, mild Behavioral Psychiatric Manifestations \- Aggressive outbursts \- Depression MISCELLANEOUS \- Onset in late-childhood to early adulthood (12 to 20 years) \- Slowly progressive \- Genetic heterogeneity (see SCA1, 164000 ) MOLECULAR BASIS \- Caused by mutation in the fibroblast growth factor gene-14 (FGF14, 601515.0001 ) ▲ 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	SPINOCEREBELLAR ATAXIA 27	c1836383	6,351	omim	https://www.omim.org/entry/609307	2019-09-22T16:06:17	{"doid": ["0050976"], "mesh": ["C537204"], "omim": ["609307"], "orphanet": ["98764"], "synonyms": ["Alternative titles", "CEREBELLAR ATAXIA, AUTOSOMAL DOMINANT, FGF14-RELATED"]}
A number sign (#) is used with this entry because Emanuel syndrome is caused by malsegregation of the t(11;22)(q23;q11.2) translocation, one of only a few recurrent non-Robertsonian constitutional translocations in humans (Fraccaro et al., 1980; Zackai and Emanuel, 1980). See also supernumerary der(22)t(8;22) syndrome (613700). Description Emanuel syndrome is characterized by multiple congenital anomalies, craniofacial dysmorphism, and significant developmental delay and mental retardation. Features include ear anomalies, preauricular tag or sinus, cleft or high-arched palate, micrognathia, microcephaly, kidney abnormalities, heart defects, and genital abnormalities in males (summary by Carter et al., 2009). Carriers of the balanced constitutional t(11;22) translocation are phenotypically normal but have a 10% risk of having progeny with supernumerary der(22)t(11;22) syndrome as a result of malsegregation of the der(22). The affected progeny are genotypically unbalanced because they carry the der(22) as a supernumerary chromosome--either 47,XX,+der(22)t(11;22) or 47,XY,+der(22)t(11;22) (Zackai and Emanuel, 1980; Lin et al., 1986). Clinical Features Carter et al. (2009) reported questionnaire-based information on 63 individuals with Emanuel syndrome, ranging in age from newborn to adult. The most common anomalies were ear pits (76%), micrognathia (60%), heart malformations (57%), and cleft palate (54%). Renal defects were found in 36%, small penis in 64%, and cryptorchidism in 46%. Dysmorphic features included hooded eyelids, deep-set eyes, upslanting palpebral fissures, low-hanging columella, micrognathia, and facial asymmetry. Micrognathia became less apparent with age. Other features included myopia, strabismus, hearing impairment, seizures, failure to thrive, and recurrent infections, particularly otitis media. Most had feeding difficulties with gastroesophageal reflux and/or constipation, resulting in poor growth. Psychomotor development was uniformly delayed. The majority of individuals (over 70%) eventually learn to walk with support, but had limited language development and ability for self-care. Cytogenetics To elucidate the mechanism of the malsegregation of the der(22), Shaikh et al. (1999) analyzed 16 families with the t(11;22) translocation using short tandem repeat polymorphism markers on both chromosomes 11 and 22. In all informative cases the proband received 2 of 3 alleles, for markers above the breakpoint on chromosome 22 and below the breakpoint on chromosome 11, from the t(11;22) translocation carrier parent. These data strongly suggested that 3:1 meiosis I malsegregation in the t(11;22) balanced translocation carrier parent was the mechanism in all 16 families. Shaikh et al. (1999) concluded that most t(11;22) translocations occur within the same genomic intervals and that most supernumerary der(22) offspring result from a 3:1 meiosis I malsegregation in the balanced translocation carrier. Diagnosis Kurahashi et al. (2000) developed a PCR-based translocation detection system for the t(11;22) translocation using PCR primers flanking the palindromic AT-rich repeats (PATRRs) of both chromosomes. They compared the translocation breakpoints of 40 unrelated carriers of the t(11;22) balanced translocation and 2 additional, independent cases with supernumerary der(22) syndrome. Similar translocation-specific junction fragments were obtained from both derivative chromosomes in all 40 carriers of the t(11;22) balanced translocation and from the der(22) in both of the offspring with unbalanced supernumerary der(22) syndrome, suggesting that the breakpoints in all cases localize within these PATRRs and that the translocation is generated by a similar mechanism. This PCR strategy provides a convenient technique for rapid diagnosis of the translocation, indicating its utility for prenatal and preimplantation diagnosis in families including carriers of the balanced translocation. Pathogenesis Kurahashi et al. (2000) identified the breakpoints of the t(11;22) translocation within palindromic AT-rich repeats on chromosomes 11 and 22, suggesting that hairpin/cruciform structures mediate double-strand breaks leading to the translocation. Kurahashi et al. (2000) sequenced the der(11) junction fragment. Kurahashi and Emanuel (2001) presented data lending support to the hypothesis that palindrome-mediated double-strand breaks in meiosis cause illegitimate recombination between 11q23 and 22q11, resulting in this recurrent translocation. Kurahashi and Emanuel (2001) described an unexpectedly high rate of de novo constitutional t(11;22) translocations in sperm from normal males. Somatic DNA from these and other normal individuals or from people with chromosomal breakage syndromes did not yield PCR junction fragments, indicating that this translocation originates during meiosis. Kato et al. (2006) found that the PATRR on chromosome 11 is variable in size in normal healthy individuals. The most common allele is about 450 basepairs, termed by them L-PATRR11, and forms a nearly perfect palindrome. Several types of short variants (S-PATRR11s) were identified that appear to be derived from the longer version primarily by deletion near the symmetric center of the palindromic structure. Kato et al. (2006) classified the S-PATRR11s into 4 groups. The most frequent 350-bp variant, S1-PATRR11, has a 50-bp deletion at both of the palindromic arms but still remains completely symmetrical. S2-PATRR11 has an asymmetric deletion at its center, but the new center manifests a symmetric palindrome. S3-PATRR11 does not possess palindromic features by virtue of a deletion at the center of the palindrome. Kato et al. (2006) identified a rare 434-bp S-PATRR11, S4-PATRR11, which sustained an asymmetric central deletion followed by the insertion of an AT-rich sequence of unknown origin. Kato et al. (2006) also identified another rare allele, EL-PATRR11, with a duplication of the proximal arm, which constitutes a 603-bp asymmetric palindrome. They then analyzed sperm DNA from individuals with various genotypes for the PATRR11. Five men homozygous for the L-PATRR11 genotype produced de novo translocations at a frequency ranging between 1.52 x 10(-5) and 1.57 x 10(-4). A heterozygote for the L-PATRR11 and S1- or S2-PATRR11 alleles produced de novo translocations at a similar overall frequency, as did homozygotes for the L-PATRR11. Further sequence variation revealed that virtually all of the de novo translocations appeared to originate from the L-PATRR11, which has an overall allele frequency in the general population of 87.1%. Kato et al. (2006) concluded that their work demonstrates genetic variation over more than 3 orders of magnitude in the susceptibility for generating the recurrent translocation in humans, and pointed to the importance of genomic sequence variation on the frequency of chromosomal rearrangements. INHERITANCE \- Inherited chromosomal imbalance GROWTH Other \- Prenatal growth retardation HEAD & NECK Head \- Microcephaly Face \- Micrognathia \- Long philtrum \- Asymmetric facies \- Broad mandible Ears \- Preauricular tag \- Preauricular sinus \- Low-set ears \- Large ears \- Hearing loss \- Recurrent otitis media Eyes \- Hooded eyelids \- Deep-set eyes \- Upslanting palpebral fissures \- Myopia \- Strabismus Nose \- Low hanging columella Mouth \- Cleft palate \- High-arched palate Teeth \- Delayed eruption of primary teeth \- Misaligned teeth \- Crowded teeth Neck \- Excess nuchal skin CARDIOVASCULAR Heart \- Atrial septal defect \- Ventricular septal defect \- Pulmonic stenosis \- Aortic stenosis Vascular \- Patent ductus arteriosus \- Truncus arteriosus RESPIRATORY \- Recurrent respiratory infections CHEST Ribs Sternum Clavicles & Scapulae \- 13 pairs of ribs Breasts \- Low-set nipples Diaphragm \- Diaphragmatic hernia ABDOMEN Gastrointestinal \- Feeding difficulties \- Gastroesophageal reflux \- Constipation \- Imperforate anus \- Tight anal sphincter \- Misplaced anus GENITOURINARY External Genitalia (Male) \- Inguinal hernia \- Micropenis Internal Genitalia (Male) \- Undescended testis Kidneys \- Absent kidney \- Hypoplastic kidney SKELETAL Spine \- Scoliosis \- Kyphosis Pelvis \- Congenital hip dislocation NEUROLOGIC Central Nervous System \- Global developmental delay \- Mental retardation \- Poor language development \- Hypotonia \- Seizures \- White matter abnormalities \- Cerebral atrophy \- Hypoplastic corpus callosum PRENATAL MANIFESTATIONS Placenta & Umbilical Cord \- Single umbilical artery LABORATORY ABNORMALITIES \- Patients have supernumerary chromosome - 47,XX(or XY), +der(22), +(11:22)(q23:q11) \- Carriers have balanced constitutional translocation - 46,XX(or XY), +(11:22)(q23:q11) MISCELLANEOUS \- Risk of affected offspring in maternal translocation carrier - 4-10% \- Risk of affected offspring in paternal translocation carrier - 0-7% MOLECULAR BASIS \- Caused by non-Robertsonian constitutional translocation, (11\|22)(q23\|q11.2) ▲ 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	EMANUEL SYNDROME	c1836929	6,352	omim	https://www.omim.org/entry/609029	2019-09-22T16:06:50	{"mesh": ["C535733"], "omim": ["609029"], "orphanet": ["96170"], "synonyms": ["Alternative titles", "SUPERNUMERARY DER(22)t(11"], "genereviews": ["NBK1263"]}
3p25.3 microdeletion syndrome is a rare chromosomal anomaly characterized by intellectual disability, epilepsy or EEG abnormalities, poor speech, ataxia, and stereotypic hand movements. [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	3p25.3 microdeletion syndrome	None	6,353	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=435638	2021-01-23T19:09:19	{"icd-10": ["Q93.5"], "synonyms": ["Del(3)p(25.3)", "Intellectual disability-epilepsy-stereotypic hand movement syndrome", "Monosomy 3p25.3"]}
Mosquito-borne infectious disease For other uses, see Malaria (disambiguation). Not to be confused with miliaria. Malaria Malaria parasite connecting to a red blood cell Pronunciation * /məˈlɛəriə/ SpecialtyInfectious disease SymptomsFever, vomiting, headache, yellow skin[1] ComplicationsSeizures, coma[1] Usual onset10–15 days post exposure[2] CausesPlasmodium spread by mosquitoes[1] Diagnostic methodExamination of the blood, antigen detection tests[1] PreventionMosquito nets, insect repellent, mosquito control, medications[1] MedicationAntimalarial medication[2] Frequency228 million (2018)[3] Deaths405,000 in 2018[3] Malaria is a mosquito-borne infectious disease that affects humans and other animals.[2] Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches.[1] In severe cases, it can cause yellow skin, seizures, coma, or death.[1] Symptoms usually begin ten to fifteen days after being bitten by an infected mosquito.[2] If not properly treated, people may have recurrences of the disease months later.[2] In those who have recently survived an infection, reinfection usually causes milder symptoms.[1] This partial resistance disappears over months to years if the person has no continuing exposure to malaria.[1] Malaria is caused by single-celled microorganisms of the Plasmodium group.[2] The disease is most commonly spread by an infected female Anopheles mosquito.[2] The mosquito bite introduces the parasites from the mosquito's saliva into a person's blood.[2] The parasites travel to the liver where they mature and reproduce.[1] Five species of Plasmodium can infect and be spread by humans.[1] Most deaths are caused by P. falciparum, whereas P. vivax, P. ovale, and P. malariae generally cause a milder form of malaria.[1][2] The species P. knowlesi rarely causes disease in humans.[2] Malaria is typically diagnosed by the microscopic examination of blood using blood films, or with antigen-based rapid diagnostic tests.[1] Methods that use the polymerase chain reaction to detect the parasite's DNA have been developed, but are not widely used in areas where malaria is common due to their cost and complexity.[4] The risk of disease can be reduced by preventing mosquito bites through the use of mosquito nets and insect repellents or with mosquito-control measures such as spraying insecticides and draining standing water.[1] Several medications are available to prevent malaria in travellers to areas where the disease is common.[2] Occasional doses of the combination medication sulfadoxine/pyrimethamine are recommended in infants and after the first trimester of pregnancy in areas with high rates of malaria.[2] As of 2020, there is one vaccine which has been shown to reduce the risk of malaria by about 40% in children in Africa.[5][6] Efforts to develop more effective vaccines are ongoing.[6] The recommended treatment for malaria is a combination of antimalarial medications that includes artemisinin.[1][2] The second medication may be either mefloquine, lumefantrine, or sulfadoxine/pyrimethamine.[7] Quinine, along with doxycycline, may be used if artemisinin is not available.[7] It is recommended that in areas where the disease is common, malaria is confirmed if possible before treatment is started due to concerns of increasing drug resistance.[2] Resistance among the parasites has developed to several antimalarial medications; for example, chloroquine-resistant P. falciparum has spread to most malarial areas, and resistance to artemisinin has become a problem in some parts of Southeast Asia.[2] The disease is widespread in the tropical and subtropical regions that exist in a broad band around the equator.[1] This includes much of sub-Saharan Africa, Asia, and Latin America.[2] In 2018 there were 228 million cases of malaria worldwide resulting in an estimated 405,000 deaths.[3] Approximately 93% of the cases and 94% of deaths occurred in Africa.[3] Rates of disease have decreased from 2010 to 2014 but increased from 2015 to 2017, during which there were 231 million cases.[3] Malaria is commonly associated with poverty and has a significant negative effect on economic development.[8][9] In Africa, it is estimated to result in losses of US$12 billion a year due to increased healthcare costs, lost ability to work, and adverse effects on tourism.[10] Play media Video summary (script) ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Cause * 2.1 Life cycle * 2.2 Recurrent malaria * 2.3 Climate change * 3 Pathophysiology * 3.1 Genetic resistance * 3.2 Liver dysfunction * 4 Diagnosis * 4.1 Classification * 5 Prevention * 5.1 Mosquito control * 5.1.1 Insecticide treated nets * 5.1.2 Indoor residual spraying * 5.1.3 Housing modifications * 5.1.4 Other mosquito control methods * 5.2 Medications * 5.3 Others * 6 Treatment * 6.1 Uncomplicated malaria * 6.2 Severe and complicated malaria * 6.3 Resistance * 7 Prognosis * 8 Epidemiology * 9 History * 10 Society and culture * 10.1 Economic impact * 10.2 Counterfeit and substandard drugs * 10.3 War * 10.4 Eradication efforts * 11 Research * 11.1 Vaccine * 11.2 Medications * 11.3 New targets * 11.4 Other * 12 Other animals * 13 References * 13.1 Citations * 13.2 Sources * 14 Further reading * 15 External links ## Signs and symptoms[edit] Main symptoms of malaria[11] The signs and symptoms of malaria typically begin 8–25 days following infection,[11] but may occur later in those who have taken antimalarial medications as prevention.[4] Initial manifestations of the disease—common to all malaria species—are similar to flu-like symptoms,[12] and can resemble other conditions such as sepsis, gastroenteritis, and viral diseases.[4] The presentation may include headache, fever, shivering, joint pain, vomiting, hemolytic anemia, jaundice, hemoglobin in the urine, retinal damage, and convulsions.[13] The classic symptom of malaria is paroxysm—a cyclical occurrence of sudden coldness followed by shivering and then fever and sweating, occurring every two days (tertian fever) in P. vivax and P. ovale infections, and every three days (quartan fever) for P. malariae. P. falciparum infection can cause recurrent fever every 36–48 hours, or a less pronounced and almost continuous fever.[14] Severe malaria is usually caused by P. falciparum (often referred to as falciparum malaria). Symptoms of falciparum malaria arise 9–30 days after infection.[12] Individuals with cerebral malaria frequently exhibit neurological symptoms, including abnormal posturing, nystagmus, conjugate gaze palsy (failure of the eyes to turn together in the same direction), opisthotonus, seizures, or coma.[12] ### Complications[edit] Malaria has several serious complications. Among these is the development of respiratory distress, which occurs in up to 25% of adults and 40% of children with severe P. falciparum malaria. Possible causes include respiratory compensation of metabolic acidosis, noncardiogenic pulmonary oedema, concomitant pneumonia, and severe anaemia. Although rare in young children with severe malaria, acute respiratory distress syndrome occurs in 5–25% of adults and up to 29% of pregnant women.[15] Coinfection of HIV with malaria increases mortality.[16] Kidney failure is a feature of blackwater fever, where haemoglobin from lysed red blood cells leaks into the urine.[12] Infection with P. falciparum may result in cerebral malaria, a form of severe malaria that involves encephalopathy. It is associated with retinal whitening, which may be a useful clinical sign in distinguishing malaria from other causes of fever.[17] An enlarged spleen, enlarged liver or both of these, severe headache, low blood sugar, and haemoglobin in the urine with kidney failure may occur.[12] Complications may include spontaneous bleeding, coagulopathy, and shock.[18] Malaria in pregnant women is an important cause of stillbirths, infant mortality, miscarriage and low birth weight,[19] particularly in P. falciparum infection, but also with P. vivax.[20] ## Cause[edit] Main article: Plasmodium Malaria parasites belong to the genus Plasmodium (phylum Apicomplexa). In humans, malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi.[21][22] Among those infected, P. falciparum is the most common species identified (~75%) followed by P. vivax (~20%).[4] Although P. falciparum traditionally accounts for the majority of deaths,[23] recent evidence suggests that P. vivax malaria is associated with potentially life-threatening conditions about as often as with a diagnosis of P. falciparum infection.[24] P. vivax proportionally is more common outside Africa.[25] There have been documented human infections with several species of Plasmodium from higher apes; however, except for P. knowlesi—a zoonotic species that causes malaria in macaques[22]—these are mostly of limited public health importance.[26] ### Life cycle[edit] The life cycle of malaria parasites. A mosquito causes an infection by a bite. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells, where they multiply into merozoites, rupture the liver cells, and return to the bloodstream. The merozoites infect red blood cells, where they develop into ring forms, trophozoites and schizonts that in turn produce further merozoites. Sexual forms are also produced, which, if taken up by a mosquito, infect the insect and continue the life cycle. In the life cycle of Plasmodium, a female Anopheles mosquito (the definitive host) transmits a motile infective form (called the sporozoite) to a vertebrate host such as a human (the secondary host), thus acting as a transmission vector. A sporozoite travels through the blood vessels to liver cells (hepatocytes), where it reproduces asexually (tissue schizogony), producing thousands of merozoites. These infect new red blood cells and initiate a series of asexual multiplication cycles (blood schizogony) that produce 8 to 24 new infective merozoites, at which point the cells burst and the infective cycle begins anew.[27] Other merozoites develop into immature gametocytes, which are the precursors of male and female gametes. When a fertilised mosquito bites an infected person, gametocytes are taken up with the blood and mature in the mosquito gut. The male and female gametocytes fuse and form an ookinete—a fertilised, motile zygote. Ookinetes develop into new sporozoites that migrate to the insect's salivary glands, ready to infect a new vertebrate host. The sporozoites are injected into the skin, in the saliva, when the mosquito takes a subsequent blood meal.[28] Only female mosquitoes feed on blood; male mosquitoes feed on plant nectar and do not transmit the disease. Females of the mosquito genus Anopheles prefer to feed at night. They usually start searching for a meal at dusk, and continue through the night until they succeed.[29] Malaria parasites can also be transmitted by blood transfusions, although this is rare.[30] ### Recurrent malaria[edit] Symptoms of malaria can recur after varying symptom-free periods. Depending upon the cause, recurrence can be classified as either recrudescence, relapse, or reinfection. Recrudescence is when symptoms return after a symptom-free period. It is caused by parasites surviving in the blood as a result of inadequate or ineffective treatment.[31] Relapse is when symptoms reappear after the parasites have been eliminated from the blood but persist as dormant hypnozoites in liver cells.[32] Relapse commonly occurs between 8–24 weeks and is often seen in P. vivax and P. ovale infections.[4] However, relapse-like P. vivax recurrences are probably being over-attributed to hypnozoite activation. Some of them might have an extra-vascular merozoite origin, making these recurrences recrudescences, not relapses.[33] One newly recognised, non-hypnozoite, possible contributing source to recurrent peripheral P. vivax parasitemia is erythrocytic forms in bone marrow.[34] P. vivax malaria cases in temperate areas often involve overwintering by hypnozoites, with relapses beginning the year after the mosquito bite.[35] Reinfection means the parasite that caused the past infection was eliminated from the body but a new parasite was introduced. Reinfection cannot readily be distinguished from recrudescence, although recurrence of infection within two weeks of treatment for the initial infection is typically attributed to treatment failure.[36] People may develop some immunity when exposed to frequent infections.[37] ### Climate change[edit] See also: Effects of global warming on human health § Malaria Global climate change is likely to affect malaria transmission, but the degree of effect and the areas affected is uncertain.[38] Greater rainfall in certain areas of India, and following an El Niño event is associated with increased mosquito numbers.[39] Since 1900 there has been substantial change in temperature and rainfall over Africa.[40] However, factors that contribute to how rainfall results in water for mosquito breeding are complex, incorporating the extent to which it is absorbed into soil and vegetation for example, or rates of runoff and evaporation.[41] Recent research has provided a more in-depth picture of conditions across Africa, combining a malaria climatic suitability model with a continental-scale model representing real-world hydrological processes.[41] ## Pathophysiology[edit] Further information: Plasmodium falciparum § Pathogenesis Micrograph of a placenta from a stillbirth due to maternal malaria. H&E stain. Red blood cells are anuclear; blue/black staining in bright red structures (red blood cells) indicate foreign nuclei from the parasites. Electron micrograph of a Plasmodium falciparum-infected red blood cell (center), illustrating adhesion protein "knobs" Malaria infection develops via two phases: one that involves the liver (exoerythrocytic phase), and one that involves red blood cells, or erythrocytes (erythrocytic phase). When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver where they infect hepatocytes, multiplying asexually and asymptomatically for a period of 8–30 days.[42] After a potential dormant period in the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells to begin the erythrocytic stage of the life cycle.[42] The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.[43] Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their host cells to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells.[42] Some P. vivax sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead, produce hypnozoites that remain dormant for periods ranging from several months (7–10 months is typical) to several years.[35] After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in P. vivax infections,[35] although their existence in P. ovale is uncertain.[44] The parasite is relatively protected from attack by the body's immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, the P. falciparum parasite displays adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen.[45] The blockage of the microvasculature causes symptoms such as those in placental malaria.[46] Sequestered red blood cells can breach the blood–brain barrier and cause cerebral malaria.[47] ### Genetic resistance[edit] Main article: Human genetic resistance to malaria According to a 2005 review, due to the high levels of mortality and morbidity caused by malaria—especially the P. falciparum species—it has placed the greatest selective pressure on the human genome in recent history. Several genetic factors provide some resistance to it including sickle cell trait, thalassaemia traits, glucose-6-phosphate dehydrogenase deficiency, and the absence of Duffy antigens on red blood cells.[48][49][50] The impact of sickle cell trait on malaria immunity illustrates some evolutionary trade-offs that have occurred because of endemic malaria. Sickle cell trait causes a change in the haemoglobin molecule in the blood. Normally, red blood cells have a very flexible, biconcave shape that allows them to move through narrow capillaries; however, when the modified haemoglobin S molecules are exposed to low amounts of oxygen, or crowd together due to dehydration, they can stick together forming strands that cause the cell to distort into a curved sickle shape. In these strands, the molecule is not as effective in taking or releasing oxygen, and the cell is not flexible enough to circulate freely. In the early stages of malaria, the parasite can cause infected red cells to sickle, and so they are removed from circulation sooner. This reduces the frequency with which malaria parasites complete their life cycle in the cell. Individuals who are homozygous (with two copies of the abnormal haemoglobin beta allele) have sickle-cell anaemia, while those who are heterozygous (with one abnormal allele and one normal allele) experience resistance to malaria without severe anaemia. Although the shorter life expectancy for those with the homozygous condition would tend to disfavour the trait's survival, the trait is preserved in malaria-prone regions because of the benefits provided by the heterozygous form.[50][51] ### Liver dysfunction[edit] Liver dysfunction as a result of malaria is uncommon and usually only occurs in those with another liver condition such as viral hepatitis or chronic liver disease. The syndrome is sometimes called malarial hepatitis.[52] While it has been considered a rare occurrence, malarial hepatopathy has seen an increase, particularly in Southeast Asia and India. Liver compromise in people with malaria correlates with a greater likelihood of complications and death.[52] ## Diagnosis[edit] Main article: Diagnosis of malaria The blood film is the gold standard for malaria diagnosis. Ring-forms and gametocytes of Plasmodium falciparum in human blood Owing to the non-specific nature of the presentation of symptoms, diagnosis of malaria in non-endemic areas requires a high degree of suspicion, which might be elicited by any of the following: recent travel history, enlarged spleen, fever, low number of platelets in the blood, and higher-than-normal levels of bilirubin in the blood combined with a normal level of white blood cells.[4] Reports in 2016 and 2017 from countries where malaria is common suggest high levels of over diagnosis due to insufficient or inaccurate laboratory testing.[53][54][55] Malaria is usually confirmed by the microscopic examination of blood films or by antigen-based rapid diagnostic tests (RDT).[56][57] In some areas, RDTs must be able to distinguish whether the malaria symptoms are caused by Plasmodium falciparum or by other species of parasites since treatment strategies could differ for non-P. falciparum infections.[58] Microscopy is the most commonly used method to detect the malarial parasite—about 165 million blood films were examined for malaria in 2010.[59] Despite its widespread usage, diagnosis by microscopy suffers from two main drawbacks: many settings (especially rural) are not equipped to perform the test, and the accuracy of the results depends on both the skill of the person examining the blood film and the levels of the parasite in the blood. The sensitivity of blood films ranges from 75 to 90% in optimum conditions, to as low as 50%. Commercially available RDTs are often more accurate than blood films at predicting the presence of malaria parasites, but they are widely variable in diagnostic sensitivity and specificity depending on manufacturer, and are unable to tell how many parasites are present.[59] However, incorporating RDTs into the diagnosis of malaria can reduce antimalarial prescription. Although RDT does not improve the health outcomes of those infected with malaria, it also does not lead to worse outcomes when compared to presumptive antimalarial treatment.[60] In regions where laboratory tests are readily available, malaria should be suspected, and tested for, in any unwell person who has been in an area where malaria is endemic. In areas that cannot afford laboratory diagnostic tests, it has become common to use only a history of fever as the indication to treat for malaria—thus the common teaching "fever equals malaria unless proven otherwise". A drawback of this practice is overdiagnosis of malaria and mismanagement of non-malarial fever, which wastes limited resources, erodes confidence in the health care system, and contributes to drug resistance.[61] Although polymerase chain reaction-based tests have been developed, they are not widely used in areas where malaria is common as of 2012, due to their complexity.[4] ### Classification[edit] Malaria is classified into either "severe" or "uncomplicated" by the World Health Organization (WHO).[4] It is deemed severe when any of the following criteria are present, otherwise it is considered uncomplicated.[62] * Decreased consciousness * Significant weakness such that the person is unable to walk * Inability to feed * Two or more convulsions * Low blood pressure (less than 70 mmHg in adults and 50 mmHg in children) * Breathing problems * Circulatory shock * Kidney failure or haemoglobin in the urine * Bleeding problems, or hemoglobin less than 50 g/L (5 g/dL) * Pulmonary oedema * Blood glucose less than 2.2 mmol/L (40 mg/dL) * Acidosis or lactate levels of greater than 5 mmol/L * A parasite level in the blood of greater than 100,000 per microlitre (µL) in low-intensity transmission areas, or 250,000 per µL in high-intensity transmission areas Cerebral malaria is defined as a severe P. falciparum-malaria presenting with neurological symptoms, including coma (with a Glasgow coma scale less than 11, or a Blantyre coma scale less than 3), or with a coma that lasts longer than 30 minutes after a seizure.[63] Various types of malaria have been called by the names below:[64] Name Pathogen Notes algid malaria Plasmodium falciparum severe malaria affecting the cardiovascular system and causing chills and circulatory shock bilious malaria Plasmodium falciparum severe malaria affecting the liver and causing vomiting and jaundice cerebral malaria Plasmodium falciparum severe malaria affecting the cerebrum congenital malaria various plasmodia plasmodium introduced from the mother via the fetal circulation falciparum malaria, Plasmodium falciparum malaria, pernicious malaria Plasmodium falciparum ovale malaria, Plasmodium ovale malaria Plasmodium ovale quartan malaria, malariae malaria, Plasmodium malariae malaria Plasmodium malariae paroxysms every fourth day (quartan), counting the day of occurrence as the first day quotidian malaria Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi paroxysms daily (quotidian) tertian malaria Plasmodium falciparum, Plasmodium ovale, Plasmodium vivax paroxysms every third day (tertian), counting the day of occurrence as the first transfusion malaria various plasmodia plasmodium introduced by blood transfusion, needle sharing, or needlestick injury vivax malaria, Plasmodium vivax malaria Plasmodium vivax ## Prevention[edit] An Anopheles stephensi mosquito shortly after obtaining blood from a human (the droplet of blood is expelled as a surplus). This mosquito is a vector of malaria, and mosquito control is an effective way of reducing its incidence. Methods used to prevent malaria include medications, mosquito elimination and the prevention of bites. As of 2020, there is one vaccine for malaria (known as RTS,S) which is licensed for use.[6][5] The presence of malaria in an area requires a combination of high human population density, high anopheles mosquito population density and high rates of transmission from humans to mosquitoes and from mosquitoes to humans. If any of these is lowered sufficiently, the parasite eventually disappears from that area, as happened in North America, Europe, and parts of the Middle East. However, unless the parasite is eliminated from the whole world, it could re-establish if conditions revert to a combination that favors the parasite's reproduction. Furthermore, the cost per person of eliminating anopheles mosquitoes rises with decreasing population density, making it economically unfeasible in some areas.[65] Prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the initial costs required are out of reach of many of the world's poorest people. There is a wide difference in the costs of control (i.e. maintenance of low endemicity) and elimination programs between countries. For example, in China—whose government in 2010 announced a strategy to pursue malaria elimination in the Chinese provinces—the required investment is a small proportion of public expenditure on health. In contrast, a similar programme in Tanzania would cost an estimated one-fifth of the public health budget.[66] In areas where malaria is common, children under five years old often have anaemia, which is sometimes due to malaria. Giving children with anaemia in these areas preventive antimalarial medication improves red blood cell levels slightly but does not affect the risk of death or need for hospitalisation.[67] ### Mosquito control[edit] Further information: Mosquito control Man spraying kerosene oil in standing water, Panama Canal Zone, 1912 Vector control refers to methods used to decrease malaria by reducing the levels of transmission by mosquitoes. For individual protection, the most effective insect repellents are based on DEET or picaridin.[68] However, there is insufficient evidence that mosquito repellents can prevent malaria infection.[69] Insecticide-treated mosquito nets (ITNs) and indoor residual spraying (IRS) are effective, have been commonly used to prevent malaria, and their use has contributed significantly to the decrease in malaria in the 21st century.[70][71][72] ITNs and IRS may not be sufficient to completely eliminate the disease as these interventions depend on how many people use nets, how many gaps in insecticide there are (low coverage areas), if people are not protected when outside of the home, and an increase in mosquitoes that are resistant to insecticides.[70] Modifications to people's houses to prevent mosquito exposure may be an important long term prevention measure.[70] Walls where indoor residual spraying of DDT has been applied. The mosquitoes remain on the wall until they fall down dead on the floor. #### Insecticide treated nets[edit] A mosquito net in use. Mosquito nets help keep mosquitoes away from people and reduce infection rates and transmission of malaria. Nets are not a perfect barrier and are often treated with an insecticide designed to kill the mosquito before it has time to find a way past the net. Insecticide-treated nets are estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with no net.[73] Between 2000 and 2008, the use of ITNs saved the lives of an estimated 250,000 infants in Sub-Saharan Africa.[74] About 13% of households in Sub-Saharan countries owned ITNs in 2007[75] and 31% of African households were estimated to own at least one ITN in 2008. In 2000, 1.7 million (1.8%) African children living in areas of the world where malaria is common were protected by an ITN. That number increased to 20.3 million (18.5%) African children using ITNs in 2007, leaving 89.6 million children unprotected[76] and to 68% African children using mosquito nets in 2015.[77] Most nets are impregnated with pyrethroids, a class of insecticides with low toxicity. They are most effective when used from dusk to dawn.[78] It is recommended to hang a large "bed net" above the center of a bed and either tuck the edges under the mattress or make sure it is large enough such that it touches the ground.[79] ITN is beneficial towards pregnancy outcomes in malaria-endemic regions in Africa but more data is needed in Asia and Latin America.[80] In areas of high malaria resistance, piperonyl butoxide combined with pyrethroids in ITN is effective in reducing malaria infection rates.[81] #### Indoor residual spraying[edit] Indoor residual spraying is the spraying of insecticides on the walls inside a home. After feeding, many mosquitoes rest on a nearby surface while digesting the bloodmeal, so if the walls of houses have been coated with insecticides, the resting mosquitoes can be killed before they can bite another person and transfer the malaria parasite.[82] As of 2006, the World Health Organization recommends 12 insecticides in IRS operations, including DDT and the pyrethroids cyfluthrin and deltamethrin.[83] This public health use of small amounts of DDT is permitted under the Stockholm Convention, which prohibits its agricultural use.[84] One problem with all forms of IRS is insecticide resistance. Mosquitoes affected by IRS tend to rest and live indoors, and due to the irritation caused by spraying, their descendants tend to rest and live outdoors, meaning that they are less affected by the IRS.[85] It is uncertain whether the use of IRS together with ITN is effective in reducing malaria cases due to wide geographical variety of malaria distribution, malaria transmission, and insecticide resistance.[86] #### Housing modifications[edit] Housing is a risk factor for malaria and modifying the house as a prevention measure may be a sustainable strategy that does not rely on the effectiveness of insecticides such as pyrethroids.[70][87] The physical environment inside and outside the home that may improve the density of mosquitoes are considerations. Examples of potential modifications include how close the home is to mosquito breeding sites, drainage and water supply near the home, availability of mosquito resting sites (vegetation around the home), the proximity to live stock and domestic animals, and physical improvements or modifications to the design of the home to prevent mosquitoes from entering.[70] #### Other mosquito control methods[edit] People have tried a number of other methods to reduce mosquito bites and slow the spread of malaria. Efforts to decrease mosquito larvae by decreasing the availability of open water where they develop, or by adding substances to decrease their development, are effective in some locations.[88] Electronic mosquito repellent devices, which make very high-frequency sounds that are supposed to keep female mosquitoes away, have no supporting evidence of effectiveness.[89] There is a low certainty evidence that fogging may have an effect on malaria transmission.[90] Larviciding by hand delivery of chemical or microbial insecticides into water bodies containing low larval distribution may reduce malarial transmission.[91] There is insufficient evidence to determine whether larvivorous fish can decrease mosquito density and transmission in the area.[92] ### Medications[edit] Main article: Malaria prophylaxis There are a number of medications that can help prevent or interrupt malaria in travellers to places where infection is common. Many of these medications are also used in treatment. In places where Plasmodium is resistant to one or more medications, three medications—mefloquine, doxycycline, or the combination of atovaquone/proguanil (Malarone)—are frequently used for prevention.[93] Doxycycline and the atovaquone/proguanil are better tolerated while mefloquine is taken once a week.[93] Areas of the world with chloroquine-sensitive malaria are uncommon.[94] Antimalarial mass drug administration to an entire population at the same time may reduce the risk of contracting malaria in the population.[95] The protective effect does not begin immediately, and people visiting areas where malaria exists usually start taking the drugs one to two weeks before they arrive, and continue taking them for four weeks after leaving (except for atovaquone/proguanil, which only needs to be started two days before and continued for seven days afterward).[96] The use of preventive drugs is often not practical for those who live in areas where malaria exists, and their use is usually given only to pregnant women and short-term visitors. This is due to the cost of the drugs, side effects from long-term use, and the difficulty in obtaining antimalarial drugs outside of wealthy nations.[97] During pregnancy, medication to prevent malaria has been found to improve the weight of the baby at birth and decrease the risk of anaemia in the mother.[98] The use of preventive drugs where malaria-bearing mosquitoes are present may encourage the development of partial resistance.[99] Giving antimalarial drugs to infants through intermittent preventive therapy can reduce the risk of having malaria infection, hospital admission, and anaemia.