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A rare primary torsion dystonia characterized by focal or segmental dystonia with onset either in the cranial-cervical region or in the upper limbs. Age of onset varies between 5 years and adulthood, with a mean age of onset of 16 years. Clinical manifestations are generally mild and slowly progressive.
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*[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 inhibitors
*[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
| Primary dystonia, DYT13 type | c1843264 | 4,800 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98807 | 2021-01-23T17:37:16 | {"gard": ["10537"], "mesh": ["C564354"], "omim": ["607671"], "umls": ["C1843264"], "icd-10": ["G24.1"], "synonyms": ["DYT13", "Primary dystonia with mixed phenotype", "Primary torsion dystonia with predominant craniocervical or upper limb onset"]} |
Dopa-responsive dystonia (DRD) due to sepiapterin reductase deficiency (SRD) is a very rare neurometabolic disorder characterized by dystonia with diurnal fluctuations, axial hypotonia, oculogyric crises, and delays in motor and cognitive development.
## Epidemiology
The prevalence is unknown. There have been approximately 43 cases reported to date.
## Clinical description
Onset usually occurs before the first year of life with manifestations of dystonia, motor and language delays, weakness, axial hypotonia (and hypotonia in a tetraplegic distribution) and oculogyric crises that show diurnal fluctuations (worse at night and better in the morning after sleeping). Sleep disturbances and psychological symptoms (anxiety, irritability) are common later in childhood. Intellectual deficits are frequently noted but some may only experience mild to moderate learning disabilities. Less common features include parkinsonism (tremor, bradykinesia, rigidity, masked facies), dysarthria, hyperreflexia, limb hypertonia, and autonomic signs. Frequently, dystonia and obvious diurnal fluctuations only develop during the course of the disease, whereas common presenting symptoms in infancy such as developmental delay and hypotonia are unspecific.
## Etiology
DRD due to an SRD is due to mutations in the SPR gene (2p14-p12), encoding the enzyme sepiapterin reductase (SR). Various mutations in this gene lead to reduced SR activity and consequently to a reduced production of monoamine neurotransmitters.
## Diagnostic methods
Distinctive cerebrospinal fluid (CSF) findings include low levels of 5-hydroxyindoleacetic (5-HIAA) and homovanillic acid (HVA), and elevated total biopterin and dihydrobiopterin (BH2). SR activity in fibroblasts is usually reduced or absent. Molecular genetic testing can identify mutations in the SPR gene, confirming the diagnosis.
## Differential diagnosis
Differential diagnoses include other forms of DRD such as autosomal recessive DRD and autosomal dominant DRD, infantile dystonia-parkinsonism, infantile-onset spastic paraplegia, some forms of epilepsy and cerebral palsy.
## Antenatal diagnosis
Prenatal diagnosis is possible in those with a known SPR mutation.
## Genetic counseling
Transmission is autosomal recessive and genetic counseling is possible and recommended.
## Management and treatment
Like other forms of DRD, DRD due to an SRD responds dramatically to levodopa (L-dopa) therapy. L-dopa is often combined with a peripheral decarboxylase inhibitor such as carbidopa or benserazide. Treatment should be initiated as early as possible to avoid irreversible neurological damage. The dosage of L-dopa given can range from 0.1 to 16.0 mg/kg/day. Transient dyskinesias frequently occur initially as a result of treatment but are usually resolved by decreasing the dosage. In patients with insufficient improvement of symptoms under L-dopa therapy, 5-hydroxytrytophan (5-HTP) at a dosage of 0.14 to 6 mg/kg/day should be given with carbidopa (to reduce side effects), since combination therapy may result in further improvements of motor and sleep symptoms. Treatment is life-long.
## Prognosis
Prognosis depends on if treatment is initiated early and on disease severity. Those who receive treatment show significant improvement, but most still experience mild motor and sometimes severe cognitive symptoms if treatment is delayed.
*[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 inhibitors
*[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
| Dopa-responsive dystonia due to sepiapterin reductase deficiency | c0268468 | 4,801 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=70594 | 2021-01-23T17:58:07 | {"gard": ["10365"], "mesh": ["C562657"], "omim": ["612716"], "umls": ["C0268468"], "icd-10": ["G24.1"], "synonyms": ["Autosomal recessive sepiapterin reductase-deficient DRD", "DRD due to SRD", "SPR deficiency", "Sepiapterin reductase deficiency"]} |
Eisenmenger syndrome
Other namesES, Eisenmenger's reaction, Eisenmenger physiology, or Tardive cyanosis
Schematic drawing showing the principles of Eisenmenger's syndrome
SpecialtyMedical genetics
Eisenmenger's syndrome is defined as the process in which a long-standing left-to-right cardiac shunt caused by a congenital heart defect (typically by a ventricular septal defect, atrial septal defect, or less commonly, patent ductus arteriosus) causes pulmonary hypertension[1][2] and eventual reversal of the shunt into a cyanotic right-to-left shunt. Because of the advent of fetal screening with echocardiography early in life, the incidence of heart defects progressing to Eisenmenger's has decreased.
Eisenmenger's syndrome in a pregnant mother can cause serious complications,[3] though successful delivery has been reported.[4] Maternal mortality ranges from 30% to 60%, and may be attributed to fainting spells, blood clots forming in the veins and traveling to distant sites, hypovolemia, coughing up blood or preeclampsia. Most deaths occur either during or within the first weeks after delivery.[5] Pregnant women with Eisenmenger syndrome should be hospitalized after the 20th week of pregnancy - or earlier if clinical deterioration occurs.
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Pathogenesis
* 4 Diagnosis
* 5 Treatment
* 6 Etymology
* 7 References
* 8 External links
## Signs and symptoms[edit]
Nail clubbing of fingers in a patient with Eisenmenger's syndrome. First described by Hippocrates, clubbing is also known as "Hippocratic fingers".