[100] Mefloquine is more effective than sulfadoxine-pyrimethamine in preventing malaria for HIV-negative pregnant women. Cotrimoxazole is effective in preventing malaria infection and reduce the risk of getting anaemia in HIV-positive women.[101] Giving sulfadoxine-pyrimethamine for three or more doses as intermittent preventive therapy is superior than two doses for HIV-positive women living in malaria-endemic areas.[102] Prompt treatment of confirmed cases with artemisinin-based combination therapies (ACTs) may also reduce transmission.[103] ### Others[edit] Community participation and health education strategies promoting awareness of malaria and the importance of control measures have been successfully used to reduce the incidence of malaria in some areas of the developing world.[104] Recognising the disease in the early stages can prevent it from becoming fatal. Education can also inform people to cover over areas of stagnant, still water, such as water tanks that are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people. This is generally used in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas.[105] Intermittent preventive therapy is another intervention that has been used successfully to control malaria in pregnant women and infants,[106] and in preschool children where transmission is seasonal.[107] ## Treatment[edit] An advertisement for quinine as a malaria treatment from 1927. Malaria is treated with antimalarial medications; the ones used depends on the type and severity of the disease. While medications against fever are commonly used, their effects on outcomes are not clear.[108] Providing free antimalarial drugs to households may reduce childhood deaths when used appropriately. Programmes which presumptively treat all causes of fever with antimalarial drugs may lead to overuse of antimalarials and undertreat other causes of fever. Nevertheless, the use of malaria rapid-diagnostic kits can help to reduce over-usage of antimalarials.[109] ### Uncomplicated malaria[edit] Simple or uncomplicated malaria may be treated with oral medications. Artemisinin drugs are effective and safe in treating uncomplicated malaria.[110] Artemisinin in combination with other antimalarials (known as artemisinin-combination therapy, or ACT) is about 90% effective when used to treat uncomplicated malaria.[74] The most effective treatment for P. falciparum infection is the use of ACT, which decreases resistance to any single drug component.[111] Artemether-lumefantrine (six-dose regimen) is more effective than the artemether-lumefantrine (four-dose regimen) or other regimens not containing artemisinin derivatives in treating falciparum malaria.[112][113] Another recommended combination is dihydroartemisinin and piperaquine.[114][115][116] Artemisinin-naphthoquine combination therapy showed promising results in treating falciparum malaria. However, more research need to establish its efficacy as a reliable treatment.[117] Artesunate plus mefloquine performs better than mefloquine alone in treating uncomplicated falciparum malaria in low transmission settings.[118] There is limited data to show atovaquone-proguanil is more effective than chloroquine, amodiaquine, and mefloquine in treating falciparum malaria.[119] Azithromycin monotherapy or combination therapy has not shown effectiveness in treating plasmodium or vivax malaria.[120] Amodiaquine plus sulfadoxine-pyrimethamine may achieve less treatment failures when compared to sulfadoxine-pyrimethamine alone in uncomplicated falciparum malaria.[121] There is insufficient data on chlorproguanil-dapsone in treating uncomplicated falciparum malaria.[122] The addition of primaquine with artemisinin-based combination therapy for falciparum malaria reduces its transmission at day 3-4 and day 8 of infection.[123] Sulfadoxine-pyrimethamine plus artesunate is better than sulfadoxine-pyrimethamine plus amodiaquine in controlling treatment failure at day 28. However, the latter is better than the former in reducing gametocytes in blood at day 7.[124] Infection with P. vivax, P. ovale or P. malariae usually does not require hospitalisation. Treatment of P. vivax requires both treatment of blood stages (with chloroquine or ACT) and clearance of liver forms with primaquine.[125] Artemisinin-based combination therapy is as effective as chloroquine in treating uncomplicated P. vivax malaria.[126] Treatment with tafenoquine prevents relapses after confirmed P. vivax malaria.[127] However, for those treated with chloroquine for blood stage infection, 14 days of primaquine treatment is required to prevent relapse. Shorter primaquine regimens may lead to higher relapse rates.[128] There is no difference in effectiveness between primaquine given for seven or 14 days for prevention of relapse in vivax malaria. The shorter regimen may be useful for those with treatment compliance problems.[129] To treat malaria during pregnancy, the WHO recommends the use of quinine plus clindamycin early in the pregnancy (1st trimester), and ACT in later stages (2nd and 3rd trimesters).[130] There is limited safety data on the antimalarial drugs in pregnancy.[131] ### Severe and complicated malaria[edit] Cases of severe and complicated malaria are almost always caused by infection with P. falciparum. The other species usually cause only febrile disease.[132] Severe and complicated malaria cases are medical emergencies since mortality rates are high (10% to 50%).[133] Recommended treatment for severe malaria is the intravenous use of antimalarial drugs. For severe malaria, parenteral artesunate was superior to quinine in both children and adults.[134] In another systematic review, artemisinin derivatives (artemether and arteether) were as efficacious as quinine in the treatment of cerebral malaria in children.[135] Treatment of severe malaria involves supportive measures that are best done in a critical care unit. This includes the management of high fevers and the seizures that may result from it. It also includes monitoring for poor breathing effort, low blood sugar, and low blood potassium.[23] Artemisinin derivatives have the same or better efficacy than quinolones in preventing deaths in severe or complicated malaria.[136] Quinine loading dose helps to shorten the duration of fever and increases parasite clearance from the body.[137] There is no difference in effectiveness when using intrarectal quinine compared to intravenous or intramuscular quinine in treating uncomplicated/complicated falciparum malaria.[138] There is insufficient evidence for intramuscular arteether to treat severe malaria.[139] The provision of rectal artesunate before transfer to hospital may reduce the rate of death for children with severe malaria.[140] Cerebral malaria is the form of severe and complicated malaria with the worst neurological symptoms.[141] There is insufficient data on whether osmotic agents such as mannitol or urea are effective in treating cerebral malaria.[142] Routine phenobarbitone in cerebral malaria is associated with fewer convulsions but possibly more deaths.[143] There is no evidence that steroids would bring treatment benefits for cerebral malaria.[144] There is insufficient evidence to show that blood transfusion is useful in either reducing deaths for children with severe anaemia or in improving their haematocrit in one month.[145] There is insufficient evidence that iron chelating agents such as deferoxamine and deferiprone improve outcomes of those with malaria falciparum infection.[146] ### Resistance[edit] Drug resistance poses a growing problem in 21st-century malaria treatment.[147] In the 2000s (decade), malaria with partial resistance to artemisins emerged in Southeast Asia.[148][149] Resistance is now common against all classes of antimalarial drugs apart from artemisinins. Treatment of resistant strains became increasingly dependent on this class of drugs. The cost of artemisinins limits their use in the developing world.[150] Malaria strains found on the Cambodia–Thailand border are resistant to combination therapies that include artemisinins, and may, therefore, be untreatable.[151] Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years and the availability of substandard artemisinins likely drove the selection of the resistant phenotype.[152] Resistance to artemisinin has been detected in Cambodia, Myanmar, Thailand, and Vietnam,[153] and there has been emerging resistance in Laos.[154][155] Resistance to the combination of artemisinin and piperaquine was first detected in 2013 in Cambodia, and by 2019 had spread across Cambodia and into Laos, Thailand and Vietnam (with up to 80 percent of malaria parasites resistant in some regions).[156] There is insufficient evidence in unit packaged antimalarial drugs in preventing treatment failures of malaria infection. However, if supported by training of healthcare providers and patient information, there is improvement in compliance of those receiving treatment.[157] ## Prognosis[edit] Disability-adjusted life year for malaria per 100,000 inhabitants in 2004 no data <10 0–100 100–500 500–1000 1000–1500 1500–2000 2000–2500 2500–2750 2750–3000 3000–3250 3250–3500 ≥3500 When properly treated, people with malaria can usually expect a complete recovery.[158] However, severe malaria can progress extremely rapidly and cause death within hours or days.[159] In the most severe cases of the disease, fatality rates can reach 20%, even with intensive care and treatment.[4] Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.[160] Chronic infection without severe disease can occur in an immune-deficiency syndrome associated with a decreased responsiveness to Salmonella bacteria and the Epstein–Barr virus.[161] During childhood, malaria causes anaemia during a period of rapid brain development, and also direct brain damage resulting from cerebral malaria.[160] Some survivors of cerebral malaria have an increased risk of neurological and cognitive deficits, behavioural disorders, and epilepsy.[162] Malaria prophylaxis was shown to improve cognitive function and school performance in clinical trials when compared to placebo groups.[160] ## Epidemiology[edit] Deaths due to malaria per million persons in 2012 0–0 1–2 3–54 55–325 326–679 680–949 950–1,358 Past and current malaria prevalence in 2009 The WHO estimates that in 2018 there were 228 million new cases of malaria resulting in 405,000 deaths.[3] Children under 5 years old are the most affected, accounting for 67% (272,000) of malaria deaths worldwide in 2018.[3] About 125 million pregnant women are at risk of infection each year; in Sub-Saharan Africa, maternal malaria is associated with up to 200,000 estimated infant deaths yearly.[19] There are about 10,000 malaria cases per year in Western Europe, and 1300–1500 in the United States.[15] The United States eradicated malaria in 1951.[163] About 900 people died from the disease in Europe between 1993 and 2003.[68] Both the global incidence of disease and resulting mortality have declined in recent years. According to the WHO and UNICEF, deaths attributable to malaria in 2015 were reduced by 60%[77] from a 2000 estimate of 985,000, largely due to the widespread use of insecticide-treated nets and artemisinin-based combination therapies.[74] In 2012, there were 207 million cases of malaria. That year, the disease is estimated to have killed between 473,000 and 789,000 people, many of whom were children in Africa.[2] Efforts at decreasing the disease in Africa since 2000 have been partially effective, with rates of the disease dropping by an estimated forty percent on the continent.[164] Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; in Sub-Saharan Africa, 85–90% of malaria fatalities occur.[165] An estimate for 2009 reported that countries with the highest death rate per 100,000 of population were Ivory Coast (86.15), Angola (56.93) and Burkina Faso (50.66).[166] A 2010 estimate indicated the deadliest countries per population were Burkina Faso, Mozambique and Mali.[167] The Malaria Atlas Project aims to map global levels of malaria, providing a way to determine the global spatial limits of the disease and to assess disease burden.[168][169] This effort led to the publication of a map of P. falciparum endemicity in 2010 and an update in 2019.[170][171][172] As of 2010, about 100 countries have endemic malaria.[173][174] Every year, 125 million international travellers visit these countries, and more than 30,000 contract the disease.[68] The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other.[175] Malaria is prevalent in tropical and subtropical regions because of rainfall, consistent high temperatures and high humidity, along with stagnant waters where mosquito larvae readily mature, providing them with the environment they need for continuous breeding.[176] In drier areas, outbreaks of malaria have been predicted with reasonable accuracy by mapping rainfall.[177] Malaria is more common in rural areas than in cities. For example, several cities in the Greater Mekong Subregion of Southeast Asia are essentially malaria-free, but the disease is prevalent in many rural regions, including along international borders and forest fringes.[178] In contrast, malaria in Africa is present in both rural and urban areas, though the risk is lower in the larger cities.[179] ## History[edit] Main articles: History of malaria and Mosquito-malaria theory Ancient malaria oocysts preserved in Dominican amber Although the parasite responsible for P. falciparum malaria has been in existence for 50,000–100,000 years, the population size of the parasite did not increase until about 10,000 years ago, concurrently with advances in agriculture[180] and the development of human settlements. Close relatives of the human malaria parasites remain common in chimpanzees. Some evidence suggests that the P. falciparum malaria may have originated in gorillas.[181] References to the unique periodic fevers of malaria are found throughout history.[182] Hippocrates described periodic fevers, labelling them tertian, quartan, subtertian and quotidian.[183] The Roman Columella associated the disease with insects from swamps.[183] Malaria may have contributed to the decline of the Roman Empire,[184] and was so pervasive in Rome that it was known as the "Roman fever".[185] Several regions in ancient Rome were considered at-risk for the disease because of the favourable conditions present for malaria vectors. This included areas such as southern Italy, the island of Sardinia, the Pontine Marshes, the lower regions of coastal Etruria and the city of Rome along the Tiber. The presence of stagnant water in these places was preferred by mosquitoes for breeding grounds. Irrigated gardens, swamp-like grounds, run-off from agriculture, and drainage problems from road construction led to the increase of standing water.[186] British doctor Ronald Ross received the Nobel Prize for Physiology or Medicine in 1902 for his work on malaria. The term malaria originates from Mediaeval Italian: mala aria—"bad air"; the disease was formerly called ague or marsh fever due to its association with swamps and marshland.[187] The term first appeared in the English literature about 1829.[183] Malaria was once common in most of Europe and North America,[188] where it is no longer endemic,[189] though imported cases do occur.[190] Scientific studies on malaria made their first significant advance in 1880, when Charles Louis Alphonse Laveran—a French army doctor working in the military hospital of Constantine in Algeria—observed parasites inside the red blood cells of infected people for the first time. He, therefore, proposed that malaria is caused by this organism, the first time a protist was identified as causing disease.[191] For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. A year later, Carlos Finlay, a Cuban doctor treating people with yellow fever in Havana, provided strong evidence that mosquitoes were transmitting disease to and from humans.[192] This work followed earlier suggestions by Josiah C. Nott,[193] and work by Sir Patrick Manson, the "father of tropical medicine", on the transmission of filariasis.[194] Chinese medical researcher Tu Youyou received the Nobel Prize for Physiology or Medicine in 2015 for her work on the antimalarial drug artemisinin. In April 1894, a Scottish physician, Sir Ronald Ross, visited Sir Patrick Manson at his house on Queen Anne Street, London. This visit was the start of four years of collaboration and fervent research that culminated in 1897 when Ross, who was working in the Presidency General Hospital in Calcutta, proved the complete life-cycle of the malaria parasite in mosquitoes.[195] He thus proved that the mosquito was the vector for malaria in humans by showing that certain mosquito species transmit malaria to birds. He isolated malaria parasites from the salivary glands of mosquitoes that had fed on infected birds.[195] For this work, Ross received the 1902 Nobel Prize in Medicine. After resigning from the Indian Medical Service, Ross worked at the newly established Liverpool School of Tropical Medicine and directed malaria-control efforts in Egypt, Panama, Greece and Mauritius.[196] The findings of Finlay and Ross were later confirmed by a medical board headed by Walter Reed in 1900. Its recommendations were implemented by William C. Gorgas in the health measures undertaken during construction of the Panama Canal. This public-health work saved the lives of thousands of workers and helped develop the methods used in future public-health campaigns against the disease.[197] In 1896, Amico Bignami discussed the role of mosquitoes in malaria.[198] In 1898, Bignami, Giovanni Battista Grassi and Giuseppe Bastianelli succeeded in showing experimentally the transmission of malaria in humans, using infected mosquitoes to contract malaria themselves which they presented in November 1898 to the Accademia dei Lincei.[195] Artemisia annua, source of the antimalarial drug artemisinin The first effective treatment for malaria came from the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. The indigenous peoples of Peru made a tincture of cinchona to control fever. Its effectiveness against malaria was found and the Jesuits introduced the treatment to Europe around 1640; by 1677, it was included in the London Pharmacopoeia as an antimalarial treatment.[199] It was not until 1820 that the active ingredient, quinine, was extracted from the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Joseph Bienaimé Caventou.[200][201] Quinine was the predominant malarial medication until the 1920s when other medications began to appear. In the 1940s, chloroquine replaced quinine as the treatment of both uncomplicated and severe malaria until resistance supervened, first in Southeast Asia and South America in the 1950s and then globally in the 1980s.[202] The medicinal value of Artemisia annua has been used by Chinese herbalists in traditional Chinese medicines for 2,000 years. In 1596, Li Shizhen recommended tea made from qinghao specifically to treat malaria symptoms in his "Compendium of Materia Medica". Artemisinins, discovered by Chinese scientist Tu Youyou and colleagues in the 1970s from the plant Artemisia annua, became the recommended treatment for P. falciparum malaria, administered in severe cases in combination with other antimalarials.[203] Tu says she was influenced by a traditional Chinese herbal medicine source, The Handbook of Prescriptions for Emergency Treatments, written in 340 by Ge Hong.[204] For her work on malaria, Tu Youyou received the 2015 Nobel Prize in Physiology or Medicine.[205] Plasmodium vivax was used between 1917 and the 1940s for malariotherapy—deliberate injection of malaria parasites to induce a fever to combat certain diseases such as tertiary syphilis. In 1927, the inventor of this technique, Julius Wagner-Jauregg, received the Nobel Prize in Physiology or Medicine for his discoveries. The technique was dangerous, killing about 15% of patients, so it is no longer in use.[206] U.S. Marines with malaria in a field hospital on Guadalcanal, October 1942 The first pesticide used for indoor residual spraying was DDT.[207] Although it was initially used exclusively to combat malaria, its use quickly spread to agriculture. In time, pest control, rather than disease control, came to dominate DDT use, and this large-scale agricultural use led to the evolution of pesticide-resistant mosquitoes in many regions. The DDT resistance shown by Anopheles mosquitoes can be compared to antibiotic resistance shown by bacteria. During the 1960s, awareness of the negative consequences of its indiscriminate use increased, ultimately leading to bans on agricultural applications of DDT in many countries in the 1970s.[84] Before DDT, malaria was successfully eliminated or controlled in tropical areas like Brazil and Egypt by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larval stages, for example by applying the highly toxic arsenic compound Paris Green to places with standing water.[208] Malaria vaccines have been an elusive goal of research. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunising mice with live, radiation-attenuated sporozoites, which provided significant protection to the mice upon subsequent injection with normal, viable sporozoites. Since the 1970s, there has been a considerable effort to develop similar vaccination strategies for humans.[209] The first vaccine, called RTS,S, was approved by European regulators in 2015.[210] ## Society and culture[edit] See also: World Malaria Day ### Economic impact[edit] Malaria clinic in Tanzania Malaria is not just a disease commonly associated with poverty: some evidence suggests that it is also a cause of poverty and a major hindrance to economic development.[8][9] Although tropical regions are most affected, malaria's furthest influence reaches into some temperate zones that have extreme seasonal changes. The disease has been associated with major negative economic effects on regions where it is widespread. During the late 19th and early 20th centuries, it was a major factor in the slow economic development of the American southern states.[211] A comparison of average per capita GDP in 1995, adjusted for parity of purchasing power, between countries with malaria and countries without malaria gives a fivefold difference (US$1,526 versus US$8,268). In the period 1965 to 1990, countries where malaria was common had an average per capita GDP that increased only 0.4% per year, compared to 2.4% per year in other countries.[212] Poverty can increase the risk of malaria since those in poverty do not have the financial capacities to prevent or treat the disease. In its entirety, the economic impact of malaria has been estimated to cost Africa US$12 billion every year. The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism.[10] The disease has a heavy burden in some countries, where it may be responsible for 30–50% of hospital admissions, up to 50% of outpatient visits, and up to 40% of public health spending.[213] Child with malaria in Ethiopia Cerebral malaria is one of the leading causes of neurological disabilities in African children.[162] Studies comparing cognitive functions before and after treatment for severe malarial illness continued to show significantly impaired school performance and cognitive abilities even after recovery.[160] Consequently, severe and cerebral malaria have far-reaching socioeconomic consequences that extend beyond the immediate effects of the disease.[214] ### Counterfeit and substandard drugs[edit] Sophisticated counterfeits have been found in several Asian countries such as Cambodia,[215] China,[216] Indonesia, Laos, Thailand, and Vietnam, and are an important cause of avoidable death in those countries.[217] The WHO said that studies indicate that up to 40% of artesunate-based malaria medications are counterfeit, especially in the Greater Mekong region. They have established a rapid alert system to rapidly report information about counterfeit drugs to relevant authorities in participating countries.[218] There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.[219] Another clinical and public health concern is the proliferation of substandard antimalarial medicines resulting from inappropriate concentration of ingredients, contamination with other drugs or toxic impurities, poor quality ingredients, poor stability and inadequate packaging.[220] A 2012 study demonstrated that roughly one-third of antimalarial medications in Southeast Asia and Sub-Saharan Africa failed chemical analysis, packaging analysis, or were falsified.[221] ### War[edit] World War II poster Throughout history, the contraction of malaria has played a prominent role in the fates of government rulers, nation-states, military personnel, and military actions.[222] In 1910, Nobel Prize in Medicine-winner Ronald Ross (himself a malaria survivor), published a book titled The Prevention of Malaria that included a chapter titled "The Prevention of Malaria in War." The chapter's author, Colonel C. H. Melville, Professor of Hygiene at Royal Army Medical College in London, addressed the prominent role that malaria has historically played during wars: "The history of malaria in war might almost be taken to be the history of war itself, certainly the history of war in the Christian era. ... It is probably the case that many of the so-called camp fevers, and probably also a considerable proportion of the camp dysentery, of the wars of the sixteenth, seventeenth and eighteenth centuries were malarial in origin."[223] In British-occupied India the cocktail gin and tonic may have come about as a way of taking quinine, known for its antimalarial properties.[224] Malaria was the most significant health hazard encountered by U.S. troops in the South Pacific during World War II, where about 500,000 men were infected.[225] According to Joseph Patrick Byrne, "Sixty thousand American soldiers died of malaria during the African and South Pacific campaigns."[226] Significant financial investments have been made to procure existing and create new antimalarial agents. During World War I and World War II, inconsistent supplies of the natural antimalaria drugs cinchona bark and quinine prompted substantial funding into research and development of other drugs and vaccines. American military organisations conducting such research initiatives include the Navy Medical Research Center, Walter Reed Army Institute of Research, and the U.S. Army Medical Research Institute of Infectious Diseases of the US Armed Forces.[227] Additionally, initiatives have been founded such as Malaria Control in War Areas (MCWA), established in 1942, and its successor, the Communicable Disease Center (now known as the Centers for Disease Control and Prevention, or CDC) established in 1946. According to the CDC, MCWA "was established to control malaria around military training bases in the southern United States and its territories, where malaria was still problematic".[228] ### Eradication efforts[edit] Members of the Malaria Commission of the League of Nations collecting larvae on the Danube delta, 1929 Several notable attempts are being made to eliminate the parasite from sections of the world or eradicate it worldwide. In 2006, the organization Malaria No More set a public goal of eliminating malaria from Africa by 2015, and the organization claimed they planned to dissolve if that goal was accomplished. In 2007, World Malaria Day was established by the 60th session of the World Health Assembly. As of 2018, they are still functioning.[229] Only one malaria vaccine is licensed for use, while several others are in clinical trials,[6] which are intended to provide protection for children in endemic areas and reduce the speed of transmission of the disease. As of 2012[update], The Global Fund to Fight AIDS, Tuberculosis, and Malaria has distributed 230 million insecticide-treated nets intended to stop mosquito-borne transmission of malaria.[230] The U.S.-based Clinton Foundation has worked to manage demand and stabilize prices in the artemisinin market.[231] Other efforts, such as the Malaria Atlas Project, focus on analysing climate and weather information required to accurately predict malaria spread based on the availability of habitat of malaria-carrying parasites.[168] The Malaria Policy Advisory Committee (MPAC) of the World Health Organization (WHO) was formed in 2012, "to provide strategic advice and technical input to WHO on all aspects of malaria control and elimination".[232] In November 2013, WHO and the malaria vaccine funders group set a goal to develop vaccines designed to interrupt malaria transmission with malaria eradication's long-term goal.[233] Malaria has been successfully eliminated or significantly reduced in certain areas. Malaria was once common in the United States and southern Europe, but vector control programs, combined with the monitoring and treatment of infected humans, eliminated it from those regions. Several factors contributed, such as the draining of wetland breeding grounds for agriculture and other changes in water management practices, and advances in sanitation, including greater use of glass windows and screens in dwellings.[234] Malaria was eliminated from most parts of the United States in the early 20th century by such methods. The use of the pesticide DDT and other means eliminated it from the South's remaining pockets in the 1950s as part of the National Malaria Eradication Program.[235] One of the targets of Goal 3 of the UN's Sustainable Development Goals is to end the malaria epidemic in all countries by 2030. In 2015 the WHO targeted a 90% reduction in malaria deaths by 2030,[236] and Bill Gates said in 2016 that he thought global eradication would be possible by 2040.[237] In 2018, WHO announced that Paraguay was free of malaria, after an eradication effort that began in 1950.[238] As of 2019, the eradication process is ongoing, but it will be tough to achieve a world free of malaria with the current approaches and tools. Approaches may require investing more in research and greater universal health care.[239] Continuing surveillance will also be important to prevent the return of malaria in countries where the disease has been eliminated.[240] ## Research[edit] The Malaria Eradication Research Agenda (malERA) initiative was a consultative process to identify which areas of research and development (R&D) must be addressed for worldwide eradication of malaria.[241][242] ### Vaccine[edit] See also: Malaria vaccine A vaccine against malaria called RTS,S/AS01 (RTS,S) was approved by European regulators in 2015.[210] As of 2019 it is undergoing pilot trials in 3 sub-Saharan African countries – Ghana, Kenya and Malawi – as part of the WHO's Malaria Vaccine Implementation Programme (MVIP).[243] Immunity (or, more accurately, tolerance) to P. falciparum malaria does occur naturally, but only in response to years of repeated infection.[37] An individual can be protected from a P. falciparum infection if they receive about a thousand bites from mosquitoes that carry a version of the parasite rendered non-infective by a dose of X-ray irradiation.[244] The highly polymorphic nature of many P. falciparum proteins results in significant challenges to vaccine design. Vaccine candidates that target antigens on gametes, zygotes, or ookinetes in the mosquito midgut aim to block the transmission of malaria. These transmission-blocking vaccines induce antibodies in the human blood; when a mosquito takes a blood meal from a protected individual, these antibodies prevent the parasite from completing its development in the mosquito.[245] Other vaccine candidates, targeting the blood-stage of the parasite's life cycle, have been inadequate on their own.[246] For example, SPf66 was tested extensively in areas where the disease was common in the 1990s, but trials showed it to be insufficiently effective.[247] ### Medications[edit] Malaria parasites contain apicoplasts, organelles usually found in plants, complete with their own genomes. These apicoplasts are thought to have originated through the endosymbiosis of algae and play a crucial role in various aspects of parasite metabolism, such as fatty acid biosynthesis. Over 400 proteins have been found to be produced by apicoplasts and these are now being investigated as possible targets for novel antimalarial drugs.[248] With the onset of drug-resistant Plasmodium parasites, new strategies are being developed to combat the widespread disease. One such approach lies in the introduction of synthetic pyridoxal-amino acid adducts, which are taken up by the parasite and ultimately interfere with its ability to create several essential B vitamins.[249][250] Antimalarial drugs using synthetic metal-based complexes are attracting research interest.[251][252] * (+)-SJ733: Part of a wider class of experimental drugs called spiroindolone. It inhibits the ATP4 protein of infected red blood cells that cause the cells to shrink and become rigid like the aging cells. This triggers the immune system to eliminate the infected cells from the system as demonstrated in a mouse model. As of 2014, a Phase 1 clinical trial to assess the safety profile in human is planned by the Howard Hughes Medical Institute.[253] * NITD246 and NITD609: Also belonged to the class of spiroindolone and target the ATP4 protein.[253] ### New targets[edit] Targeting Plasmodium liver-stage parasites selectively is emerging as an alternative strategy in the face of resistance to the latest frontline combination therapies against blood stages of the parasite. [254] In a research conducted in 2019, using experimental analysis with knockout (KO) mutants of Plasmodium berguei the authors were able to identify genes that are potentially essential in the liver stage. Moreover, they generated a computational model to analyse pre–erytrocytic development and liver–stage metabolism. Combining both methods they identified seven metabolic subsystems that become essential compared to the blood stage. Some of these metabolic pathways are fatty acid synthesis and elongation, tricarboxylic acid, amino acid and heme metabolism among others.[254] Specifically, they studied 3 subsystems: fatty acid synthesis and elongation, and amino sugar biosynthesis. For the first two pathways they demonstrated a clear dependence of the liver stage on its own fatty acid metabolism.[254] They proved for the first time the critical role of amino sugar biosynthesis in the liver stage of P. berghei. The uptake of N–acetyl–glucosamine appears to be limited in the liver stage, being its synthesis needed for the parasite development.[254] These findings and the computational model provide a basis for the design of antimalarial therapies targeting metabolic proteins.[254] ### Other[edit] A non-chemical vector control strategy involves genetic manipulation of malaria mosquitoes. Advances in genetic engineering technologies make it possible to introduce foreign DNA into the mosquito genome and either decrease the lifespan of the mosquito, or make it more resistant to the malaria parasite. Sterile insect technique is a genetic control method whereby large numbers of sterile male mosquitoes are reared and released. Mating with wild females reduces the wild population in the subsequent generation; repeated releases eventually eliminate the target population.[73] Genomics is central to malaria research. With the sequencing of P. falciparum, one of its vectors Anopheles gambiae, and the human genome, the genetics of all three organisms in the malaria life cycle can be studied.[255] Another new application of genetic technology is the ability to produce genetically modified mosquitoes that do not transmit malaria, potentially allowing biological control of malaria transmission.[256] In one study, a genetically-modified strain of Anopheles stephensi was created that no longer supported malaria transmission, and this resistance was passed down to mosquito offspring.[257] Gene drive is a technique for changing wild populations, for instance to combat or eliminate insects so they cannot transmit diseases (in particular mosquitoes in the cases of malaria, zika,[258] dengue and yellow fever).[236] ## Other animals[edit] Nearly 200 parasitic Plasmodium species have been identified that infect birds, reptiles, and other mammals,[259] and about 30 species naturally infect non-human primates.[260] Some malaria parasites that affect non-human primates (NHP) serve as model organisms for human malarial parasites, such as P. coatneyi (a model for P. falciparum) and P. cynomolgi (P. vivax). Diagnostic techniques used to detect parasites in NHP are similar to those employed for humans.[261] Malaria parasites that infect rodents are widely used as models in research, such as P. berghei.[262] Avian malaria primarily affects species of the order Passeriformes, and poses a substantial threat to birds of Hawaii, the Galapagos, and other archipelagoes. The parasite P. relictum is known to play a role in limiting the distribution and abundance of endemic Hawaiian birds. Global warming is expected to increase the prevalence and global distribution of avian malaria, as elevated temperatures provide optimal conditions for parasite reproduction.[263] ## References[edit] ### Citations[edit] 1. ^ a b c d e f g h i j k l m n o p Caraballo H (2014). "Emergency department management of mosquito-borne illness: Malaria, dengue, and west Nile virus". Emergency Medicine Practice. 16 (5): 1–23, quiz 23–4. PMID 25207355. 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"A day dedicated to raising awareness of the disease is a good opportunity to ask how far malaria research has come and which methods are needed for further breakthroughs." ## External links[edit] Classification D * ICD-10: B50-B54 * ICD-9-CM: 084 * OMIM: 248310 * MeSH: D008288 * DiseasesDB: 7728 External resources * MedlinePlus: 000621 * eMedicine: med/1385 emerg/305 ped/1357 * Patient UK: Malaria * Orphanet: 673 * Scholia: Q12156 Wikipedia's health care articles can be viewed offline with the Medical Wikipedia app. Wikiquote has quotations related to: Malaria Malariaat Wikipedia's sister projects * Definitions from Wiktionary * Media from Wikimedia Commons * News from Wikinews * Texts from Wikisource * Textbooks from Wikibooks * Travel guide from Wikivoyage * Resources from Wikiversity * Malaria at Curlie * WHO site on malaria * UNHCO site on malaria * Global Malaria Action Plan (2008) * Doctors Without Borders/Médecins Sans Frontières – Malaria information pages * WHO/TDR Malaria 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Organizations * 80,000 Hours * Animal Charity Evaluators * Animal Ethics * Against Malaria Foundation * Center for High Impact Philanthropy * Centre for the Study of Existential Risk * Deworm the World Initiative * Faunalytics * Future of Humanity Institute * Future of Life Institute * Founders Pledge * GiveDirectly * GiveWell * Giving What We Can * Good Ventures * The Good Food Institute * The Humane League * Mercy for Animals * Machine Intelligence Research Institute * Malaria Consortium * Open Philanthropy Project * Raising for Effective Giving * Schistosomiasis Control Initiative * Sentience Institute Focus areas * Aid effectiveness * Biotechnology risk * Climate change * Cultured meat * Disease burden * Economic stability * Existential risk from artificial general intelligence * Global catastrophic risk * Global health * Global poverty * Immigration reform * Intensive animal farming * Land use reform * Life extension * Malaria prevention * Mass deworming * Neglected tropical diseases * Wild animal suffering Literature * Doing Good Better * The End of Animal Farming * Famine, Affluence, and Morality * The Life You Can Save * Living High and Letting Die * The Most Good You Can Do * Practical Ethics * The Precipice Authority control * GND: 4037197-9 * NARA: 10638168 * NDL: 00567482 [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	Malaria	c0024530	6,354	wikipedia	https://en.wikipedia.org/wiki/Malaria	2021-01-18T18:54:58	{"gard": ["6961"], "mesh": ["D008288"], "umls": ["C0024530"], "orphanet": ["673"], "wikidata": ["Q12156"]}
A rare disorder characterised by the absence of the upper limbs and severe underdevelopment of the lower limbs. Minor facial abnormalities (depressed nasal root, upturned nose, infra-orbital creases, prominent cheeks and micrognathia) were also reported. The syndrome has been described in three foetuses born to non consanguineous parents. [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 recessive amelia	c1832432	6,355	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1027	2021-01-23T17:03:17	{"mesh": ["C563338"], "omim": ["601360"], "umls": ["C1832432"], "icd-10": ["Q73.0"]}
Hypomagnesemia with secondary hypocalcemia is an inherited condition caused by the body's inability to absorb and retain magnesium that is taken in through the diet. As a result, magnesium levels in the blood are severely low (hypomagnesemia). Hypomagnesemia impairs the function of the parathyroid glands, which are small hormone-producing glands located in the neck. Normally, the parathyroid glands release a hormone that increases blood calcium levels when they are low. Magnesium is required for the production and release of parathyroid hormone, so when magnesium is too low, insufficient parathyroid hormone is produced and blood calcium levels are also reduced (hypocalcemia). The hypocalcemia is described as "secondary" because it occurs as a consequence of hypomagnesemia. Shortages of magnesium and calcium can cause neurological problems that begin in infancy, including painful muscle spasms (tetany) and seizures. If left untreated, hypomagnesemia with secondary hypocalcemia can lead to developmental delay, intellectual disability, a failure to gain weight and grow at the expected rate (failure to thrive), and heart failure. ## Frequency Hypomagnesemia with secondary hypocalcemia is thought to be a rare condition, but its prevalence is unknown. ## Causes Hypomagnesemia with secondary hypocalcemia is caused by mutations in the TRPM6 gene. This gene provides instructions for making a protein that acts as a channel, which allows charged atoms (ions) of magnesium (Mg2+) to flow into cells; the channel may also allow small amounts of calcium ions (Ca2+) to pass into cells. Magnesium is involved in many cell processes, including production of cellular energy, maintenance of DNA building blocks (nucleotides), protein production, and cell growth and death. Magnesium and calcium are also required for the normal functioning of nerve cells that control muscle movement (motor neurons). The TRPM6 channel is embedded in the membrane of epithelial cells that line the large intestine, structures in the kidneys known as distal convoluted tubules, the lungs, and the testes in males. When the body needs additional Mg2+, the TRPM6 channel allows it to be absorbed in the intestine and filtered from the fluids that pass through the kidneys by the distal convoluted tubules. When the body has sufficient or too much Mg2+, the TRPM6 channel does not filter out the Mg2+ from fluids but allows the ion to be released from the kidney cells into the urine. The channel also helps to regulate Ca2+, but to a lesser degree. Most TRPM6 gene mutations that cause hypomagnesemia with secondary hypocalcemia result in a lack of functional protein. A loss of functional TRPM6 channels prevent Mg2+ absorption in the intestine and cause excessive amounts of Mg2+ to be excreted by the kidneys and released in the urine. A lack of Mg2+ in the body impairs the production of parathyroid hormone, which likely reduces blood Ca2+ levels. Additionally, hypomagnesemia and hypocalcemia can disrupt many cell processes and impair the function of motor neurons, leading to neurological problems and movement disorders. If the condition is not effectively treated and low Mg2+ levels persist, signs and symptoms can worsen over time and may lead to early death. ### Learn more about the gene associated with Hypomagnesemia with secondary hypocalcemia * TRPM6 ## 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	Hypomagnesemia with secondary hypocalcemia	c1865974	6,356	medlineplus	https://medlineplus.gov/genetics/condition/hypomagnesemia-with-secondary-hypocalcemia/	2021-01-27T08:25:04	{"mesh": ["C566593"], "omim": ["602014"], "synonyms": []}
A number sign (#) is used with this entry because Hermansky-Pudlak syndrome-3 (HPS3) is caused by homozygous or compound heterozygous mutation in the HPS3 gene (606118) on chromosome 3q24. For a phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (203300). Clinical Features Hazelwood et al. (1997) ascertained 2 individuals with Hermansky-Pudlak syndrome from central Puerto Rico who lacked the 16-bp duplication in the HPS1 gene (604982.0001), exhibited significant amounts of normal-sized HPS1 gene mRNA by Northern blot analysis, and had haplotypes in the HPS1 region of chromosome 10 that were different from the haplotype of every 16-bp duplication patient. Moreover, these 2 individuals displayed no mutations in their HPS1 cDNA sequences. Both patients exhibited pigment dilution, impaired visual acuity, nystagmus, bleeding diathesis, and absent platelet dense bodies, confirming the diagnosis of HPS. The findings appeared to indicate locus heterogeneity of this disorder in Puerto Rico, consistent with the existence of several mouse strains manifesting both pigment dilution and a platelet storage-pool deficiency. By examining 6 families from Aibonito, Naranjito, and Barranquitas, rural towns south of San Juan, Anikster et al. (2001) identified a second genetic isolate of HPS in central Puerto Rico. Thirteen affected individuals had a bleeding diathesis, horizontal nystagmus, decreased vision, and very mild pigment dilution of hair, skin, and irides. The diagnosis of HPS was confirmed by demonstrating an absence of platelet-dense bodies by wet-mount electron microscopy. All patients lacked the 16-bp duplication in HPS1. Mapping By homozygosity mapping on pooled DNA of 6 families from central Puerto Rico with HPS, Anikster et al. (2001) localized the HPS3 gene to a 1.6-cM interval on chromosome 3q24. Molecular Genetics Anikster et al. (2001) identified a homozygous mutation in the HPS3 gene (606118.0001) on chromosome 3q24 in families within central Puerto Rico, some members of which had been studied by Hazelwood et al. (1997). They stated that this was the second example of a founder mutation causing HPS in central Puerto Rico. They estimated that the large deletion in the HPS3 gene arose between 1880 and 1890. At that time the ancestors of 3 of the 6 HPS3 families emigrated from the town of Ciales to the towns of Aibonito, Barranquitas, and Naranjito. Each of the 3 families also traced its ancestry to 1 individual, Calixto Rivera, who brought his relatives to Aibonito and the surrounding area to deforest his land for tobacco growing. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Reduced vision \- Horizontal nystagmus \- Iris transillumination \- Hypopigmentation of retina \- Hypopigmentation of choroid SKIN, NAILS, & HAIR Skin \- Skin pigment dilution relative to unaffected family members \- Easy bruising Hair \- Hair pigment dilution relative to unaffected family members HEMATOLOGY \- Bleeding diathesis \- Absence of platelet dense bodies \- Lack of secondary aggregation response of platelets MISCELLANEOUS \- Less severe phenotype than patients with other forms of HPS MOLECULAR BASIS \- Caused by mutation in the HPS3 gene (HPS3, 606118.0001 ) ▲ 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	HERMANSKY-PUDLAK SYNDROME 3	c0079504	6,357	omim	https://www.omim.org/entry/614072	2019-09-22T15:56:37	{"doid": ["0060541"], "mesh": ["D022861"], "omim": ["614072"], "orphanet": ["79430", "231512"], "genereviews": ["NBK1287"]}
Tarsal-carpal coalition syndrome is characterised by fusion of the carpals, tarsals, and phalanges. ## Epidemiology Less than 10 affected families have been described so far. ## Clinical description At birth, patients present with stiffness of the proximal interphalangeal joint of the fifth digit, with or without bony synostosis. Proximo-distal progression leads to involvement of the fourth, third and then the second digits. Other anomalies include brachydactyly, humeroradial synostoses and, in some cases, short stature. ## Etiology Causative mutations in the NOG gene have recently been identified, showing that this syndrome is an allelic variant of symphalangism. ## Differential diagnosis Tarsal-carpal coalition syndrome can be distinguished from multiple synostoses syndrome and proximal symphalangism (see these terms) by the absence of hearing loss. ## Genetic counseling Transmission is autosomal dominant. [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	Tarsal-carpal coalition syndrome	c1861305	6,358	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1412	2021-01-23T17:54:33	{"gard": ["9225"], "mesh": ["C536943"], "omim": ["186400", "186570"], "umls": ["C1861305"], "icd-10": ["Q74.8"]}
## Clinical Features Castro-Gago et al. (1983) described a brother and sister with microcephaly, oculocutaneous albinism, and digital anomalies (hypoplasia of the distal phalanx of right fingers I, III, and IV, and left fingers I, III, IV and V with agenesis of the distal part of the right first toe). [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	ALBINISM-MICROCEPHALY-DIGITAL ANOMALIES SYNDROME	c1859910	6,359	omim	https://www.omim.org/entry/203340	2019-09-22T16:31:24	{"mesh": ["C537322"], "omim": ["203340"], "orphanet": ["2513"], "synonyms": ["Alternative titles", "MICROCEPHALY-ALBINISM-DIGITAL ANOMALIES SYNDROME"]}
A number sign (#) is used with this entry because of evidence that susceptibility to microvascular complications of diabetes-3 is associated with variation in the gene encoding angiotensin I-converting enzyme (ACE; 106180) on chromosome 17q23. For a discussion of genetic heterogeneity of susceptibility to microvascular complications of diabetes, see MVCD1 (603933). Molecular Genetics Marre et al. (1994) and Doria et al. (1994) reported that the I/D polymorphism of the ACE gene (106180.0001) was associated with diabetic nephropathy, but this association was disputed by others, e.g., Tarnow et al. (1995) and Schmidt et al. (1995). Marre et al. (1997) performed a large-scale, multicenter study on individuals with insulin-dependent diabetes mellitus (IDDM; 222100) at risk of kidney complications due to long-term exposure to hyperglycemia, i.e., those who had developed proliferative diabetic retinopathy, to test the relationship between genetic factors and renal involvement in IDDM. The degree of renal involvement of the patients was classified according to the genetic polymorphism of ACE and 2 other elements of the renin-angiotensin system, AGT (106150) and AT2R1 (106165). The study concluded that the ACE gene is involved in both the susceptibility to diabetic nephropathy and its progression toward renal failure. Polymorphisms in the other 2 genes were found not to be contributive alone, but an interaction between the ACE I/D and AGT M235T (106150.0001) polymorphisms was found that could account for the degree of renal involvement in the patients studied. Vleming et al. (1999) studied the contribution of the ACE I/D polymorphism in 79 patients with end-stage renal failure due to diabetic nephropathy and in 82 age-matched controls with 15 years of IDDM but without microalbuminuria and found significant overrepresentation of the DD genotype with a significant increase of the D-allele frequency in the cases compared to controls. The presence of the DD genotype increased the risk of end-stage renal failure compared to other genotypes (odds ratio, 2.1); the presence of 1 D-allele, however, did not increase the risk. Suehiro et al. (2004) demonstrated that the D allele of the ACE I/D polymorphism leads to higher expression of the ACE mRNA and suggested that this may affect the renin-angiotensin system in local regions. Animal Model As indicated by the work of Marre et al. (1994), Doria et al. (1994), and others, nephropathy of type 1 diabetes is associated with the D allele of the insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene. The D allele determines higher enzyme levels. To address causality underlying this association, Huang et al. (2001) induced diabetes in mice having 1, 2, or 3 copies of the Ace gene, normal blood pressure, and an enzyme level range (65-162% of wildtype) comparable to that seen in humans. Twelve weeks later, the 3-copy diabetic mice had increased blood pressure and overt proteinuria. Proteinuria was correlated to plasma ACE level in the 3-copy diabetic mice. Thus, a modest genetic increase in ACE levels was sufficient to cause nephropathy in diabetic 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	MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 3	c2675470	6,360	omim	https://www.omim.org/entry/612624	2019-09-22T16:01:20	{"omim": ["612624"], "synonyms": ["Alternative titles", "NEPHROPATHY, DIABETIC, SUSCEPTIBILITY TO", "END-STAGE RENAL DISEASE, DIABETIC, SUSCEPTIBILITY TO"]}
Foot of a draft horse Chronic progressive lymphedema (CPL) is a disease of some breeds of draft horse, whereby the lower legs becomes progressively more swollen.[1] There is no cure;[1] the aim of treatment is to manage the signs and slow progression of the disease. The cause of CPL is not known, although it is suspected that a genetic disorder of elastin metabolism prevents the lymphatic vessels from functioning properly, leading to edema of the lower limbs.[2] CPL resembles the human disease elephantiasis verrucosa nostra.[3] ## Contents * 1 Signs * 2 Management * 3 Epidemiology * 4 References ## Signs[edit] CPL is a progressive disease, which begins below the fetlock and gradually moves up the leg.[4] All legs are affected, the hindlimbs usually more seriously so.[5] Initial signs include thickening, crusting and folding of the skin.[6] These early signs may be hidden by the long hair (feather) on the horse's lower legs.[5] Affected areas are itchy, causing the horse to stamp its feet and rub its legs, and painful, so that the horse may be reluctant to allow its legs to be touched.[3] As CPL progresses, ulcers develop on the pasterns, and fibrosis leads to hardening of the skin and the development of nodules which may become baseball sized.[5] Secondary infections with microbes or mites commonly cause complications.[5] Infestations with the mange mite Chorioptes equi are very itchy, and lead to self-trauma and dermatitis.[5] The quality of the hoof is often poor; hooves are prone to cracks, splits and the development of thrush and abscesses;[3] horses may develop laminitis.[1] Chestnuts and ergots are often misshapen and irregular.[3] ## Management[edit] There is no cure for CPL; the aim of treatment is to relieve the signs of the disease, and to slow the progression.[4] Management requires daily care to prevent infection of the affected skin.[3] The first step is to trim the feather from the lower leg, to ensure no affected areas are missed, and to allow application of treatments directly to the affected skin.[3] Bacterial infections can be treated by gentle washing and drying of the skin.[4] Topical treatments are required to treat chorioptic mange (caused by the mite Chorioptes equi), as the mites are not vulnerable to oral or systemic treatments when they are within the crusts on the skin.[4] Daily exercise assists with the flow of lymph.[3] Combined decongestive therapy involves massage of the leg to move the lymph, followed by specialized compression bandaging which creates a pressure gradient up the leg.[3] Horses with CPL often have poor-quality hoof, so regular trimming is required to help keep the hoof healthy.[3] ## Epidemiology[edit] Affected breeds include the Shire, Clydesdale, Belgian, Gypsy cob, and Friesian.[4] Signs are usually only seen in horses older than two years.[4] Both sexes are affected.[5] ## References[edit] 1. ^ a b c Affolter, Verena K. (2015). "Chapter 24. Draft horse lymphedema". In Sprayberry, Kim A.; Robinson, N. Edward (eds.). Robinson's Current Therapy in Equine Medicine (7th ed.). W B Saunders Co. pp. 521–524. ISBN 978-1-4557-4555-5. 2. ^ Miller, Lisa M.; Gal, Arnon (2017). "Chapter 10. Cardiovascular system and lymphatic vessels. Disorders of horses. Chronic progressive lymphedema in draft horses". In Zachary, James F. (ed.). Pathologic basis of veterinary disease (6th ed.). Elsevier. p. 604. ISBN 978-0-323-35775-3. 3. ^ a b c d e f g h i Affolter, VK (December 2013). "Chronic progressive lymphedema in draft horses". The Veterinary clinics of North America. Equine practice. 29 (3): 589–605. doi:10.1016/j.cveq.2013.08.007. PMID 24267677. 4. ^ a b c d e f de Keyser, K; Janssens, S; Buys, N (May 2015). "Chronic progressive lymphoedema in draught horses". Equine Veterinary Journal. 47 (3): 260–6. doi:10.1111/evj.12256. PMID 24593274. 5. ^ a b c d e f Scott, Danny W.; Miller, William H., Jr. (2011). "Chronic progressive lymphedema". Equine dermatology (2nd ed.). Maryland Heights, Missouri: Elsevier/Saunders. pp. 431–433. ISBN 9781437709216. 6. ^ Mair, Tim S.; Divers, Thomas J. (2016). "Answers. Case 76". Self-Assessment Color Review Equine Internal Medicine (2nd ed.). CRC Press. p. 232. ISBN 9781482225372. [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	Chronic progressive lymphedema	None	6,361	wikipedia	https://en.wikipedia.org/wiki/Chronic_progressive_lymphedema	2021-01-18T19:06:25	{"wikidata": ["Q5113997"]}
Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency is a rare, syndromic intellectual disability characterized by intellectual disability of various severity, hypotonia, feeding difficulties, dysmorphic features, autism and behavioral issues. Growth retardation, congenital heart anomalies, gastrointestinal and genitourinary defects have been rarely associated. [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	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	c3810406	6,362	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=404440	2021-01-23T17:41:30	{"omim": ["615761"], "icd-10": ["Q87.0"]}
This article is about bovine postparturient hypocalcemia. For human illness caused by ingestion of milk or meat contaminated by trematol, see Milk sickness. Typical milk fever posture; cow in sternal recumbency with its head tucked into its flank. Milk fever, postparturient hypocalcemia, or parturient paresis is a disease, primarily in dairy cattle[1] but also seen in beef cattle and non-bovine domesticated animals,[2] characterized by reduced blood calcium levels (hypocalcemia). It occurs following parturition, at onset of lactation, when demand for calcium for colostrum and milk production exceeds the body's ability to mobilize calcium.[3] "Fever" is a misnomer, as body temperature during the disease is generally not elevated. Milk fever is more commonly seen in older animals (which have reduced ability to mobilize calcium from bone) and in certain breeds (such as Channel Island breeds).[4] ## Contents * 1 Clinical signs * 1.1 Stage 1 * 1.2 Stage 2 * 1.3 Stage 3 * 2 Cause * 3 Mechanism * 4 Prevention * 4.1 Diet * 4.2 Calcium Salts * 5 Treatment * 6 Prognosis * 7 History * 7.1 Early Theories * 7.1.1 Potassium Iodide * 7.1.2 Udder Inflation * 7.2 Later Theories * 8 References * 9 External links ## Clinical signs[edit] Cow lying in sternal recumbency (with sternum in contact with the ground). The clinical signs of milk fever can be divided into three distinct stages: ### Stage 1[edit] Cows are mobile but show signs of hypersensitivity and excitability such as restlessness,[5] tremors, ear twitching, head bobbing, and mild ataxia.[6] If not treated, symptoms usually progress to stage 2.[7] ### Stage 2[edit] Cows can no longer stand and present in sternal recumbency.[6] Tachycardia, weakened heart contraction and peripheral pulses. Cows appear dull, have dry muzzles, cold extremities and a lower than normal body temperature. Smooth muscle paralysis can cause bloat, and the inability to urinate or defecate. Cows often tuck their heads into their flanks.[7] Cow lying on its side (lateral recumbency) ### Stage 3[edit] Lateral recumbency,[8] muscle flaccidity,[5] unresponsiveness to stimuli, and loss of consciousness progressing to coma. Heart rate can approach 120 bpm, with peripheral pulses becoming undetectable. If untreated, progression will continue to death.[7] ## Cause[edit] During the dry period (late gestation, non-lactating), dairy cattle have relatively low calcium requirements, with a need to replace approximately 30 g of calcium per day due to utilization for fetal growth and fecal and urinary losses. At parturition, the requirement for calcium is greatly increased due to initiation of lactation, when mammary drainage of calcium may exceed 50g per day.[4] Due to this large increase in demand for calcium, most cows will experience some degree of hypocalcemia for a short period following parturition as the metabolism adjusts to the increased demand. When the mammary drain of plasma calcium causes hypocalcemia severe enough to compromise neuromuscular function, the cow is considered to have clinical milk fever.[3] ## Mechanism[edit] In normal calcium regulation, a decrease in plasma calcium levels causes the parathyroid glands to secrete parathyroid hormone (PTH), which regulates the activation of Vitamin D3 in the kidney. These two compounds act to increase blood calcium levels by increasing absorption of dietary calcium from the intestine, increasing renal tubular reabsorption of calcium in the kidney, and increasing resorption of calcium from bones.[4] It has been found that tissue is less responsive to parathyroid hormone prepartum, compared to postpartum. It is believed that hypocalcemia causing milk fever is due to a lower level of responsiveness of the cow's tissues to circulating parathyroid hormone.[3] The resultant decreased plasma calcium causes hyperexcitability of the nervous system and weakened muscle contractions, which result in both tetany and paresis.[7] ## Prevention[edit] ### Diet[edit] Proper dietary management will prevent most cases of milk fever. This generally involves close attention to mineral and fiber levels in the diet prior to calving, as well as improving cow comfort to eliminate other problems that may interfere with appetite (and so trigger hypocalcemia). General advice is to restrict calcium intake before calving, as this leads to the parathyroid gland stimulating the release of calcium from bones.[9] ### Calcium Salts[edit] A synthetic analogue of 25-hydroxycholecalciferol can be given by injection in the days leading up to calving, although the timing of this prophylactic makes it difficult to use.[9] Oral administration of a dose of a calcium salt in a gel has been advised by some veterinarians.[10] An orally administered bolus containing a much higher concentration of calcium than the injectable solutions can also be given so long as the cow is standing or sitting up. If the cow is lying 'flat out' then immediate intravenous therapy is required to avoid death. ## Treatment[edit] Urination and defecation commonly occurring during calcium treatment Treatment generally involves calcium injection by intravenous, intramuscular or subcutaneous routes. Before calcium injection was employed, treatment comprised inflation of the udder using a pneumatic pump. Inflation of the udder worked because the increased pressure created in the udder pushed the calcium in the udder back into the bloodstream of the cow.[11] Intravenous calcium, though indicated in many cases, is potentially fatal through "heart blockade", or transient high calcium levels stopping the heart, so should be administered with care. Cows are to be fed jaggery along with the lime water mixture. In unclear cases of downer cows, intravenous calcium injection can lead to diagnosis. The typical reaction will be a generalized tremor of the skeletal muscles, and sometimes cardiac arrhythmia. Defecation, urination and eructation are frequent during the treatment, due to pharmacological effect of calcium on the smooth muscles. ## Prognosis[edit] The prognosis is generally good, even in advanced cases. However, some cows can relapse the following day,[11] and even a third time the day after.[12] Without treatment, between 60% and 80% of cows usually die,[13][14] although death rates as high as 90% have been recorded.[5] ## History[edit] It is thought that milk fever has existed for a very long time in dairy cattle.[15] The first reports in veterinary literature can be traced to around 1793.[13] ### Early Theories[edit] Early treatments involved venesection, but this proved ineffective.[9] #### Potassium Iodide[edit] In the late 1800s, Jurgens Schmidt proposed the use of an infused solution of potassium iodide for treatment.[15] A follow-up study of this treatment by Danish veterinarians showed that 90% of cows recovered after use of the treatment,[15] compared with only 20-40% survival without.[13][14] A study in Iowa showed that 76.5% of cows recovered after use of the treatment.[15] However, the premise of the Schmidt treatment was misleading, as later veterinarians used water alone to the same success rate.[13] #### Udder Inflation[edit] In 1901, Anderson and Evers trialled a treatment of udder inflation with air, which reduced mortality rates to just 1%.[13][16] although with the added complication of mastitis.[16] Although this was an effective treatment (and is still used as a backup today),[11] it was not understood at the time why it worked, and remains the source of some debate. Some scientists believed that udder inflation could cause stimulation that then prevents calcium loss.[17] Other scientists suggested that udder inflation prevented milk secretion, reducing calcium loss overall.[18][19] This may prevent calcium being taken from the blood plasma.[18] ### Later Theories[edit] The true cause of milk fever was first suggested by Prof John Russell Greig and Henry Dryerre in March 1925,[13] at the Moredun Research Institute in Scotland.[20] This idea was later confirmed experimentally by Little and Wright in May 1925.[13] By 1933, Pulles began treatments with magnesium chloride and calcium chloride, which is the basis for modern pharmaceutical treatments.[9] ## References[edit] 1. ^ "Parturient Paresis in Cows - Metabolic Disorders". Veterinary Manual. Retrieved 2020-10-10. 2. ^ "Parturient Paresis in Sheep and Goats - Metabolic Disorders". Veterinary Manual. Retrieved 2020-10-10. 3. ^ a b c Horst, RL; Goff, JP; Reinhardt, TA; Buxton, DR (July 1997). "Strategies for preventing milk fever in dairy cattle". Journal of Dairy Science. 80 (7): 1269–80. doi:10.3168/jds.S0022-0302(97)76056-9. PMID 9241589. 4. ^ a b c DeGaris, Peter J.; Lean, Ian J. (2008-04-01). "Milk fever in dairy cows: A review of pathophysiology and control principles". The Veterinary Journal. Special Issue: Production Diseases of the Transition Cow. 176 (1): 58–69. doi:10.1016/j.tvjl.2007.12.029. PMID 18329301. 5. ^ a b c "Parturient paresis \| animal disease". Encyclopedia Britannica. Retrieved 2020-10-11. 6. ^ a b "Parturient Paresis - an overview \| ScienceDirect Topics". www.sciencedirect.com. Retrieved 2020-10-11. 7. ^ a b c d "Parturient Paresis in Cows: Disorders of Calcium Metabolism: Merck Veterinary Manual". www.merckvetmanual.com. Retrieved 2015-11-06. 8. ^ Oetzel, G. R. (July 1988). "Parturient paresis and hypocalcemia in ruminant livestock". The Veterinary Clinics of North America. Food Animal Practice. 4 (2): 351–364. doi:10.1016/s0749-0720(15)31053-7. ISSN 0749-0720. PMID 3264754. 9. ^ a b c d Murray, R. D.; Horsfield, J. E.; McCormick, W. D.; Williams, H. J.; Ward, D. (2008-11-08). "Historical and current perspectives on the treatment, control and pathogenesis of milk fever in dairy cattle". Veterinary Record. 163 (19): 561–565. doi:10.1136/vr.163.19.561. ISSN 0042-4900. PMID 18997185. 10. ^ Haalstra, RT (1 June 1973). "[A veterinary approach to the relationship between the diet and milk fever on farms]". Tijdschrift voor Diergeneeskunde (in Dutch). 98 (11): 529–37. PMID 4736359. 11. ^ a b c Niedermeier, R.P.; Smith, Vearl R. (1950), "The effect of udder inflation upon blood levels of calcium, magnesium and phosphorus in cows with parturient paresis", Journal of Dairy Science, 33: 38–42, doi:10.3168/jds.S0022-0302(50)91862-5 12. ^ Lucien Mahin (1977–2008), Observations on diseases of cattle in Morocco (unpublished data) 13. ^ a b c d e f g Hibbs, J.W. (October 1950). "Milk Fever (Parturient Paresis) in Dairy Cows—A Review". Journal of Dairy Science. 33 (10): 758–789. doi:10.3168/jds.s0022-0302(50)91966-7. ISSN 0022-0302. 14. ^ a b Horst, R.L.; Goff, J.P.; Reinhardt, T.A.; Buxton, D.R. (July 1997). "Strategies for Preventing Milk Fever in Dairy Cattle". Journal of Dairy Science. 80 (7): 1269–1280. doi:10.3168/jds.s0022-0302(97)76056-9. ISSN 0022-0302. 15. ^ a b c d Repp, John J. (1901-01-01). "The Schmidt treatment for parturient paralysis". Journal of Comparative Pathology and Therapeutics. 14: 313–321. doi:10.1016/S0368-1742(01)80063-1. ISSN 0368-1742. 16. ^ a b Goings, Richard Lewis. Efficacy of a prepartum, calcium-deficient diet in prevention of bovine parturient paresis (Thesis). Iowa State University. doi:10.31274/rtd-180813-2830. 17. ^ Dryerre, Henry; Greig, J. Russell (July 1985). "Milk Fever: Its Possible Association with Derangements in the Internal Secretions". The Canadian Veterinary Journal. 26 (7): 224–227. ISSN 0008-5286. PMC 1680093. PMID 17422555. 18. ^ a b Petersen, W. E.; Rigor, T. V. (1932-11-01). "Relation of Pressure to Rate and Quality of Milk Secreted". Proceedings of the Society for Experimental Biology and Medicine. 30 (2): 254–256. doi:10.3181/00379727-30-6444. ISSN 0037-9727. 19. ^ Garrison, E. R. ; Turner, C. W. (1936). "CAB Direct". www.cabdirect.org. Retrieved 2020-10-10.CS1 maint: multiple names: authors list (link) 20. ^ "Phone call reveals links to Moredun's past". Moredun Magazine. No. 6. 2013. p. 1. Archived from the original on 21 August 2016. ## External links[edit] * Prevention of Milk Fever, University of Kentucky * Parturient Paresis in Cows (Milk fever, Hypocalcemia), The Merck Veterinary Manual Wikimedia Commons has media related to Hypocalcemia in ruminants. [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	Milk fever	c0030612	6,363	wikipedia	https://en.wikipedia.org/wiki/Milk_fever	2021-01-18T18:35:51	{"mesh": ["D010319"], "wikidata": ["Q1934459"]}
A number sign (#) is used with this entry because distal myopathy-1 (MPD1), also known as Laing distal myopathy, is caused by heterozygous mutation in the MYH7 gene (160760), which encodes the myosin heavy chain of type 1 fibers of skeletal muscle and cardiac ventricles, on chromosome 14q11. The MYH7 gene is mutated in both hypertrophic (see 192600) and dilated (see 115200) cardiomyopathy as well as in myosin storage myopathy (608358). Clinical Features Laing et al. (1995) described a family with an autosomal dominant distal myopathy closely resembling that described in the original report of Gowers (1902). Scoppetta et al. (1995) and Voit et al. (2001) reported 2 families with autosomal dominant distal myopathy with clinical features similar to those reported by Laing et al. (1995). Characteristics common to both families included onset in the second or third year of life, selective wasting and weakness of the anterior tibial and extensor digitorum longus muscles, a slowly progressive course, and, at later stages, involvement of hand extensors, neck flexor, and abdominal muscles. Some patients developed tremor. Zimprich et al. (2000) described an Austrian family with a similar phenotype. In a family with 9 affected members spanning 3 generations, Mastaglia et al. (2002) described selective weakness of the ankle dorsiflexors and toe extensors, in particular the extensor hallucis longus. Ankle plantar flexors were normal, even in the most advanced cases. There was also weakness and atrophy of the anterior compartment muscles. Most cases had selective weakness of the long finger extensor muscles. None of the affected individuals had cardiomyopathy. Age at onset varied from 4 to 5 years to the early twenties. Muscle MRI showed atrophy of affected muscles, EMG gave a myopathic pattern, and muscle biopsy of 2 affected patients showed myopathic changes without rimmed vacuoles. Hedera et al. (2003) reported a large Italian American kindred in which at least 11 members spanning 3 generations were affected with an autosomal dominant distal myopathy. Clinical features included weakness of foot and toe extensor muscles, and some patients had proximal weakness. No patient had distal weakness of the upper extremities or neck muscles, even in advanced stages of the disease. The average age at symptom onset was 20 years. Two affected patients had signs of idiopathic dilated cardiomyopathy. Hedera et al. (2003) noted that their family differed from the family reported by Laing et al. (1995) by the absence of upper extremity weakness and neck muscle weakness. Darin et al. (2007) reported a Tanzanian boy with distal myopathy and mild dilated cardiomyopathy. He began walking on the toes at age 11 months and had Achilles tenotomy at age 6 years. Examination at age 7 showed weakness of the great toe and ankle dorsiflexors, atrophy of the anterior tibial muscles, weakness of the hip flexors, and decreased reflexes. Echocardiography showed mild left atrial enlargement and prolonged isovolumetric relaxation time. Skeletal muscle biopsy showed hypotrophy of type 1 fibers and apparent absence of type 2B fibers. Serum creatine kinase was mildly elevated. ### Clinical Variability Muelas et al. (2010) identified the same mutation in the MYH7 gene (lys1729del; 160760.0044) in 29 clearly affected individuals from 4 unrelated families in the Safor region of Spain. There was great phenotypic variability. The age at onset ranged from congenital to 50 years, with a mean of 14 years. All patients presented with weakness of great toe/ankle dorsiflexors, and many had associated neck flexor (78%), finger extensor (78%), mild facial (70%), or proximal muscle (65%) weakness. There was atrophy of the anterior lower leg compartment muscles, which contrasted with calf hypertrophy. Some had more widespread proximal muscle involvement, resembling that seen in the allelic disorder myosin storage myopathy (608358). Variable findings included quadriceps atrophy, ankle retraction, pes cavus, scoliosis, claw toes, and high-arched palate. Five patients had cardiac abnormalities, including dilated cardiomyopathy, left ventricular relaxation impairment, and conduction abnormalities. The spectrum of disability ranged from asymptomatic to wheelchair-confined, but life expectancy was not affected. EMG showed myopathic as well as neurogenic features, and muscle biopsies yielded various findings, such as fiber type disproportion, core/minicore lesions, and mitochondrial abnormalities. Most patients had slow progression, but some were severely disabled, and many had myalgias. These findings expanded the phenotypic spectrum of Laing myopathy, but the wide spectrum associated with a single mutation was noteworthy. Muelas et al. (2010) also noted that the variable features could lead to misdiagnosis of neurogenic atrophy, congenital myopathies, or even mitochondrial myopathies. Mapping The disorder in the family studied by Laing et al. (1995) showed linkage of the locus, symbolized MPD1, to chromosome 14. A multipoint analysis assuming 100% penetrance and using MYH7 (160760) and 5 other markers gave a lod score of exactly 3 at MYH7. Analysis at a penetrance of 80% gave a lod score of 2.8 at this marker. Linkage analysis in a large family with autosomal dominant distal myopathy reported by Mastaglia et al. (2002) yielded a maximum 2-point lod score of 2.9 at marker D14S262, and further analysis refined the candidate locus to a 24-cM region between D14S283 and D14S49. In a large family with autosomal dominant distal myopathy, Hedera et al. (2003) found linkage to chromosome 14q11-q13 (maximum 2-point lod score of 3.99 at marker D14S1459). Mutation analysis excluded the PABP2 gene (602279). Molecular Genetics In affected members of 7 separate families with Laing distal myopathy, Meredith et al. (2004) sequenced the MYH7 gene, a positional candidate for the site of the causative mutation. They identified 5 heterozygous mutations in 6 families (see 160760.0029-160760.0030) and no mutations in the seventh family. The family reported by Hedera et al. (2003) had a deletion of lys1729 (160760.0044). In a Tanzanian boy with Laing myopathy and mild cardiac involvement, Darin et al. (2007) identified a heterozygous mutation in the MYH7 gene (160760.0036). Population Genetics Meredith et al. (2004) identified a heterozygous mutation in the MYH7 gene (lys1729del; 160760.0044) in affected members of an Italian American family with Laing distal myopathy reported by Hedera et al. (2003). Muelas et al. (2010) identified the lys1729del mutation in 29 clearly affected individuals from 4 unrelated families in the Safor region of Spain. Muelas et al. (2012) demonstrated a common 41.2-kb short haplotype including the lys1729del mutation in both Spanish patients from the Safor region and in the Italian American family reported by Hedera et al. (2003), indicating a founder effect. However, microsatellite markers both up- and downstream of the mutation did not match, indicating multiple recombination events. The mutation was estimated to have been introduced into the Safor population about 375 to 420 years ago (15 generations ago). The region is located in the southeast of Valencia on the Mediterranean coast of Spain. Muelas et al. (2012) hypothesized that the families from Safor were descendants of the Genoese who had repopulated this Spanish region in the 17th century after the Muslims were expelled; in fact, many of the surnames of the Safor families with Laing myopathy had an Italian origin. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Facial muscle weakness, mild Mouth \- High-arched palate Neck \- Neck muscle weakness CARDIOVASCULAR Heart \- Dilated cardiomyopathy may occur SKELETAL Spine \- Scoliosis Feet \- Pes cavus MUSCLE, SOFT TISSUES \- Weakness of ankle and toe extensor (dorsiflexor) muscles \- Atrophy of ankle and toe extensor (dorsiflexor) muscles \- Weakness of anterior compartment tibial muscles \- Atrophy of anterior compartment tibial muscles \- 'Hanging' big toe \- Gait difficulties \- Myalgia \- Hypertrophy of calf muscles \- Weakness of long finger extensor muscles (occurs later) \- Weakness of neck muscles may occur later \- Atrophy of neck muscles may occur later \- Proximal muscle weakness (occasional) \- EMG shows myopathic or neurogenic changes \- Biopsy shows nonspecific myopathy without rimmed vacuoles \- Angulated atrophic fibers \- Hypotrophy of type 1 fibers \- Type 1 fiber predominance \- Fiber type grouping \- Mitochondrial proliferation \- Ragged red fibers \- Sarcoplasmic inclusions \- Cores or minicores \- Abnormalities in myofibril organization LABORATORY ABNORMALITIES \- Normal to mildly increased serum creatine kinase MISCELLANEOUS \- Onset in infancy or childhood \- Later onset has been reported \- Slowly progressive \- Variable phenotype \- Allelic to myosin storage myopathy ( 608358 ) MOLECULAR BASIS \- Caused by mutation in the myosin, heavy polypeptide-7, cardiac muscle, beta gene (MYH7, 160760.0029 ) ▲ 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	MYOPATHY, DISTAL, 1	c4552004	6,364	omim	https://www.omim.org/entry/160500	2019-09-22T16:37:42	{"doid": ["0070197"], "mesh": ["D049310"], "omim": ["160500"], "orphanet": ["59135"], "synonyms": ["Distal myopathy type 1", "MYOPATHY, LATE DISTAL HEREDITARY", "Gowers disease", "Alternative titles", "MYOPATHY, DISTAL, EARLY-ONSET, AUTOSOMAL DOMINANT", "MPD1", "LAING DISTAL MYOPATHY"], "genereviews": ["NBK1433"]}
A number sign (#) is used with this entry because Meckel syndrome type 5 (MKS5) is caused by homozygous or compound heterozygous mutation in the RPGRIP1L gene (610937) on chromosome 16q12. For a general description of Meckel syndrome, see MKS1 (249000). See also Joubert syndrome-7 (JBTS7; 611560), an allelic disorder with a less severe phenotype. Clinical Features Delous et al. (2007) reported 3 fetuses with Meckel syndrome diagnosed at 15 to 16 weeks' gestation by ultrasound. Two were sibs of Moroccan origin. Ultrasound and post-termination examination showed anencephaly, occipital encephalocele, postaxial polydactyly, cleft lip and palate, microphthalmia, severe cystic kidney disease, and hepatic bile duct proliferation, and bowing of the long bones. Molecular Genetics In 3 fetuses with Meckel syndrome type 5, Delous et al. (2007) identified homozygous or compound heterozygous truncating mutations in the RPGRIP1L gene (610937.0005-610937.0007) that all resulted in complete loss of protein function. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Microphthalmia Mouth \- Cleft lip \- Cleft palate ABDOMEN Liver \- Bile duct proliferation GENITOURINARY Kidneys \- Cystic renal disease SKELETAL Limbs \- Bowing of the long bones Hands \- Postaxial polydactyly Feet \- Postaxial polydactyly NEUROLOGIC Central Nervous System \- Occipital encephalocele \- Anencephaly MISCELLANEOUS \- Prenatal or perinatal death \- Genetic heterogeneity \- See Joubert syndrome 7 ( 611560 ), an allelic disorder with a less severe phenotype MOLECULAR BASIS \- Caused by mutation in the RPGRIP1-like gene (RPGRIP1L, 610937.0005 ). ▲ 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	MECKEL SYNDROME, TYPE 5	c0265215	6,365	omim	https://www.omim.org/entry/611561	2019-09-22T16:03:07	{"doid": ["0070119"], "omim": ["611561"], "orphanet": ["564"]}
Cornell's sign Differential diagnosisPyramidal tract lesions Cornell's sign is a clinical sign in which scratching along the inner side of the extensor hallucis longus tendon elicits an extensor plantar reflex. It is found in patients with pyramidal tract lesions, and is one of a number of Babinski-like responses.[1] It was named after the American neuropsychologist and neuropsychiatrist Ethel Letitia Cornell (1892–1963). ## References[edit] 1. ^ Kumar SP, Ramasubramanian D (December 2000). "The Babinski sign--a reappraisal". Neurol India. 48 (4): 314–18. PMID 11146592. Retrieved 2009-04-13. This medical sign 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	Cornell's sign	None	6,366	wikipedia	https://en.wikipedia.org/wiki/Cornell%27s_sign	2021-01-18T19:01:09	{"wikidata": ["Q5171488"]}