Signs and symptoms of Eisenmenger syndrome include the following:[citation needed]
* Cyanosis (a blue tinge to the skin resulting from lack of oxygen)
* High red blood cell count
* Swollen or clubbed finger tips (clubbing)
* Fainting (also known as syncope)
* Heart failure
* Abnormal heart rhythms
* Bleeding disorders
* Coughing up blood
* Iron deficiency
* Infections (endocarditis and pneumonia)
* Kidney problems
* Stroke
* Gout (rarely) due to increased uric acid resorption and production with impaired excretion[6]
* Gallstones
## Causes[edit]
A number of congenital heart defects can cause Eisenmenger syndrome, including atrial septal defects, ventricular septal defects, patent ductus arteriosus, and more complex types of acyanotic heart disease.[1]
## Pathogenesis[edit]
The reason Eisenmenger's syndrome often presents later in life can be explained by alterations of the normal physiology of the heart and the maladaptive responses that occur over time. The larger and more muscular left side of the heart must generate the high pressure required to supply blood to the extensive, high-resistance systemic circulation. In contrast, the smaller, right side of the heart must generate a much lower pressure in order to pass blood through the low-resistance, high compliance circulation of the lungs. The lungs are able to accomplish this low-resistance circulation largely due to the fact that the length of the pulmonary circulation is smaller, and because much of the circuitry is in parallel rather than in series.[citation needed]
If a significant anatomic defect (i.e. a hole or breach) exists between the two sides of the heart, a shunt will occur, causing blood to flow down the normal pressure gradient from the left side to the right side. The amount of blood shunted is proportional to the size of the defect, and the beat-to-beat volume of blood pumped through a left-to-right breach is a percentage of anticipated cardiac output (CO) of the left ventricle. Clinically a low index or percentage of CO ejected through a shunt is harmless; a high index or percentage of CO ejected through a left-to-right shunt heralds Eisenmenger's physiology.[citation needed]
The left-to-right shunting of blood results in abnormally high blood flow and pressure directed to the right heart circulation, gradually leading to maladaptive changes that ultimately result in pulmonary hypertension. Increased right-sided blood volume and pressure causes a cascade of pathologic damage to the delicate pulmonary capillaries, causing them to be incrementally replaced with scar tissue. Scar (dead lung tissue) does not contribute to oxygen transfer, therefore decreasing the useful volume of the pulmonary vasculature. The scar tissue also provides less flexibility and compliance than normal lung tissue, causing further increases in pulmonary blood pressure, and the weakened heart must pump harder to continue supplying the lungs, leading to damage of more capillaries. It is because of this maladaptive response that at the onset of Eisenmenger's syndrome, the damage is considered irreversible, even if the underlying heart defect is corrected after the fact.[citation needed]
Eventually, due to increased resistance and decreased compliance of the pulmonary vessels, elevated pulmonary pressures cause the myocardium of the right heart to hypertrophy (RVH). The onset of Eisenmenger's syndrome begins when right ventricular hypertrophy causes right heart pressures to exceed that of the left heart, leading to reversal of blood flow through the shunt (i.e., blood moves from the right side of the heart to the left side). As a consequence, deoxygenated blood returning from the body bypasses the lungs through the reversed shunt and proceeds directly to systemic circulation, leading to cyanosis and resultant organ damage.[citation needed]
The defect, now a right-to-left shunt, causes reduced oxygen saturation in the arterial blood due to mixing of oxygenated blood returning from the lungs with the deoxygenated blood returning from systemic circulation. This decreased saturation is sensed by the kidneys, resulting in a compensatory increase in erythropoietin production and an increased production of red blood cells in an attempt to increase oxygen delivery. As the bone marrow increases erythropoiesis, the systemic reticulocyte count and the risk for hyperviscosity syndrome increases. Reticulocytes are less efficient at carrying oxygen as mature red cells, and they are less deformable, causing impaired transit through capillary beds. This contributes to the death of pulmonary capillary beds.[citation needed]
A person with Eisenmenger's syndrome is paradoxically subject to the possibility of both uncontrolled bleeding due to damaged capillaries and high pressure, as well as spontaneous clots due to hyperviscosity and stasis of blood.[citation needed]
## Diagnosis[edit]
By echo study that shows right to left shunt. Catheterization for assessment of the pulmonary artery pressure if its two thirds of systemic pressure this will preclude repair of the defects.[citation needed]
## Treatment[edit]
If the inciting defect in the heart is identified before it causes significant pulmonary hypertension, it can normally be repaired through surgery, preventing the disease.[7] After pulmonary hypertension is sufficient to reverse the blood flow through the defect, however, the maladaptation is considered irreversible, and a heart–lung transplant or a lung transplant with repair of the heart is the only curative option. Transplantation is the final therapeutic option and only for patients with poor prognosis and quality of life. Timing and appropriateness of transplantation remain difficult decisions.[5] 5-year and 10-year survival ranges between 70% and 80%, 50% and 70%, 30% and 50%, respectively.[8][9][10] Since the average life expectancy of patients after lung transplantation is as low as 30% at 5 years, patients with reasonable functional status related to Eisenmenger syndrome have improved survival with conservative medical care compared with transplantation.[citation needed]
Various medicines and therapies for pulmonary hypertension are under investigation for treatment of the symptoms.[11] Air filters for intravenous lines are recommended for persons with Eisenmenger's syndrome who have been hospitalized to reduce the risk of accidental introduction of air into the veins due to the increased risk for paradoxical air embolism. If air is introduced into the veins and travels through the ventricular septal defect into the arterial circulation, a stroke may occur.[citation needed]
## Etymology[edit]
Eisenmenger syndrome was named[12] by Dr. Paul Wood after Dr. Victor Eisenmenger, who first described[13] the condition in 1897.[14]
## References[edit]
1. ^ a b Jensen AS, Iversen K, Vejlstrup NG, Hansen PB, Søndergaard L (April 2009). "[Eisenmenger syndrome]". Ugeskrift for Laeger (in Danish). 171 (15): 1270–5. PMID 19416617.
2. ^ "Eisenmenger syndrome" at Dorland's Medical Dictionary
3. ^ Siddiqui S, Latif N (2008). "PGE1 nebulisation during caesarean section for Eisenmenger's syndrome: a case report". J Med Case Rep. 2 (1): 149. doi:10.1186/1752-1947-2-149. PMC 2405798. PMID 18466628.
4. ^ Makaryus AN, Forouzesh A, Johnson M (November 2006). "Pregnancy in the patient with Eisenmenger's syndrome". Mt. Sinai J. Med. 73 (7): 1033–6. PMID 17195894. Archived from the original on 2009-03-05. Retrieved 2008-12-20.
5. ^ a b Curr Cardiol Rev. 2010 November; 6(4): 363–372.The Adult Patient with Eisenmenger Syndrome: A Medical Update after Dana Point Part III: Specific Management and Surgical Aspects Erwin Oechslin, Siegrun Mebus, Ingram Schulze-Neick, Koichiro Niwa, Pedro T Trindade, Andreas Eicken, Alfred Hager, Irene Lang, John Hess, and Harald Kaemmerer PMC 3083818
6. ^ Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine. P 1617-1618. Ann Intern Med 1998; 128:745-755
7. ^ "Eisenmenger syndrome". NIH MedLine Plus. 2010-02-05.
8. ^ Goerler H, Simon A, Gohrbandt B, et al. Heart-lung and lung transplantation in grown-up congenital heart disease: long-term single centre experience. Eur J Cardiothorac Surg. 2007;32(6):926–31. [PubMed]
9. ^ Waddell TK, Bennett L, Kennedy R, Todd TR, Keshavjee SH. Heart-lung or lung transplantation for Eisenmenger syndrome. J Heart Lung Transplant. 2002;21(7):731–7. [PubMed]
10. ^ Heart-lung transplantation for Eisenmenger syndrome: early and long-term results. Stoica SC, McNeil KD, Perreas K, Sharples LD, Satchithananda DK, Tsui SS, Large SR, Wallwork J Ann Thorac Surg. 2001 Dec; 72(6):1887-91.
11. ^ "Eisenmenger Syndrome Treatment & Management". MedScape Reference. 2008-06-05. Cite journal requires `|journal=` (help)
12. ^ Wood, P (1958). "Pulmonary hypertension with special reference to the vasoconstrictive factor". British Heart Journal. 20 (4): 557–70. doi:10.1136/hrt.20.4.557. PMC 491807. PMID 13584643.
13. ^ Eisenmenger V. Die angeborenen Defekte der Kammerscheidewände des Herzens. The condition was first mentioned by Hippocrates, the Greek physician. Zeitschr Klin Med 1897;32(Supplement):1-28.
14. ^ synd/3034 at Who Named It?
## External links[edit]
Classification
D
* ICD-10: Q21.8
* ICD-9-CM: 745.4 (CDC/BPA 745.410)
* MeSH: D004541
* DiseasesDB: 4143
External resources
* MedlinePlus: 007317
* eMedicine: article/154555
* Orphanet: 97214
Wikimedia Commons has media related to Eisenmenger's syndrome.