## Description Since the initial discovery of the human electroencephalogram (EEG) by Berger (1929), it has been speculated that neural oscillations play a broad role in nervous systems and form the basis for higher cognitive functions and consciousness. The presence of a beta/gamma oscillation (18 to 50 Hz) is thought to represent an activated state of the underlying neuronal network. These beta (12-29 Hz) and gamma (30-50 Hz) brain rhythms involve gamma-aminobutyric acid type A (GABA-A) receptor action (Haenschel et al., 2000; summary by Porjesz et al., 2002). Inheritance Stassen et al. (1988) reviewed the evidence on the genetically determined component of the resting electroencephalogram. They concluded that the individual characteristics of the resting EEG are primarily determined by genetic factors for the following reasons: with respect to their EEGs, monozygotic twins are only slightly less like one another than each person is to himself over time; the average within-pair EEG similarity in dizygotic twins is significantly above the interindividual EEG similarity between unrelated persons; and the EEGs of monozygotic twins reared apart are as similar to each other as are the EEGs of the same person over time. Van Beijsterveldt et al. (1996) measured the EEG in 91 MZ and 122 DZ twins, aged 16 years. The EEG was recorded on 14 scalp positions during quiet resting with eyes closed; spectral powers were calculated for 4 frequency bands: delta, theta, alpha, and beta. Twin correlations pointed toward high genetic influences for all these powers and scalp locations. The largest part of the variants in the EEG was explained by additive genetic factors. The average heritabilities for the delta (1.5-3.5 Hz), theta (4.0-7.5 Hz), alpha (8.0-12.5 Hz), and beta (13-25 Hz) frequencies were 76%, 89%, 89%, and 86%, respectively. Multivariate analyses suggested that the same genes for EEG alpha rhythm are expressed in different brain areas in the left and right hemisphere. Thus, the authors concluded that brain functioning, as indexed by rhythmic brain-electrical activity, is one of the most heritable characteristics in humans. Mapping To identify genes underlying the heritability of EEG, Porjesz et al. (2002) conducted a linkage and linkage-disequilibrium study concerning the 3 beta frequency bands (13 to 28 Hz) of the human EEG. Their studies demonstrated maximum lod scores with the GABRB1 gene (137190) on chromosome 4p13-p12 between markers D4S1627 and D4S1645. The linkage-disequilibrium analysis indicated that a quantitative trait locus for the beta EEG phenotype is located in or near the GABRB1 gene. Lab \- EEG patterns 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	ELECTROENCEPHALOGRAPHIC PATTERN, BETA FREQUENCY, QUANTITATIVE TRAIT LOCUS	c3549684	6,367	omim	https://www.omim.org/entry/130190	2019-09-22T16:41:46	{"omim": ["130190"]}
A number sign (#) is used with this entry because severe congenital neutropenia-1 (SCN1) is caused by heterozygous mutation in the neutrophil elastase gene (ELANE; 130130) on chromosome 19p13. See also cyclic neutropenia (162800), which is an allelic disorder. Description Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections (Skokowa et al., 2007). About 60% of affected individuals of European and Middle Eastern ancestry have dominant ELANE mutations, resulting in a form of severe congenital neutropenia, which is designated here as SCN1. ### Genetic Heterogeneity of Severe Congenital Neutropenia Severe congenital neutropenia is a genetically heterogeneous disorder showing autosomal dominant, autosomal recessive, and X-linked inheritance. Another autosomal dominant form, SCN2 (613107), is caused by mutation in the protooncogene GFI1 (600871) on 1p22. Autosomal recessive forms include SCN3 (610738), caused by mutation in the HAX1 gene (605998) on 1q21; SCN4 (612541), caused by mutation in the G6PC3 gene (611045) on 17q21; SCN5 (615285), caused by mutation in the VPS45 gene (610035) on 1q21; SCN6 (616022), caused by mutation in the JAGN1 gene (616012) on 3p25; and SCN7 (617014) is caused by mutation in the CSF3R gene (138971) on 1p34. X-linked SCN (SCNX; 300299) is caused by mutation in the WAS gene (300392) on Xp11. See also adult chronic idiopathic nonimmune neutropenia (607847) and chronic benign familial neutropenia (162700). ### Susceptibility to Myelodysplastic Syndrome/Acute Myeloid Leukemia SCN patients with acquired mutations in the granulocyte colony-stimulating factor receptor (CSF3R; 138971) in hematopoietic cells define a group with high risk for progression to myelodysplastic syndrome and/or acute myeloid leukemia. Approximately 80% of SCN patients who develop AML are heterozygous for somatic CSF3R mutations (summary by Klimiankou et al., 2016). Clinical Features Gilman et al. (1970) described prolonged survival and death from acute monocytic leukemia at age 14 years and 10 months. About three-fourths of patients die before age 3 years. Fungal and viral infections had not been a problem. Freedman et al. (2000) stated that the Severe Chronic Neutropenia International Registry (SCNIR) in Seattle had data on 696 neutropenic patients, including 352 patients with congenital neutropenia, treated with GCSF from 1987 to 2000. The 352 congenital patients were observed for a mean of 6 years (range, 0.1 to 11 years) while being treated. Of these patients, 31 developed myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), for a crude rate of malignant transformation of nearly 9%. None of the 344 patients with idiopathic or cyclic neutropenia developed MDS/AML. Transformation was associated with acquired marrow cytogenetic clonal changes: 18 patients developed a partial or complete loss of chromosome 7, and 9 patients manifested abnormalities of chromosome 21 (usually trisomy 21; 190685). For each yearly treatment interval, the annual rate of MDS/AML development was less than 2%. Freedman et al. (2000) concluded that although the data did not support a cause-and-effect relationship between development of MDS/AML and GCSF therapy or other patient demographics, they could not exclude a direct contribution of GCSF in the pathogenesis of MDS/AML. Improved survival of congenital neutropenia patients receiving GCSF therapy may allow time for expression of the leukemic predisposition that characterizes the natural history of these disorders. In a review of immunodeficiencies caused by defects in phagocytes, Lekstrom-Himes and Gallin (2000) discussed severe congenital neutropenia. Clinical Management Bonilla et al. (1989) administered recombinant human granulocyte colony-stimulating factor (GCSF; 138970) to 5 patients. All 5 patients showed a response and had sustained neutrophil counts of 1,000 cells per microliter or more for 9 to 13 months while receiving subcutaneous maintenance therapy. Preexisting chronic infections resolved and the number of new infectious episodes decreased. Bonilla et al. (1989) raised the possibility that the receptors are defective and do not respond to GCSF unless it is administered in pharmacologic doses. This possibility appeared to be confirmed by the findings of Dong et al. (1994) of somatic mutation in the GCSFR gene (138971). In SCN, absolute neutrophil counts are usually less than 200 cells per cubic millimeter, with a remainder of the blood counts relatively normal (Dale et al., 2000). Treatment with GCSF leads to an increase in neutrophil counts to more than 1,000 cells per cubic millimeter in 90% of patients and results in significant improvements in survival and quality of life (Dale et al., 1993; Bonilla et al., 1994). Yakisan et al. (1997) noted that although r-metHuGCSF treatment of children with severe congenital neutropenia has substantially improved the patients' quality of life and life expectancy, bone pain and unusual fractures have been reported in treated patients. The authors reviewed roentgenograms in 29 of 30 patients to evaluate bone loss before and during treatment and assessed bone mineral status in 17 of the 30 patients. Their data indicated a high incidence of bone mineral loss in children with severe congenital neutropenia. The investigators concluded that it is more likely that the bone loss was caused by the pathophysiologic features of the underlying disease; however, they could not rule out the possibility that r-metHuGCSF accelerates bone mineral loss. Biochemical Features Myeloid precursor cells from patients with severe congenital neutropenia (SCN) require pharmacologic dosages of recombinant human granulocyte colony-stimulating factor (GCSF) to differentiate normal neutrophils. Because JAK2 (147796), a nonreceptor tyrosine kinase, is involved in the signaling pathway of GCSF, Rauprich et al. (1995) studied the expression and activity of JAK2 in neutrophils from SCN patients during therapy. The immunoprecipitated JAK2 protein showed increased tyrosine phosphorylation in neutrophils from SCN patients as compared with that in neutrophils from healthy controls. Rauprich et al. (1995) pointed out that only a few patients, who subsequently develop acute myeloid leukemia, have a point mutation in the cytoplasmic region of the GCSF receptor, resulting in a truncation from the C terminus of the receptor and an inability of the receptor to transduce the signal on GCSF stimulation. Thus they suspected that various defects are responsible for SCN. That pharmacologic doses of GCSF are required to overcome the neutropenia suggested a defect of other specific molecules in the GCSF signal transduction pathway. The primary defect does not appear to be in JAK2; it may be that the phosphotyrosines on the receptor create binding sites for STAT proteins (signal transducers and activators of transcription; see 600555). Skokowa et al. (2006) found significantly decreased or absent LEF1 (153245) expression in arrested promyelocytes from patients with congenital neutropenia. LEF1 decrease resulted in defective expression of downstream target genes, including CCND1 (168461), MYC (190080), and BIRC5 (603352). Promyelocytes from healthy individuals showed highest LEF1 expression. Reconstitution of LEF1 in early hematopoietic progenitors from 2 individuals with congenital neutropenia resulted in the differentiation of these progenitors into mature granulocytes. LEF1 directly bound to and regulated the transcription factor CEBPA (116897). The findings indicated that LEF1 plays a role in granulopoiesis. Molecular Genetics After demonstrating mutations in the ELA2 gene (ELANE; 130130) in patients with cyclic neutropenia (162800), Dale et al. (2000) hypothesized that congenital neutropenia is also due to mutation in this gene. They performed mutation analysis by sequencing PCR-amplified genomic DNA for each of the 5 exons of the ELA2 gene and 20 bases of the flanking regions. In 22 of 25 patients with congenital neutropenia, 18 different heterozygous mutations were found. All 4 patients with cyclic neutropenia, but none of the 3 patients with Shwachman-Diamond syndrome (260400), had mutations of ELA2. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. In the congenital neutropenia patients, 5 different mutations were found in families with 2 or more affected members. Three instances of father-daughter pairs, 1 mother-son pair, and 1 mother with 2 affected sons by different fathers suggested autosomal dominant inheritance. Ishikawa et al. (2008) identified heterozygous mutations in the ELA2 gene in 11 (61%) of 18 Japanese patients with severe congenital neutropenia. Five (28%) patients had SCN3 (610738) due to mutation in the HAX1 gene. Among 109 probands with SCN, Smith et al. (2008) found that 33 (30%) had 24 different ELA2 mutations, 2 (2%) had WAS (300392) mutations, and 4 (4%) had HAX1 mutations. ### Progression to Myelodysplastic Syndrome and Acute Myeloid Leukemia Dong et al. (1994) used RT-PCR to amplify cDNA for granulocyte colony-stimulating factor receptor (CSF3R; 138971) in patients with severe congenital neutropenia, referred to as Kostmann syndrome, and screened for mutations by single-strand conformation polymorphism (SSCP) analysis. In 1 patient, they identified a somatic point mutation that resulted in the cytoplasmic truncation of the GCSF receptor protein. The mutation was present predominantly in the granulocytic lineage. Further functional characterization demonstrated that the truncated receptor was unable to transduce a maturation signal. Dong et al. (1994) suggested that the mutant receptor chain may act in a dominant-negative manner to block granulocyte maturation. Dong et al. (1994) commented that congenital neutropenia may be a heterogeneous group of disorders with different basic etiologies. They also commented that cases of this disorder that terminated in acute leukemia had been reported (Gilman et al., 1970; Lui et al., 1978; Rosen and Kang, 1979) and that some patients with the disorder developed leukemia or myelodysplastic syndrome following treatment with GCSF. Dong et al. (1995) described mutations in the GCSFR gene in hematopoietic cells from 2 patients with acute myeloid leukemia and histories of severe congenital neutropenia. Like the mutation in the patient reported by Dong et al. (1994), the mutations truncated the C-terminal cytoplasmic region of the GCSF receptor. The mutation in one of the patients was already present in the neutropenic phase that preceded the development of acute myeloid leukemia. SCN patients are at increased risk of developing acute myelogenous leukemia (AML) or myelodysplasia (MDS). In the series of Welte and Dale (1996), 10% of the patients with SCN followed for 5 or more years developed AML or MDS. Patients with GCSFR mutations appeared to be at the greatest risk; Welte and Touw (1997) found that 8 of 16 patients with SCN and GCSFR mutations developed AML or MDS. Conversely, no patients with SCN and without a mutation of the CSF3R gene had been reported who developed AML or MDS. This striking association led to speculation that CSF3R mutations may contribute to leukemogenesis in these patients. Tidow et al. (1997) concluded that GCSFR mutations are acquired abnormalities detected in the process of evolution to acute myelocytic leukemia (AML). Dale et al. (2000) stated that prevalence data suggested that a minority of patients manifest this mutation, and it seemed much more likely that mutations of the ELA2 gene lead to compromised myeloid differentiation and create the risk for development of AML. Among 82 patients with SCN, Rosenberg et al. (2007) found no difference in the risk of MDS/AML in patients with mutant ELA2 (63%) compared to those with wildtype ELA2 (37%). The cumulative incidences at 15 years were 36% and 25%, respectively. Two of 4 patients with the G185R mutation (130130.0011) developed MDS/AML by 15 years follow-up, whereas none of 7 patients with the P110L (130130.0006) mutation or 5 patients with the S97L (130130.0008) mutation had developed MDS/AML. ### Associations Pending Confirmation For discussion of a possible association between autosomal dominant severe congenital neutropenia and variation in the TCIRG1 gene, see 604592.0008. Animal Model To test the hypothesis that CSF3R mutations may contribute to leukemogenesis in SCN patients, McLemore et al. (1998) generated mice carrying a targeted, 'knock-in' mutation of their Csf3r gene that reproduced the mutation found in a patient with SCN and AML. A point mutation (C to T at nucleotide 2403) was introduced into exon 17 of the Csf3r gene, using homologous recombination in embryonic stem cells. The mutation generated a premature stop codon that led to truncation of the C-terminal 96 amino acids and reproduced the mutation found in a patient with SCN by Dong et al. (1995). The mutant allele was expressed in a myeloid-specific fashion at levels comparable to the wildtype allele. Mice heterozygous or homozygous for this mutation had normal levels of circulating neutrophils and no evidence for a block in myeloid maturation, indicating that resting granulopoiesis was normal. However, in response to GCSF treatment, these mice demonstrated a significantly greater increase in the level of circulating neutrophils. This effect appeared to be due to increased neutrophil production as the absolute number of GCSF-responsive progenitors in the bone marrow and their proliferation in response to GCSF was increased. Furthermore, the in vitro survival and GCSF-dependent suppression of apoptosis of mutant neutrophils were normal. Despite this evidence for a hyperproliferative response to GCSF, no cases of AML were detected. These data demonstrated that the GCSFR mutation found in patients with SCN is not sufficient to induce either an SCN phenotype or AML in mice. McLemore et al. (1998) suggested that the results represent strong evidence that these mutations are not responsible for the impaired granulopoiesis present in patients with SCN. In fact, the results of the study suggested that expression of the mutant GCSFR on myeloid progenitors may render them hyperresponsive to GCSF. Whether this altered GCSF-responsiveness contributes to the development of AML and/or MDS in patients with SCN will require further study. At about the same time as the report by McLemore et al. (1998), Hermans et al. (1998) reported that mice either heterozygous or homozygous for a mutation in the Csf3r gene had no normal resting granulopoiesis and had reduced numbers of neutrophils in their blood, indicating a block in maturation due to the truncation of the GCSF receptor. Hermans (1998) suggested that the increased expression of truncated GCSF receptor in the model of McLemore et al. (1998) may have compensated for the mutation and explained the absence of neutropenia. History Hedenberg (1959) found that addition of sulfur-containing amino acids to tissue cultures led to maturation of white cells. L'Esperance et al. (1973) showed that the disease could be reproduced in tissue culture. Barak et al. (1971) also cultured marrow cells from a patient with this disease. L'Esperance et al. (1975) proposed heterogeneity of this disorder because in soft agar cultures of bone marrow one patient showed 'loose' colonies developing only to promyelocytes, whereas a second produced normal neutrophil colonies. Maturation arrest occurs at the promyelocyte stage. Hansen et al. (1977) found association with HLA-B12 (see 142830) and postulated linkage disequilibrium. A gene controlling neutrophil differentiation was presumably closely linked to the HLA complex. Hansen et al. (1977) suggested that the relationship may reflect a basic function of the histocompatibility system, namely, coding for cell-surface determinants fundamental to cell-cell recognition and to control of cellular differentiation. INHERITANCE \- Autosomal dominant HEMATOLOGY \- Increased absolute neutrophil count (ANC) within 0.0-0.2 x 10(9)/l \- Anemia, mild \- Thrombocytosis \- Increase in blood monocytes (2-3 times normal) \- Eosinophilia \- Increased promyelocytes \- Maturation arrest of neutrophil precursors seen on bone marrow biopsy \- Promyelocytes have atypical nuclei and vacuolization of the cytoplasm IMMUNOLOGY \- Recurrent severe infections MISCELLANEOUS \- Onset in infancy MOLECULAR BASIS \- Caused by mutation in the neutrophil-expressed elastase gene (ELANE, 130130.0006 ) ▲ 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	NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT	c1859966	6,368	omim	https://www.omim.org/entry/202700	2019-09-22T16:31:22	{"mesh": ["C565969"], "omim": ["202700"], "orphanet": ["486"], "synonyms": [], "genereviews": ["NBK1533"]}
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: "Small fiber peripheral neuropathy" – news · newspapers · books · scholar · JSTOR (October 2009) (Learn how and when to remove this template message) Small fiber peripheral neuropathy SpecialtyNeurology Small fiber peripheral neuropathy is a type of peripheral neuropathy that occurs from damage to the small unmyelinated peripheral nerve fibers. These fibers, categorized as C fibers and small Aδ fibers, are present in skin, peripheral nerves, and organs.[1] The role of these nerves is to innervate the skin (somatic fibers) and help control autonomic function (autonomic fibers). It is estimated that 15–20 million people in the United States have some form of peripheral neuropathy.[2] ## Contents * 1 Signs and symptoms * 1.1 Topographic pattern * 2 Causes * 3 Diagnosis * 3.1 Skin biopsy * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Small fiber neuropathy is a condition characterized by severe pain. Symptoms typically begin in the feet or hands but can start in other parts of the body. Some people initially experience a more generalized, whole-body pain. The pain is often described as stabbing or burning, or abnormal skin sensations such as tingling or itchiness. In some individuals, the pain is more severe during times of rest or at night. The signs and symptoms of small fiber neuropathy can occur at any point in life depending on the underlying cause. Individuals with small fiber neuropathy often cannot feel pain that is concentrated in a very small area, such as the prick of a pin. However, they have an increased sensitivity to pain in general (hyperalgesia) and experience pain from stimulation that typically does not cause pain (allodynia). People affected with this condition may also have a reduced ability to differentiate between hot and cold. In some instances, the small fibers of the autonomic nervous system can be affected, leading to urinary or bowel problems, episodes of rapid heartbeat (palpitations), dry eyes or mouth, or abnormal sweating. They can also experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting. Small fiber neuropathy is considered a form of peripheral neuropathy because it affects the peripheral nervous system, which connects the brain and spinal cord to muscles and to cells that detect sensations such as touch, smell, and pain. Insensitivity to pain can be particularly problematic. One may be bleeding or have a skin injury without even knowing it.[3] ### Topographic pattern[edit] Like many polyneuropathies, the symptoms are typically length-dependent, starting in the longer nerves and progressively attacking shorter nerves. This means that symptoms often start in the hands and feet before progressing upwards, and that symptoms are usually more severe in the extremities. Some patients have a widespread, non-length dependent, or "patchy", presentation which is sporadic and can affect many nerves. Patients with Fabry disease have isolated small fiber engagement, and can have a more widespread small fiber disruption. ## Causes[edit] Mutations in the SCN9A or SCN10A gene can cause small fiber neuropathy. These genes provide instructions for making pieces (the alpha subunits) of sodium channels. The SCN9A gene instructs the production of the alpha subunit for the NaV1.7 sodium channel and the SCN10A gene instructs the production of the alpha subunit for the NaV1.8 sodium channel. Sodium channels transport positively charged sodium atoms (sodium ions) into cells and play a key role in a cell's ability to generate and transmit electrical signals. The NaV1.7 and NaV1.8 sodium channels are found in nerve cells called nociceptors that transmit pain signals to the spinal cord and brain. The SCN9A gene mutations that cause small fiber neuropathy result in NaV1.7 sodium channels that do not close completely when the channel is turned off. Many SCN10A gene mutations result in NaV1.8 sodium channels that open more easily than usual. The altered channels allow sodium ions to flow abnormally into nociceptors. This increase in sodium ions enhances transmission of pain signals, causing individuals to be more sensitive to stimulation that might otherwise not cause pain. In this condition, the small fibers that extend from the nociceptors through which pain signals are transmitted (axons) degenerate over time. The cause of this degeneration is unknown, but it likely accounts for signs and symptoms such as the loss of temperature differentiation and pinprick sensation. The combination of increased pain signaling and degeneration of pain-transmitting fibers leads to a variable condition with signs and symptoms that can change over time. SCN9A gene mutations have been found in approximately 30 percent of individuals with small fiber neuropathy; SCN10A gene mutations are responsible for about 5 percent of cases. In some instances, other health conditions cause this disorder. Diabetes mellitus and impaired glucose tolerance are the most common diseases that lead to this disorder, with 6 to 50 percent of diabetics or pre-diabetics developing small fiber neuropathy. Other causes of this condition include a metabolic disorder called Fabry disease, immune disorders such as celiac disease or Sjogren syndrome, an inflammatory condition called sarcoidosis, and human immunodeficiency virus (HIV) infection.[4] Recently several studies have suggested an association between autonomic small fiber neuropathy and postural orthostatic tachycardia syndrome.[5] Other notable studies have shown a link between erythromelalgia,[6] fibromyalgia,[7] and Ehlers-Danlos Syndrome.[8] ## Diagnosis[edit] The diagnosis of small fiber neuropathy often requires ancillary testing.[9] Nerve conduction studies and electromyography are commonly used to evaluate large myelinated sensory and motor nerve fibers, but are ineffective in diagnosing small fiber neuropathies.[10] Quantitative sensory testing (QST) assesses small fiber function by measuring temperature and vibratory sensation. Abnormal QST results can be attributed to dysfunction in the central nervous system. Furthermore, QST is limited by a patient's subjective experience of pain sensation.[11] Quantitative sudomotor axon reflex testing (QSART) measures sweating response at local body sites to evaluate the small nerve fibers that innervate sweat glands.[9] ### Skin biopsy[edit] A skin biopsy for the measurement of epidermal nerve fiber density is an increasingly common technique for the diagnosis of small fiber peripheral neuropathy.[9] Physicians can biopsy the skin with a 3-mm circular punch tool and immediately fix the specimen in 2% paraformaldehyde lysine-periodate or Zamboni's fixative.[12] Specimens are sent to a specialized laboratory for processing and analysis where the small nerve fibers are quantified by a neuropathologist to obtain a diagnostic result.[10] This skin punch biopsy measurement technique is called intraepidermal nerve fiber density (IENFD).[13] The following table describes the IENFD values in males and females of a 3 mm biopsy 10-cm above the lateral malleolus (above ankle outer side of leg).[13] Any value measured below the 0.05 Quantile IENFD values per age span, is considered a reliable positive diagnosis for Small Fiber Peripheral Neuropathy.[13] Intraepidermal nerve fiber density (IENFD) normative values for clinical use[13] Females Males Age in years 0.05 Quantile IENFD values per age span Median IENFD values per age span 0.05 Quantile IENFD values per age span Median IENFD values per age span 20–29 8.4 13.5 6.1 10.9 30–39 7.1 12.4 5.2 10.3 40–49 5.7 11.2 4.4 9.6 50–59 4.3 9.8 3.5 8.9 60–69 3.2 8.7 2.8 8.3 70–79 2.2 7.6 2.1 7.7 ≥80 1.6 6.7 1.7 7.2 ## Treatment[edit] Treatment is based on the underlying cause, if any. Where the likely underlying condition is known, treatment of this condition is indicated treated to reduce progression of the disease and symptoms. For cases without those conditions, there is only symptomatic treatment.[14] ## See also[edit] * Neuropathy * Polyneuropathy * Wartenbergs migratory sensory neuropathy * Burning feet syndrome[15] ## References[edit] 1. ^ Overview of Small Fiber Neuropathy. Therapath Neuropathology. 2. ^ Tavee, Jinny; Zhou, Lan (May 2009). "Small fiber neuropathy: A burning problem". Cleveland Clinic Journal of Medicine. 76 (5): 297–305. doi:10.3949/ccjm.76a.08070. ISSN 0891-1150. PMID 19414545. 3. ^ https://ghr.nlm.nih.gov/condition/small-fiber-neuropathy 4. ^ https://ghr.nlm.nih.gov/condition/small-fiber-neuropathy#genes 5. ^ http://www.neurology.org/cgi/content/meeting_abstract/80/1_MeetingAbstracts/S37.005 6. ^ Davis, Mark DP; Weenig, Roger H; Genebriera, Joseph; Wendelschafer-Crabb, Gwen; Kennedy, William R; Sandroni, Paola (September 2006). "Histopathologic findings in primary erythromelalgia are nonspecific: special studies show a decrease in small nerve fiber density". Journal of the American Academy of Dermatology. 55 (3): 519–522. doi:10.1016/j.jaad.2006.04.067. ISSN 0190-9622. PMID 16908366. 7. ^ McGreevey, Sue (31 July 2013). "Nerve damage and fibromyalgia". The Harvard Gazette. Retrieved 1 June 2018. 8. ^ Cazzato, Daniele; Castori, Marco; Lombardi, Raffaella; Caravello, Francesca; Bella, Eleonora Dalla; et al. (July 2016). "Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes". Neurology. 87 (2): 155–159. doi:10.1212/WNL.0000000000002847. eISSN 1526-632X. PMC 4940063. PMID 27306637. 9. ^ a b c Hovaguimian A, Gibbons CH (June 2011). "Diagnosis and treatment of pain in small-fiber neuropathy". Curr Pain Headache Rep. 15 (3): 193–200. doi:10.1007/s11916-011-0181-7. PMC 3086960. PMID 21286866. 10. ^ a b Lauria G, Hsieh ST, Johansson O, et al. (July 2010). "European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy". Eur. J. Neurol. 17 (7): 903–12, e44–9. doi:10.1111/j.1468-1331.2010.03023.x. hdl:2434/530580. PMID 20642627. 11. ^ Lacomis D (August 2002). "Small-fiber neuropathy". Muscle Nerve. 26 (2): 173–88. doi:10.1002/mus.10181. PMID 12210380. 12. ^ Hays, AP; et al. (January 2016). "Fixation of skin biopsies for determination of epidermal nerve fiber density". Clinical Neuropathology. 35 (1): 44–45. doi:10.5414/NP300891. ISSN 0722-5091. PMID 26365464. 13. ^ a b c d Lauria, G; Bakkers, M; Schmitz, C; Lombardi, R; Penza, P; Devigili, G; Smith, AG; Hsieh, ST; Mellgren, SI; Umapathi, T; Ziegler, D; Faber, CG; Merkies, IS (September 2010). "Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study". Journal of the Peripheral Nervous System : JPNS. 15 (3): 202–7. doi:10.1111/j.1529-8027.2010.00271.x. PMID 21040142. 14. ^ Chan, Amanda C. Y.; Wilder-Smith, Einar P. (May 2016). "Small fiber neuropathy: Getting bigger!". Muscle & Nerve. 53 (5): 671–682. doi:10.1002/mus.25082. ISSN 1097-4598. PMID 26872938. 15. ^ Levine, Todd D; Saperstein, David S (March 2015). "Routine use of punch biopsy to diagnose small fiber neuropathy in fibromyalgia patients". Clinical Rheumatology. 34 (3): 413–417. doi:10.1007/s10067-014-2850-5. ISSN 0770-3198. PMC 4348533. PMID 25535201. ## External links[edit] Classification D * ICD-10: G63.3 G60.8 G62.8 * MeSH: D000071075 * Peripheral Neuropathy Fact Sheet – NINDS * [1] [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	Small fiber peripheral neuropathy	c3276706	6,369	wikipedia	https://en.wikipedia.org/wiki/Small_fiber_peripheral_neuropathy	2021-01-18T19:03:21	{"mesh": ["D000071075"], "icd-10": ["G63.3", "G62.8", "G60.8"], "wikidata": ["Q2642518"]}
Hypotrichosis simplex of the scalp (HSS) is characterized by diffuse progressive hair loss that is confined to the scalp. ## Epidemiology Prevalence is unknown but HSS has been described in multiple members (males and females) of several large families. ## Clinical description Progressive hair loss generally begins during the first decade of life and most patients are completely bald by the third decade of life. In contrast to the generalized form of hypotrichosis simplex (see this term), body, axillary and facial hair, as well as the eyebrows and eye lashes are unaffected in HSS. There are no anomalies of the skin, nails and teeth. ## Etiology The causative gene CDSN (encoding the keratinocyte adhesion molecule, corneodesmosin) has been mapped to chromosome 6p21.3. ## Genetic counseling HSS is transmitted in an autosomal dominant 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	Hypotrichosis simplex of the scalp	c1840299	6,370	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90368	2021-01-23T17:57:45	{"mesh": ["C564143"], "omim": ["146520", "613981"], "umls": ["C1840299"], "icd-10": ["L65.8"], "synonyms": ["Hereditary hypotrichosis simplex of the scalp"]}
An X-linked syndromic intellectual disability characterized by clinical manifestations commencing with early childhood onset hearing loss, followed by adolescent onset progressive dystonia or ataxia, visual impairment from early adulthood onwards and dementia from the 4th decade onwards. ## Epidemiology Mohr-Tranebjaerg syndrome (MTS) prevalence is unknown. More than 90 cases (37 families) are known, but not all cases have been reported in the literature. ## Clinical description The onset of rapidly progressive prelingual or postlingual sensorineural hearing loss, the only typical symptom, occurs in early childhood (18 months). The audiological phenotype is characterized by auditory neuropathy, characterized by preserved OAE (oto- acoustic emissions,) abnormal ABR (Auditory brain stem response), very poor speech discrimination, worsening in noisy environment and questionable benefit of treatment with cochlear implants (very few cases reported). Neuropsychologic manifestations, such as personality changes, paranoia, and mild intellectual deficit may emerge at the same time. A slowly progressive movement disorder, appearing as gegenhalten (diffuse resistance to limb movement), dystonia (mostly generalized or focal) or ataxia develops from early adolescence and is associated with brisk tendon reflexes, ankle clonus and extensor plantar responses. Patients experience reduced visual acuity, photophobia, acquired color vision defect and central scotomas starting from about 20 years of age and leading to legal blindness at around age 30 to 40. Slowly progressive dementia develops from the 4th decade onwards. In those with a contiguous gene deletion syndrome (CGS), recurrent infections may be present. Carrier females may be mildly affected with mild hearing impairment and focal dystonia. Despite the X linked recessive inheritance of the disease, there are a few cases where the proband was a female with dystonia. ## Etiology MTS is caused by either a mutation in the TIMM8A gene (located to Xq22) or by a CGS at Xq22, resulting in a deafness-dystonia peptide 1 (DDP1) deficiency. If the CGS includes the Bruton agammaglobulinemia tyrosine kinase (BTK) gene, recurrent infections secondary to this X-linked agammaglobulinemia (XLA) are present. ## Diagnostic methods A combination of hearing impairment and recurrent infections due to XLA in a male patient should elicit sequencing of the TIMM8A gene. Neuroimaging is employed to verify the presence of cerebral atrophy. In cases of suspected CGS; testing for XLA is possible. ## Differential diagnosis Differential diagnosis includes MELAS syndrome; mitochondrial DNA depletion syndrome (encephalomyopathic form with methylmalonic aciduria); Arts syndrome; X-linked spinocerebellar ataxia type 3 and 4; McLeod neuroacanthocytosis syndrome; Usher syndrome type 1 and 2; Wolfram syndrome; autosomal recessive nonsyndromic sensorineural deafness type DFNB; Pendred syndrome; and other forms of dystonia or rarely Friedreich ataxia. ## Antenatal diagnosis Prenatal diagnosis may be proposed to affected couples or parents for further pregnancies. ## Genetic counseling The pattern of inheritance is X-linked recessive and gentic counselling should be offerend to affected families. Where the female is a carrier, the risk to male offspring inheriting the disease is 50%, female offspring have a 50% risk of being carriers. Where a male is affected, female offspring are obligate carriers, and male offspring do not inherit the pathogenic mutation. ## Management and treatment Treatment of MTS is symptomatic and evolves over time. Hearing aids are used with variable success. For mild hearing loss, a hearing device and cochlear implants are an option whereas hearing aids with visual clues are used in cases with more severe hearing loss. The management of the hearing impairment is challenged by the fact that it is an auditory neuropathy. Management of dystonia and ataxia includes treatment with GABA-agonists together with psycho-motor re-education and physical therapy. Other supportive measures include therapies for the deaf-blind, addressing progressive sensory deficits, such as tactile sign language. In those with secondary complications, intravenous immunoglobulin may prevent infections in XLA. Furthermore, live viral vaccines should be avoided in cases of XLA. In adulthood, regular neurological evaluation (assessment for dementia and/or psychiatric manifestations) should be maintained. ## Prognosis Prognosis is poor. The combination of deafness and blindness severely affects communication, while the ongoing movement disorder results in an increasingly unstable gait. Life expectancy is highly variable and can range from death in the teenage years (after a rapidly progressive dystonia) to those that live into their 60's. [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	Mohr-Tranebjaerg syndrome	c0796074	6,371	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=52368	2021-01-23T19:03:44	{"gard": ["8331"], "mesh": ["C535808"], "omim": ["304700"], "umls": ["C0796074"], "icd-10": ["E88.8"], "synonyms": ["DDON syndrome", "Deafness-dystonia-optic neuronopathy syndrome", "Hearing loss-dystonia-optic neuronopathy syndrome"]}
A number sign (#) is used with this entry because of evidence that holoprosencephaly-9 (HPE9) is caused by heterozygous mutation in the GLI2 gene (165230) on chromosome 2q14. Mutation in the GLI2 gene can also cause Culler-Jones syndrome (CJS; 615849), which is a less severe disorder. Description Holoprosencephaly-9 refers to a disorder characterized by a wide phenotypic spectrum of brain developmental defects, with or without overt forebrain cleavage abnormalities. It usually includes midline craniofacial anomalies involving the first branchial arch and/or orbits, pituitary hypoplasia with panhypopituitarism, and postaxial polydactyly. The disorder shows incomplete penetrance and variable expressivity (summary by Roessler et al., 2003 and Bertolacini et al., 2012). For general phenotypic information and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100). Clinical Features Roessler et al. (2003) reported affected members of 2 families with a distinctive phenotype (within the HPE spectrum) whose primary features included defective anterior pituitary formation and panhypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like midfacial hypoplasia, In 1 family, the disorder was transmitted through unaffected mutation carriers. A deceased male in the first generation was reported to have had cleft lip and palate in addition to polydactyly. The proband in the fourth generation had midface hypoplasia, repaired cleft lip and palate, postaxial polydactyly, and absent pituitary on MRI associated with panhypopituitarism. Male twin brothers of the female proband had panhypopituitarism. One died at age 5 months with midline cleft lip and palate, hypotelorism, flat midface, absent pituitary, and partial agenesis of the corpus callosum. The father and paternal aunt of the proband (in the third generation) carried the mutation and had normal intelligence and postaxial polydactyly that may represent a microform. In the other family, the proband had bilateral cleft lip and palate, microcephaly, hypotelorism, single central incisor, postaxial hexadactyly, growth hormone deficiency associated with pituitary hypoplasia, and no other obvious forebrain anomalies. The proband's sister, whose DNA was unavailable for analysis, was found at autopsy to have hypotelorism, single nostril, hypoplastic palate and maxilla, normal digits, absent anterior lobe of the pituitary, alobar HPE, and hydrocephalus. Rahimov et al. (2006) reported 4 Brazilian patients with GLI2 mutations and a wide phenotypic spectrum. Two girls had lobar HPE and HPE-like phenotype, respectively, but lacked pituitary involvement or polydactyly. Another patient had anophthalmia, branchial arch anomalies, and CNS abnormalities, including asymmetric ventricles, right hemisphere migration defects, and abnormal cerebellar foliation. The fourth patient had heminasal aplasia and orbital anomalies. Ribeiro et al. (2005) described a Brazilian male infant with macrocephaly, widened cranial sutures, large forehead, hypotelorism, microphthalmia, flat nasal bridge, midline cleft lip/palate, right microtia with meatal atresia and left preauricular skin tag, short and large neck, and mesocardiac systolic/diastolic heart murmur. X-ray examination showed vertebral developmental defects, and echocardiography revealed dextroposition of the aortic arch, ventricular septal defect, patent foramen ovale, and pulmonic stenosis. CT scan showed microphthalmia with colobomatous eyes and semilobar holoprosencephaly. Chromosomal analysis was normal, and no mutations were found in the SHH (600725), TGIF (602630), or SIX3 (603714) genes. Ribeiro et al. (2005) stated that this patient had the same syndrome as that previously reported by Guion-Almeida et al. (1999), who described a Brazilian female infant with holoprosencephaly, bilateral clinical anophthalmia, and agenesis of the eye globes and optic nerves. She presented with severe respiratory distress at birth, required resuscitation, and subsequently died at 9 days of age. She had microcephaly, sloping forehead, hypotelorism, abnormal nares with septal agenesis, absent columella, midline cleft lip/palate with premaxilla agenesis, bilateral preauricular skin tags, abnormal helix, prominent antihelix, and hypoplastic tragus. CT scan showed alobar holoprosencephaly; autopsy confirmed the CNS involvement and also revealed the additional finding of pulmonary hypoplasia. Ribeiro et al. (2005) also suggested that the holoprosencephaly cases with first arch anomalies (cases 14 and 24) reported by Blaas et al. (2002), the features of which included dysmorphic ears, preauricular tags, thoracic hemivertebrae, tetralogy of Fallot, aortic coarctation, and ventricular septal defect, might represent the same syndrome. Guion-Almeida et al. (2008) reported 3 unrelated Brazilian patients with holoprosencephaly and variable central nervous system involvement, microphthalmia, and first branchial arch anomalies. All were born of nonconsanguineous parents, and G-banded chromosomes in peripheral lymphocytes were normal in all 3 patients. Genetic analysis excluded mutations in the SHH, TGIF, or SIX3 genes in 1 of the patients. Guion-Almeida et al. (2008) concluded that this syndrome represents a recurrent pattern involving the prosencephalon, first branchial arch, and eye primordium, and stated that mutations in the GLI2 and PTCH (601309) genes could not be ruled out. Bertolacini et al. (2012) reported 6 unrelated Brazilian patients with variable manifestations of HPE9 resulting from a heterozygous mutation in the GLI2 gene (see, e.g., 165230.0004-165230.0007). The patients were identified from a larger cohort of 110 individuals with diverse craniofacial anomalies who were screened specifically for GLI2 mutations. The phenotype in patients with GLI2 mutations ranged from isolated cleft lip/palate with polydactyly, to branchial arch anomalies, to semilobar holoprosencephaly. Some patients had marked involvement of the temporomandibular joint and derivatives of the first branchial arch. Only 1 patient had neurodevelopmental delay. Three of the mutations were inherited from a mother with very mild manifestations, and 1 mutation occurred de novo. Molecular Genetics In affected members of 2 families with HPE9, Roessler et al. (2003) identified heterozygous mutations in the GLI2 gene (165230.0001-165230.0002). Rahimov et al. (2006) reported 4 patients with GLI2 missense mutations, including 1 girl with an HPE-like phenotype who was double heterozygous for mutations in GLI2 (165230.0003) and PTCH1 (601309.0012). INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature (in some patients) HEAD & NECK Head \- Microcephaly Face \- Midface hypoplasia \- First branchial arch anomalies \- Temporomandibular joint abnormalities Ears \- Abnormal ears \- Abnormal helix \- Prominent antihelix \- Hypoplastic tragus \- First branchial arch anomalies Eyes \- Microphthalmia \- Anophthalmia \- Optic nerve hypoplasia \- Hypotelorism Nose \- Flat nasal bridge \- Single nares Mouth \- Cleft lip \- Cleft palate Teeth \- Solitary median maxillary central incisor GENITOURINARY External Genitalia (Male) \- Micropenis Internal Genitalia (Male) \- Cryptorchidism SKELETAL Hands \- Postaxial polydactyly Feet \- Postaxial polydactyly NEUROLOGIC Central Nervous System \- Holoprosencephaly \- Delayed psychomotor development \- Seizures \- Anterior pituitary hypoplasia ENDOCRINE FEATURES \- Hypopituitarism MISCELLANEOUS \- Variable phenotype \- Incomplete penetrance \- Variable expressivity MOLECULAR BASIS \- Caused by mutation in the GLI-kruppel family member 2 gene (GLI2, 165230.0001 ) ▲ 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	HOLOPROSENCEPHALY 9	c0751617	6,372	omim	https://www.omim.org/entry/610829	2019-09-22T16:04:08	{"doid": ["0110873"], "mesh": ["D016142"], "omim": ["610829"], "orphanet": ["93926", "280195", "220386", "93925", "280200", "93924", "2162"], "synonyms": ["MIH type HPE", "Middle interhemispheric fusion variant", "MIH", "Alternative titles", "Syntelencephaly", "PITUITARY ANOMALIES WITH HOLOPROSENCEPHALY-LIKE FEATURES", "HOLOPROSENCEPHALY WITH MICROPHTHALMIA AND FIRST BRANCHIAL ARCH ANOMALIES", "MIHF", "Middle interhemispheric variant of holoprosencephaly", "Septopreoptic HPE", "MIHV"], "genereviews": ["NBK1530"]}
A rare hemorrhagic disorder due to a constitutional haemostatic factors defect characterized by premature lysis of hemostatic clots and a moderate bleeding tendency. ## Epidemiology Congenital plasminogen activator inhibitor type 1 (PAI-1) prevalence and incidence remain unknown. Both partial and total PAI-1 deficiencies are extremely rare disorders. In the Amish community (Indiana, USA), eighteen homozygous patients with clinical symptoms and more than 100 heterozygous patients without bleeding symptoms have been reported to date. Additional cases have been reported from North America, Europe and Asia. ## Clinical description Clinical signs of congenital PAI-1 deficiency may appear in early childhood. Spontaneous bleeding is rarely observed, whereas easy bruising or moderate hemorrhage localized to the joints (knees, elbows), nose and gingiva are usually triggered by mild trauma. Menstrual bleeding may be severe, and prolonged bleeding after surgery is common. Hemorrhage is less frequent and less severe (or absent) in heterozygous individuals (partial deficiency) and clinical manifestations, if any, may appear late in life after a traumatic or surgical event. ## Etiology Affected patients carry one (heterozygote) or two (homozygote) alleles with a mutation in the SERPINE1 gene (7q22.1), resulting in partial or total antigenic PAI-1 deficiency. PAI-1 is the physiological inhibitor of tissue-type plasminogen activator (t-PA), the main source of intravascular fibrinolysis. PAI-1 deficiency is a quantitative defect; however, in some patients the protein is present but functionally inactive. ## Diagnostic methods The diagnosis is based on antigenic (ELISA) and functional (plasminogen activator inhibition test) assays of PAI-1. A genotype analysis may be necessary in family studies. Molecular genetic testing confirms the diagnosis. ## Differential diagnosis Differential diagnosis includes acquired PAI-1 deficiency and alpha2-antiplasmin deficiency. ## Genetic counseling Heterozygotes are asymptomatic carriers. Carrier testing must be performed for relatives of affected patients with the SERPINE1 genetic variant. ## Management and treatment Prompt diagnosis is essential since hemorrhages can be safely and efficiently treated with fibrinolysis inhibitors (epsilon amino-caproic acid or tranexamic acid), avoiding the use of blood and derivatives. Menstruation and pregnancy require special consideration with regard to diagnosis and treatment with antifibrinolytics. ## Prognosis The prognosis is generally good as bleeding can be prevented and controlled with antifibrinolytic treatment. [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 plasminogen activator inhibitor type 1 deficiency	c2750067	6,373	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=465	2021-01-23T17:01:41	{"gard": ["4381"], "mesh": ["C567640"], "omim": ["613329"], "umls": ["C2750067"], "icd-10": ["D68.8"], "synonyms": ["Congenital PAI-1 deficiency"]}
Xia-Gibbs syndrome is a rare disorder of intellectual disability. People with this syndrome usually present with developmental delay (especially delays in speech), low muscule tone (hypotonia), failure to thrive, mildly unusual facial features (broad forehead, widely-spaced eyes (hypertelorism), big and low-set ears, flat nasal bridge, and thin upper lip), and breathing difficulties when sleeping (sleep apnea). The sleep apnea may be due to a collapse of the airway when breathing (tracheomalacia). Other signs and symptoms may include autistic features, seizures, lack of coordination (ataxia), behavioral problems, crossed-eyes (strabismus), and an abnormal lateral curvature of the spine (scoliosis). Males usually have more severe symptoms than females. Brain MRI may show several structural brain defects, such as thinning of the corpus callosum and posterior fossa cysts. Xia-Gibbs syndrome is caused by variants (mutations) in the AHDC1 gene. Inheritance is autosomal dominant but all reported cases to date have been due to new mutations (de novo), in individuals with no family history. Treatment and management is supportive, and ideally, should involve several specialists. This may include careful monitoring of the airways, continuous positive airway pressure at night, frequent growth assessments, physical therapy and early interventions to maximize developmental potential. [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	Xia-Gibbs syndrome	c4014419	6,374	gard	https://rarediseases.info.nih.gov/diseases/13409/xia-gibbs-syndrome	2021-01-18T17:57:01	{"omim": ["615829"], "orphanet": ["412069"], "synonyms": ["Autosomal dominant intellectual disability 25", "AHDC1-related intellectual disability-obstructive sleep apnea-mild dysmorphism syndrome", "Xia-Gibbs syndrome"]}
Autosomal dominant polycystic kidney disease Other namesAutosomal dominant PKD, adult-onset PKD Polycystic kidneys SpecialtyMedical genetics Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent, potentially lethal, monogenic human disorder.[1] It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes.[1] It is also the most common of the inherited cystic kidney diseases — a group of disorders with related but distinct pathogenesis, characterized by the development of renal cysts and various extrarenal manifestations, which in case of ADPKD include cysts in other organs, such as the liver, seminal vesicles, pancreas, and arachnoid membrane, as well as other abnormalities, such as intracranial aneurysms and dolichoectasias, aortic root dilatation and aneurysms, mitral valve prolapse, and abdominal wall hernias.[1][2][3] Over 50% of patients with ADPKD eventually develop end stage kidney disease and require dialysis or kidney transplantation.[1][4] ADPKD is estimated to affect at least one in every 1000 individuals worldwide, making this disease the most common inherited kidney disorder with a diagnosed prevalence of 1:2000 and incidence of 1:3000-1:8000 in a global scale.[5][6][7][8][9] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 5.1 Aquaretic medication * 5.2 Analgesic medication * 5.3 Renal cyst aspiration * 5.4 Laparoscopic cyst decortication * 5.5 Neurolysis * 5.6 Nephrectomy * 5.7 Dialysis * 5.8 Kidney transplant * 6 Prognosis * 7 References * 8 External links ## Signs and symptoms[edit] * Acute loin pain * Blood in the urine * Ballotable kidneys * Subarachnoid hemorrhage (berry aneurysm) * Hypertension * Associated liver cysts * Uremia due to kidney failure * Anemia due to chronic kidney disease * Increase RBC or erythropoietin secretion ## Genetics[edit] ADPKD is genetically heterogeneous with two genes identified: PKD1 (chromosome region 16p13.3; around 85% cases) and PKD2 (4q21; around 15% cases).[1] Several genetic mechanisms probably contribute to the phenotypic expression of the disease.[1] Although evidence exists for a two-hit mechanism (germline and somatic inactivation of two PKD alleles) explaining the focal development of renal and hepatic cysts,[10][11] haploinsufficiency is more likely to account for the vascular manifestations of the disease.[12][13] Additionally, new mouse models homozygous for PKD1 hypomorphic alleles 22 and 23 and the demonstration of increased renal epithelial cell proliferation in PKD2 +/− mice suggest that mechanisms other than the two-hit hypothesis also contribute to the cystic phenotype.[1] Large interfamilial and intrafamilial variability occurs in ADPKD.[1] Most individuals with PKD1 mutations have kidney failure by age 70 years, whereas more than 50% of individuals with PKD2 mutations have adequate renal function at that age (mean age of onset of end-stage renal disease: 54·3 years with PKD1; 74·0 years with PKD2).[14] The significant intrafamilial variability observed in the severity of renal and extrarenal manifestations points to genetic and environmental modifying factors that may influence the outcome of ADPKD, and results of an analysis of the variability in renal function between monozygotic twins and siblings support the role of genetic modifiers in this disease.[1][15] It is estimated that 43–78% of the variance in age to ESRD could be due to heritable modifying factors,[16][17] with parents as likely as children to show more severe disease in studies of parent-child pairs.[1][18] ## Pathophysiology[edit] In many patients with ADPKD, kidney dysfunction is not clinically apparent until 40 or 50 years of life.[4] However, an increasing body of evidence suggests the formation of renal cysts starts in utero.[19] Cysts initially form as small dilations in renal tubules, which then expand to form fluid-filled cavities of different sizes.[19] Factors suggested to lead to cystogenesis include a germline mutation in one of the polycystin gene alleles, a somatic second hit that leads to the loss of the normal allele, and a third hit, which can be anything that triggers cell proliferation, leading to the dilation of the tubules.[19] In the progression of the disease, continued dilation of the tubules through increased cell proliferation, fluid secretion, and separation from the parental tubule lead to the formation of cysts.[20][21] ADPKD, together with many other diseases that present with renal cysts, can be classified into a family of diseases known as ciliopathies.[22] Epithelial cells of the renal tubules, including all the segments of the nephron and the collecting ducts (with the exception of intercalated cells) show the presence of a single primary apical cilium.[23] Polycystin-1, the protein encoded by the PKD1 gene, is present on these cilia and is thought to sense the flow with its large extracellular domains, activating the calcium channels associated with polycystin-2, the product of gene PKD2,[24] as a result of the genetic setting of ADPKD as explained in the genetics sub-section above. Epithelial cell proliferation and fluid secretion that lead to cystogenesis are two hallmark features in ADPKD.[25] During the early stages of cystogenesis, cysts are attached to their parental renal tubules and a derivative of the glomerular filtrate enters the cysts.[19] Once these cysts expand to approximately 2 mm in diameter, the cyst closes off from its parental tubule and after that fluid can only enter the cysts through transepithelial secretion, which in turn is suggested to increase due to secondary effects from an increased intracellular concentrations of cyclic AMP (cAMP).[19] Clinically, the insidious increase in the number and size of renal cysts translates as a progressive increment in kidney volume.[1][19] Studies led by Mayo Clinic professionals established that the total kidney volume (TKV) in a large cohort of ADPKD patients was 1060 ± 642ml with a mean increase of 204ml over three years, or 5.27% per year in the natural course of the disease, among other important, novel findings that were extensively studied for the first time.[26] Illustration of PKD1 and PKD2 proteins at the cell membrane ## Diagnosis[edit] Usually, the diagnosis of ADPKD is initially performed by renal imaging using ultrasound, CT scan, or MRI.[27] However, molecular diagnostics can be necessary in the following situations: 1- when a definite diagnosis is required in young individuals, such as a potential living related donor in an affected family with equivocal imaging data;[27] 2- in patients with a negative family history of ADPKD, because of potential phenotypic overlap with several other kidney cystic diseases;[27] 3- in families affected by early-onset polycystic kidney disease, since in this cases hypomorphic alleles and/or oligogenic inheritance can be involved;[27][28] and 4- in patients requesting genetic counseling, especially in couples wishing a pre-implantation genetic diagnosis.[27][29] The findings of large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD are diagnostic. In the absence of a family history of ADPKD, the presence of bilateral renal enlargement and cysts, with or without the presence of hepatic cysts, and the absence of other manifestations suggestive of a different renal cystic disease provide presumptive, but not definite, evidence for the diagnosis. In some cases, intracranial aneurysms can be an associated sign of ADPKD, and screening can be recommended for patients with a family history of intracranial aneurysm.[30] Molecular genetic testing by linkage analysis or direct mutation screening is clinically available; however, genetic heterogeneity is a significant complication to molecular genetic testing. Sometimes, a relatively large number of affected family members need to be tested in order to establish which one of the two possible genes is responsible within each family. The large size and complexity of PKD1 and PKD2 genes, as well as marked allelic heterogeneity, present obstacles to molecular testing by direct DNA analysis. The sensitivity of testing is nearly 100% for all patients with ADPKD who are age 30 years or older and for younger patients with PKD1 mutations; these criteria are only 67% sensitive for patients with PKD2 mutations]] who are younger than age 30 years.[citation needed] * Adult polycystic kidney * Diagram of autosomal dominant polycystic disease with a normal kidney inset for comparison * Abdominal CT scan of an adult with autosomal dominant polycystic kidney disease: Extensive cyst formation is seen over both kidneys, with a few cysts in the liver, as well. (Coronal plane) ## Treatment[edit] Currently, the only clinical/pharmacological treatment available for ADPKD consists in reducing the speed in gain of total kidney volume (TKV) with aquaretics (i.e. tolvaptan), which can alleviate pain while giving the patients a better quality of life for over a mean of 3 years. After this period, patients can restart gaining TKV at pretreatment rates and may eventually have to go through dialysis and kidney transplant. Palliative treatment modalities involve symptomatic medications (nonopioid and opioid analgesics) for abdominal/retroperitoneal pain. Before the advent of aquaretic medication, the only option for analgesic-resistant pain was simple or complex surgical procedures (i.e. renal cyst aspiration, cyst decortication, renal denervation and nephrectomy), which can result in complications inherent to surgery.[citation needed] ### Aquaretic medication[edit] In 2014, Japan was the first country in the world to approve a pharmacological treatment for ADPKD[26] followed by Canada and Europe, which approved the drug tolvaptan for ADPKD patients in the beginning of 2015. The USA FDA approved the use of tolvaptan in the treatment of ADPKD in 2018.[31] Tolvaptan, an aquaretic drug, is a vasopressin receptor 2 (V2) antagonist.[8] Pre-clinical studies had suggested that the molecule cAMP could be involved in the enlargement of ADPKD cysts,[32] and studies on rodents confirmed the role of vasopressin in increasing the levels of cAMP in the kidney, which laid the basis for the conduction of clinical studies.[33] Because data from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) led by Mayo Clinic showed that total kidney volume (TKV) predicted the risk of developing chronic kidney disease in patients with ADPKD,[26][34] the TEMPO 3:4 trial, which enrolled patients from 129 sites worldwide from 2007 to 2009, evaluated TKV as a primary end-point to test the efficacy of tolvaptan in ADPKD patients.[8][9] That study showed a significant decrease in the ratio of TKV increase and deterring of renal function decline in ADPKD patients after treatment with tolvaptan;[8][35] however, because laboratory test results regarding liver function appeared elevated in a percentage of patients enrolled in that study, the approval of the drug was either delayed by regulatory agencies or, as in case of the US, altogether denied.[9][36] ### Analgesic medication[edit] Chronic pain in patients with ADPKD is often refractory to conservative, noninvasive treatments, but nonopioid analgesics and conservative interventions can be first used before opioid analgesics are considered; if pain continues, then surgical interventions can target renal or hepatic cysts to directly address the cause of pain, with surgical options including renal cyst decortication, renal denervation, and nephrectomy.[37] ### Renal cyst aspiration[edit] Aspiration with ethanol sclerotherapy can be performed for the treatment of symptomatic simple renal cysts, but can be impractical in advanced patients with multiple cysts.[38] The procedure itself consists in the percutaneous insertion of a needle into the identified cyst, under ultrasound guidance, with subsequent draining the contained liquid; the sclerotherapy is used to avoid liquid reaccumulation that can occur in the cyst, which can result in symptom recurrence.[38][39] ### Laparoscopic cyst decortication[edit] Laparoscopic cyst decortication (also referred to as marsupialization) consists in the removal of one or more kidney cysts through laparoscopic surgery, during which cysts are punctured, and the outer wall of the larger cysts is excised with care not to incise the renal parenchyma.[40][41] This procedure can be useful for pain relief in patients with ADPKD, and is usually indicated after earlier cyst aspiration has confirmed that the cyst to be decorticated is responsible for pain.[41] Nonrandomised controlled trials conducted in the '90s showed that patients with symptomatic simple renal cysts who had recurrence of symptoms after initial response to simple aspiration could be safely submitted to cyst decortication, with a mean pain-free life between 17 and 24 months after surgery.[40][42] Laparoscopic decortication presents a 5% recurrence rate of renal cysts compared to an 82% recurrence rate obtained with sclerotherapy.[39] ### Neurolysis[edit] A novel treatment of specifically the chronic pain suffered by many sufferers of ADPKD is Celiac plexus neurolysis.[43][44] This involves the chemical ablation of the celiac plexus, to cause a temporary degeneration of targeted nerve fibers. When the nerve fibers degenerate, it causes an interruption in the transmission of nerve signals. This treatment, when successful, provides significant pain relief for a period ranging from a few days to over a year. The procedure may be repeated when the affected nerves have healed and the pain returns.[citation needed] ### Nephrectomy[edit] Many ADPKD patients suffer symptomatic sequelae in consequence of the disease, such as cyst hemorrhage, flank pain, recurrent infections, nephrolithiasis, and symptoms of mass effect (i.e., early satiety, nausea and vomiting, and abdominal discomfort), from their enlarged kidneys.[45][46][47] In such cases, nephrectomy can be required due to intractable symptoms or when in the course of preparing for kidney transplantation, the native kidneys are found to impinge upon the true pelvis and preclude the placement of a donor allograft.[46][47][48][49] Additionally, native nephrectomy may be undertaken in the presence of suspected malignancy, as renal cell carcinoma (RCC) is two to three times more likely in the ADPKD population in end-stage kidney disease (ESKD) than in the ESKD patients without ADPKD.[47][50] Although the indications for nephrectomy in ADPKD may be related to kidney size, the decision to proceed with native nephrectomy is often undertaken on an individual basis, without specific reference to kidney size measurements.[47] ### Dialysis[edit] Two modalities of dialysis can be used in the treatment of ADPKD patients: peritoneal dialysis and hemodialysis.[51] Epidemiological data shows that ADPKD affects 5-13.4% of patients undergoing hemodialysis in Europe and in the United States,[52][53][54] and about 3% in Japan.[55] Peritoneal dialysis has usually been contra-indicated in ADPKD patients with large kidney and liver volumes, due to expected physical difficulties in the procedure and possible complications;[51][56] however, no difference is seen in long-term morbidity between hemodialysis and peritoneal dialysis in ADPKD.[51] ### Kidney transplant[edit] Kidney transplantation is accepted as the preferred treatment for ADPKD patients with ESRD.[1] Among American patients on the kidney-transplant waiting list (as of December 2011), 7256 (8.4%) were listed due to cystic kidney disease and of the 16,055 renal transplants performed in 2011, 2057 (12.8%) were done for patients with cystic kidney disease, with 1,189 from deceased donors and 868 from living donors.[57] ## Prognosis[edit] In ADPKD patients, gradual cyst development and expansion result in kidney enlargement, and during the course of the disease, glomerular filtration rate remains normal for decades before kidney function starts to progressively deteriorate, making early prediction of renal outcome difficult.[58] The CRISP study,[26][34] mentioned in the treatment section above, contributed to build a strong rationale supporting the prognostic value of total kidney volume (TKV) in ADPKD; TKV (evaluated by MRI) increases steadily and a higher rate of kidney enlargement correlated with accelerated decline of GFR, while patient height-adjusted TKV (HtTKV) ≥600 ml/m predicts the development of stage 3 chronic kidney disease within 8 years.[58] Besides TKV and HtTKV, the estimated glomerular filtration rate (eGFR) has also been tentatively used to predict the progression of ADPKD.[58] After the analysis of CT or MRI scans of 590 patients with ADPKD treated at the Mayo Translational Polycystic Kidney Disease Center, Irazabal and colleagues developed an imaging-based classification system to predict the rate of eGFR decline in patients with ADPKD.[58][59] In this prognostic method, patients are divided into five subclasses of estimated kidney growth rates according to age-specific HtTKV ranges (1A, <1.5%; 1B, 1.5–3.0%; 1C, 3.0–4.5%; 1D, 4.5–6.0%; and 1E, >6.0%) as delineated in the CRISP study.[58][59] The decline in eGFR over the years following initial TKV measurement is significantly different between all five patient subclasses, with those in subclass 1E having the most rapid decline.[58] Some of the most common causes of death in patients with ADPKD are various infections (25%), a ruptured berry aneurysm (15%), or coronary/hypertensive heart disease (40%).[60] ## References[edit] 1. ^ a b c d e f g h i j k l Torres VE, Harris PC, Pirson Y (2007). 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"Clinical pattern of adult polycystic kidney disease in a northeastern region of Italy". Clin. Nephrol. 72 (4): 259–267. doi:10.5414/CNP72259. PMID 19825331. 55. ^ Higashihara E, Nutahara K, Kojima M, Tamakoshi A, Yoshiyuki O, Sakai H, Kurokawa K (1998). "Prevalence and renal prognosis of diagnosed autosomal dominant polycystic kidney disease in Japan". Nephron. 80 (4): 421–427. doi:10.1159/000045214. PMID 9832641. S2CID 22124996. 56. ^ Hamanoue S, Hoshino J, Suwabe T, Marui Y, Ueno T, Kikuchi K, Hazue R, Mise K, Kawada M, Imafuku A, Hayami N, Sumida K, Hiramatsu R, Hasegawa E, Sawa N, Takaichi K, Ubara Y (2015). "Peritoneal Dialysis is Limited by Kidney and Liver Volume in Autosomal Dominant Polycystic Kidney Disease". Ther. Apher. Dial. 19 (3): 207–11. doi:10.1111/1744-9987.12272. PMID 25612237. 57. ^ Matas AJ, Smith JM, Skeans MA, Lamb KE, Gustafson SK, Samana CJ, Stewart DE, Snyder JJ, Israni AK, Kasiske BL (2013). "OPTN/SRTR 2011 Annual Data Report: kidney". Am. J. Transplant. 13 (Suppl 1): 11–46. doi:10.1111/ajt.12019. PMC 5527691. PMID 23237695. 58. ^ a b c d e f Cornec-Le Gall E, Le Meur Y (2014). "Polycystic kidney disease: Kidney volume--a crystal ball for ADPKD prognosis?". Nature Reviews Nephrology. 10 (9): 485–486. doi:10.1038/nrneph.2014.132. PMID 25092148. S2CID 22042874. 59. ^ a b Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, Bae KT, Chapman AB, Grantham JJ, Mrug M, Hogan MC, El-Zoghby ZM, Harris PC, Erickson BJ, King BF, Torres VE (2015). "Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials". J. Am. Soc. Nephrol. 26 (1): 160–172. doi:10.1681/ASN.2013101138. PMC 4279733. PMID 24904092. 60. ^ Kumar, Vinay; Abbas, Abul K.; Aster, Jon C. (2014). Robbins and Cotran pathologic basis of disease. Kumar, Vinay, 1944-, Abbas, Abul K.,, Aster, Jon C.,, Perkins, James A. (Ninth ed.). Philadelphia, PA. p. 947. ISBN 9781455726134. OCLC 879416939. ## External links[edit] * https://web.archive.org/web/20110608142128/http://kidney.niddk.nih.gov/kudiseases/pubs/polycystic/index.htm * https://www.ncbi.nlm.nih.gov/disease/PKD.html Classification D * ICD-10: Q61 * ICD-9-CM: 753.1 * OMIM: 601313 173910 * MeSH: D016891 * DiseasesDB: 10262 External resources * MedlinePlus: 000502 * eMedicine: radio/68 * Orphanet: 730 Wikimedia Commons has media related to Autosomal dominant polycystic kidney disease. * v * t * e Congenital malformations and deformations of urinary system Abdominal Kidney * Renal agenesis/Potter sequence, Papillorenal syndrome * cystic * Polycystic kidney disease * Meckel syndrome * Multicystic dysplastic kidney * Medullary sponge kidney * Horseshoe kidney * Renal ectopia * Nephronophthisis * Supernumerary kidney * Pelvic kidney * Dent's disease * Alport syndrome Ureter * Ectopic ureter * Megaureter * Duplicated ureter Pelvic Bladder * Bladder exstrophy Urethra * Epispadias * Hypospadias * Posterior urethral valves * Penoscrotal transposition Vestigial Urachus * Urachal cyst * Urachal fistula * Urachal sinus * v * t * e Cystic diseases Respiratory system * Langerhans cell histiocytosis * Lymphangioleiomyomatosis * Cystic bronchiectasis Skin * stratified squamous: follicular infundibulum * Epidermoid cyst and Proliferating epidermoid cyst * Milia * Eruptive vellus hair cyst * outer root sheath * Trichilemmal cyst and Pilar cyst and Proliferating trichilemmal cyst and Malignant trichilemmal cyst * sebaceous duct * Steatocystoma multiplex and Steatocystoma simplex * Keratocyst * nonstratified squamous: Cutaneous ciliated cyst * Hidrocystoma * no epithelium: Pseudocyst of the auricle * Mucocele * other and ungrouped: Cutaneous columnar cyst * Keratin implantation cyst * Verrucous cyst * Adenoid cystic carcinoma * Breast cyst Human musculoskeletal system * Cystic hygroma Human digestive system * oral cavity: Cysts of the jaws * Odontogenic cyst * Periapical cyst * Dentigerous cyst * Odontogenic keratocyst * Nasopalatine duct cyst * liver: Polycystic liver disease * Congenital hepatic fibrosis * Peliosis hepatis * bile duct: Biliary hamartomas * Caroli disease * Choledochal cysts * Bile duct hamartoma Nervous system * Cystic leukoencephalopathy Genitourinary system * Polycystic kidney disease * Autosomal dominant polycystic kidney * Autosomal recessive polycystic kidney * Medullary cystic kidney disease * Nephronophthisis * Congenital cystic dysplasia Other conditions * Hydatid cyst * Von Hippel–Lindau disease * Tuberous 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	Autosomal dominant polycystic kidney disease	c0085413	6,375	wikipedia	https://en.wikipedia.org/wiki/Autosomal_dominant_polycystic_kidney_disease	2021-01-18T18:36:20	{"gard": ["10413"], "mesh": ["D016891"], "icd-9": ["753.13"], "icd-10": ["Q61"], "wikidata": ["Q2732398"]}
Congenital muscular dystrophy with cerebellar involvement is a rare, congenital muscular dystrophy due to dystroglycanopathy characterized by proximal muscule weakness with a tendency for muscle hypertrophy and pseudohypertrophy, variable cognitive impairment, microcephaly, cerebellar hypoplasia with or without cysts, and other structural brain anomalies. [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 muscular dystrophy with cerebellar involvement	c1847759	6,376	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=370959	2021-01-23T17:30:23	{"mesh": ["C564691"], "omim": ["606612", "613151", "613155", "613156", "615351"], "icd-10": ["G71.2"], "synonyms": ["CMD with cerebellar involvement", "CMD-CRB"]}
Diagram of the causes of mortality in the army in the East, F. Nightingale, 1858 Zymotic disease was a 19th-century medical term for acute infectious diseases,[1] especially "chief fevers and contagious diseases (e.g. typhus and typhoid fevers, smallpox, scarlet fever, measles, erysipelas, cholera, whooping-cough, diphtheria, etc.)".[2] Zyme or microzyme was the name of the organism presumed to be the cause of the disease. > As originally employed by Dr W. Farr, of the British Registrar-General's department, the term included the diseases which were "epidemic, endemic and contagious," and were regarded as owing their origin to the presence of a morbific principle in the system, acting in a manner analogous to, although not identical with, the process of fermentation.[2] In the late 19th century, Antoine Béchamp proposed that tiny organisms he termed microzymas, and not cells, are the fundamental building block of life. Bechamp claimed these microzymas are present in all things—animal, vegetable, and mineral—whether living or dead[when?]. Microzymas coalesce to form blood clots and bacteria. Depending upon the condition of the host, microzymas assume various forms. In a diseased body, the microzymas become pathological bacteria and viruses. In a healthy body, microzymas form healthy cells. When a plant or animal dies, the microzymas live on.[clarification needed] His ideas did not gain acceptance.[3] The word zymotic comes from the Greek word ζυμοῦν zumoûn which means "to ferment". It was in British official use from 1839.[4] This term was used extensively in the English Bills of Mortality as a cause of death from 1842. Robert Newstead (1859–1947) used this term in a 1908 publication in the Annals of Tropical Medicine and Parasitology, to describe the contribution of house flies (Musca domestica) towards the spread of infectious diseases. However, by the early 1900s, bacteriology "displaced the old fermentation theory",[2] and so the term became obsolete. In her Diagram of the causes of mortality in the army in the East, Florence Nightingale depicts > The blue wedges measured from the centre of the circle represent area for area the deaths from Preventible or Mitigable Zymotic diseases; the red wedges measured from the centre the deaths from wounds, & the black wedges measured from the centre the deaths from all other causes. ## References[edit] 1. ^ Kennedy, Evor (1869). Hospitalism and Zymotic Disease (2nd ed.). London: Longmans, Green, and Co. 2. ^ a b c Chisholm, Hugh, ed. (1911). "Zymotic Diseases" . Encyclopædia Britannica (11th ed.). Cambridge University Press. 3. ^ Hess, David J. (1997). Can bacteria cause cancer?: alternative medicine confronts big science. NYU Press. pp. 76–77. ISBN 0-8147-3561-4. 4. ^ Marjorie Cruickshank (1 January 1981). Children and Industry: Child Health and Welfare in the North-west Textile Towns During the Nineteenth Century. Manchester University Press. p. 67. ISBN 978-0-7190-0809-2. Retrieved 23 June 2013. [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	Zymotic disease	None	6,377	wikipedia	https://en.wikipedia.org/wiki/Zymotic_disease	2021-01-18T19:10:41	{"wikidata": ["Q8075930"]}
A very rare mitochondrial respiratory chain deficiency characterized clinically by transient but life-threatening liver failure with elevated liver enzymes, jaundice, vomiting, coagulopathy, hyperbilirubinemia, and lactic acidemia. [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 infantile liver failure due to synthesis defect of mtDNA-encoded proteins	c3278664	6,378	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=217371	2021-01-23T18:37:13	{"omim": ["613070"], "icd-10": ["K72.0"], "synonyms": ["Acute infantile liver failure due to synthesis defect of mitochondrial DNA-encoded proteins"]}
A number sign (#) is used with this entry because of evidence that susceptibility to ankylosing spondylitis can be conferred by variation in the HLA-B27 allele (142830.0001) on chromosome 6p21.3. Description Spondyloarthropathy (SpA), one of the commonest chronic rheumatic diseases, includes a spectrum of related disorders comprising the prototype ankylosing spondylitis (AS), a subset of psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy (Miceli-Richard et al., 2004). These phenotypes are difficult to differentiate because they may occur simultaneously or sequentially in the same patient. Studies have suggested that a predominant shared component, including HLA-B27, predisposes to all phenotypic subsets, and that these subsets should be considered as various phenotypic expressions of the same disease (Said-Nahal et al., 2000, Said-Nahal et al., 2001). Braun and Sieper (2007) provided a detailed review of ankylosing spondylitis, including clinical features, pathogenesis, and management. ### Genetic Heterogeneity of Susceptibility to Spondyloarthropathy Additional susceptibility loci for spondyloarthropathy have been identified on chromosome 9q31-q34 (SPDA2; 183840) and chromosome 2q36 (SPDA3; 613238). Clinical Features Kidd et al. (1995) described a family in which 7 of 12 members had early onset oligo- or polyarthritis, enthesitis, or both, and fulfilled established criteria for spondyloarthropathy, although none had radiologic evidence of sacroiliitis. The mean age at first symptom was 22 years, with only 1 individual having the first symptom beyond the age of 30 years. All subjects were rheumatoid factor negative. Histocompatibility showed association with HLA-B7. None had psoriasis or inflammatory bowel disease. Monnet et al. (2004) analyzed the ocular and extraocular manifestations in 175 consecutive patients with HLA-B27-associated uveitis. The male-to-female ratio was 1.3:1. The median age at first attack of uveitis was 31 years. An HLA-B27-associated extraocular disorder was seen in 136 (77.7%) patients. Ankylosing spondylitis was diagnosed in 81 (46.3%) patients and presumed in 17 (9.7%); undifferentiated spondyloarthropathy was seen in 21 (12%) patients and other HLA-B27-associated diseases in 17 (9.7%). Monnet et al. (2004) concluded that uveitis is frequently the first indication of a previously undiagnosed HLA-B27-associated extraocular disease. Inheritance Karten et al. (1962) demonstrated familial aggregation. Rheumatoid arthritis and positive tests for rheumatoid factor were found no more often in the relatives of spondylitics than in those of controls, suggesting that rheumatoid arthritis and ankylosing spondylitis are distinct entities. De Blecourt et al. (1961) found spondylitis 22.6 times more frequently in the relatives of spondylitic patients than in the relatives of controls. They suggested autosomal dominant inheritance with greater penetrance in males than in females. O'Connell (1959) arrived at the same conclusion. The familial incidence was higher when the proband was female. Kornstad and Kornstad (1960) described 2 families in which only females were affected. Emery and Lawrence (1967) presented data that they interpreted as indicating multifactorial inheritance, however. Linkage data were published by Kornstad and Kornstad (1960) and earlier by Riecker et al. (1950). Schlosstein et al. (1973) found HLA specificity w27 in 35 of 40 cases (87.5%) of ankylosing spondylitis and in only 8% of normal controls. The HLA findings brought thinking about the genetics full-circle. Autosomal dominant inheritance with reduced penetrance seemed to be established. Calin and Elswood (1989) analyzed 42 sib pairs concordant for ankylosing spondylitis. They found that the correlation coefficient was not significant for age at onset but was much higher, reaching a level of significance at the 0.01 level, for calendar year of onset. This was interpreted as consistent with environmental factors playing a greater role in the timing of onset. Concordance with the presence or absence of uveitis was only 43%, again suggesting that genetic factors are less significant than environment. Conversely, genetic factors appeared to be more important than environment in influencing prognosis as measured by a disability and pain index and by the severity of radiologic findings. Brown et al. (1997) found that 6 of 8 monozygotic twin pairs (75%) were concordant for ankylosing spondylitis, compared with 4 of 15 B27-positive dizygotic twin pairs (27%) and 4 of 32 dizygotic twin pairs overall (12.5%). The twins with ankylosing spondylitis had been identified in the database maintained at the Royal National Hospital for Rheumatic Diseases in Bath, England. Mapping Gu et al. (2009) conducted a genomewide scan followed by fine mapping analysis in a 4-generation Han Chinese family with ankylosing spondylitis and obtained a maximum lod score of 4.02 at D6S273 (theta = 0.0) on chromosome 6, verifying the HLA-B locus. ### Linkage Heterogeneity To identify major loci controlling clinical manifestations of AS, Brown et al. (2003) performed genomewide linkage analysis on 188 affected sib-pair families containing 454 affected individuals. Heritabilities of the traits studied were as follows: age at symptom onset, 0.33 (p = 0.005); disease activity assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), 0.49 (p = 0.0001); and functional impairment assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI), 0.76 (p = 0.0000001). No linkage was observed between the MHC and any of the traits studied. Significant linkage (lod = 4.0) was observed between a region on chromosome 18p and the BASDAI. Age at symptom onset showed suggestive linkage to chromosome 11p (lod = 3.3). Maximum linkage with the BASFI was seen at chromosome 2q (lod = 2.9; see SPDA3, new). Brown et al. (2003) concluded that these clinical manifestations are largely determined by a small number of genes not encoded within the MHC. In a multistage study involving 12,701 SNPs and patients with autoimmune diseases, including ankylosing spondylitis, the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium (2007) identified significant association with SNPs in the ARTS1 gene (ERAP1; 606832) (combined results, p = 1.2 x 10(-8) to 3.4 x 10(-10)) on chromosome 5q15. Association was also found with SNPs in the IL23R gene (607562) on chromosome 1p31.3: in combined analysis, the strongest association was at rs11209032 (odds ratio, 1.3; p = 7.5 x 10(-9)). The association remained strong when only individuals who self-reported as not having inflammatory bowel disease (see IBD17, 612261) were considered, and was still strongest at rs11209032 (p = 6.9 x 10(-7)). The Australo-Anglo-American Spondyloarthritis Consortium (2010) undertook a genomewide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; p less than 10(-800)), The Australo-Anglo-American Spondyloarthritis Consortium (2010) found association with SNPs in 2 gene deserts at 2p15 (rs10865331; combined p = 1.9 x 10(-19)) and 21q22 (rs2242944; p = 8.3 x 10(-20)), as well as in the genes ANTXR2 (608041) (rs4333130; p = 9.3 x 10(-8)), and IL1R2 (147811) (rs2310173; p = 4.8 x 10(-7)). The Australo-Anglo-American Spondyloarthritis Consortium (2010) also replicated previously reported associations at IL23R (607562) (rs11209026; p = 9.1 x 10(-14)) and ERAP1 (606832) (rs27434; p = 5.3 x 10(-12)). The Australo-Anglo-American Spondyloarthritis Consortium (2010) concluded that their study identified a major role for the IL23 and IL1 cytokine pathways in ankylosing spondylitis disease susceptibility. The Australo-Anglo-American Spondyloarthritis Consortium and Wellcome Trust Case Control Consortium 2 (2011) reported the identification of 3 variants in the RUNX3 (600210), LTBR-TNFRSF1A (600979, 191190), and IL12B (161561) regions convincingly associated with ankylosing spondylitis (p less than 5 x 10(-8) in the combined discovery and replication datasets) and a further 4 loci at PTGER4 (601586), TBKBP1 (608476), ANTXR2, and CARD9 (607212) that showed strong association across all their datasets (p less than 5 x 10(-6) overall, with support in each of the 3 datasets studied). This group also showed that polymorphisms of ERAP1 (rs30187, combined p = 1.8 x 10(-27)), which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, affect ankylosing spondylitis risk only in HLA-B27-positive individuals. The authors concluded that their findings provided strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides. Pathogenesis Nuki (1998) summarized the hypotheses put forward to explain the association between HLA-B27 and the spondyloarthropathies, as well the evidence supporting these hypotheses. Luthra-Guptasarma and Singh (2004) reviewed hypotheses concerning the mechanism by which HLA-B27 predisposes to ankylosing spondylitis. They proposed that beta-2-microglobulin (B2M; 109700)-free, peptide-free heavy chains support a helix-coil transition in the segment leading from the alpha-2 domain to the alpha-3 domain, facilitating rotation of backbone angles around residues 167/168, and allowing residues 169-181 (identical to a known B27 ligand) to loop around and occupy the molecule's own peptide-binding cleft. They suggested that this 'auto-display,' occurring either within or between B27 molecules, could provoke autoimmune attack. Diagnosis Gran and Husby (1995) expressed the view that the HLA-B27 test is of limited usefulness and cannot be used for confirming a diagnosis of spondyloarthropathy or predicting the prognosis in patients with an established diagnosis of inflammatory rheumatic disease. The test can be used in 3 ways: first, if the likelihood of spondyloarthropathy based on symptoms and signs is greater than 50%, a B27-positive test result significantly increases the chance for correct diagnosis. A high pretest likelihood, however, required reliable diagnostic criteria. Second, in patients with back pain and stiffness, a negative B27 test result very strongly indicates that the complaints are caused by disorders other than AS. In the absence of concurrent psoriasis or inflammatory bowel disease, a negative B27 test result virtually excludes a diagnosis of AS. Third, a positive B27 test in children with established inflammatory joint disease may help the physician focus on the possible development of seronegative spondyloarthropathy. Molecular Genetics The finding of B27 in 16 of 17 AS cases in India and in 2 of 60 controls (Sengupta et al., 1977) appeared to exclude genetic linkage as the basis of the association. Calin et al. (1983) studied 499 available first-degree relatives of 79 HLA-B27-positive patients with ankylosing spondylitis and 69 HLA-B27-positive healthy blood donors. The rate of ankylosing spondylitis cases was estimated to be 10.6% as compared with 1.9% in B27-positive relatives of healthy persons (p less than 0.025). This suggested a genetic difference between B27-positive diseased persons and B27-positive healthy persons. It was thought that complete sequencing of HLA-B27 cDNA might help identify whether this polymorphic marker is directly related in the etiology