*[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 inhibitors
*[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
| Eisenmenger's syndrome | c0013743 | 4,802 | wikipedia | https://en.wikipedia.org/wiki/Eisenmenger%27s_syndrome | 2021-01-18T18:39:11 | {"gard": ["6323"], "mesh": ["D004541"], "umls": ["C0013743"], "icd-9": ["745.4"], "icd-10": ["Q21.8"], "orphanet": ["97214"], "wikidata": ["Q572695"]} |
A rare coronary artery congenital malformation characterized by an anomalous origin of the left (ALCAPA) or right (ARCAPA) coronary artery from the pulmonary artery, with variable clinical presentation, ranging from asymptomatic to early heart failure and death depending on the degree of development of collateral circulation between the left and right coronary artery systems, as well as the pressure level of the pulmonary artery. Infants typically present with feeding difficulties, failure to thrive, dyspnea, irritability, hyperhidrosis, heart murmurs, tachypnea, tachycardia and/or chest pain while adults usually associate dyspnea, chest pain, syncope, and intolerance to physical exercise. Sudden death may occur due to congestive heart failure, myocardial infarction, valvular insufficiencies or ventricular arrhythmias. The majority of cases reported are of an ALCAPA, while ARCAPA is rarely observed.
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*[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 inhibitors
*[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
| Anomalous origin of coronary artery from the pulmonary artery | c4023252 | 4,803 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=541507 | 2021-01-23T18:55:52 | {"icd-10": ["Q24.5"], "synonyms": ["ACAPA"]} |
A number sign (#) is used with this entry because retinal macular dystrophy-2 (MCDR2) is caused by mutation in the prominin-1 gene (PROM1; 604365).
For a general description and a discussion of genetic heterogeneity of retinal macular dystrophy, see MCDR1 (136550).
Clinical Features
Michaelides et al. (2003) described a nonconsanguineous British family in which 11 members in 5 generations had a 'bull's eye' macular dystrophy first evident in the first or second decade of life. All of those affected had mild visual impairment and central scotomata. Electrophysiologic testing indicated that most individuals had disease confined to the central retina, but older subjects had more widespread rod and cone abnormalities, as demonstrated by flash electroretinogram.
Michaelides et al. (2010) examined affected members of 3 families known to carry the R373C mutation in the PROM1 gene (604365.0003), including a Caribbean family with Stargardt disease-4 (STGD4; 603786), originally reported by Kniazeva et al. (1999), the British family with MCDR2, originally reported by Michaelides et al., 2003, and an Italian family with cone-rod dystrophy-12 (CORD12; 612657), originally reported by Yang et al. (2008), as well as 2 newly ascertained British families with MCDR2 (families 'D' and 'E'). The authors observed that in contrast to PROM1 mutations that cause a severe form of autosomal recessive retinitis pigmentosa (RP41; 612095), the R373C mutation produces an autosomal dominant, fully penetrant retinopathy characterized by the consistent finding of bull's eye maculopathy, with variable rod or rod-cone dysfunction displaying marked intra- and interfamilial variability, and phenotypes ranging from isolated maculopathy without generalized photoreceptor dysfunction to maculopathy associated with very severe rod-cone dysfunction. Michaelides et al. (2010) noted that all reported patients with the R373C mutation exhibited only an ocular phenotype, despite ubiquitous expression of PROM1 in plasma membrane protrusions.
Arrigoni et al. (2011) reexamined affected members of 2 families with autosomal dominant macular degeneration and the R373C PROM1 mutation, i.e., the family reported by Michaelides et al. (2003) and family 'D' (Sisodiya, 2011) reported by Michaelides et al. (2010). Because of the putative role of PROM1 in hippocampal neurogenesis, Arrigoni et al. (2011) studied brain structure and function, and also examined other parameters including measures of vascular and endothelial function and angiogenic capacity. They found that 3 of the 4 members examined from 1 family had empty sella turcica on brain MRI, 2 of whom also had impaired olfaction; MRI was normal in the 2 patients examined from the second family, although 1 also had impaired olfaction. Aspects of endothelial function assayed ex vivo were abnormal in patients with the R373C mutation compared to controls, with impaired adhesion capacity and higher levels of cellular damage. Renal infections, hematuria, and recurrent miscarriages were also noted in these patients. Arrigoni et al. (2011) stated that further studies were needed to confirm these findings.
Mapping
In a British family with an autosomal dominant 'bull's eye' macular dystrophy, Michaelides et al. (2003) found linkage of the disorder to chromosome 4p16.3-p15.2 with a maximum lod score of 3.03 at a recombination faction of 0.00 for marker D4S391. The locus, which the authors termed MCDR2, was situated between markers D4S3023 and D4S3022, and overlapped the locus for Stargardt disease-4 (STGD4; 603786).
Molecular Genetics
In affected members of a 5-generation British family with autosomal dominant 'bull's eye' macular dystrophy, previously reported by Michaelides et al. (2003), Yang et al. (2008) identified heterozygosity for a missense mutation in the PROM1 gene (604365.0003). Yang et al. (2008) identified the same mutation in a family with Stargardt disease-4 and in a family with cone-rod dystrophy (CORD12; 612657); the mutation was not found in 400 matched controls.
INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Bilateral macular retinal pigment epithelial mottling \- Bilateral macular retinal pigment epithelial atrophy \- Bilateral red-speckled retinal pigment epithelium \- Ring of moderately increased perifoveal autofluorescence \- Dyschromatopsia \- Gradual progressive loss of central visual acuity \- Central scotomata \- Electro-oculogram (EOG), flash electroretinogram (ERG) and pattern ERG (PERG) initially normal \- Greatly reduced light-adapted scotopic and photopic ERG by 7th decade \- Unrecordable PERG by 7th decade MOLECULAR BASIS \- Caused by mutation in the prominin 1 gene (PROM1, 604365.0003 ) ▲ Close
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*[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 inhibitors
*[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
| MACULAR DYSTROPHY, RETINAL, 2 | c0339512 | 4,804 | omim | https://www.omim.org/entry/608051 | 2019-09-22T16:08:22 | {"mesh": ["C562746"], "omim": ["608051"], "orphanet": ["319640"]} |
A rare disorder that disrupts the synthesis of estradiol, resulting in hirsutism of mothers during gestation of an affected child; pseudohermaphroditism and virilization in women; and tall stature, osteoporosis and obesity in men.
## Epidemiology
Fewer than 20 cases have been reported to date.
## Clinical description
Affected female newborns present with different degrees of ambiguous genitalia, virilization and non-palpable gonads, in one case female genitalia were present. Female internal genitalia differentiation is unaffected. Ovarian cystic follicles may appear in childhood, even at birth, or adolescence when patients manifest primary amenorrhea and no pubertal growth spurt. Breasts remain hypoplastic after initial development during puberty, while pubic hairs develop in a normal fashion. Males may present with cryptorchidism, but are generally asymptomatic until after puberty when patients present with bone pain and tall stature. The pubertal growth spurt is absent, but linear growth continues due to incomplete epiphyseal closure and progressive genu valgum, eunuchoid proportion of the skeleton and osteoporosis manifest. For these reasons the diagnosis is often overlooked in men. Metabolic co-morbidities may manifest as obesity, steatohepatitis, insulin resistance with acanthosis nigricans and dyslipidemia. Fertility is partially or completely disrupted in male patients.
## Etiology
Aromatase (CYP19A1, 15q21.1), or cytochrome P450, synthesizes estradiol from androgens. Several null mutations have been identified, placental expression of aromatase converts androgens to estradiol; excess androgens affect both the mother and fetal development. One reported case of a promoter region mutation exclusively inhibited placental expression.
## Diagnostic methods
Females are generally diagnosed at birth. Male patients are usually diagnosed during adulthood due to continuing linear growth in height and unfused epiphyses are revealed by hand radiographs. Measurement of serum estradiol, testosterone and luteinizing hormone may be followed by genetic testing.
## Differential diagnosis
In female patients, differential diagnosis includes congenital adrenal hyperplasia (see this term); in male patients, estrogen resistance syndrome 46,XY disorder of sex development due to isolated 17, 20 lyase deficiency, congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency and congenital hypogonadotropic hypogonadism (see these terms).
## Antenatal diagnosis
During the third trimester of gestation, mothers exhibit severe acne, deep voice and in some cases clitoral enlargement and hirsutism, symptoms resolve spontaneously post-partum. Genetic testing is recommended in these cases.