of AS and, if so, what the mechanism of that involvement is (Szots et al., 1986). Despite the strong association between HLA-B27 and ankylosing spondylitis, linkage of this phenotype to the major histocompatibility complex region had not been established before the study of Rubin et al. (1992, 1994) involving 15 multiplex AS families. Among affected family members, 13 of 15 females and 46 of 49 males were B27 positive, as compared with 22 of 43 unaffected females and 16 of 40 unaffected males. The linkage analysis was based on a genetic model with a frequency of the AS gene of 1.8%; the risk of AS for homozygotes was placed at 99.5% and for heterozygotes at 43% with a sporadic risk of 0.1%. Analysis showed linkage with the MHC region, with a lod score of 3.36 at no recombination. The B27 haplotype did not consistently segregate with disease in 2 families, but both families still supported linkage. In a second analysis in which the population association of HLA-B27 with AS was taken into account, the maximum lod score was 7.5 at theta = 0.05. Identity-by-descent analyses showed a significant departure from random segregation among affected avuncular (uncle/nephew-niece) and cousin pairs. The presence of HLA-B40 in HLA-B27 positive individuals increased the risk for disease more than 3-fold, confirming previous reports. Disease susceptibility modeling suggested an autosomal dominant pattern of inheritance with penetrance of approximately 20%. In this study, which involved families from Toronto and Newfoundland, B27 alleles were detected by hybridization with sequence-specific oligonucleotide probes (SSOP) after amplification of genomic DNA by PCR. Scofield et al. (1993) used protein sequence databases to test a series of hypotheses: first, they asked whether the primary amino acid sequence of the hypervariable regions of HLA-B27 shares short sequences with the proteins of gram-negative enteric bacteria. They found that, unique among the HLA-B molecules, the hypervariable regions of HLA-B27 shared short peptide sequences with proteins from these bacteria, indicating the possibility of antigen mimicry. Second, they asked whether the enteric proteins satisfy the structural requirements for peptide binding to B27. This hypothesis also tended to be true. Scofield et al. (1993) concluded that HLA-B27 and enteric gram-negative bacteria have undergone convergent evolution. The regions of the enteric bacterial proteins that are contiguous with the short sequences shared with B27 tend to have structures that are also predicted to bind B27. The observation suggested a mechanism for autoimmunity and led to the prediction that the B27-associated diseases are mediated by a subset of T-cell receptors, B27, and the peptides bound by B27. HLA-B27 shares sequence with proteins from enteric bacteria. Scofield et al. (1995) pointed out that the B2705 sequence contains a nonapeptide (LRRYLENGK) predicted to bind in the binding cleft of B27. Some nonapeptides from enteric organisms that share sequence with this nonapeptide of B27 also bind B27. Thus, peptides that both mimic and bind B27 may constitute the molecular components of a mechanism for spondyloarthropathies. Brown et al. (2000) performed a linkage study of chromosome 22 in 200 families with AS-affected sib pairs. Association of alleles of the debrisoquine hydroxylase gene (CYP2D6; 124030) was examined by both case-control and within-family means. While homozygosity for poor-metabolizer alleles was found to be associated with AS, heterozygosity for the most frequent poor-metabolizer allele (CYP2D64) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D64 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. The authors hypothesized that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS. ### Spondyloarthropathy Unassociated with HLA-B27 Gaucher et al. (1989) described a French family in which 18 members in 4 generations had spondyloarthropathy, radiologically proved in 16. The disease started during the third decade of life as an asymmetric, destructive arthropathy, predominantly affecting the wrists. Six patients had sacroiliitis. Rheumatoid serologic tests were all negative. After a destructive phase, repair took the form of ossification. Superti-Furga et al. (1990) stated that HLA-B27 antigen was not found in any members of the family and the disease did not segregate with the HLA locus. Because of the evidence that familial osteoarthrosis is sometimes linked genetically (and presumably etiologically) to the type II collagen gene (COL2A1; 120140), Superti-Furga et al. (1990) tested for linkage of COL2A1 and the arthropathy in this family. Linkage analysis excluded COL2A1 as the disease-causing locus in this family. It was significant that the Finnish families in which linkage to the cartilage collagen gene was demonstrated had no clinical or other evidence of inflammation, whereas in this French family the arthritis was inflammatory in nature and often asymmetric. Other Features James (1991) suggested an ingenious explanation for the fact that, in conditions suspected of multifactorial inheritance, the sex ratio (proportion of males) of randomly ascertained probands is more extreme than that of their affected relatives. He used a simple model, based on multifactorial inheritance with liability varying by sex, and the following assumptions: (1) the variances of male and female liability are equal; (2) the variances of liability in male and female sibs of probands take the same value; and (3) the difference between the mean liabilities of males and females in the general population is equal to the difference between the mean liabilities of male and female sibs of cases. With a pair of diagrams, one for the male and female distributions in the general population and one for the relatives of probands, he demonstrated that the proportion of males above the threshold is less markedly different from the proportion of females in the case of relatives. The conditions with unusual sex ratio that were studied included ankylosing spondylitis, infantile pyloric stenosis (179010), otosclerosis (166800), congenital dislocation of the hip (142700), and systemic lupus erythematosus (152700). Population Genetics The overall prevalence of ankylosing spondylitis is between 0.1% and 1.4%, with most of these data coming from Europe. In mid-Europe, the prevalence is about 0.3 to 0.5% for ankylosing spondylitis and 1 to 2% for the whole group of spondyloarthritides. The incidence of ankylosing spondylitis is between 0.5 and 14 per 100,000 people per year in studies from different countries (Braun and Sieper, 2007). Animal Model Mahowald et al. (1988) analyzed the features of murine progressive ankylosis, an autosomal recessive mutation first described by Sweet and Green (1981). Peripheral joints were inflamed initially, then became ankylosed in a predictable sequence from distal to proximal. Axial joint involvement produced severe spinal ankylosis. Vertebral syndesmophytes produced a 'bamboo' spine. Mahowald et al. (1988) suggested that this is a useful animal model for study of the human spondyloarthropathies. INHERITANCE \- Multifactorial HEAD & NECK Eyes \- Anterior uveitis CARDIOVASCULAR Heart \- Aortic insufficiency \- Aortitis \- Cardiac conduction abnormalities ABDOMEN Gastrointestinal \- Inflammatory bowel disease (Crohn disease and ulcerative colitis) SKELETAL Spine \- Accentuated kyphosis \- Back stiffness \- Nocturnal back pain \- Ankylosing spondylitis \- Sacroiliitis \- 'Bamboo' spine Pelvis \- Arthritis (hip) Limbs \- Peripheral arthritis (oligoarticular or polyarticular) \- Peripheral enthesitis SKIN, NAILS, & HAIR Skin \- Psoriasis LABORATORY ABNORMALITIES \- HLA-B27 haplotype association (95% patients) \- Rheumatoid factor negative MISCELLANEOUS \- Overall prevalence is between 0.5 and 14 per 100,000 people per year \- Genetic heterogeneity (see spondyloarthropathy, susceptibility to, 2 183840 ) \- Spondyloarthropathy includes a spectrum of related disorders, including, 1 - ankylosing spondylitis (AS), 2 - a subset of psoriatic arthritis (PsA), 3 - reactive arthritis (ReA), 4 - arthritis associated with inflammatory bowel disease (AIBD), 5 - undifferentiated spondyloarthropathy (USpA) MOLECULAR BASIS \- Susceptibility conferred by mutation in the major histocompatibility complex, class I, B gene (HLA-B, 142830.0001 ) ▲ 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	SPONDYLOARTHROPATHY, SUSCEPTIBILITY TO, 1	c1862852	6,379	omim	https://www.omim.org/entry/106300	2019-09-22T16:45:00	{"omim": ["106300"], "synonyms": ["Alternative titles", "ANKYLOSING SPONDYLITIS, SUSCEPTIBILITY TO", "MARIE-STRUMPELL SPONDYLITIS", "BECHTEREW SYNDROME"]}
Spinocerebellar ataxia type 8 (SCA8) is an inherited neurodegenerative condition characterized by slowly progressive ataxia (problems with movement, balance, and coordination). This condition typically occurs in adulthood and usually progresses over decades. Common initial symptoms include dysarthria, slow speech, and trouble walking. Some affected individuals experience nystagmus and other abnormal eye movements. Life span is typically not shortened. This condition is inherited in an autosomal dominant manner, although not all individuals with abnormalities in the disease-causing gene will develop the disease (called reduced penetrance). [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 8	c1837454	6,380	gard	https://rarediseases.info.nih.gov/diseases/4956/spinocerebellar-ataxia-8	2021-01-18T17:57:35	{"mesh": ["C537307"], "omim": ["608768", "603680"], "umls": ["C1837454"], "orphanet": ["98760"], "synonyms": ["SCA8", "Spinocerebellar ataxia type 8"]}
Hereditary sensory and autonomic neuropathy type 1E (HSAN1E) is a progressive disorder of the central and peripheral nervous systems. Symptoms typically begin by age 20 to 35 and include sensory impairment of the lower legs and feet; loss of sweating in the hands and feet; sensorineural hearing loss; and gradual decline of mental ability (dementia). The severity of symptoms and age of onset vary, even within the same family. HSAN1E is caused by a mutation in the DNMT1 gene and is inherited in an autosomal dominant manner. There is no effective treatment, but management may include injury prevention, the use of hearing aids, and sedative or antipsychotic medications for symptoms of dementia. [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	Hereditary sensory and autonomic neuropathy type 1E	c3279885	6,381	gard	https://rarediseases.info.nih.gov/diseases/11927/hereditary-sensory-and-autonomic-neuropathy-type-1e	2021-01-18T18:00:02	{"mesh": ["C580162"], "omim": ["614116"], "orphanet": ["456318"], "synonyms": ["Hereditary sensory neuropathy with hearing loss and dementia", "HSNIE", "Hereditary sensory neuropathy-deafness-dementia syndrome", "Hereditary sensory neuropathy type IE", "Hereditary sensory neuropathy-sensorineural hearing loss-dementia syndrome", "HSN1E", "DNMT1-Related Dementia, Deafness, and Sensory Neuropathy", "HSAN1E"]}
Fatal infantile lactic acidosis with methylmalonic aciduria is a rare neurometabolic disease characterized by infantile onset of severe encephalomyopathy, lactic acidosis and elevated methylmalonic acid urinary excretion. Clinically it manifests with severe psychomotor delay, hypotonia, failure to thrive, feeding difficulties and dystonia. Epilepsy and multiple congenital anomalies may be associated. [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	Fatal infantile lactic acidosis with methylmalonic aciduria	c3151476	6,382	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=17	2021-01-23T18:36:20	{"omim": ["245400"], "icd-10": ["E71.1"]}
A number sign (#) is used with this entry because of evidence that muscle glycogen storage disease-0 (GSD0B) is caused by homozygous mutation in the GYS1 gene (138570), which encodes muscle glycogen synthase, on chromosome 19q13. Clinical Features Among the offspring of consanguineous parents of Syrian origin, Kollberg et al. (2007) described cardiomyopathy and exercise intolerance associated with complete absence of muscle glycogen. The oldest brother developed normally until the age of 4 years, when he had an episode of tonic-clonic seizures. At the age of 10.5 years, while playing outside his school, he suddenly collapsed as the result of cardiac arrest. At autopsy, the heart weighed 200 g (normal range, 139 to 178). The left ventricular wall was thickened. The cause of death was listed as hypertrophic cardiomyopathy. Two years later, an 11-year-old brother was investigated. After the age of 6 years, he had been unable to keep up with the physical activity of his peers and had muscle symptoms similar to those of patient 1. He likewise had signs of hypertrophic cardiomyopathy and an abnormal heart rate and blood pressure while exercising. Low normal IQ was reported. A 2-year-old sister had no clinical symptoms and had normal psychomotor development, however, cardiac exam indicated cardiac involvement ('subtly impaired systolic function at rest'). In muscle biopsy specimens obtained from the 2 younger sibs there was lack of glycogen, predominance of oxidative fibers, and mitochondrial proliferation. Glucose tolerance was normal. Cameron et al. (2009) reported an 8-year-old boy, born to consanguineous parents of South Indian ancestry, who died suddenly while exercising with classmates at school. He had been healthy and had no history of exercise intolerance. At autopsy, the heart appeared structurally normal, with appropriate size, weight, and ventricular wall thickness; however, skeletal muscle showed evidence suggestive of an underlying mitochondrial abnormality, with proliferation of mitochondria, pre-ragged-red fibers, and type 1 fiber predominance. Cytochrome oxidase activity was preserved, but mitochondrial ultrastructure appeared to be abnormal, and glycogen stores were depleted. Some cardiac mitochondria appeared to have an abnormal ultrastructure similar to that seen in skeletal muscle. Family history revealed a sister who had died at 6 days of life of undetermined cause. Molecular Genetics In 3 sibs with muscle and heart glycogen deficiency, Kollberg et al. (2007) found a premature termination mutation in the muscle glycogen synthase gene (R462X; 138570.0001). Several findings in the patients reported by Kollberg et al. (2007) were in accord with the findings in muscle glycogen synthase knockout mice: increased cardiac mass, absence of muscle glycogen, predominance of oxidative muscle fibers, and normal-to-improved glucose clearance (Pederson et al. (2004, 2005, 2005)) The first patient had epilepsy; whether this was coincidental to the glycogen storage disease was not clear. Glycogen is stored in the normal brain, and one hypothesis is that the primary function of the cerebral glycogen pool is to help provide energy to support rapid glutamate neurotransmitter clearance by astrocytes (Shulman et al., 2001). In an 8-year-old boy who died suddenly after exercise and had abnormal mitochondrial ultrastructure and pre-ragged-red fibers seen on autopsy, Cameron et al. (2009) performed extensive metabolic mitochondrial testing but found no mitochondrial DNA mutations. Due to similarities to the family previously studied by Kollberg et al. (2007), including type 1 fiber predominance, lack of glycogen staining, and increased numbers of mitochondria, Cameron et al. (2009) sequenced the GYS1 gene using DNA from patient fibroblasts and identified homozygosity for a 2-bp deletion (138570.0002). The unaffected parents and an unaffected sib were heterozygous for the mutation. Nomenclature Kollberg et al. (2007) suggested that the entity they described be termed muscle glycogen storage disease 0 in analogy with the disease caused by liver glycogen synthase deficiency (240600). INHERITANCE \- Autosomal recessive CARDIOVASCULAR Heart \- Left ventricular hypertrophy \- Left atrial enlargement \- Decrease in stroke volume on exercise testing \- Myocyte hypertrophy without disarray or fibrosis seen on biopsy \- Lack of glycogen in cardiomyocytes ABDOMEN Liver \- Glycogen present in normal amount on biopsy MUSCLE, SOFT TISSUES \- Muscle fatigability \- Low maximum workload on exercise testing \- Glycogen deficiency in muscle fibers \- Predominance of oxidative fibers \- Mitochondrial proliferation NEUROLOGIC Central Nervous System \- Seizures, tonic-clonic (rare) MISCELLANEOUS \- Risk of sudden death in childhood due to cardiac arrest MOLECULAR BASIS \- Caused by mutation in glycogen synthase 1 gene (GYS1, 138570.0001 ) ▲ 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 0, MUSCLE	c1969054	6,383	omim	https://www.omim.org/entry/611556	2019-09-22T16:03:07	{"mesh": ["C566917"], "omim": ["611556"], "orphanet": ["137625"], "synonyms": ["GSD type 0b", "Glycogenosis type 0b", "MUSCLE GLYCOGEN SYNTHASE DEFICIENCY", "Glycogenosis due to muscle and heart glycogen synthase deficiency", "Alternative titles", "GSD 0b", "Glycogen storage disease type 0b", "MUSCLE GLYCOGEN STORAGE DISEASE 0", "GSD due to muscle and heart glycogen synthase deficiency"]}
Congenital eye disorder Senior–Løken syndrome Other namesRenal dysplasia-retinal aplasia syndrome Senior–Løken syndrome is an autosomal recessive inherited condition SpecialtyMedical genetics Senior–Løken syndrome is a congenital eye disorder, first characterized in 1961.[1][2][3] It is a rare, ciliopathic, autosomal recessive disorder characterized by juvenile nephronophthis and progressive eye disease.[4] ## Contents * 1 Genetics * 2 Pathophysiology * 2.1 Relation to other rare genetic disorders * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Genetics[edit] Genes involved include: Type OMIM Genes SLSN1 266900 NPHP1 SLSN3 606995 unknown SLSN4 606996 NPHP4 SLSN5 609254 NPHP5/IQCB1[5] SLSN6 610189 NPHP6/CEP290 SLSN7 613615 SDCCAG8 ## Pathophysiology[edit] The cause of Senior–Løken syndrome type 5 has been identified to mutation in the NPHP1 gene which adversely affects the protein formation mechanism of the cilia.[6] ### Relation to other rare genetic disorders[edit] Recent findings in genetic research have suggested that a large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical root cause of the widely varying, phenotypically-observed disorders. Such diseases are becoming known as ciliopathies. Known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome and some forms of retinal degeneration.[4] ## Diagnosis[edit] This section is empty. You can help by adding to it. (August 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (August 2017) ## References[edit] 1. ^ synd/1861 at Who Named It? 2. ^ Senior B, Friedmann AI, Brando JL (1961). "Juvenile familial nephropathy with tapetoretinal degeneration. A new oculorenal dystrophy". Am. J. Ophthalmol. 52: 625–33. doi:10.1016/0002-9394(61)90147-7. PMID 13910672. 3. ^ Loken AC, Hanssen O, Halvorsen S, Jolster NJ (1961). "Hereditary renal dysplasia and blindness". Acta Paediatrica. 50 (2): 177–84. doi:10.1111/j.1651-2227.1961.tb08037.x. PMID 13763238. S2CID 221396498. 4. ^ a b Badano, Jose L.; Norimasa Mitsuma; Phil L. Beales; Nicholas Katsanis (2006). "The Ciliopathies: An Emerging Class of Human Genetic Disorders". Annual Review of Genomics and Human Genetics. 7 (1): 125–148. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803.. 5. ^ Otto EA, Loeys B, Khanna H, et al. (March 2005). "Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin". Nat. Genet. 37 (3): 282–8. doi:10.1038/ng1520. PMID 15723066. S2CID 4972004. 6. ^ Davenport, James R.; Bradley K. Yoder (2005). "An incredible decade for the primary cilium : a look at a once-forgotten organelle". American Journal of Physiology. Renal Physiology. American Physiological Society. 289 (6): F1159–F1169. doi:10.1152/ajprenal.00118.2005. PMID 16275743.. ## External links[edit] * OMIM: 266900 Senior-Løken syndrome; Renal dysplasia retinal aplasia; Juvenile nephronophthisis with Leber amaurosis at NIH's Office of Rare Diseases * OMIM: 606996 Senior-Løken syndrome 4 at NIH's Office of Rare Diseases * NCBI Genetic Testing Registry Classification D * ICD-10: Q61.5 * OMIM: 266900 606996 609254 * MeSH: C537580 * DiseasesDB: 29875 External resources * Orphanet: 3156 * v * t * e Diseases of cilia Structural * receptor: Polycystic kidney disease * cargo: Asphyxiating thoracic dysplasia * basal body: Bardet–Biedl syndrome * mitotic spindle: Meckel syndrome * centrosome: Joubert syndrome Signaling * Nephronophthisis Other/ungrouped * Alström syndrome * Primary ciliary dyskinesia * Senior–Løken syndrome * Orofaciodigital syndrome 1 * McKusick–Kaufman syndrome * Autosomal recessive polycystic kidney See also: ciliary proteins This genetic disorder 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	Senior–Løken syndrome	c0403553	6,384	wikipedia	https://en.wikipedia.org/wiki/Senior%E2%80%93L%C3%B8ken_syndrome	2021-01-18T18:37:38	{"gard": ["322"], "mesh": ["C537580"], "umls": ["C0403553"], "orphanet": ["3156"], "wikidata": ["Q4354267"]}
A rare, genetic, movement disorder characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side of the body, which are present in various first-degree members of a family, persist beyond the first decade of life, and have no associated comorbidities. [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 congenital mirror movements	c1834870	6,385	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=238722	2021-01-23T18:59:25	{"gard": ["12551"], "omim": ["157600", "614508", "616059", "618264"], "synonyms": ["Familial congenital controlateral synkinesia", "Hereditary congenital controlateral synkinesia", "Hereditary congenital mirror movements", "Isolated congenital controlateral synkinesia", "Isolated congenital mirror movements"]}
Combined oxidative phosphorylation deficiency type 3 is an extremely rare clinically heterogenous disorder described in about 5 patients to date. Clinical signs included hypotonia, lactic acidosis, and hepatic insufficiency, with progressive encephalomyopathy or hypertrophic cardiomyopathy. [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	Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3	c1864840	6,386	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=168566	2021-01-23T18:36:21	{"mesh": ["C566467"], "omim": ["610505"], "umls": ["C1864840"], "icd-10": ["E88.8"], "synonyms": ["Fatal mitochondrial disease due to COXPD3"]}
For the psychological condition, see The seven-year itch. Human disease Scabies Other namesSeven-year itch[1] Magnified view of a burrowing trail of the scabies mite. The scaly patch on the left was caused by scratching and marks the mite's entry point into the skin. The mite has burrowed to the top-right, where it can be seen as a dark spot at the end. SpecialtyInfectious disease, dermatology Symptomsitchiness, pimple-like rash[2] Usual onset2–6 weeks (first infection), ~1 day (subsequent infections)[2] CausesSarcoptes scabiei mite spread by close contact[3] Risk factorsCrowded living conditions (child care facilities, group homes, prisons), lack of access to water[3][4] Diagnostic methodBased on symptoms[5] Differential diagnosisSeborrheic dermatitis, dermatitis herpetiformis, pediculosis, atopic dermatitis[6] MedicationPermethrin, crotamiton, lindane, ivermectin[7] Frequency204 million / 2.8% (2015)[8] Scabies (also known as the seven-year itch[1]) is a contagious skin infestation by the mite Sarcoptes scabiei.[1][3] The most common symptoms are severe itchiness and a pimple-like rash.[2] Occasionally, tiny burrows may appear on the skin.[2] In a first-ever infection, the infected person will usually develop symptoms within two to six weeks.[2] During a second infection, symptoms may begin within 24 hours.[2] These symptoms can be present across most of the body or just certain areas such as the wrists, between fingers, or along the waistline.[2] The head may be affected, but this is typically only in young children.[2] The itch is often worse at night.[2] Scratching may cause skin breakdown and an additional bacterial infection in the skin.[2] Scabies is caused by infection with the female mite Sarcoptes scabiei var. hominis, an ectoparasite.[3] The mites burrow into the skin to live and deposit eggs.[3] The symptoms of scabies are due to an allergic reaction to the mites.[2] Often, only between 10 and 15 mites are involved in an infection.[2] Scabies is most often spread during a relatively long period of direct skin contact with an infected person (at least 10 minutes) such as that which may occur during sex or living together.[3][9] Spread of the disease may occur even if the person has not developed symptoms yet.[10] Crowded living conditions, such as those found in child-care facilities, group homes, and prisons, increase the risk of spread.[3] Areas with a lack of access to water also have higher rates of disease.[4] Crusted scabies is a more severe form of the disease.[3] It typically only occurs in those with a poor immune system and people may have millions of mites, making them much more contagious.[3] In these cases, spread of infection may occur during brief contact or by contaminated objects.[3] The mite is very small and usually not directly visible.[3] Diagnosis is based on the signs and symptoms.[5] A number of medications are available to treat those infected, including permethrin, crotamiton, and lindane creams and ivermectin pills.[7] Sexual contacts within the last month and people who live in the same house should also be treated at the same time.[10] Bedding and clothing used in the last three days should be washed in hot water and dried in a hot dryer.[10] As the mite does not live for more than three days away from human skin, more washing is not needed.[10] Symptoms may continue for two to four weeks following treatment.[10] If after this time symptoms continue, retreatment may be needed.[10] Scabies is one of the three most common skin disorders in children, along with ringworm and bacterial skin infections.[11] As of 2015, it affects about 204 million people (2.8% of the world population).[8] It is equally common in both sexes.[12] The young and the old are more commonly affected.[5] It also occurs more commonly in the developing world and tropical climates.[5] The word scabies is from Latin: scabere, "to scratch".[13] Other animals do not spread human scabies.[3] Infection in other animals is typically caused by slightly different but related mites and is known as sarcoptic mange.[14] ## Contents * 1 Signs and symptoms * 1.1 Itching * 1.2 Rash * 1.3 Crusted scabies * 2 Cause * 2.1 Scabies mite * 2.2 Transmission * 3 Pathophysiology * 4 Diagnosis * 4.1 Differential diagnosis * 5 Prevention * 6 Management * 6.1 Permethrin * 6.2 Ivermectin * 6.3 Others * 6.4 Communities * 7 Epidemiology * 8 History * 9 Society and culture * 10 Scabies in animals * 11 Research * 12 References * 13 External links ## Signs and symptoms[edit] Commonly involved sites of rashes of scabies[15] The characteristic symptoms of a scabies infection include intense itching and superficial burrows.[16] Because the host develops the symptoms as a reaction to the mites' presence over time, typically a delay of four to six weeks occurs between the onset of infestation and the onset of itching. Similarly, symptoms often persist for one to several weeks after successful eradication of the mites. As noted, those re-exposed to scabies after successful treatment may exhibit symptoms of the new infestation in a much shorter period—as little as one to four days.[17] ### Itching[edit] In the classic scenario, the itch is made worse by warmth, and is usually experienced as being worse at night, possibly because distractions are fewer.[16] As a symptom, it is less common in the elderly.[16] ### Rash[edit] The superficial burrows of scabies usually occur in the area of the finger webs, feet, ventral wrists, elbows, back, buttocks, and external genitals.[16] Except in infants and the immunosuppressed, infection generally does not occur in the skin of the face or scalp. The burrows are created by excavation of the adult mite in the epidermis.[16] Acropustulosis, or blisters and pustules on the palms and soles of the feet, are characteristic symptoms of scabies in infants.[18] * Scabies of the foot * Scabies of the arm * Scabies of the hand * Scabies of the finger In most people, the trails of the burrowing mites are linear or S-shaped tracks in the skin often accompanied by rows of small, pimple-like mosquito or insect bites. These signs are often found in crevices of the body, such as on the webs of fingers and toes, around the genital area, in stomach folds of the skin, and under the breasts of women.[18] Symptoms typically appear two to six weeks after infestation for individuals never before exposed to scabies. For those having been previously exposed, the symptoms can appear within several days after infestation. However, symptoms may appear after several months or years.[19] ### Crusted scabies[edit] Crusted scabies in a person with AIDS The elderly, disabled, and people with an impaired immune system, such as those with HIV, cancer, or those on immunosuppressive medications, are susceptible to crusted scabies (also called Norwegian scabies).[16][19][20] On those with weaker immune systems, the host becomes a more fertile breeding ground for the mites, which spread over the host's body, except the face. The mites in crusted scabies are not more virulent than in noncrusted scabies; however, they are much more numerous (up to two million). People with crusted scabies exhibit scaly rashes, slight itching, and thick crusts of skin that contain large numbers of scabies mites. For this reason, persons with crusted scabies are more contagious to others than those with typical scabies.[3][21] Such areas make eradication of mites particularly difficult, as the crusts protect the mites from topical miticides/scabicides, necessitating prolonged treatment of these areas.[citation needed] ## Cause[edit] ### Scabies mite[edit] Main article: Sarcoptes scabiei Play media Video of the Sarcoptes scabiei mite Life cycle of scabies[15] In the 18th century, Italian biologists Giovanni Cosimo Bonomo and Diacinto Cestoni (1637–1718) described the mite now called Sarcoptes scabiei, variety hominis, as the cause of scabies. Sarcoptes is a genus of skin parasites and part of the larger family of mites collectively known as scab mites. These organisms have eight legs as adults, and are placed in the same phylogenetic class (Arachnida) as spiders and ticks.[citation needed] S. scabiei mites are under 0.5 mm in size, but are sometimes visible as pinpoints of white. Gravid females tunnel into the dead, outermost layer (stratum corneum) of a host's skin and deposit eggs in the shallow burrows. The eggs hatch into larvae in three to ten days. These young mites move about on the skin and molt into a "nymphal" stage, before maturing as adults, which live three to four weeks in the host's skin. Males roam on top of the skin, occasionally burrowing into the skin. In general, the total number of adult mites infesting a healthy hygienic person with noncrusted scabies is small, about 11 females in burrows, on average.[22] The movement of mites within and on the skin produces an intense itch, which has the characteristics of a delayed cell-mediated inflammatory response to allergens. IgE antibodies are present in the serum and the site of infection, which react to multiple protein allergens in the body of the mite. Some of these cross-react to allergens from house dust mites. Immediate antibody-mediated allergic reactions (wheals) have been elicited in infected persons, but not in healthy persons; immediate hypersensitivity of this type is thought to explain the observed far more rapid allergic skin response to reinfection seen in persons having been previously infected (especially having been infected within the previous year or two).[23] ### Transmission[edit] Scabies is contagious and can be contracted through prolonged physical contact with an infested person.[24] This includes sexual intercourse, although a majority of cases are acquired through other forms of skin-to-skin contact. Less commonly, scabies infestation can happen through the sharing of clothes, towels, and bedding, but this is not a major mode of transmission; individual mites can survive for only two to three days, at most, away from human skin at room temperature.[25][26] As with lice, a latex condom is ineffective against scabies transmission during intercourse, because mites typically migrate from one individual to the next at sites other than the sex organs.[27] Healthcare workers are at risk of contracting scabies from patients, because they may be in extended contact with them.[28] ## Pathophysiology[edit] The symptoms are caused by an allergic reaction of the host's body to mite proteins, though exactly which proteins remains a topic of study. The mite proteins are also present from the gut, in mite feces, which are deposited under the skin. The allergic reaction is both of the delayed (cell-mediated) and immediate (antibody-mediated) type, and involves IgE (antibodies are presumed to mediate the very rapid symptoms on reinfection).[22] The allergy-type symptoms (itching) continue for some days, and even several weeks, after all mites are killed. New lesions may appear for a few days after mites are eradicated. Nodular lesions from scabies may continue to be symptomatic for weeks after the mites have been killed.[22] Rates of scabies are negatively related to temperature and positively related to humidity.[29] ## Diagnosis[edit] A photomicrograph of an itch mite (S. scabiei) Scabies may be diagnosed clinically in geographical areas where it is common when diffuse itching presents along with either lesions in two typical spots or itchiness is present in another household member.[11] The classical sign of scabies is the burrow made by a mite within the skin.[11] To detect the burrow, the suspected area is rubbed with ink from a fountain pen or a topical tetracycline solution, which glows under a special light. The skin is then wiped with an alcohol pad. If the person is infected with scabies, the characteristic zigzag or S pattern of the burrow will appear across the skin; however, interpreting this test may be difficult, as the burrows are scarce and may be obscured by scratch marks.[11] A definitive diagnosis is made by finding either the scabies mites or their eggs and fecal pellets.[11] Searches for these signs involve either scraping a suspected area, mounting the sample in potassium hydroxide and examining it under a microscope, or using dermoscopy to examine the skin directly.[16] ### Differential diagnosis[edit] Symptoms of early scabies infestation mirror other skin diseases, including dermatitis, syphilis, erythema multiforme, various urticaria-related syndromes, allergic reactions, ringworm-related diseases, and other ectoparasites such as lice and fleas.[30] ## Prevention[edit] Mass-treatment programs that use topical permethrin or oral ivermectin have been effective in reducing the prevalence of scabies in a number of populations.[11] No vaccine is available for scabies. The simultaneous treatment of all close contacts is recommended, even if they show no symptoms of infection (asymptomatic), to reduce rates of recurrence.[11] Since mites can survive for only two to three days without a host, other objects in the environment pose little risk of transmission except in the case of crusted scabies. Therefore cleaning is of little importance.[11] Rooms used by those with crusted scabies require thorough cleaning.[31] ## Management[edit] A number of medications are effective in treating scabies. Treatment should involve the entire household, and any others who have had recent, prolonged contact with the infested individual.[11] Options to control itchiness include antihistamines and prescription anti-inflammatory agents.[32] Bedding, clothing and towels used during the previous three days should be washed in hot water and dried in a hot dryer.[33] ### Permethrin[edit] Permethrin, a pyrethroid insecticide, is the most effective treatment for scabies,[34] and remains the treatment of choice.[11][35] It is applied from the neck down, usually before sleep, and left on for about eight to 14 hours, then washed off in the morning.[11] Care should be taken to coat the entire skin surface, not just symptomatic areas; any patch of skin left untreated can provide a "safe haven" for one or more mites to survive. One application is normally sufficient, as permethrin kills eggs and hatchlings, as well as adult mites, though many physicians recommend a second application three to seven days later as a precaution. Crusted scabies may require multiple applications, or supplemental treatment with oral ivermectin (below).[11][35][36] Permethrin may cause slight irritation of the skin that is usually tolerable.[16] ### Ivermectin[edit] Oral ivermectin is effective in eradicating scabies, often in a single dose.[4][11] It is the treatment of choice for crusted scabies, and is sometimes prescribed in combination with a topical agent.[11][16] It has not been tested on infants, and is not recommended for children under six years of age.[16] Topical ivermectin preparations have been shown to be effective for scabies in adults, though only one such formulation is available in the United States at present, and it is not FDA-approved as a scabies treatment.[37] It has also been useful for sarcoptic mange (the veterinary analog of human scabies).[38][39] ### Others[edit] Other treatments include lindane, benzyl benzoate, crotamiton, malathion, and sulfur preparations.[11][16] Lindane is effective, but concerns over potential neurotoxicity have limited its availability in many countries.[16] It is banned in California,[40] but may be used in other states as a second-line treatment.[41] Sulfur ointments or benzyl benzoate are often used in the developing world due to their low cost;[16] Some 10% sulfur solutions have been shown to be effective,[42] and sulfur ointments are typically used for at least a week, though many people find the odor of sulfur products unpleasant.[16] Crotamiton has been found to be less effective than permethrin in limited studies.[16] Crotamiton or sulfur preparations are sometimes recommended instead of permethrin for children, due to concerns over dermal absorption of permethrin.[11] * Day 4 * Day 8 (treatment begins) * Day 12 (under treatment) * Healed ### Communities[edit] Scabies is endemic in many developing countries,[43] where it tends to be particularly problematic in rural and remote areas. In such settings, community-wide control strategies are required to reduce the rate of disease, as treatment of only individuals is ineffective due to the high rate of reinfection. Large-scale mass drug administration strategies may be required where coordinated interventions aim to treat whole communities in one concerted effort.[44] Although such strategies have shown to be able to reduce the burden of scabies in these kinds of communities, debate remains about the best strategy to adopt, including the choice of drug.[44][45] The resources required to implement such large-scale interventions in a cost-effective and sustainable way are significant. Furthermore, since endemic scabies is largely restricted to poor and remote areas, it is a public health issue that has not attracted much attention from policy makers and international donors.[44][45] ## Epidemiology[edit] Scabies is one of the three most common skin disorders in children, along with tinea and pyoderma.[11] As of 2010, it affects about 100 million people (1.5% of the population) and its frequency is not related to gender.[12] The mites are distributed around the world and equally infect all ages, races, and socioeconomic classes in different climates.[21] Scabies is more often seen in crowded areas with unhygienic living conditions.[46] Globally as of 2009, an estimated 300 million cases of scabies occur each year, although various parties claim the figure is either over- or underestimated.[19][47] About 1–10% of the global population is estimated to be infected with scabies, but in certain populations, the infection rate may be as high as 50–80%.[11] ## History[edit] Wax figurine of a man with Norwegian scabies Scabies has been observed in humans since ancient times. Archeological evidence from Egypt and the Middle East suggests scabies was present as early as 494 BC.[17][48] In the fourth century BC, Aristotle reported on "lice" that "escape from little pimples if they are pricked" – a description consistent with scabies.[49] Arab physician, Ibn Zuhr is believed to have been the first to discover the scabies mites.[50] The Roman encyclopedist and medical writer Aulus Cornelius Celsus (c. 25 BC – 50 AD) is credited with naming the disease "scabies" and describing its characteristic features.[49] The parasitic etiology of scabies was documented by the Italian physician Giovanni Cosimo Bonomo (1663–1696) in his 1687 letter, "Observations concerning the fleshworms of the human body".[49] Bonomo's description established scabies as one of the first human diseases with a well-understood cause.[17][48] In Europe in the late 19th through mid-20th centuries, a sulfur-bearing ointment called by the medical eponym of Wilkinson's ointment was widely used for topical treatment of scabies. The contents and origins of several versions of the ointment were detailed in correspondence published in the British Medical Journal in 1945.[51] ## Society and culture[edit] Public health worker Stefania Lanzia using a soft toy scabies mite to publicise the condition in a 2016 campaign The International Alliance for the Control of Scabies was started in 2012,[5][45][52] and brings together over 150 researchers, clinicians, and public-health experts from more than 15 different countries. It has managed to bring the global health implications of scabies to the attention of the World Health Organization.[45] Consequently, the WHO has included scabies on its official list of neglected tropical diseases and other neglected conditions.[53] ## Scabies in animals[edit] Main articles: Sarcoptic mange and Acariasis A street dog in Bali, Indonesia, suffering from sarcoptic mange. Scabies may occur in a number of domestic and wild animals; the mites that cause these infestations are of different subspecies from the one typically causing the human form.[16] These subspecies can infest animals that are not their usual hosts, but such infections do not last long.[16] Scabies-infected animals suffer severe itching and secondary skin infections. They often lose weight and become frail.[22] The most frequently diagnosed form of scabies in domestic animals is sarcoptic mange, caused by the subspecies Sarcoptes scabiei canis, most commonly in dogs and cats. Sarcoptic mange is transmissible to humans who come into prolonged contact with infested animals,[54] and is distinguished from human scabies by its distribution on skin surfaces covered by clothing. Scabies-infected domestic fowl suffer what is known as "scaly leg". Domestic animals that have gone feral and have no veterinary care are frequently afflicted with scabies and a host of other ailments.[55] Nondomestic animals have also been observed to suffer from scabies. Gorillas, for instance, are known to be susceptible to infection by contact with items used by humans.[56] ## Research[edit] Moxidectin is being evaluated as a treatment for scabies.[57] It is established in veterinary medicine to treat a range of parasites, including sarcoptic mange. Its advantage over ivermectin is its longer half life in humans and, thus, potential duration of action.[58] Tea tree oil appears to be effective in the laboratory setting.[59] ## References[edit] 1. ^ a b c Gates, Robert H. (2003). Infectious disease secrets (2nd ed.). Philadelphia: Elsevier, Hanley Belfus. p. 355. ISBN 978-1-56053-543-0. 2. ^ a b c d e f g h i j k l "Parasites – Scabies Disease". Center for Disease Control and Prevention. November 2, 2010. Archived from the original on 2 May 2015. Retrieved 18 May 2015. 3. ^ a b c d e f g h i j k l m "Epidemiology & Risk Factors". Centers for Disease Control and Prevention. November 2, 2010. Archived from the original on 29 April 2015. Retrieved 18 May 2015. 4. ^ a b c "WHO -Water-related Disease". World Health Organization. Archived from the original on 2010-10-22. Retrieved 2010-10-10. 5. ^ a b c d e "Scabies". World Health Organization. Archived from the original on 18 May 2015. Retrieved 18 May 2015. 6. ^ Ferri, Fred F. (2010). "Chapter S". Ferri's differential diagnosis : a practical guide to the differential diagnosis of symptoms, signs, and clinical disorders (2nd ed.). Philadelphia, PA: Elsevier/Mosby. ISBN 978-0323076999. 7. ^ a b "Parasites – Scabies Medications". Center for Disease Control and Prevention. November 2, 2010. Archived from the original on 30 April 2015. Retrieved 18 May 2015. 8. ^ a b GBD 2015 Disease and Injury Incidence and Prevalence, Collaborators. (8 October 2016). 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Orlando Sentinel archive Archived 2015-02-16 at the Wayback Machine. Retrieved February 16, 2015. 55. ^ "Bali Animal Welfare Association". Archived from the original on 2010-02-26. Retrieved 2009-07-28. 56. ^ "Uganda: Out of the Wild". Frontline. PBS. Archived from the original on 2013-11-05. Transcript \| A Death In Tehran \| FRONTLINE \| PBS (section on rare diseases in Uganda). Retrieved Nov 4, 2013. 57. ^ Mounsey, Kate E.; Bernigaud, Charlotte; Chosidow, Olivier; McCarthy, James S. (2016-03-17). "Prospects for Moxidectin as a New Oral Treatment for Human Scabies". PLOS Neglected Tropical Diseases. 10 (3): e0004389. doi:10.1371/journal.pntd.0004389. ISSN 1935-2727. PMC 4795782. PMID 26985995. 58. ^ Prichard, Roger; Ménez, Cécile; Lespine, Anne (2012-12-01). "Moxidectin and the avermectins: Consanguinity but not identity". International Journal for Parasitology. Drugs and Drug Resistance. 2: 134–53. doi:10.1016/j.ijpddr.2012.04.001. ISSN 2211-3207. PMC 3862425. PMID 24533275. 59. ^ Thomas, Jackson; Dettwiller, Pascale; Spelman, Tim; Carson, Christine F.; Davey, Rachel C.; Baby, Kavya E.; Cooper, Gabrielle M.; Kyle, Greg; Naunton, Mark (2016-02-03). "Therapeutic Potential of Tea Tree Oil for Scabies". The American Journal of Tropical Medicine and Hygiene. 94 (2): 258–266. doi:10.4269/ajtmh.14-0515. ISSN 0002-9637. PMC 4751955. PMID 26787146. ## External links[edit] Wikimedia Commons has media related to Scabies. * American Academy of Dermatology pamphlet on Scabies * Scabies FAQ from the National Pediculosis Association Classification D * ICD-10: B86 * ICD-9-CM: 133.0 * MeSH: D012532 * DiseasesDB: 11841 External resources * MedlinePlus: 000830 * eMedicine: derm/382 emerg/517 ped/2047 * Patient UK: Scabies * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma * 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 * t * e Sexually transmitted infections (STI) Bacterial * Chancroid (Haemophilus ducreyi) * Chlamydia, lymphogranuloma venereum (Chlamydia trachomatis) * Donovanosis (Klebsiella granulomatis) * Gonorrhea (Neisseria gonorrhoeae) * Mycoplasma hominis infection (Mycoplasma hominis) * Syphilis (Treponema pallidum) * Ureaplasma infection (Ureaplasma urealyticum) Protozoal * Trichomoniasis (Trichomonas vaginalis) Parasitic * Crab louse * Scabies Viral * AIDS (HIV-1/HIV-2) * Cancer * cervical * vulvar * penile * anal * Human papillomavirus (HPV) * Genital warts (condyloma) * Hepatitis B (Hepatitis B virus) * Herpes simplex * HSV-1 & HSV-2 * Molluscum contagiosum (MCV) General inflammation female Cervicitis Pelvic inflammatory disease (PID) male Epididymitis Prostatitis either Proctitis Urethritis/Non-gonococcal urethritis (NGU) [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	Scabies	c0024710	6,387	wikipedia	https://en.wikipedia.org/wiki/Scabies	2021-01-18T18:31:59	{"mesh": ["D012532"], "wikidata": ["Q167178"]}