## Genetic counseling
Genetic testing is recommended for families who have had one affected child, transmission is autosomal recessive.
## Management and treatment
Female patients are candidates for surgical modification of genitalia depending on the degree of ambiguity and must be monitored for ovarian cysts. Upon puberty, daily treatment with estrogen must be administered (0.625 mg/twice weekly increasing to daily) and may be supplemented with progesterone-like hormone and monthly treatments of gonadotrophin-releasing hormone antagonists. Adult men should be treated immediately upon diagnosis: daily transdermal administration of up to 50 µg of estradiol (serum estradiol at 40 pg/ml) for 6-9 months to complete skeletal maturation. Upon epiphyseal closure, estradiol replacement may be reduced to 25 µg daily. Hypocaloric diet should be complemented with calcium, vitamin D and physical activity. Dyslipidemia, glucose intolerance or insulin resistance must be treated symptomatically.
## Prognosis
Lifetime hormone replacement therapy is obligatory. In male patients with late diagnosis, skeletal defects remain even after successful hormonal treatment and may require surgical correction. Furthermore, adiposity and fertility defects are not alleviated by estradiol 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 inhibitors
*[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
| Aromatase deficiency | c1960539 | 4,805 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=91 | 2021-01-23T17:18:26 | {"gard": ["365"], "mesh": ["C537436"], "omim": ["613546"], "umls": ["C0853662", "C0878680", "C1960539"], "icd-10": ["E25.8"], "synonyms": ["Congenital estrogen deficiency"]} |
Lymphedema-cerebral arteriovenous anomaly syndrome is characterised by the variable association of a cerebrovascular malformation, foot lymphoedema and primary pulmonary hypertension. It has been described in a woman and four of her children.
*[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 inhibitors
*[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
| Lymphedema-cerebral arteriovenous anomaly syndrome | c1835272 | 4,806 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86914 | 2021-01-23T17:27:12 | {"gard": ["9217"], "mesh": ["C563612"], "omim": ["152900"], "umls": ["C1835272"]} |
Permanent neonatal diabetes mellitus
Other namesPNDM
SpecialtyNeonatology
Permanent neonatal diabetes mellitus (PNDM) is a newly identified and potentially treatable form of monogenic diabetes. This type of neonatal diabetes is caused by activating mutations of the KCNJ11 gene, which codes for the Kir6.2 subunit of the beta cell KATP channel.[1][2] This disease is considered to be a type of maturity onset diabetes of the young (MODY).
## Contents
* 1 Cause
* 2 Diagnosis
* 3 Treatment
* 4 See also
* 5 References
* 6 External links
## Cause[edit]
It can be associated with GCK, KCNJ11, INS, and ABCC8.[3]
## Diagnosis[edit]
This results in congenital impairment of insulin release, although in the past, this was always being thought to be unusually early type 1 diabetes mellitus. The insulin deficiency results in intrauterine growth retardation with birth weight small for gestational age. The diabetes is usually diagnosed in the first 3 months of life due to continuing poor weight gain, polyuria, or diabetic ketoacidosis. Rare cases have been recognized as late as 6 months of age.
## Treatment[edit]
Remarkably, this type of diabetes often responds well to sulfonylureas and insulin may not be necessary. More severe mutations in the KCNJ11 gene can cause early-onset diabetes which does not respond to the sulfonylurea drugs, as well as a syndrome of developmental delay and neurological features called the DEND syndrome. These forms of diabetes are very rare conditions, appearing in about 1/100,000 to 1/200,000 live births, and accounting for about 1/1000 of type 1 diabetes cases. Fewer than 5% of the cases assumed to exist have been diagnosed, and most diabetes clinics around the world are checking for KCNJ11 mutations in any persons who developed apparent insulin-dependent diabetes without the typical type 1 antibodies before 6 months of age. At least some of these people have been able to change from insulin to sulfonylurea pills after decades of injections.[citation needed]
## See also[edit]
* Transient neonatal diabetes mellitus
## References[edit]
1. ^ Hattersley A, Gloyn A, Pearson E, Edgehill E, Flanagan S, Ellard S. Novel monogenic diabetes results from activating mutations in Kir6.2 Presented at the First Meeting for the European Group for the Study of Monogenic Diabetes ("MODY in Malaga"); Malaga, Spain, 21 October 2004. Published form should be available in 2005.
2. ^ Letha S, Mammen D, Valamparampil JJ (October 2007). "Permanent neonatal diabetes due to KCNJ11 gene mutation". Indian J Pediatr. 74 (10): 947–9. doi:10.1007/s12098-007-0175-y. PMID 17978456. Archived from the original on June 10, 2008.
3. ^ Online Mendelian Inheritance in Man (OMIM): 606176
## External links[edit]
* GeneReviews/NCBI/NIH/UW entry on Permanent Neonatal Diabetes Mellitus
* DiabetesGenes - Information about diagnosis, testing and treatment of neonatal diabetes
Classification
D
* OMIM: 606176
External resources
* GeneReviews: Permanent Neonatal Diabetes Mellitus
* v
* t
* e
Diabetes
Types
* Type 1
* Type 2
* LADA
* Gestational diabetes
* Diabetes and pregnancy
* Prediabetes
* Impaired fasting glucose
* Impaired glucose tolerance
* Insulin resistance
* KPD
* MODY
* Neonatal
* Transient
* Permanent
* Type 3c (pancreatogenic)
* Type 3
Blood tests
* Blood sugar level
* Glycosylated hemoglobin
* Glucose tolerance test
* Postprandial glucose test
* Fructosamine
* Glucose test
* C-peptide
* Noninvasive glucose monitor
* Insulin tolerance test
Management
* Diabetic diet
* Anti-diabetic drugs
* Insulin therapy
* intensive
* conventional
* pulsatile
* Cure
* Embryonic stem cells
* Artificial pancreas
* Other
* Gastric bypass surgery
Complications
* Diabetic comas
* Hypoglycemia
* Ketoacidosis
* Hyperosmolar hyperglycemic state
* Diabetic foot
* ulcer
* Neuropathic arthropathy
* Organs in diabetes
* Blood vessels
* Muscle
* Kidney
* Nerves
* Retina
* Heart
* Diabetic skin disease
* Diabetic dermopathy
* Diabetic bulla
* Diabetic cheiroarthropathy
* Neuropathic ulcer
* Hyperglycemia
* Hypoglycemia
Other
* Glossary of diabetes
* History of diabetes
* Notable people with type 1 diabetes
*[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 inhibitors
*[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
| Permanent neonatal diabetes | c1833104 | 4,807 | wikipedia | https://en.wikipedia.org/wiki/Permanent_neonatal_diabetes | 2021-01-18T18:47:15 | {"gard": ["10457"], "mesh": ["C563425"], "umls": ["C1833104"], "orphanet": ["79134", "99885"], "wikidata": ["Q17143640"]} |
Mucolipidosis type 4 is a metabolic condition that affects the body's ability to process certain carbohydrates and fats. As a result, these materials accumulate in cells leading to the various signs and symptoms of the condition. Most people with mucolipidosis type 4 develop severe psychomotor (mental and motor skills) delay by the end of the first year of life and visual impairment that worsens over time. Other common features of the condition include limited or absent speech; intellectual disability; hypotonia that gradually progresses to spasticity; problems controlling hand movements; impaired production of stomach acids; and iron deficiency. Approximately 5% of affected people have a mild form of the condition (known as atypical mucolipidosis type 4) which is associated with milder psychomotor delay and less severe eye abnormalities. Mucolipidosis type 4 is caused by changes (mutations) in the MCOLN1 gene and is inherited in an autosomal recessive manner. Treatment is based on the signs and symptoms present in each person.
*[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 inhibitors
*[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
| Mucolipidosis type 4 | c0238286 | 4,808 | gard | https://rarediseases.info.nih.gov/diseases/94/mucolipidosis-type-4 | 2021-01-18T17:58:57 | {"mesh": ["D009081"], "omim": ["252650"], "umls": ["C0238286"], "orphanet": ["578"], "synonyms": ["ML 4", "Berman syndrome", "Ganglioside neuraminidase deficiency", "Ganglioside sialidase deficiency", "Mucolipidosis type IV"]} |
Otic polyp
Other namesAural polyp
An intermediate magnification of a H&E stained biopsy from an otic polyp.
SpecialtyENT surgery
An otic polyp is a benign proliferation of chronic inflammatory cells associated with granulation tissue, in response to a longstanding inflammatory process of the middle ear.[1][2]
## Contents
* 1 Signs and symptoms
* 2 Diagnosis
* 2.1 Imaging
* 2.2 Pathology
* 2.3 Immunohistochemistry
* 2.4 Differential diagnoses
* 3 Management
* 4 Epidemiology
* 5 References
* 6 Further reading
* 7 External links
## Signs and symptoms[edit]
Patients usually present with otorrhea, conductive hearing loss, and otalgia, while bleeding and a sensation of a mass are much less common.[2]
## Diagnosis[edit]
### Imaging[edit]
Although imaging is not required to yield a diagnosis, it may be obtained to exclude other disorders, such as a concurrent cholesteatoma.
### Pathology[edit]
By gross description, there is usually a solitary, polypoid, reddish mass behind an intact ear drum (tympanic membrane). The tissue is often friable, measuring <2 cm in most cases. All tissue should be processed in order to exclude a concurrent cholesteatoma.[3]
By microscopic exam, the polypoid appearance is maintained, showing a granulation-type tissue reaction with edematous stroma and a rich investment by capillaries. The surface of the polyp is covered by stratified squamous epithelium with a prominent granular cell layer. The tissue is filled with lymphocytes, plasma cells, mast cells, histiocytes, and eosinophils. It is not uncommon to see plasma cells with Russell bodies and Mott cell formation. Depending on length of symptoms, multinucleated giant cells and calcifications may be seen. Other disorders may be concurrently present, especially since this is a post infectious/inflammatory disorder, and these include a cholesterol granuloma, "tunnel clusters" (glandular epithelial inclusions below the surface epithelium), and cholesteatoma.[3][4][5]
### Immunohistochemistry[edit]
Immunohistochemistry is unnecessary for the diagnosis, but will highlight a mixed B- and T-cell population within the lymphoid component, without light chain (kappa or lambda) restriction. Any muscle markers would be negative.
### Differential diagnoses[edit]
The lesion presents in young patients, so the differential for a "polyp", especially when the lymphoid component is crushed or dominant, would include a rhabdomyosarcoma, extramedullary plasmacytoma, and a neuroendocrine adenoma of the middle ear.
## Management[edit]
Since this lesion is usually a complication of long standing otitis media, it is important to use an appropriate antibiotic therapy regimen. If the patient fails first line antibiotics, then second-line therapies should be employed, especially after appropriate culture and sensitivity testing. Surgery may be required if there is extension into the mastoid bone, or if a concurrent cholesteatoma is identified during surgery or biopsy. In general, patients have an excellent outcome after appropriate therapy.[1][2][3]
## Epidemiology[edit]
This is an uncommon lesion, usually affecting young patients (mean age, 30 years), with a male to female ratio of 2:1. The middle ear is involved, although it may extend to the external auditory canal if there is tympanic membrane perforation.[1][2][3]
## References[edit]
1. ^ a b c Prasannaraj, T.; De, N. S.; Narasimhan, I. (2003). "Aural polyps: Safe or unsafe disease?". American Journal of Otolaryngology. 24 (3): 155–158. doi:10.1016/s0196-0709(02)32426-8. PMID 12761701.
2. ^ a b c d Gliklich, R. E.; Cunningham, M. J.; Eavey, R. D. (1993). "The cause of aural polyps in children". Archives of Otolaryngology–Head & Neck Surgery. 119 (6): 669–671. doi:10.1001/archotol.1993.01880180089016. PMID 8499099.
3. ^ a b c d Friedmann, I. (1990). "Pathological lesions of the external auditory meatus: A review". Journal of the Royal Society of Medicine. 83 (1): 34–37. doi:10.1177/014107689008300115. PMC 1292463. PMID 2406442.
4. ^ Nair, S.; Watts, S.; Flood, L. (2006). "Fibroblast growth factor receptor expression in aural polyps: Predictor of cholesteatoma?". The Journal of Laryngology & Otology. 118 (5): 338–342. doi:10.1258/002221504323086507. PMID 15165306.
5. ^ Hussain, S. S.; Hopkinson, J. M. (1995). "Mast cells in aural polyps: A preliminary report". The Journal of Laryngology and Otology. 109 (6): 491–494. doi:10.1017/s0022215100130543. PMID 7543918.
## Further reading[edit]
Lester D. R. Thompson; Bruce M. Wenig (2011). Diagnostic Pathology: Head and Neck: Published by Amirsys. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 7:16–17. ISBN 978-1-931884-61-7.
## External links[edit]
Classification
D
External resources
* MedlinePlus: 001638
*[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 inhibitors
*[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
| Otic polyp | c0271466 | 4,809 | wikipedia | https://en.wikipedia.org/wiki/Otic_polyp | 2021-01-18T19:09:16 | {"umls": ["C0271466"], "wikidata": ["Q7108724"]} |
Ineffective erythropoiesis is active erythropoiesis with premature death of red blood cells, a decreased output of RBCs from the bone marrow, and, consequently, anemia. It is a condition characterised by the presence or abundance of dysfunctional progenitor cells.[1]
## See also[edit]
* Congenital dyserythropoietic anemias
* List of hematologic conditions
## References[edit]
1. ^ Nelson Textbook of Pediatrics, 18th ed
*[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 inhibitors
*[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
| Ineffective erythropoiesis | c0392708 | 4,810 | wikipedia | https://en.wikipedia.org/wiki/Ineffective_erythropoiesis | 2021-01-18T19:01:15 | {"umls": ["C0392708"], "wikidata": ["Q2380264"]} |
A rare genetic neurodegenerative disease characterized by neonatal to infantile onset of hypotonia, developmental delay, regression of motor skills with distal amyotrophy, ataxia, and spasticity, absent speech or dysarthria, and moderate to severe cognitive impairment. Optic atrophy may also be associated. Brain imaging shows cerebellar atrophy and thin corpus callosum, as well as brain iron accumulation in the pallidum and substantia nigra beginning during the second decade of life.
*[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 inhibitors
*[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
| Early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome | c4310667 | 4,811 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=496756 | 2021-01-23T19:05:58 | {"omim": ["617207"], "icd-10": ["G11.0"]} |
Metabolic myopathy due to lactate transporter defect is a rare metabolic myopathy characterized by muscle cramping and/or stiffness after exercise (especially during heat exposure), post-exertional rhabdomyolysis and myoglobinuria, and elevation of serum creatine kinase.
*[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 inhibitors
*[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
| Metabolic myopathy due to lactate transporter defect | c1855577 | 4,812 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=171690 | 2021-01-23T18:37:50 | {"mesh": ["C565449"], "omim": ["245340"], "umls": ["C1855577"], "icd-10": ["G72.8"], "synonyms": ["Erythrocyte lactate transporter defect"]} |
Spinocerebellar ataxia type 23 (SCA23) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by gait ataxia, dysarthria, slowed saccades, ocular dysmetria, Babinski sign and hyperreflexia.