## Summary ### Clinical characteristics. WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus (DM) and optic atrophy (OA) before age 16 years, and typically associated with other endocrine abnormalities, sensorineural hearing loss, and progressive neurologic abnormalities (cerebellar ataxia, peripheral neuropathy, dementia, psychiatric illness, and urinary tract atony). Although DM is mostly insulin-dependent, overall the course is milder (with lower prevalence of microvascular disease) than that seen in isolated DM. OA typically results in significantly reduced visual acuity in the first decade. Sensorineural hearing impairment ranges from congenital deafness to milder, sometimes progressive, hearing impairment. ### Diagnosis / testing. The diagnosis of WFS1-WSSD is established in a proband with suggestive findings and biallelic pathogenic variants in WFS1 by molecular genetic testing. ### Management. Treatment of manifestations: Recommendations (based on detailed clinical guidelines for Wolfram syndrome) include routine management by multidisciplinary specialists for the following: insulin-dependent DM; OA; hearing impairment; mobility and activities of daily living; dysarthria; dysphagia; endocrine disorders; developmental delay/intellectual disability; neurogenic bladder; and psychiatric/behavioral issues. Surveillance: Routine follow up evaluations to assess effectiveness of ongoing care and to identify new disease manifestations. ### Genetic counseling. WFS1-WSSD is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for a WFS1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the WFS1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. ## Diagnosis ### Suggestive Findings WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) should be suspected in individuals with the following clinical findings and family history. Clinical findings [Barrett et al 1995, Urano 2016]: * Diabetes mellitus (onset age <15 years) * Optic atrophy (onset age <15 years) * High-tone sensorineural hearing impairment (sometimes congenital and severe) * Cerebellar ataxia * Dementia / intellectual disability (Both may occur, but intellectual disability is rare.) * Psychiatric disease * Neurogenic bladder or bladder dyssynergia * Other endocrine findings: * Central diabetes insipidus * Delayed / absent puberty; hypogonadism in males * Non-autoimmune hypothyroidism * Growth retardation * Cardiomyopathy and structural congenital heart defects Family history consistent with autosomal recessive inheritance ### Establishing the Diagnosis The diagnosis of WFS1-WSSD is established in a proband with biallelic pathogenic variants in WFS1 identified by molecular genetic testing (see Table 1). Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of WFS1-WSSD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of WFS1-WSSD has not been considered are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 Single-gene testing. Sequence analysis of WFS1 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step typically is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, to date such variants have not been identified as a cause of WFS1-WSSD. A deafness multigene panel that includes WFS1 and other genes of interest (see Differential Diagnosis) 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. 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. #### Option 2 Comprehensive genomic testing does not require the clinician to determine which gene[s] are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis; however, to date such variants have not been identified as a cause of WFS1-WSS. 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 WFS1 Wolfram Syndrome Spectrum Disorder View in own window Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method WFS1Sequence analysis 3>95% 4 Gene-targeted deletion/duplication analysis 53 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\. Hardy et al [1999], Khanim et al [2001], Smith et al [2004], Chaussenot et al [2015] and data derived from subscription-based professional view Human Gene Mutation Database [Stenson et al 2017] 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\. Three intragenic deletions of one or more exons have been described [Smith et al 2004, Elli et al 2012, Chaussenot et al 2015]. ## Clinical Characteristics ### Clinical Description Typical autosomal recessive WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) features are childhood-onset diabetes mellitus, optic atrophy, hearing impairment/deafness, diabetes insipidus, neurologic abnormalities, and psychiatric abnormalities (see Table 2). Note: This GeneReview focuses on Wolfram syndrome spectrum disorder caused by biallelic WFS1 pathogenic variants. Wolfram syndrome-like disorder, caused by heterozygous WFS1 pathogenic variants and associated with a clinical spectrum overlapping that of autosomal recessive WFS1-WSSD, is addressed in Genetically Related Disorders. ### Table 2. Select Features of WFS1-WSSD View in own window FeatureCommonUncommon Diabetes mellitus● Optic atrophy● Sensorineural hearing impairment● Cerebellar ataxia● Autonomic dysfunction● Bulbar dysfunction● Respiratory● Development delay (young children)● Intellectual disability (older children & adults)● Psychiatric disease● Urinary tract problemsFunctional: Neurogenic bladder● Structural: Upper urinary tract dilation Bowel dysfunction● Seizures● Other endocrineCentral diabetes insipidus● Hypogonadism● Hypothyroidism● Growth retardation● A comprehensive review of WFS1 and its role in different clinical presentations is available [Tranebjærg 2008]. WFS1-WSSD is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus and optic atrophy before age 15 years, and typically associated with sensorineural hearing loss, progressive neurologic abnormalities, and other endocrine abnormalities. Almost every organ system may be affected; however, because only a minority of published cases have had extensive clinical workup, the natural history of these multiorgan findings in WFS1-WSSD is largely unknown. The natural history of Wolfram syndrome was described in 45 individuals in 29 families in the UK [Barrett et al 1995]. Hearing impairment was present in 64% by age 20 years. Sixty percent of all individuals studied (mean age 16 years, range 5-32 years) had one or more of the following: cerebellar ataxia, peripheral neuropathy, intellectual disability, dementia, psychiatric illness, and urinary tract atony. Life span was considerably shortened. In the families of British, Pakistani, and mixed Arab/African origin, WFS1 pathogenic variants were subsequently identified in 17 of 19 probands [Hardy et al 1999]. Diabetes mellitus (DM). Median age of onset of DM was before age ten years (age range <1-17 years). Almost all with DM were insulin dependent. DM may present with ketoacidosis; however, overall the course is milder than that seen in isolated DM, with lower prevalence of microvascular disease [Cano et al 2007a] and microvascular retinopathy. Optic atrophy (OA). OA occurs eventually in all known individuals with WSSD. OA is progressive: the median age of onset is before ten years; after a median of eight years visual acuity is reduced to about 6/60 in most individuals [Barrett et al 1995]. Note: Visual acuity of 6/60, signifying that the tested person sees at six meters what an average person sees at 60 meters, is the definition of "registered blind" in the UK and "legally blind" in the US. Other ophthalmologic findings reported in WSSD but not confirmed as part of the phenotype: * Cataract, described in eight individuals [Hansen et al 2005]. Cataract may be a frequent, but underdiagnosed, finding. See Genetically Related Disorders for a description of isolated autosomal dominant congenital cataract due to a pathogenic missense variant in WFS1. * Pigmentary retinopathy rather than optic atrophy in one person [Dhalla et al 2006] * Nystagmus Sensorineural hearing impairment, present in about 66% of individuals with WSSD, ranges from congenital deafness to a milder, sometimes progressive sensorineural hearing impairment. Median age of onset was 12.5 years [Barrett et al 1995]. Audiograms show a downsloping progressive pattern of hearing loss [Pennings et al 2004]. Among individuals with inactivating WFS1 variants, five females were significantly more hearing impaired than four males, giving rise to speculation that hormonal factors may modulate hearing loss [Pennings et al 2004]. A multicenter study confirmed the preferential involvement of high frequencies and the slowly progressive rate of hearing loss, but did not confirm any gender differences in degree of hearing loss [Plantinga et al 2008]. Deterioration in speech recognition score with increasing age is more pronounced than could be explained by age-related decline in hearing alone, suggesting that progressive central nervous system involvement may also account for difficulties with speech over time [Pennings et al 2004]. Note: Although experience is limited, abnormal vestibular function does not appear to be a prominent feature of WFS1-WSSD. Among six individuals with WFS1-WSSD who were evaluated, only one had vestibular areflexia [Pennings et al 2004]. Balance problems may be the result of neurologic movement abnormalities. Neurologic abnormalities were present in 62% of the individuals (mean age 30 years, range 5-44 years) studied by Barrett et al [1995] before molecular confirmation of the diagnosis was possible. However, very limited data are available regarding the frequency of the types of neurologic abnormalities. Current experience indicates the presence of neurologic findings by the fourth decade with an onset typically between the first and second decade. Neurologic findings are progressive and result from general brain atrophy with brain stem and cranial nerve involvement [Barrett et al 1995, Pakdemirli et al 2005, Domenech et al 2006]. Abnormal cerebral MRIs found in eight of 45 individuals typically showed generalized brain atrophy most prominently of the cerebellum, medulla, and pons; and reduced signal intensity of the optic nerves and the posterior part of hypothalamus [Barrett et al 1995]. The correlation between brain atrophy on MRI and clinical findings is not always strong [Ito et al 2007]. * Truncal or gait ataxia was found in 15 of 45 individuals studied [Barrett et al 1995]. * Episodes of apnea, a serious manifestation, occurred in five of 45 individuals studied [Barrett et al 1995]. * Dementia is seen as part of the wider neurodegeneration in older patients. Intellectual disability is not common. * A significantly increased risk of suicidal behavior and psychiatric illness requiring hospitalization has been observed [Swift et al 1998]. Other endocrine findings * Diabetes insipidus of central origin occurred in 72% with a median age of onset of 15.5 years. The range in age of onset is broad, possibly because of delays in establishing the correct diagnosis. * Hypogonadism is more prevalent in males than in females. It can be either hypogonadotropic (i.e., central) or hypergonadotropic (i.e., secondary to gonadal failure). The underlying pathology of either type is not understood. Females usually retain their ability to become pregnant; about six successful pregnancies are described in the literature. One female had absence of the uterus [Tranebjærg, personal observation]. * Hypothyroidism. Frequency is not known. * Growth retardation. Most adults have normal height, but growth retardation is not infrequent. The age of onset of puberty varies. Urinary tract. Dilated renal outflow tracts (hydroureter), urinary incontinence, and recurrent infections are common signs of neurogenic bladder. Fifty-five percent of 29 index patients had such signs with median age of onset of 22 years (age range: 10-44 years) [Barrett et al 1995]. Urodynamic examinations showed incomplete bladder emptying or complete bladder atony. Gastrointestinal dysmotility and celiac disease. Constipation, chronic diarrhea, and other bowel dysfunction is reported in 25% of individuals with WFS1-WSSD, sometimes the result of gluten intolerance, which is 20 times more frequent in those who have had diabetes mellitus for several years [Barera et al 2002, Skovbjerg et al 2005, Liu et al 2006] (see Celiac Disease). Cardiomyopathy. No data on frequency are available. Causes of death. Ten of the 45 individuals reported in the study of Barrett et al [1995] had died. The median age at death was 30 years. Reports suggest 65% mortality by age 35 years. It must be kept in mind, however, that a bias toward reporting the most severe cases of WSSD in the literature may skew these figures. The causes of death were hypoglycemic coma, status epilepticus, end-stage renal disease from recurrent urinary tract infection, and suicide. Three individuals died from central respiratory failure associated with brain stem atrophy. Neuropathology. Currently the only published reports are of clinically diagnosed individuals; neuropathology of molecularly confirmed cases has not yet been published. In two cases the findings included atrophy of the olfactory bulbs, optic nerves, pontine nuclei, inferior olive, and dentate nuclei of the cerebellum; loss of cochlear ganglion cells; and mild loss of neurons in the spinal cord [Genís et al 1997, Shannon et al 1999]. ### Genotype-Phenotype Correlations The clinical course of WFS1-WSSD is highly variable, even within a family, and is not predictable from the type or location of the pathogenic variant. Cano et al [2007a] found that two WFS1 alleles, both with inactivating pathogenic variants, predisposed to an earlier age of onset of both diabetes mellitus and optic atrophy. Moreover, the clinical expression of WSSD was more complete and occurred earlier in individuals with no missense variant. ### Nomenclature Wolfram syndrome has sometimes been referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). ### Prevalence More than 90 individuals from more than 60 families have been described worldwide [Khanim et al 2001, Tessa et al 2001, Domènech et al 2002, Colosimo et al 2003, Cryns et al 2003, Simsek et al 2003, van den Ouweland et al 2003, Smith et al 2004, Giuliano et al 2005, Hansen et al 2005, Cano et al 2007b]. A study from the UK estimated a prevalence of WSS of 1:550,000 children in the UK [Barrett et al 1995]. ## Differential Diagnosis Wolfram syndrome type 2 (WS2) (OMIM 604928) is an autosomal recessive disorder caused by biallelic pathogenic variants in CISD2. Like WFS1-WSSD, WS2 presents as a continuum of clinical features; however, the full clinical spectrum of WS2 abnormalities has not yet been fully established because so few affected individuals have been described. To date, the following clinical features have been reported in individuals with WS2: * Juvenile-onset diabetes mellitus, optic atrophy, high-frequency sensorineural hearing impairment, urinary tract dilatation, impaired renal function, hypogonadism, and severe gastrointestinal ulcer and bleeding in four Jordanian families described by El-Shanti et al [2000], al-Sheyyab et al [2001], and Amr et al [2007]; abnormal facial features were described in one family [Amr et al 2007]. * Diabetes insipidus, psychiatric abnormalities, and variable degrees of optic atrophy in individuals from Italy and Morocco [Mozzillo et al 2014, Rondinelli et al 2015, Rouzier et al 2017]. Peptic ulcers, mucocutaneous bleeding, and defective platelet aggregation were also described in a subset of these individuals. Note: A novel CISD2 pathogenic variant (c.215A>G; p.Asn72Ser) was identified in an affected individual who met all the diagnostic criteria for Wolfram syndrome spectrum but did not have WFS1 pathogenic variants [Rouzier et al 2017]. Hearing impairment. See Hereditary Hearing Loss and Deafness Overview. Neurodegenerative disorders with diabetes mellitus (DM). See Table 5. ### Table 5. Neurodegenerative Disorders with DM in the Differential Diagnosis of WFS1-WSSD View in own window Gene(s) / Genetic MechanismDisorderMOISelected Features of This Disorder Endocrine abnormalitiesEye findingsHearing lossNeurologic abnormalities ALMS1Alström syndromeARInsulin resistance / type 2 DM often presents in teen yrs / 2nd decade. Other endocrine abnormalities incl hypogonadotropic hypogonadism in boys, polycystic ovaries in girls, & hypothyroidism.Cone-rod dystrophy presents as progressive visual impairment, photophobia, & nystagmus starting between birth & age 15 mos; no light perception by age 20 yrs in many individualsProgressive SNHL begins in 1st decade in ~70% of individuals. Hearing loss may become moderate to severe (40-70 dB) by end of 1st-2nd decade.Detrusor-urethral dyssynergia in females in their late teens BBS1 BBS2 BBS4 BBS7 BBS9 BBS10 BBS12 MKKS MKS1 TTC8 1Bardet-Biedl syndromeARNon-insulin-dependent DM/type 2 usually evident in adolescence or adulthood; male hypogonadotropic hypogonadismCone-rod dystrophy; night blindness usually evident by age 7-8 yrs; mean age of legal blindness is 15.5 yrs.~50% of adults develop a subclinical SNHL that is only detectable by audiometrySignificant learning difficulties in majority of individuals; severe impairment on IQ testing in a minority DMPKMyotonic dystrophy type 1 (DM1)ADDM is common in mild DM1 & classic DM1Cataract in mild DM1 & classic DM1No data availableMild myotonia (sustained muscle contraction) in mild DM1; muscle weakness/wasting & myotonia in classic DM1 FXNFriedreich ataxiaAR30% have DMOptic nerve atrophy, often asymptomatic, occurs in ~25%. Progressive diminution of contrast acuity is typical w/disease progression.SNHL in 13% of individualsSlowly progressive ataxia w/mean onset age 10-15 yrs (usually <25 yrs); dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, & loss of position & vibration sense mtDNA deletionKearns-Sayre syndrome (See Mitochondrial DNA Deletion Syndromes.)MatDM, hypoparathyroidism, & growth hormone deficiencyPigmentary retinopathy & progressive external ophthalmoplegia w/onset age <20 yrsSNHL in some individualsCerebellar ataxia; impaired intellect (ID &/or dementia) SLC19A2Thiamine-responsive megaloblastic anemia syndromeARDM; non-type I in nature w/age of onset from infancy to adolescenceOA (when commented on in case reports) appears common.Progressive SNHL w/generally early onset; can be detected in toddlers. SNHL is irreversible & not prevented by thiamine treatmentSignificant neurologic deficit incl stroke & focal or generalized epilepsy reported in early childhood in 27% of individuals Ristow [2004], Barrett [2007] AD = autosomal dominant; AR = autosomal recessive; DM = diabetes mellitus; ID = intellectual disability; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA; OA = optic atrophy; SNHL = sensorineural hearing loss 1\. Listed genes represent the most commonly associated genes; at least 19 genes are associated with Bardet-Biedl syndrome (see Bardet-Biedl Syndrome). Optic atrophy associated with hearing impairment. See Table 6. ### Table 6. Disorders with Optic Atrophy Associated with Hearing Impairment in the Differential Diagnosis of WFS1-WSSD View in own window GeneDisorderMOISelected Features of the DIfferential Disorder Eye findingsHearing lossNeurologic abnormalities OPA1Optic atrophy type 1ADBilateral & symmetric optic nerve pallor assoc w/insidious ↓ in visual acuity usually age 4-6 yrs; visual field defects; color vision defects. Visual impairment is usually moderate (6/10-2/10), but ranges from mild or even insignificant to severe (legal blindness w/acuity <1/20)Auditory neuropathy → SNHL ranging from severe & congenital to subclinical 1~20% have assoc additional clinical features, especially neurologic signs. PRPS1Charcot-Marie-Tooth neuropathy X type 5XLOptic neuropathy in males; onset of visual impairment at age 7-20 yrsEarly-onset (prelingual) bilateral profound SNHL in malesPeripheral neuropathy in males w/onset age 5-12 yrs TIMM8A 2Deafness-dystonia-optic neuronopathy syndromeXLSlowly progressive ↓ visual acuity from OA beginning at ~20 yrs in malesPrelingual or postlingual SNHL in early childhood in males; females may have mild hearing impairment.Slowly progressive dystonia or ataxia in the teens; dementia beginning at age ~40 yrs; psychiatric symptoms (e.g., personality change, paranoia) may appear in childhood & progress. Females may have focal dystonia. AD = autosomal dominant; Mat = maternal; MOI = mode of inheritance; OA = optic atrophy; SNHL = sensorineural hearing loss; XL = X-linked 1\. Identified by specific audiologic testing only. 2\. The diagnosis of deafness-dystonia-optic neuronopathy syndrome is established in either a male proband who has a hemizygous TIMM8A pathogenic variant, or a female proband who has a heterozygous TIMM8A pathogenic variant or a contiguous gene deletion of Xp22.1 involving TIMM8A. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD), the evaluations summarized in Table 7 (if not performed as part of the evaluation that led to the diagnosis) are recommended. See also Wolfram Syndrome Clinical Management Guidelines, page 5 for recommended baseline investigations. ### Table 7. Recommended Evaluations Following Initial Diagnosis in Individuals with WFS1-WSSD View in own window System/ConcernEvaluationComment Diabetes mellitusFasting plasma glucose & HbA1cDiabetic ketoacidosis is rare; prolonged remission phase is common. Optic atrophyOphthalmologic evaluationAssess: * Extraocular movement, best corrected visual acuity, color vision testing, visual field testing, visual evoked potentials, OCT, fundus examination * Need for visual aids Sensorineural hearing impairmentAudiologic examinationIncluding: * ABRs to confirm pathology & provide baseline * Evoked otoacoustic emissions to identify type of hearing impairment * Speech discrimination tests Motor disabilityNeurologic examination incl brain MRI (if not performed previously) & cognitive assessmentUse standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS). 1 Evaluate for: * Peripheral neuropathy * Anosmia or hyposmia * Decreased ability to taste * Possible seizures * Hypersomnolence * Headaches Mental health assessment as warranted Refer to neuromuscular clinic (OT/PT / rehabilitation specialist)To assess: * Gross motor & fine motor skills * Mobility, activities of daily living, & need for adaptive devices * Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Autonomic dysfunctionObtain history of orthostatic hypotension, anhidrosis, hypohydrosis, constipation, gastroparesis, hypothermia, hyperpyrexia. Bulbar dysfunctionAssessment by speech & language pathologistAssess for speech disorder (dysarthria) & swallowing disorder (dysphagia). Respiratory functionPolysomnographyCentral apnea can occur secondary to brain stem dysfunction. Development (young children)Developmental assessmentTo incl motor, adaptive, cognitive, & speech/language evaluation & evaluation for early intervention / special education Cognitive impairment (older children & adults)To incl: motor & speech/language evaluation; general cognitive skills Psychiatric/BehavioralNeuropsychiatric evaluationIndividuals age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD Neurogenic bladderHistory of spastic bladder symptoms: urgency, frequency, difficulty voiding, urinary incontinence, recurrent infectionsReferral to urologist; consider urodynamic evaluation & imaging of urinary tract & kidneys for dilated ureters; assessment of renal function Bowel dysfunctionHistory of constipation, gastroparesis Other endocrineDiabetes insipidusAssess concentrating ability of urine.Morning paired urine & fasting plasma osmolarity & sodium concentration after nocturnal & morning euglycemia HypogonadismHistory of absent of delayed puberty &/or infertilityRefer to endocrinologist to assess for primary gonadal failure &/or hypogonadotropic hypogonadism. HypothyroidismThyroid function testsTo assess thyroid function Growth retardationPlot height, weight, & head circumference on standard growth charts.To identify growth failure &/or provide a baseline Genetic counselingBy genetics professionals 2To inform patients & families re nature, MOI, & implications of WFS1-WSSD in order to facilitate medical & personal decision making Family support / Resources * Contact w/a patient advocacy organization may provide additional benefit. * Assess need for social work involvement for caregiver support. * Need for help coordinating multidisciplinary care * Use of community resources & support/advocacy organizations (e.g., Parent to Parent) ABRs = auditory brain stem responses; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; MOI = mode of inheritance; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia 1\. Bürk & Sival [2018] 2\. Medical geneticist, certified genetic counselor, certified advanced genetic nurse ### Treatment of Manifestations See also Wolfram Syndrome Clinical Management Guidelines, pages 6-12 for management recommendations. ### Table 8. Treatment of Manifestations in Individuals with WFS1-WSSD View in own window Manifestation/ConcernTreatmentConsiderations / Other Diabetes mellitusRoutine practice for insulin-dependent DM Optic atrophyCorrection of refractive errorEvaluate for visual aids. Community vision services through early intervention or school district. Idebenone and docoshexaenoic acid are of no benefit. Sensorineural hearing impairmentTreatment of SNHL depends on the degree of hearing impairment. 1Hearing loss affects high frequencies first. MobilityFeet: appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores. Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) Activities of daily livingPhysical therapistTransfers (e.g., from bed to wheelchair, wheelchair to car); training on how to fall to minimize risk of injury Occupational therapistTo accomplish tasks incl mobility, washing, dressing, eating, cooking, & grooming; to assist w/household modifications to meet special needs DysphagiaDetermine the exact cause of swallowing malfunction; modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing. Attention to oral hygiene & dental care as dysphagia may lead to impaired clearance of organisms & pathogenic colonization DysarthriaSpeech and language pathologistHelp maintain vocal control, improve speech, breathing techniques, & communication in general. Brain stem dysfunctionTreatment of central apnea Development in young childrenSee Developmental Delay / Intellectual Disability Management Issues Cognitive decline / Intellectual disability Psychiatric / BehavioralPer standard treatment by psychiatric professional (psychiatrist, psychologist, neuropsychologist) as neededWatch for personality changes. Neurogenic bladderAnticholinergic drugs; clean intermittent self-catheterization or indwelling catheter; treatment of recurrent urinary tract infections Bowel dysfunctionDietary managementFrequent small meals, ↑ dietary fiber, ↑ water intake Other endocrineDiabetes insipidusPer standard treatment Hypogonadism Hypothyroidism Growth retardation Family/CommunityEnsure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.Consider involvement in adaptive sports or Special Olympics. DM = diabetes mellitus; SNHL = sensorineural hearing loss 1\. See Hereditary Hearing Loss and Deafness Overview for details about treatment options. #### Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided. All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider: * Individualized education plan (IEP) services: * An IEP provides specially designed instruction and related services to children who qualify. * IEP services will be reviewed annually to determine whether any changes are needed. * As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. * Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. * PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. * As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. * A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. * Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. * Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. #### Motor Dysfunction Gross motor dysfunction * Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). * Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing. Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, and in many cases can improve it. #### Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ### Surveillance See also Wolfram Syndrome Clinical Management Guidelines, pages 6-12 for surveillance recommendations. ### Table 9. Recommended Surveillance for Individuals with WFS1-WSSD View in own window System/ConcernEvaluationFrequency Diabetes mellitusSee footnote 1.See footnote 1. Complications of diabetes mellitusNephropathyAnnual screening starting at age 12 yrs RetinopathyIn those w/duration of diabetes >5 yrs: annual screening NeuropathyAnnual screening for numbness, pain, cramps, parathethesias DyslipidemiaSee footnote 1. HypertensionAt least annually Optic atrophyEye examination (visual acuity, color vision testing, slit lamp examination for cataracts, fundoscopy, visual fields); need for low vision aidsAnnually Sensorineural hearing impairmentAudiogram incl assessment of speech discriminationEvery 1-2 yrs NeurologicNeurologic examination incl assessment of cerebellar ataxia as well as memory, personality changesEvery 1-2 yrs Activities of daily living & mobilityPhysical medicine, OT/PT assessment of mobility, self-help skillsPer treating clinicians DysphagiaAssess swallowing.Per treating clinician DysarthriaSpeech & language pathologistPer treating speech-language pathologist Development in young childrenMonitor developmental progress & educational needs.Annually Cognitive decline / Intellectual disabilityPer treating clinicianAnnually Psychiatric/BehavioralAssess for signs of depression, suicidal behavior, changes in personal appearance, & social behaviorPer treating clinician Neurogenic bladderUrodynamic examination & assess bladder emptying. Routine urine cultures when there is bladder dysfunction or other urinary tract abnormalityAnnually Other endocrineDiabetes insipidusAssess concentrating ability of urine.Per treating clinician HypogonadismMonitor for signs of onset of pubertyPer treating clinician HypothyroidismMonitor linear growth in children using standard growth charts.Per treating clinician Growth retardationPer treating clinician Family/CommunityEnsure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. OT = occupational therapy; PT = physical therapy 1\. For details see Wolfram Syndrome Clinical Management Guidelines, pages 6-12. ### Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment for the earliest manifestations of WFS1-WSSD: diabetes mellitus, optic atrophy, and sensorineural hearing loss. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Pregnant women with insulin-dependent diabetes mellitus have a two- to eightfold higher risk than pregnant women without diabetes of having a child with a birth defect or a pattern of birth defects (diabetic embryopathy). These defects can involve the craniofacial, cardiovascular, gastrointestinal, urogenital, musculoskeletal, and central nervous systems. Optimizing glucose control before and during pregnancy can reduce but does not eliminate the risk for diabetic embryopathy. High-resolution fetal ultrasonography and fetal echocardiogram are recommended to screen for congenital anomalies during pregnancy. Consultation with a maternal fetal medicine specialist during pregnancy should also be considered. Because women with WFS1-WSSD may develop diabetes insipidus during pregnancy [Rugolo et al 2002], monitoring for diabetes insipidus during pregnancy is warranted. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Groups exploring novel potential treatment strategies for WFS1-WSSD include Abreu & Urano [2019] and Pallotta et al [2019]. 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. [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	WFS1 Wolfram Syndrome Spectrum Disorder	None	6,388	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK4144/	2021-01-18T20:49:51	{"synonyms": []}
Phosphofructokinase deficiency Other namesGlycogen storage disease type VII or Tarui's disease[1][2] A rendering of the human muscular form of phosphofructokinase. Mutations in the production of this enzyme are the cause of Tarui's disease.[3] The symmetry of the enzyme is a result of its tetrameric structure. SpecialtyEndocrinology Phosphofructokinase deficiency, is a rare muscular metabolic disorder, with an autosomal recessive inheritance pattern. It may affect humans as well as other mammals (especially dogs).[4] It was named after the Japanese physician, Seiichiro Tarui (1927– ) who first observed the condition in 1965.[5] ## Contents * 1 Presentation * 1.1 In humans * 1.1.1 Classic form * 1.1.2 Late-onset form * 1.1.3 Infantile form * 1.1.4 Hemolytic form * 1.2 In dogs * 2 Risk factors * 2.1 In humans * 2.2 In dogs * 3 Pathophysiology * 3.1 In humans * 3.2 In dogs * 4 Diagnosis and treatment * 4.1 In humans * 4.2 In dogs * 5 References * 6 External links ## Presentation[edit] ### In humans[edit] Human PFK deficiency is categorized into four types: classic, late-onset, infantile and hemolytic. These types are differentiated by age at which symptoms are observed and which symptoms present.[6] #### Classic form[edit] Classic phosphofructokinase deficiency is the most common type of this disorder. This type presents with exercise-induced muscle cramps and weakness (sometimes rhabdomyolysis), myoglobinuria, as well as with haemolytic anaemia causing dark urine a few hours later.[7] Hyperuricemia is common, due to the kidneys' inability to process uric acid following damage resulting from processing myoglobin. Nausea and vomiting following strenuous exercise is another common indicator of classic PFK deficiency. Many patients will also display high levels of bilirubin, which can lead to a jaundiced appearance. Symptoms for this type of PFK deficiency usually appear in early childhood. #### Late-onset form[edit] Late-onset PFK deficiency, as the name suggests, is a form of the disease that presents later in life. Common symptoms associated with late-onset phosphofructokinase deficiency are myopathy, weakness and fatigue. Many of the more severe symptoms found in the classic type of this disease are absent in the late-onset form. #### Infantile form[edit] Phosphofructokinase deficiency also presents in a rare infantile form. Infants with this deficiency often display floppy infant syndrome (hypotonia), arthrogryposis, encephalopathy and cardiomyopathy. The disorder can also manifest itself in the central nervous system, usually in the form of seizures. PFK deficient infants also often have some type of respiratory issue. Survival rate for the infantile form of PFK deficiency is low, and the cause of death is often due to respiratory failure. #### Hemolytic form[edit] The defining characteristic of this form of the disorder is hemolytic anemia, in which red blood cells break down prematurely. Muscle weakness and pain are not as common in patients with hemolytic PFK deficiency. ### In dogs[edit] Presentation of the canine form of the disease is similar to that of the human form. Most notably, PFK deficient dogs suffer from mild, but persistent, anemia with hemolytic episodes, exercise intolerance, hemoglobinuria, and pale or jaundiced mucous membranes.[8] Muscle weakness and cramping are not uncommon symptoms, but they are not as common as they are in human PFKM deficiency. ## Risk factors[edit] ### In humans[edit] In order to get Tarui's disease, both parents must be carriers of the genetic defect so that the child is born with the full form of the recessive trait. The best indicator of risk is a family member with PFK deficiency.[9] ### In dogs[edit] Canine phosphofructokinase deficiency is found mostly in English Springer Spaniels and American Cocker Spaniels, but has also been reported in Whippets and Wachtelhunds.[10][11] Mixed-breed dogs descended from any of these breeds are also at risk to inherit PFK deficiency. ## Pathophysiology[edit] Phosphofructokinase is a tetrameric enzyme that consists of three types of subunits: PFKL (liver), PFKM (muscle), and PFKP (platelet). The combination of these subunits varies depending on the tissue in question.[12] In this condition, a deficiency of the M subunit (PFKM) of the phosphofructokinase enzyme impairs the ability of cells such as erythrocytes and rhabdomyocytes (skeletal muscle cells) to use carbohydrates (such as glucose) for energy. Unlike most other glycogen storage diseases, it directly affects glycolysis.[13] The mutation impairs the ability of phosphofructokinase to phosphorylate fructose-6-phosphate prior to its cleavage into glyceraldehyde-3-phosphate which is the rate limiting step in the glycolysis pathway. Inhibition of this step prevents the formation of adenosine triphosphate (ATP) from adenosine diphosphate (ADP), which results in a lack of available energy for muscles during heavy exercise. This results in the muscle cramping and pain that are common symptoms of the disease.[14] ### In humans[edit] Genetic mutation is the cause of phosphofructokinase deficiency. Several different mutations in the gene that encodes for PFKM have been reported in humans, but the result is production of PFKM subunits with little to no function.[15] As a result, affected individuals display only about 50–65% of total normal phosphofructokinase enzyme function.