## Epidemiology
This subtype has only been described in 4 Dutch families. Age of onset is from 43 to 56 years.
## Clinical description
The clinical features, head magnetic resonance imaging (MRI), and neuropathological findings are indistinguishable from other SCA subtypes.
## Etiology
SCA23 maps to chromosome region 20p12.3-p13 and missense mutations in the prodynorphin PDYN gene appear to cause the disease.
## Prognosis
Prognosis may be good in some cases. Disease progression can be slow. Wheelchair dependence can occur more than 20 years after symptomatic disease onset.
*[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 inhibitors
*[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
| Spinocerebellar ataxia type 23 | c1853250 | 4,813 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=101108 | 2021-01-23T17:31:26 | {"gard": ["9950"], "mesh": ["C537201"], "omim": ["610245"], "umls": ["C1853250"], "icd-10": ["G11.2"], "synonyms": ["SCA23"]} |
Medical condition involving extreme fatigue among other symptoms
Chronic fatigue syndrome
Other namesMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS),[1] myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), systemic exertion intolerance disease (SEID), others[2]:20
SpecialtyPrimary care, neurology, rheumatology, infectious diseases, physical therapy, occupational therapy, mental health, behavioral health[2]:223
SymptomsWorsening of symptoms with activity, long-term fatigue, others[1]
Usual onset40 to 60 years old[3]
DurationOften years[4]
CausesUnknown[1]
Risk factorsFemale gender, virus and bacterial infections, genetics, major injury, bodily response to severe stress and others[5][6]:1–2
Diagnostic methodBased on symptoms[1]
TreatmentSymptomatic[7][8]
FrequencyAbout 0.68 to 1% globally[9][10]
Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME) and ME/CFS, is a complex, fatiguing, long-term medical condition diagnosed by required primary symptoms and criteria, often involving a broad range of symptoms. Distinguishing core symptoms are lengthy exacerbations or "flares" of the illness after ordinary minor physical or mental activity, known as post-exertional malaise (PEM);[11][12] greatly diminished capacity to accomplish tasks that were routine before the illness; and sleep disturbances.[11][13][1][4][2]:7 Orthostatic intolerance (difficulty sitting and standing upright) and cognitive dysfunction are also diagnostic. Other common symptoms may involve numerous body systems, and chronic pain is common.[13][1]
While the cause is not understood, proposed mechanisms include biological, genetic, infectious, and physical or psychological stress affecting the biochemistry of the body.[5][14] Diagnosis is based on the patient's symptoms because no confirmed diagnostic test is available.[15] The fatigue in CFS is not due to strenuous ongoing exertion, is not much relieved by rest, and is not due to a previous medical condition.[13] Fatigue is a common symptom in many illnesses, but the unexplained fatigue and severity of functional impairment in CFS are relatively rare in these other illnesses.[16]
Persons with CFS may recover or improve over time, but some will become severely affected and disabled for an extended period.[17] No therapies or medications are approved to treat the cause of the illness; treatment is aimed at symptomatology.[7][18] The CDC recommends pacing (personal activity management) to keep mental and physical activity from making symptoms worse.[7] Limited evidence suggests that rintatolimod, counseling, and graded exercise helps some patients.[19]
About 1% of primary-care patients have CFS; estimates of incidence vary widely because epidemiological studies define the illness dissimilarly.[10][15][9] It has been estimated that 836,000 to 2.5 million Americans and 250,000 to 1,250,000 people in the United Kingdom have CFS.[1][20] CFS occurs 1.5 to 2 times as often in women as in men.[10] It most commonly affects adults between ages 40 and 60 years;[3] it can occur at other ages, including childhood.[21] Other studies suggest that about 0.5% of children have CFS, and that it is more common in adolescents than in younger children.[2]:182[21] Chronic fatigue syndrome is a major cause of school absence.[2]:183 CFS reduces health, happiness, and productivity; but there is controversy over many aspects of the disorder. Physicians, researchers, and patient advocates promote different names[22] and diagnostic criteria; and evidence of proposed causes and treatments is often poor or contradictory.[23]
## Contents
* 1 Signs and symptoms
* 1.1 Other common symptoms
* 1.2 Onset
* 1.3 Physical functioning
* 1.4 Cognitive functioning
* 2 Cause
* 2.1 Risk factors
* 2.2 Viral and other infections
* 3 Pathophysiology
* 3.1 Neurological
* 3.2 Immunological
* 3.3 Endocrine
* 3.4 Energy metabolism
* 4 Diagnosis
* 4.1 Suggested diagnostic tools
* 4.2 Definitions
* 4.3 Differential diagnosis
* 5 Management
* 5.1 Pacing
* 5.1.1 Energy envelope theory
* 5.2 Exercise
* 5.3 Counseling
* 5.4 Nutrition
* 6 Therapies
* 6.1 Cognitive behavioral therapy
* 6.2 Graded exercise therapy
* 6.3 Adaptive pacing therapy
* 6.4 Rintatolimod
* 7 Prognosis
* 8 Epidemiology
* 9 History
* 9.1 Myalgic encephalomyelitis
* 9.2 Chronic fatigue syndrome
* 9.3 Other medical terms
* 10 Society and culture
* 10.1 Naming
* 10.2 Economic impact
* 10.3 Awareness day
* 10.4 Doctor–patient relations
* 10.5 Blood donation
* 10.6 Controversy
* 10.7 Research funding
* 10.7.1 United Kingdom
* 10.7.2 United States
* 10.8 Notable cases
* 11 Research
* 12 References
* 13 External links
## Signs and symptoms[edit]
The United States Centers for Disease Control and Prevention (CDC) recommends these criteria for diagnosis:[13]
1. Greatly lowered ability to do activities that were usual before the illness. This drop in activity level occurs along with fatigue and must last six months or longer.
2. Worsening of symptoms after physical or mental activity that would not have caused a problem before the illness. The amount of activity that might aggravate the illness is difficult for a person to predict, and the decline often presents 12 to 48 hours after the activity.[24] The 'relapse', or 'crash', may last days, weeks or longer. This is known as post-exertional malaise (PEM).
3. Sleep problems; people may still feel weary after full nights of sleep, or may struggle to stay awake, fall asleep or stay asleep.
Additionally, one of the following symptoms must be present:[13]
* Problems with thinking and memory (cognitive dysfunction, sometimes described as "brain fog")
* While standing or sitting upright; lightheadedness, dizziness, weakness, fainting or vision changes may occur (orthostatic intolerance)
### Other common symptoms[edit]
Many, but not all people with ME/CFS report:[13]
* Muscle pain, joint pain without swelling or redness, and headache
* Tender lymph nodes in the neck or armpits
* Sore throat
* Irritable bowel syndrome
* Chills and night sweats
* Allergies and sensitivities to foods, odors, chemicals, lights, or noise
* Shortness of breath
* Irregular heartbeat
The CDC proposes that persons with symptoms resembling those of CFS consult a physician to rule out several treatable illnesses: Lyme disease,[25][failed verification] "sleep disorders, major depressive disorder, alcohol/substance abuse, diabetes mellitus, hypothyroidism, mononucleosis (mono), lupus, multiple sclerosis (MS), chronic hepatitis and various malignancies."[26][failed verification] Medications can also cause side effects that mimic symptoms of CFS.[25][failed verification] Central sensitization, or increased sensitivity to sensory stimuli such as pain have been observed in CFS. Sensitivity to pain increases after exertion, which is opposite to the normal pattern.[27]
### Onset[edit]
Gradual or sudden onset of the illness may occur, and studies have mixed results as to which occurs more frequently.[2]:158:181
### Physical functioning[edit]
The functional capacity of individuals with CFS varies greatly.[28] Some persons with CFS lead relatively normal lives; others are totally bed-ridden and unable to care for themselves.[29] For the majority of persons with CFS, work, school, and family activities are significantly reduced for extended periods of time.[30] The severity of symptoms and disability is the same regardless of gender,[31] and many experience strongly disabling chronic pain.[32] Persons report critical reductions in levels of physical activity.[33] Also, a reduction in the complexity of activity has been observed.[34] Reported impairment is comparable to other fatiguing medical conditions[35] including late-stage AIDS,[36] lupus, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and end-stage kidney disease.[37][failed verification] CFS affects a person's functional status and well-being more than major medical conditions such as multiple sclerosis, congestive heart failure, or type II diabetes mellitus.[38][39]
Often, courses of remission and relapse of symptoms occur, which make the illness difficult to manage. Persons who feel better for a period may overextend their activities, and the result can be a worsening of their symptoms with a relapse of the illness.[24]
About 25% of people with CFS are house-bound or bed-ridden for long periods during their illness, often for decades.[2]:32[4] An estimated 75% are unable to work because of their illness.[40] More than half were on disability benefits or temporary sick leave, and less than a fifth worked full-time.[29] Children who become ill with CFS are a major cause of school absence.
[2]:183
People with CFS have decreased scores on the SF-36 quality of life questionnaire, especially in the sub scales on vitality, physical functioning, general health, physical role, and social functioning; however, the sub scales for "role emotional" and mental health in CFS patients were consistent with or not substantially lower than healthy controls.[41] Direct healthcare costs are estimated at between $9 and $14 billion annually in the U.S. alone.[40]
### Cognitive functioning[edit]
Cognitive dysfunction is one of the more disabling aspects of CFS due to its negative impact on occupational and social functioning. 50 to 80 % of persons with CFS are estimated to have serious problems with cognition.[42] Cognitive symptoms are mainly due to deficits in attention, memory, and reaction time. Measured cognitive abilities are found to be below projected normal values and likely to affect day-to-day activities; for example, increases in common mistakes, forgetting scheduled tasks, or having difficulty responding when spoken to are observed.[43]
Simple and complex information-processing speed, and functions entailing working memory over long time periods are moderately to extensively impaired. These deficits are generally consistent with the patient's perceptions. Perceptual abilities, motor speed, language, reasoning, and intelligence do not appear to be significantly altered. When poorer health status was reported, a person's perception of their cognitive problems was frequently greater. Better physical functioning in people with CFS is associated with less visuoperceptual difficulty and fewer language-processing complaints.[43]
Inconsistencies of subjective and observed values of cognitive dysfunction reported across multiple studies are likely caused by a number of factors. Differences of research participants' cognitive abilities pre and post illness onset are naturally variable, and are difficult to measure because of a lack of specialized analytical tools that can consistently quantify the specific cognitive difficulties in CFS.[43]
The frequency of neuropsychiatric and neuropsychological symptoms is increased in the population of persons with CFS; the understanding of why this occurs is unresolved. Various hypotheses have been advanced to try to explain the relationship between the cognitive symptoms and the illness. Some researchers believe psychiatric causes underlie or contribute to the illness, while other researchers believe the illness causes biochemical and sociological changes in people that produce the symptoms.[42]
## Cause[edit]
The cause of CFS is unknown.[44] Genetic, physiological, and psychological factors are thought to work together to precipitate and perpetuate the condition.[14] A 2016 report by the Institute of Medicine states that CFS is a biologically based illness, but that the biologic abnormalities are not sensitive or specific enough to be useful as a diagnosis.[44]
Because it may begin as an influenza-like illness with a sudden onset, various infectious causes have been proposed, but evidence is insufficient to support such causation.[45][2] Infections proposed include mononucleosis, Chlamydophila pneumoniae, human herpesvirus 6, and Lyme disease. Inflammation may be involved.[46] Often, the illness will follow a viral illness, such as mononucleosis or gastroenteritis.[47]
### Risk factors[edit]
All ages, ethnic groups, and income levels are susceptible to the illness. The CDC states that Caucasians may be diagnosed more frequently than other races in America,[4] but the illness is at least as prevalent among African Americans and Hispanics.[3] A 2009 meta-analysis showed that compared with Caucasians, African Americans, and Native Americans have a higher risk of CFS, though it specifically excluded other more common ethnicities worldwide, and it acknowledged that studies and data were limited.[48]
More women than men get CFS.[4] A large 2020 meta-analysis estimated that between 1.5 and 2.0 times more cases are women. The review acknowledged that different case definitions and diagnostic methods within datasets yielded a wide range prevalence rates.[10] The CDC estimates CFS occurs up to four times more often in women than in men.[3] The illness can occur at any age, but most frequently in persons between the ages of 40 and 60.[3] CFS is less prevalent among children and adolescents than among adults.[21]
Blood relatives of those who have CFS appear to be more predisposed, implying that genetic factors may increase the risk of susceptibility to the illness.[12]
Psychological stress, childhood trauma, perfectionist personalities, old age, lower middle education, low physical fitness, preexisting psychological illness, and allergies may be risk factors for developing chronic fatigue syndrome. This has led some to believe that stress-related visceral responses underlie CFS.[49][50] Pre-existing depressive and anxiety disorders, as well as high expectation of parents and family history were predisposing factors identified in another review.[51]
People with CFS and their relatives tend to attribute their illness to physical causes (such as a virus or pollution) rather than to psychological causes,[14][52] and these attributions are associated with increased symptoms and impairment, and worse outcomes over time.[14] According to the CDC, "CFS is a biological illness, not a psychologic disorder", and those affected "are neither malingering nor seeking secondary gain".[53] The World Health Organization (WHO) classifies CFS as a neurological disease in the ICD-11 for Mortality and Morbidity Statistics (ICD-11).[54]
### Viral and other infections[edit]
The term post-viral fatigue syndrome (PVFS) is used to describe CFS-like symptoms that occur after a viral infection.[6] A recent review found Epstein-Barr Virus (EBV) antibody activity to be higher in patients with CFS, and that a subset of patients with CFS were likely to have increased EBV activity compared to controls.[55] Viral infection is a significant risk factor for CFS, with one study finding 22% of people with Epstein-Barr virus experience fatigue six months later, and 9% having strictly defined CFS.[56] A systematic review found that fatigue severity was the main predictor of prognosis in CFS, and did not identify psychological factors linked to prognosis.[57] One review found risk factors for developing CFS after mononucleosis, dengue fever or the bacterial infection Q-fever include longer bed-rest during the illness, poorer pre-illness physical fitness, attributing symptoms to physical illness, belief that a long recovery time is needed, as well as pre-infection distress and fatigue. The same review found biological factors such as CD4 and CD8 activation and liver inflammation are predictors of sub-acute fatigue, but not CFS,[58] however these findings are not generally accepted due to the use of the Oxford criteria in selecting patients. The CDC does not recognize attribution of symptoms as a risk factor.[5]
A study comparing diagnostic labels found that people labelled with ME had the worst prognosis, while those with PVFS had the best. Whether this is due to those with more severe or longer lasting symptoms results in a label with the description of ME, or if being labelled with ME adversely causes a more severe or prolonged illness is unclear.[59]
## Pathophysiology[edit]
### Neurological[edit]
> Brain imagining, comparing adolescents with CFS and healthy controls showing abnormal network activity in regions of the brain.