[16] ### In dogs[edit] PFK deficiency is believed to be the result of a nonsense mutation in the gene that encodes for PFKM. This results in an unstable, truncated protein that lacks normal function. This results in a near complete loss of PFKM activity in the skeletal muscle. Dogs with the mutation display 10–20% of normal PFK activity in their erythrocytes, due to a higher proportion of PFKM in those cells.[17] ## Diagnosis and treatment[edit] Symptoms of phosphofructokinase deficiency can closely resemble those of other metabolic diseases, include deficiencies of phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, beta-enolase and aldolase A.[7] Thus, proper diagnosis is important to determine a treatment plan. ### In humans[edit] Glycogen deposits in the muscle of a human patient, shown by electron microscopy. The presence of this excess glycogen in muscle tissue is a result of phosphofructokinase deficiency[18] A diagnosis can be made through a muscle biopsy that shows excess glycogen accumulation. Glycogen deposits in the muscle are a result of the interruption of normal glucose breakdown that regulates the breakdown of glycogen. Blood tests are conducted to measure the activity of phosphofructokinase, which would be lower in a patient with this condition.[19] Patients also commonly display elevated levels of creatine kinase.[7] Treatment usually entails that the patient refrain from strenuous exercise to prevent muscle pain and cramping. Avoiding carbohydrates is also recommended.[20] A ketogenic diet also improved the symptoms of an infant with PFK deficiency. The logic behind this treatment is that the low-carb high fat diet forces the body to use fatty acids as a primary energy source instead of glucose. This bypasses the enzymatic defect in glycolysis, lessening the impact of the mutated PFKM enzymes. This has not been widely studied enough to prove if it is a viable treatment, but testing is continuing to explore this option.[21] Genetic testing to determine whether or not a person is a carrier of the mutated gene is also available. ### In dogs[edit] Diagnosis of canine phosphofructokinase deficiency is similar to the blood tests used in diagnosis of humans. Blood tests measuring the total erythrocyte PFK activity are used for definitive diagnosis in most cases.[22] DNA testing for presence of the condition is also available.[23] Treatment mostly takes the form of supportive care. Owners are advised to keep their dogs out of stressful or exciting situations, avoid high temperature environments and strenuous exercise. It is also important for the owner to be alert for any signs of a hemolytic episode. Dogs carrying the mutated form of the gene should be removed from the breeding population, in order to reduce incidence of the condition. ## References[edit] 1. ^ synd/3022 at Who Named It? 2. ^ Tarui S, OKuno G, Ikura Y, Tanaka T, Suda M, Nishikawa M (1965). "Phosphofructokinase Deficiency In Skeletal Muscle. A New Type Of Glycogenosis". Biochem. Biophys. Res. Commun. 19 (4): 517–523. doi:10.1016/0006-291X(65)90156-7. PMID 14339001. 3. ^ Kloos, M; Straeter, N (2014). "4OMT". Acta Crystallogr F. 70: 578–582. doi:10.2210/pdb4omt/pdb. 4. ^ Stedman, H.; Stedman, H; Rajpurohit, Y; Henthorn, PS; Wolfe, JH; Patterson, DF; Giger, U (1996). "Molecular Basis of Canine Muscle Type Phosphofructokinase Deficiency". Journal of Biological Chemistry. 271 (33): 20070–20074. doi:10.1074/jbc.271.33.20070. PMID 8702726. 5. ^ Wu, Pei-Ling; Yang, Yung-Ning; Tey, Shu-Leei; Yang, San-Nan; Lin, Chien-Seng (25 June 2015). "Infantile form of muscle phosphofructokinase deficiency in a premature neonate". Pediatrics International. 57 (4): 746–749. doi:10.1111/ped.12616. PMID 26108272. 6. ^ "Glycogen Storage Disease Type VII". Genetics Home Reference. US National Library of Medicine. 7. ^ a b c Toscano A, Musumeci O (October 2007). "Tarui disease and distal glycogenoses: clinical and genetic update". Acta Myol. 26 (2): 105–107. PMC 2949577. PMID 18421897. 8. ^ "Phosphofructokinase (PFK) deficiency". Canine Inherited Disorders Database. University of Prince Edward Island. 9. ^ Kassir, Kari. "Glycogen Storage Diseases (Glycogenoses; GSD)". Mount Sinai Hospital. 10. ^ "Phosphofructokinase Deficiency (PFK)". PennGen Laboratories. University of Pennsylvania. 11. ^ Inal Gultekin, G; Raj, K; Lehman, S; Hillstrom, A; Giger, U (December 2012). "Missense mutation in PFKM associated with muscle-type phosphofructokinase deficiency in the Wachtelhund dog". Molecular and Cellular Probes. 26 (6): 243–247. doi:10.1016/j.mcp.2012.02.004. PMC 3485442. PMID 22446493. 12. ^ Musumeci, Olimpia; Bruno, Claudio; Mongini, Tiziana; Rodolico, Carmelo; Aguennouz, M'hammed; Barca, Emanuele; Amati, Angela; Cassandrini, Denise; Serlenga, Luigi; Vita, Giuseppe; Toscano, Antonio (2012). "Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII)". Neuromuscular Disorders. 22 (4): 325–330. doi:10.1016/j.nmd.2011.10.022. PMID 22133655. 13. ^ Nakajima H, Raben N, Hamaguchi T, Yamasaki T (2002). "Phosphofructokinase deficiency; past, present and future". Curr. Mol. Med. 2 (2): 197–212. doi:10.2174/1566524024605734. PMID 11949936. 14. ^ Layzer, Robert; Rowland, Lewis; Ranney, Helen (November 1967). "Muscle Phosphofructokinase Deficiency". Journal of the American Medical Association. 17 (5): 512–523. doi:10.1001/archneur.1967.00470290066009. 15. ^ Raben, N; Sherman, JB (1995). "Mutations in muscle phosphofructokinase gene". Human Mutation. 6 (1): 1–6. doi:10.1002/humu.1380060102. PMID 7550225. 16. ^ Vora, Shobhana; Giger, Urs; Turchen, Steven; Harvey, John (December 1985). "Characterization of the enzymatic lesion in inherited phosphofructokinase deficiency in the dog: an animal analogue of human glycogen storage disease type VII". Proceedings of the National Academy of Sciences of the United States of America. 82 (23): 8109–8113. Bibcode:1985PNAS...82.8109V. doi:10.1073/pnas.82.23.8109. PMC 391452. PMID 2933748. 17. ^ Harvey, J.W.; Smith, J.E. (June 1994). "Haematology and Clinical Chemistry of English Springer Spaniel Dogs with Phosphofructokinase Deficiency". Comparative Harmatology International. 4 (2): 70–75. doi:10.1007/BF00368272. 18. ^ Malfatti, Edoardo; Birouk, Nazha; Romero, Norma B.; Piraud, Monique; Petit, François M.; Hogrel, Jean-Yves; Laforêt, Pascal (2012-05-15). "Juvenile-onset permanent weakness in muscle phosphofructokinase deficiency". Journal of the Neurological Sciences. 316 (1–2): 173–177. doi:10.1016/j.jns.2012.01.027. PMID 22364848. 19. ^ Ronquist, Gunnar. "Tarui disease". The Swedish Information Center for Rare Diseases. University of Gothenburg. 20. ^ "Glycogen Storage Disease Type VII". Rare Disease Database. National Organization for Rare Disorders. 21. ^ Swoboda, Kathryn; Specht, Linda; Jones, Royden; Shapiro, Frederic; DiMauro, Salvatore; Korson, Mark (December 1997). "Infantile phosphofructokinase deficiency with arthrogryposis: Clinical benefit of a ketogenic diet". The Journal of Pediatrics. 131 (6): 932–934. doi:10.1016/s0022-3476(97)70048-9. PMID 9427905. 22. ^ Gerber, Karen; Harvey, John; D'Agorne, Sara; Wood, Jonathan; Giger, Urs (March 2009). "Hemolysis, myopathy, and cardiac disease associated with hereditary phosphofructokinase deficiency in two Whippets". Veterinary Clinical Pathology. 38 (1): 46–51. doi:10.1111/j.1939-165X.2008.00089.x. PMC 2692053. PMID 19228357. 23. ^ Giger, U; Kimmel, A; Overlery, D; Schwartz, B; Smith, B; Rajpurohit, Y. "Frequency of Phosphofructokinase (PFK) Deficiency in English Springer Spaniels: A Longitudinal and Randomized Study". English Springer Spaniel Field Trial Association. ## External links[edit] * Media related to Phosphofructokinase deficiency at Wikimedia Commons * Glycogen storage disease type 7; Muscle phosphofructokinase deficiency; Tarui disease at NIH's Office of Rare Diseases Classification D * ICD-10: E74.0 * ICD-9-CM: 271.0 * OMIM: 232800 * MeSH: D006014 * DiseasesDB: 5314 External resources * eMedicine: med/913 * v * t * e Inborn error of carbohydrate metabolism: monosaccharide metabolism disorders Including glycogen storage diseases (GSD) Sucrose, transport (extracellular) Disaccharide catabolism * Congenital alactasia * Sucrose intolerance Monosaccharide transport * Glucose-galactose malabsorption * Inborn errors of renal tubular transport (Renal glycosuria) * Fructose malabsorption Hexose → glucose Monosaccharide catabolism Fructose: * Essential fructosuria * Fructose intolerance Galactose / galactosemia: * GALK deficiency * GALT deficiency/GALE deficiency Glucose ⇄ glycogen Glycogenesis * GSD type 0 (glycogen synthase deficiency) * GSD type IV (Andersen's disease, branching enzyme deficiency) * Adult polyglucosan body disease (APBD) Glycogenolysis Extralysosomal: * GSD type III (Cori's disease, debranching enzyme deficiency) * GSD type VI (Hers' disease, liver glycogen phosphorylase deficiency) * GSD type V (McArdle's disease, myophosphorylase deficiency) * GSD type IX (phosphorylase kinase deficiency) Lysosomal (LSD): * GSD type II (Pompe's disease, glucosidase deficiency) Glucose ⇄ CAC Glycolysis * MODY 2/HHF3 * GSD type VII (Tarui's disease, phosphofructokinase deficiency) * Triosephosphate isomerase deficiency * Pyruvate kinase deficiency Gluconeogenesis * PCD * Fructose bisphosphatase deficiency * GSD type I (von Gierke's disease, glucose 6-phosphatase deficiency) Pentose phosphate pathway * Glucose-6-phosphate dehydrogenase deficiency * Transaldolase deficiency * 6-phosphogluconate dehydrogenase deficiency Other * Hyperoxaluria * Primary hyperoxaluria * Pentosuria * Aldolase A deficiency [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	Phosphofructokinase deficiency	c0017926	6,389	wikipedia	https://en.wikipedia.org/wiki/Phosphofructokinase_deficiency	2021-01-18T18:28:01	{"gard": ["5686"], "mesh": ["D006014"], "umls": ["C0017926"], "icd-9": ["271.0"], "orphanet": ["371"], "wikidata": ["Q1251847"]}
White and Fulton (1937) described ovoid pupils that were large and reacted poorly to constricting stimuli in a woman of Russian-Jewish extraction and both of her identical twin daughters. Eyes \- Large ovoid pupils \- Poorly pupillary reaction to constricting stimuli 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	PUPIL, EGG-SHAPED	c1867405	6,390	omim	https://www.omim.org/entry/178800	2019-09-22T16:35:22	{"mesh": ["C566731"], "omim": ["178800"]}
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: "Pipecolic acidemia" – news · newspapers · books · scholar · JSTOR (July 2008) (Learn how and when to remove this template message) This article needs editing for compliance with Wikipedia's Manual of Style. In particular, it has problems with not using MEDMOS. Please help improve it if you can. (August 2017) (Learn how and when to remove this template message) Pipecolic acidemia Other namesHyperpipecolic acidemia or Hyperpipecolatemia[1] Pipecolic acid SpecialtyMedical genetics, endocrinology Pipecolic acidemia, is a very rare autosomal recessive metabolic disorder that is caused by a peroxisomal defect. Pipecolic acidemia can also be an associated component of Refsum disease with increased pipecolic acidemia (RDPA),[2] as well as other peroxisomal disorders, including both infantile and adult Refsum disease,[3][4][5] and Zellweger syndrome.[6] The disorder is characterized by an increase in pipecolic acid levels in the blood, leading to neuropathy and hepatomegaly. ## See also[edit] * AASDHPPT * PHYH ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): 239400 2. ^ Online Mendelian Inheritance in Man (OMIM): 600964 3. ^ Tranchant C, Aubourg P, Mohr M, Rocchiccioli F, Zaenker C, Warter JM (Oct 1993). "A new peroxisomal disease with impaired phytanic and pipecolic acid oxidation". Neurology. 43 (10): 2044–2048. doi:10.1212/wnl.43.10.2044. PMID 8413964. S2CID 30110852. 4. ^ Online Mendelian Inheritance in Man (OMIM): 266510 5. ^ Online Mendelian Inheritance in Man (OMIM): 266500 6. ^ Brul, S.; Westerveld, A.; Strijland, A.; Wanders, R.; Schram, A.; Heymans, H.; Schutgens, R.; Van Den Bosch, H.; Tager, J. (June 1988). "Genetic heterogeneity in the cerebrohepatorenal (Zellweger) syndrome and other inherited disorders with a generalized impairment of peroxisomal functions. A study using complementation analysis". Journal of Clinical Investigation (Free full text). 81 (6): 1710–1715. doi:10.1172/JCI113510. PMC 442615. PMID 2454948. ## External links[edit] Classification D * ICD-9-CM: 270.7 * OMIM: 239400 600964 * v * t * e Inborn error of amino acid metabolism K→acetyl-CoA Lysine/straight chain * Glutaric acidemia type 1 * type 2 * Hyperlysinemia * Pipecolic acidemia * Saccharopinuria Leucine * 3-hydroxy-3-methylglutaryl-CoA lyase deficiency * 3-Methylcrotonyl-CoA carboxylase deficiency * 3-Methylglutaconic aciduria 1 * Isovaleric acidemia * Maple syrup urine disease Tryptophan * Hypertryptophanemia G G→pyruvate→citrate Glycine * D-Glyceric acidemia * Glutathione synthetase deficiency * Sarcosinemia * Glycine→Creatine: GAMT deficiency * Glycine encephalopathy G→glutamate→ α-ketoglutarate Histidine * Carnosinemia * Histidinemia * Urocanic aciduria Proline * Hyperprolinemia * Prolidase deficiency Glutamate/glutamine * SSADHD G→propionyl-CoA→ succinyl-CoA Valine * Hypervalinemia * Isobutyryl-CoA dehydrogenase deficiency * Maple syrup urine disease Isoleucine * 2-Methylbutyryl-CoA dehydrogenase deficiency * Beta-ketothiolase deficiency * Maple syrup urine disease Methionine * Cystathioninuria * Homocystinuria * Hypermethioninemia General BC/OA * Methylmalonic acidemia * Methylmalonyl-CoA mutase deficiency * Propionic acidemia G→fumarate Phenylalanine/tyrosine Phenylketonuria * 6-Pyruvoyltetrahydropterin synthase deficiency * Tetrahydrobiopterin deficiency Tyrosinemia * Alkaptonuria/Ochronosis * Tyrosinemia type I * Tyrosinemia type II * Tyrosinemia type III/Hawkinsinuria Tyrosine→Melanin * Albinism: Ocular albinism (1) * Oculocutaneous albinism (Hermansky–Pudlak syndrome) * Waardenburg syndrome Tyrosine→Norepinephrine * Dopamine beta hydroxylase deficiency * reverse: Brunner syndrome G→oxaloacetate Urea cycle/Hyperammonemia (arginine * aspartate) * Argininemia * Argininosuccinic aciduria * Carbamoyl phosphate synthetase I deficiency * Citrullinemia * N-Acetylglutamate synthase deficiency * Ornithine transcarbamylase deficiency/translocase deficiency Transport/ IE of RTT * Solute carrier family: Cystinuria * Hartnup disease * Iminoglycinuria * Lysinuric protein intolerance * Fanconi syndrome: Oculocerebrorenal syndrome * Cystinosis Other * 2-Hydroxyglutaric aciduria * Aminoacylase 1 deficiency * Ethylmalonic encephalopathy * Fumarase deficiency * Trimethylaminuria This genetic disorder 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	Pipecolic acidemia	c0282526	6,391	wikipedia	https://en.wikipedia.org/wiki/Pipecolic_acidemia	2021-01-18T18:31:22	{"mesh": ["D018901"], "umls": ["C0268537"], "icd-9": ["270.7"], "orphanet": ["34"], "wikidata": ["Q7197254"]}
A congenital vascular malformation characterized by dilation of the embryonic precursor of the vein of Galen. It is a sporadic lesion that occurs during embryogenesis. ## Epidemiology The lesion is rare, with less than 800 cases (representing less than 10% of all cerebral arteriovenous malformations) reported so far. Vein of Galen aneurysmal malformation (VGAM) is more frequent in males than in females. ## Clinical description Cardiac insufficiency of variable severity is the principle manifestation that leads to detection of the malformation in newborns. It is sometimes associated with respiratory problems and/or hepatic, renal, and/or cerebral (encephalomalacia) manifestations, the main concern for therapeutic management. In infants, macrocrania may lead to suspicion of VGAM. Epilepsy, neuropsychological delay and neurologic deficiency are indicators of the malformation in older children. Cerebral hemorrhage only occurs in older children with progressive forms of VGAM. ## Diagnostic methods In newborns, the cardiac manifestations dominate the clinical picture. Trans-fontanel ultrasonography should be conducted before MRI. ## Differential diagnosis It is important to differentiate VGAM from congenital cardiopathy (by means of trans-fontanel ultrasonography). ## Antenatal diagnosis VGAMs are sometimes detected through ultrasound examinations during the third trimester of pregnancy. In this case, only two findings justify medical termination of the pregnancy: severe cardiac insufficiency and cerebral damage detected by fetal MRI. ## Genetic counseling In infants with macrocrania, the diagnosis relies on MRI. During the neonatal period, investigations for encephalomalacia (antenatal MRI, trans-fontanel ultrasonography, CT scans) are essential. ## Management and treatment Monitoring of a newborn with a VGAM that is either naturally well tolerated or controlled by medical treatment should consist of monthly clinical and neuropsychological examinations, and MRI or CT scans from birth to 3 months of age. During the neonatal period, early emergency treatment is only required in case of severe or poorly tolerated cardiac insufficiency. The child should be managed by a pediatric intensive care unit and an experienced team of pediatric neurologists. For asymptomatic infants, therapeutic management of the VGAM should be delayed until four or five months after birth, but may be required earlier if the VGAM is life-threatening or may affect cerebral development. Treatment is endovascular, using a femoral transarterial approach. Arteriovenous shunts are embolized with a glue, usually requiring two or three interventions. Hydrocephaly due to venous congestion may require a ventricular diversion valve or a ventriculocisternostomy. Radiosurgery is not a therapeutic option. Surgery is not indicated as a treatment for VGAM, except in very rare cases. Patients undergoing VGAM treatment should have regular programmed clinical and morphological examinations. The aim of these examinations is to detect rapid increases in cranial circumference, delays in psychomotor development, or pial or more profound venous reflux. Additional interventions involving targeted embolisation may be required, using either a venous or arterial approach depending on the architecture of the lesion. ## Prognosis The neurological prognosis for VGAM with early treatment is excellent; however, the prognosis is poorer for patients with severe neonatal malformations. [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	Vein of Galen aneurysmal malformation	c0431420	6,392	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1053	2021-01-23T19:13:02	{"gard": ["5467"], "mesh": ["C536535"], "omim": ["618196"], "umls": ["C0431420"], "icd-10": ["Q28.2"], "synonyms": ["Vein of Galen arteriovenous malformations"]}
Pyruvate dehydrogenase phosphatase deficiency is a very rare subtype of pyruvate dehydrogenase deficiency (PDHD, see this term) characterized by lactic acidemia in the neonatal period. ## Epidemiology Prevalence is unknown but this form of PDHD appears to be very rare, with only three patients reported. ## Clinical description All three patients presented in the newborn period with lactic acidosis and hypotonia. Two siblings from one family have had a prolonged course on a ketogenic diet, surviving into teenage years with exercise intolerance and mild developmental delay. The third patient died at age 6 months. ## Etiology The disorder is caused by mutations in the PDP1 gene (8q22.1) encoding pyruvate dehyrogenase phosphatase isoform 1, an enzyme which regulates the activity of the pyruvate dehydrogenase complex. ## Genetic counseling The pattern of inheritance is 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	Pyruvate dehydrogenase phosphatase deficiency	c1837429	6,393	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79246	2021-01-23T17:20:00	{"gard": ["9888"], "mesh": ["C536258"], "omim": ["608782"], "umls": ["C1837429"], "icd-10": ["E74.4"], "synonyms": ["PDH phosphatase deficiency"]}
Oculotrichodysplasia is characterised by retinitis pigmentosa, trichodysplasia, dental anomalies, and onychodysplasia. It has been described in two siblings (brother and sister) born to first cousin parents. Transmission appears to be 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	Oculotrichodysplasia	c1850332	6,394	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2718	2021-01-23T18:27:07	{"mesh": ["C564934"], "omim": ["257960"], "umls": ["C1850332"], "synonyms": ["Cecato de Lima-Pinheiro syndrome"]}
Microcephaly-polymicrogyria-corpus callosum agenesis syndrome is a rare, genetic, central nervous system malformation syndrome characterized by marked prenatal-onset microcephaly, severe motor delay with hypotonia, bilateral polymicrogyria, corpus callosum agenesis, ventricular dilation, small cerebellum and early lethality. [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	Microcephaly-polymicrogyria-corpus callosum agenesis syndrome	None	6,395	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=171703	2021-01-23T17:30:32	{"icd-10": ["Q04.3"]}
A rare toxic dermatosis disease characterized by the rapid development of numerous, nonfollicular, sterile, pinhead-sized pustules on an edematous and erythematous base, predominantly occurring on the trunk, intertriginous and flexural areas, with rare, mostly oral, mucosal involvement. Acute onset of fever (>38°C), peripheral blood leukocytosis, and mild eosinophilia are accompanying features. Systemic involvement, with hepatic, renal or pulmonary dysfunction, occasionally occurs. Histologically reveals characteristic spongiform, subcorneal and/or intraepidermal, pustules, as well as marked edema of the papillary dermis, a perivascularly accentuated, neutrophil-rich inflammatory infiltrate, and intrapustular or intradermal eosinophils. [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 generalized exanthematous pustulosis	c0853331	6,396	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=293173	2021-01-23T18:37:11	{"umls": ["C0853331", "C0877055"], "synonyms": ["AGEP", "Pustular drug eruption", "Toxic pustuloderma"]}
Delayed ejaculation Other namesRetarded ejaculation, inhibited ejaculation SpecialtyUrology Delayed ejaculation describes a man's inability or persistent difficulty in achieving orgasm, despite typical sexual desire and sexual stimulation. Generally, a man can reach orgasm within a few minutes of active thrusting during sexual intercourse, whereas a man with delayed ejaculation either does not have orgasms at all or cannot have an orgasm until after prolonged intercourse which might last for 30–45 minutes or more.[1] In most cases, delayed ejaculation presents the condition in which the man can climax and ejaculate only during masturbation, but not during sexual intercourse. It is the least common of the male sexual dysfunctions, and can result as a side effect of some medications. In one survey, 8% of men reported being unable to achieve orgasm over a two-month period or longer in the previous year.[2] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Treatment * 3.1 Sex therapy * 3.2 Other * 4 See also * 5 References * 6 External links ## Signs and symptoms[edit] Delayed ejaculation can be mild (men who still experience orgasm during intercourse, but only under certain conditions), moderate (cannot ejaculate during intercourse, but can during fellatio or manual stimulation), severe (can ejaculate only when alone), or most severe (cannot ejaculate at all).[2] All forms may result in a sense of sexual frustration.[3] ## Causes[edit] Medical conditions that can cause delayed ejaculation include hypogonadism, thyroid disorders, pituitary disorders such as Cushing's disease, prostate surgery outcome, and drug and alcohol use.[2] Difficulty in achieving orgasm can also result from pelvic surgery that involved trauma to pelvic nerves responsible for orgasm. Some men report a lack of sensation in the nerves of the glans penis, which may or may not be related to external factors, including a history of circumcision.[4] Delayed ejaculation is a possible side effect of certain medications, including selective serotonin reuptake inhibitors (SSRIs), opiates such as morphine, methadone, or oxycodone, many benzodiazepines such as Valium, certain antipsychotics, and antihypertensives.[5][6] Psychological and lifestyle factors have been discussed as potential contributors, including insufficient sleep, distraction due to worry, distraction from the environment, anxiety about pleasing their partner and anxiety about relationship problems.[7] One proposed cause of delayed ejaculation is adaptation to a certain masturbatory technique.[8] Lawrence Sank (1998) wrote about the "Traumatic masturbatory syndrome", when the sensations a man feels when masturbating may bear little resemblance to the sensations he experiences during intercourse. Factors such as pressure, angle and grip during masturbation can make for an experience so different from sex with a partner that the ability to ejaculate is reduced or eliminated. ## Treatment[edit] ### Sex therapy[edit] Therapy usually involves homework assignments and exercises intended to help a man get used to having orgasms through insertional intercourse, vaginal, anal, or oral, that is through the way to which he is not accustomed. Commonly, the couple is advised to go through three stages.[9] At the first stage, a man masturbates in the presence of his partner. Sometimes, this is not an easy matter as a man may be used to having orgasms alone. After a man learns to ejaculate in the presence of his partner, the man's hand is replaced with the hand of his partner. In the final stage, the receptive partner inserts the insertive partner's penis into the partner's vagina, anus, or mouth as soon as the ejaculation is felt to be imminent. Thus, a man gradually learns to ejaculate inside the desired orifice by an incremental process.[2] ### Other[edit] Meditation has demonstrated effectiveness in case studies.[10] There is yet no reliable medication for delayed ejaculation. PDE5 inhibitors such as Viagra have little effect.[11] In fact, Viagra has a delaying effect on ejaculation, possibly through additional effect in the brain or decrease of sensitivity in the head of the penis.[12] ## See also[edit] * Anorgasmia * Edging (sexual practice) * Premature ejaculation * Retrograde ejaculation * Sexual repression ## References[edit] 1. ^ Knowles, David R. (2005-06-01). "Delayed ejaculation". A.D.A.M. Medical Encyclopedia. A.D.A.M., Inc. Retrieved 2007-05-24. 2. ^ a b c d Strassberg, D. S., & Perelman, M. A. (2009). Sexual dysfunctions. In P. H. Blaney & T. Millon (Eds.), Oxford textbook of psychopathology (2nd ed.), (pp. 399–430). NY: Oxford University Press. 3. ^ Hatzimouratidis, Konstantinos, et al. "Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation." European urology 57.5 (2010): 804-814. 4. ^ Dias J, Freitas R, Amorim R, Espiridião P, Xambre L, Ferraz L, Adult circumcision and male sexual health: a retrospective analysis, Andrologia, 20 April 2013 doi:10.1111/and.12101 [1] 5. ^ drugs.com > Delayed ejaculation Archived 2019-02-20 at the Wayback Machine Review Date: 6/5/2007. Reviewed By: Marc Greenstein, DO, Urologist, North Jersey Center for Urologic Care 6. ^ Smith, Shubulade; Robin Murray; Veronica O'Keane (2002). "Sexual dysfunction in patients taking conventional antipsychotic medication". The British Journal of Psychiatry. 181: 49–55. doi:10.1192/bjp.181.1.49. PMID 12091263. 7. ^ Mann, Jay (1976). "Retarded ejaculation and treatment". International Congress of Sexology. 8. ^ Sank, Lawrence (1998). "Traumatic masturbatory syndrome". Journal of Sex & Marital Therapy. 24 (1): 37–42. doi:10.1080/00926239808414667. PMID 9509379. 9. ^ Dr. David Delvin (2007-06-25). "Delayed ejaculation (retarded ejaculation)". NetDoctor.co.uk. Retrieved 2007-10-25. 10. ^ M. M. Delmonte (June 1984). "Case reports on the use of meditative relaxation as an intervention strategy with retarded ejaculation". Biofeedback and Self-Regulation. 9 (2): 209–214. doi:10.1007/BF00998835. PMID 6391563. S2CID 40959207. 11. ^ The Carlat Psychiatry Report > PDE-5 Inhibitors: Which to Choose? Published in The Carlat Psychiatry Report. December 2004, Volume 2, Number 12 12. ^ WebMD Health News > Viagra, Paxil Help Premature Ejaculation. May 29, 2002. By Martin F. Downs. ## External links[edit] Classification D * ICD-10: N53.11 * ICD-9-CM: 608.89 External resources * MedlinePlus: 001954 * Medline Plus Medical Encyclopedia \- Delayed ejaculation. * v * t * e Outline of human sexuality Physiology and biology * Erection * Insemination * Intersex * Libido * Nocturnal emission * Orgasm * Female and male ejaculation * Pelvic thrust * Pre-ejaculate * Pregnancy * Sexual arousal * Sexual stimulation Health and education * Birth control * Condom * Masters and Johnson * Reproductive medicine * Andrology * Gynaecology * Urology * Safe sex * Sex education * Sex therapy (PLISSIT model) * Sexology * Sexual dysfunction * Erectile dysfunction * Hypersexuality * Hyposexuality * Sexual medicine * Sexual surrogate * Sexually transmitted infection Identity and diversity * Gender binary * Gender identity * Men who have sex with men * Sexual identity * Sexual orientation * Women who have sex with women Law * Age of consent * Criminal transmission of HIV * Child sexual 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Mass psychogenic illness * Nosophobia * Psychogenic pain * Somatization disorder Physiological and physical behavior Eating * Anorexia nervosa * Bulimia nervosa * Rumination syndrome * Other specified feeding or eating disorder Nonorganic sleep * Hypersomnia * Insomnia * Parasomnia * Night terror * Nightmare * REM sleep behavior disorder Postnatal * Postpartum depression * Postpartum psychosis Sexual dysfunction Arousal * Erectile dysfunction * Female sexual arousal disorder Desire * Hypersexuality * Hypoactive sexual desire disorder Orgasm * Anorgasmia * Delayed ejaculation * Premature ejaculation * Sexual anhedonia Pain * Nonorganic dyspareunia * Nonorganic vaginismus Psychoactive substances, substance abuse and substance-related * Drug overdose * Intoxication * Physical dependence * Rebound effect * Stimulant psychosis * Substance dependence * Withdrawal Schizophrenia, schizotypal and delusional Delusional * Delusional disorder * Folie à deux Psychosis and schizophrenia-like * Brief reactive psychosis * Schizoaffective disorder * Schizophreniform disorder Schizophrenia * Childhood schizophrenia * Disorganized (hebephrenic) schizophrenia * Paranoid schizophrenia * Pseudoneurotic schizophrenia * Simple-type schizophrenia Other * Catatonia Symptoms and uncategorized * Impulse control disorder * Klüver–Bucy syndrome * Psychomotor agitation * Stereotypy [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	Delayed ejaculation	c0234047	6,397	wikipedia	https://en.wikipedia.org/wiki/Delayed_ejaculation	2021-01-18T18:37:03	{"icd-9": ["608.89"], "icd-10": ["N53.11"], "wikidata": ["Q1142563"]}
Hearing loss with craniofacial syndromes is a common occurrence. Many of these multianomaly disorders involve structural malformations of the outer or middle ear, making a significant hearing loss highly likely. ## Contents * 1 Treacher Collins syndrome * 2 Pierre Robin sequence * 3 Stickler syndrome * 4 Apert syndrome * 5 Crouzon syndrome * 6 Pfeiffer syndrome * 7 Ectrodactyly–ectrodermal dysplasia–cleft syndrome * 8 Saethre–Chotzen syndrome * 9 Velocardiofacial syndrome * 10 Hemifacial microsomia * 11 Nager syndrome * 12 See also * 13 References * 14 External links ## Treacher Collins syndrome[edit] Main article: Treacher Collins syndrome Individuals with Treacher Collins syndrome often have both cleft palate and hearing loss, in addition to other disabilities. Hearing loss is often secondary to absent, small or unusually formed ears (microtia) and commonly results from malformations of the middle ear. Researchers have found that most patients with Treacher Collins syndrome have symmetric external ear canal abnormalities and symmetrically dysmorphic or absent ossicles in the middle ear space. Inner ear structure is largely normal. Most patients show a moderate hearing impairment or greater, and the type of loss is generally a conductive hearing loss. Patients with Treacher Collins syndrome exhibit hearing losses similar to those of patients with malformed or missing ossicles (Pron et al., 1993). ## Pierre Robin sequence[edit] Main article: Pierre Robin syndrome Persons with Pierre Robin sequence (PRS) are at greater risk for hearing impairment than persons with cleft lip and/or palate without PRS. One study showed an average of 83% hearing loss in PRS, compared to 60% in cleft individuals without PRS (Handzic et al., 1995). Similarly, PRS individuals typically exhibit conductive, bilateral hearing losses that are greater in degree than in cleft individuals without PRS. Middle ear effusion is generally apparent, with no middle ear or inner ear malformations. Accordingly, management by ear tubes (myringotomy tubes) is often effective and may restore normal levels of hearing (Handzic et al., 1995). ## Stickler syndrome[edit] Main article: Stickler syndrome The hearing loss most typical in patients with Stickler syndrome is a sensorineural hearing loss, indicating that the source of the deficit lies in the inner ear, the vestibulocochlear nerve or the processing centers of the brain. Szymko-Bennett et al. (2001) found that the overall hearing loss in Type I Stickler Syndrome is generally mild and is not significantly progressive. Hearing loss is more common in the higher frequencies, from about 4000–8000 Hz (Szymko-Bennett et al., 2001). This mildly progressive sensorineural loss, or more significant losses (associated with Types II and III Stickler syndrome) is present in about 80% of patients with Stickler syndrome. However, other patients are also susceptible to conductive losses, similar to nonsyndromic cleft patients (Peterson-Falzone et al., 2001). ## Apert syndrome[edit] Main article: Apert syndrome Patients with Apert syndrome have a high occurrence of middle ear disease, otitis media and conductive hearing loss (Perterson-Fazone et al., 2001). Conductive hearing loss is frequently seen in this population due to almost constant middle ear disease (Gould et al., 1982). Furthermore, inner ear anomalies have been described in Apert syndrome, such as dilatation of the vestibule, dysplastic semicircular canals and cochlear malformations (Zhou G et al. Otol Neurotol. 2009 Feb;30(2):184-9) ## Crouzon syndrome[edit] Main article: Crouzon syndrome Patients with Crouzon syndrome sometimes exhibit malformations of the external ear and/or the middle ear, such as malalignment of the pinna (Peterson-Falzone et al., 2001). Literature has suggested that persons with Crouzon syndrome typically have conductive hearing loss caused by middle ear effusion (or fluid in the middle ear) and perforation to ossicular fixation (ossicles), intratympanic bony masses (tympanic membrane), ossicular anomalies and closure of the oval window. Patients with a sensorineural hearing loss have also been reported but are less likely to occur. ## Pfeiffer syndrome[edit] Main article: Pfeiffer syndrome A conductive hearing loss along with middle ear disease is most commonly seen in patients with Pfeiffer syndrome; although, there have been reports of mixed hearing loss as well. The hearing loss is most typically caused by stenosis or atresia of the auditory canal, middle ear hypoplasia and ossicular hypoplasia (Vallino-Napoli, 1996). ## Ectrodactyly–ectrodermal dysplasia–cleft syndrome[edit] Main article: Ectrodactyly–ectodermal dysplasia–cleft syndrome Conductive hearing loss has been reported by many with ectrodactyly–ectodermal dysplasia–cleft (EEC) syndrome in association with a cleft palate (Perterson-Falzone, 2001). ## Saethre–Chotzen syndrome[edit] Main article: Saethre–Chotzen syndrome In Saethre–Chotzen syndrome, the ears may be low set, posteriorly rotated, have other minor anomalies and there may be a presence of a conductive hearing loss or a mixed hearing loss (Perterson-Falszone, 2001). Hearing loss in this group can also be caused by middle ear disease when a cleft palate is present.[1] ## Velocardiofacial syndrome[edit] Main article: Velocardiofacial syndrome About 70% of individuals with velocardiofacial syndrome (VCFS) have minor auricular malformations, or malformations of the ear. In this syndrome, the ears are typically low-set and somewhat posteriorly rotated. In addition to external malformations, individuals with VCFS are more vulnerable to otitis media because of the presence of a cleft or other form of velopharyngeal inadequacy. The hearing loss associated with VCFS is conductive when otitis media is present (Peterson-Falzone et al., 2001). There are also sporadic reports of sensorineural hearing loss and a mixed hearing loss. Of individuals with VCFS who have a hearing loss, only 11% had a sensorineural loss and 5% a mixed loss (Reyes et al., 1999). ## Hemifacial microsomia[edit] Main article: Hemifacial microsomia Individuals with hemifacial microsomia, also called oculoauriculo-vertebral spectrum, often have ear malformations. These malformations can be in the form of preauricular ear pits, complete absence of the auricle, stenosis or atresia of the external auditory canal, ossicular malformations, middle ear deformities, and incomplete pneumatization of the temporal bone. Rahbar et al. (2001) found that 95% of individuals with this syndrome have an ear malformation of some type. In addition to ear malformations, a conductive hearing loss can be present, typically ranging from mild to severe. There are also reported cases of cochlear involvement and sensorineural hearing loss. Rahbar et al. (2001) found that 86% of patients with Hemifacial Microsomia have a conductive hearing loss and 10% have a sensorineural hearing loss. There is no correlation between the severity of dysmorphic features and the degree of hearing loss, meaning individuals with mild malformations can have severely impaired hearing. ## Nager syndrome[edit] Main article: Nager syndrome Individuals with Nager syndrome typically have the malformations of the auricle, external auditory canal and middle ear, including the ossicles. These malformations were found in 80% of individuals with Nager syndrome. Inner ear malformations, however, are not typically seen in this population. Middle ear disease is common among individuals with Nager syndrome. Chronic otitis media and Eustachian tube deformity can result in conductive hearing loss. For this reason, early detection and treatment for middle ear disease is crucial in this population. Sensorineural hearing loss is not a typical characteristic of Nager syndrome; however, a subset of individuals present with a mixed hearing loss, due to a progressive sensorineural component combined with the typical conductive hearing loss (Herrman et al., 2005). ## See also[edit] * 22q11.2 deletion syndrome ## References[edit] 1. ^ "The World Craniofacial Foundation: Dedicated to helping children and families who experience deformities of the head and/or face by providing support and access to life-changing procedures". Archived from the original on 2007-02-17. Retrieved 2018-03-05. * Gould, H. J.; D. D. Caldarelli (June 1982). "Hearing and otopathology in Apert syndrome". Archives of Otolaryngology. 108 (6): 347–349. doi:10.1001/archotol.1982.00790540019006. PMID 7201310. * Handžic, Jadranka; Marijo Bagatin; Radovan Subotic; Višeslay Cuk (January 1995). "Hearing levels in Pierre Robin Syndrome". Cleft Palate-Craniofacial Journal. 32 (1): 30–36. doi:10.1597/1545-1569(1995)032<0030:HLIPRS>2.3.CO;2. PMID 7727485. * Herrman, Brian W.; Roanne Karzon; David W. Molter (August 2005). "Otologic and audiologic features of Nager acrofacial dysostosis". International Journal of Pediatric Otorhinolaryngology. 69 (8): 1053–1059. doi:10.1016/j.ijporl.2005.02.011. PMID 16005346. * Orvidas, Laura J.; Lee Fabry; Svetlana Diacova; Thomas J. McDonald (September 1999). "Hearing and otopathology in Crouzon Syndrome". Laryngoscope. 109 (9): 1372–1375. doi:10.1097/00005537-199909000-00002. PMID 10499038. * Peterson-Falzone, Sally J.; Mary A. Hardin-Jones; Michael P. Karnell (2001). Cleft Palate Speech (3rd ed.). St. Louis: Mosby. ISBN 0-8151-3153-4. * Pron, Gaylene; Cheryl Galloway; Derek Armstrong; Jeffrey Posnick (January 1993). "Ear malformation and hearing loss in patients with Treacher Collins syndrome". Cleft Palate-Craniofacial Journal. 30 (1): 97–103. doi:10.1597/1545-1569(1993)030<0097:EMAHLI>2.3.CO;2. PMID 8418881. * Rahbar, Reza; Caroline D. Robson; John B. Mulliken; Lynn Schwartz; James DiCanzio; Margaret A. Kenna; Trevor J. McGill; Gerald B. Healy (March 2001). "Craniofacial, temporal bone, and audiologic abnormalities in the spectrum of hemifacial microsomia". Archives of Otolaryngology. 127 (3): 265–271. doi:10.1001/archotol.127.3.265. PMID 11255470. * Reyes, Maria Rina T.; Etoile M. LeBlanc; Maha K. Bassila (March 1999). "Hearing loss and otitis media in velocardiofacial syndrome". International Journal of Pediatric Otorhinolaryngology. 47 (3): 227–233. doi:10.1016/S0165-5876(98)00180-3. PMID 10321777. * Szymko-Bennett YM, Mastroianni MA, Shotland LI, Davis J, Ondrey FG, Balog JZ, Rudy SF, McCullagh L, Levy HP, Liberfarb RM, Francomano CA, Griffith AJ (September 2001). "Auditory dysfunction in Stickler syndrome". Archives of Otolaryngology. 127 (9): 1061–1068. doi:10.1001/archotol.127.9.1061. PMID 11556853. * Vallino-Napoli, Linda D. (November 1996). "Audiologic and otologic characteristics of Pfeiffer syndrome". Cleft Palate-Craniofacial Journal. 33 (6): 524–529. doi:10.1597/1545-1569(1996)033<0524:AAOCOP>2.3.CO;2. PMID 8939381. ## External links[edit] * Cleft Palate-Craniofacial Journal Online for scholarly, peer-reviewed articles on topics related to clefting. [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	Hearing loss with craniofacial syndromes	None	6,398	wikipedia	https://en.wikipedia.org/wiki/Hearing_loss_with_craniofacial_syndromes	2021-01-18T19:04:35	{"wikidata": ["Q5691660"]}
Familial lambdoid synostosis is a rare, genetic cranial malformation characterized by unilateral or bilateral synostosis of the lambdoid suture in multiple members of a single family. Unilateral cases typically present ipsilateral occipitomastoid bulge, compensatory contralateral parietal and frontal bossing, displacement of one ear, lateral deviation of jaw and compensatory deformation of cervical spine while bilateral cases usually manifest with flat and widened occiput, displacement of both ears and frequent occurrence of raised intracranial pressure. [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 lambdoid synostosis	c3806917	6,399	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3267	2021-01-23T18:48:44	{"omim": ["600775"], "icd-10": ["Q75.0"]}

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