>
> A range of neurological structural and functional abnormalities is found in people with CFS, including lowered metabolism at the brain stem, and reduced blood flow to areas of the brain; these differences are consistent with neurological illness, but not depression or psychological illness.[6] The World Health Organization classes chronic fatigue syndrome as a central nervous system disease.[60]
>
>
> Some neuroimaging studies have observed prefrontal and brainstem hypometabolism; however, sample size was limited.[61] Neuroimaging studies in persons with CFS have identified changes in brain structure, and correlations with various symptoms. Results were not consistent across the neuroimaging brain structure studies, and more research is needed to resolve the discrepancies found between the disparate studies.[62][61]
>
> Tentative evidence suggests a relationship between autonomic nervous system dysfunction and diseases such as CFS, fibromyalgia, irritable bowel syndrome, and interstitial cystitis. However, it is unknown if this relationship is causative.[63] Reviews of CFS literature have found autonomic abnormalities such as decreased sleep efficiency, increased sleep latency, decreased slow wave sleep, and abnormal heart rate response to tilt table tests suggesting a role of the autonomic nervous system in CFS. However, these results were limited by inconsistency.[64][65][66]
### Immunological[edit]
Immunological abnormalities are frequently observed in those with CFS. Decreased NK cell activity is found more often in people with CFS and this correlates with severity of symptoms.[5][67] People with CFS have an abnormal response to exercise, including increased production of complement products, increased oxidative stress combined with decreased antioxidant response, and increased Interleukin 10, and TLR4, some of which correlates with symptom severity.[68] Increased levels of cytokines have been proposed to account for the decreased ATP production and increased lactate during exercise;[69][70] however, the elevations of cytokine levels are inconsistent in specific cytokine, albeit frequently found.[2][71] Similarities have been drawn between cancer and CFS with regard to abnormal intracellular immunological signaling. Abnormalities observed include hyperactivity of Ribonuclease L, a protein activated by IFN, and hyperactivity of NF-κB.[72]
### Endocrine[edit]
Evidence points to abnormalities in the hypothalamic-pituitary-adrenal axis (HPA axis) in some, but not all, persons with CFS, which may include slightly low cortisol levels,[73] a decrease in the variation of cortisol levels throughout the day, decreased responsiveness of the HPA axis, and a high serotonergic state, which can be considered to be a "HPA axis phenotype" that is also present in some other conditions, including post-traumatic stress disorder and some autoimmune conditions.[74] It is unclear whether or not decreased cortisol levels of the HPA axis plays a primary role as a cause of CFS,[75][76][77] or has a secondary role in the continuation or worsening of symptoms later in the illness.[78] In most healthy adults, the cortisol awakening response shows an increase in cortisol levels averaging 50% in the first half-hour after waking. In people with CFS, this increase apparently is significantly less, but methods of measuring cortisol levels vary, so this is not certain.[79]
Autoimmunity has been proposed to be a factor in CFS, but the only relevant finding is a subset of patients with increased B cell activity and autoantibodies, possibly as a result of decreased NK cell regulation or viral mimicry.[80]
### Energy metabolism[edit]
Studies have observed mitochondrial abnormalities in cellular energy production, but recent focus has concentrated on secondary effects that may result in aberrant mitochondrial function because inherent problems with the mitochondria structure or genetics have not been replicated.[81]
## Diagnosis[edit]
No characteristic laboratory abnormalities are approved to diagnose CFS; while physical abnormalities can be found, no single finding is considered sufficient for diagnosis.[82][6] Blood, urine, and other tests are used to rule out other conditions that could be responsible for the symptoms.[83][84][2] The CDC states that a medical history should be taken and a mental and physical examination should be done to aid diagnosis.[83]
### Suggested diagnostic tools[edit]
The CDC recommends considering the questionnaires and tools described in the Institute of Medicine report, which include:
* The Chalder Fatigue Scale
* Multidimensional Fatigue Inventory
* Fisk Fatigue Impact Scale
* The Krupp Fatigue Severity Scale
* DePaul Symptom Questionnaire
* CDC Symptom Inventory for CFS
* Work and Social Adjustment Scale (WSAS)
* SF-36 / RAND-36[2]:270
A two-day cardiopulmonary exercise test (CPET) is not necessary for diagnosis, although lower readings on the second day may be helpful in supporting a claim for social security disability. A two-day CPET cannot be used to rule out chronic fatigue syndrome.[2]:216
### Definitions[edit]
Main article: Clinical descriptions of chronic fatigue syndrome
Notable definitions include:[85]
* Centers for Disease Control and Prevention (CDC) definition (1994),[86] the most widely used clinical and research description of CFS,[14] is also called the Fukuda definition and is a revision of the Holmes or CDC 1988 scoring system.[87] The 1994 criteria require the presence of four or more symptoms beyond fatigue, while the 1988 criteria require six to eight.[88]
* The ME/CFS 2003 Canadian Clinical working definition[89] states: "A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain; have two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations; and the illness persists for at least 6 months".
* The Myalgic Encephalomyelitis International Consensus Criteria (ICC) published in 2011 is based on the Canadian working definition and has an accompanying primer for clinicians[90][6] The ICC does not have a six months waiting time for diagnosis. The ICC requires post-exertional neuroimmune exhaustion (PENE) which has similarities with post-exertional malaise, plus at least three neurological symptoms, at least one immune or gastrointestinal or genitourinary symptom, and at least one energy metabolism or ion transportation symptom. Unrefreshing sleep or sleep dysfunction, headaches or other pain, and problems with thinking or memory, and sensory or movement symptoms are all required under the neurological symptoms criterion.[90] According to the ICC, patients with post-exertional neuroimmune exhaustion but only partially meet the criteria should be given the diagnosis of atypical myalgic encephalomyelitis.[6]
* The 2015 definition by the National Academy of Medicine (then referred to as the "Institute of Medicine") is not a definition of exclusion (differential diagnosis is still required).[2] "Diagnosis requires that the patient have the following three symptoms: 1) A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and 2) post-exertional malaise* 3) Unrefreshing sleep*; At least one of the two following manifestations is also required: 1) Cognitive impairment* 2) Orthostatic intolerance" and notes that "*Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half the time with moderate, substantial, or severe intensity."[2]
Clinical practice guidelines are generally based on case descriptions, with the aim of improving diagnosis, management and treatment. An example is the CFS/ME guideline for the National Health Services in England and Wales, produced in 2007,[88] (presently being updated).[91] Other guidance can be found at the New York Department of Health.[92]
### Differential diagnosis[edit]
Certain medical conditions can cause chronic fatigue and must be ruled out before a diagnosis of CFS can be given. Hypothyroidism, anemia,[93] coeliac disease (that can occur without gastrointestinal symptoms),[94] diabetes and certain psychiatric disorders are a few of the diseases that must be ruled out if the patient presents with appropriate symptoms.[88][86][93] Other diseases, listed by the Centers for Disease Control and Prevention, include infectious diseases (such as Epstein–Barr virus, influenza, HIV infection, tuberculosis, Lyme disease), neuroendocrine diseases (such as thyroiditis, Addison's disease, adrenal insufficiency, Cushing's disease), hematologic diseases (such as occult malignancy, lymphoma), rheumatologic diseases (such as fibromyalgia, polymyalgia rheumatica, Sjögren's syndrome, giant-cell arteritis, polymyositis, dermatomyositis), psychiatric diseases (such as bipolar disorder, schizophrenia, delusional disorders, dementia, anorexia/bulimia nervosa), neuropsychologic diseases (such as obstructive sleep apnea, parkinsonism, multiple sclerosis), and others (such as nasal obstruction from allergies, sinusitis, anatomic obstruction, autoimmune diseases, some chronic illness, alcohol or substance abuse, pharmacologic side effects, heavy metal exposure and toxicity, marked body weight fluctuation).[93] Ehlers Danlos syndromes (EDS) may also have similar symptoms.[95]
Persons with fibromyalgia (FM, or fibromyalgia syndrome, FMS), like those with CFS, have muscle pain, severe fatigue and sleep disturbances. The presence of allodynia (abnormal pain responses to mild stimulation) and of extensive tender points in specific locations differentiates FM from CFS, although the two diseases often co-occur.[96]
Depressive symptoms, if seen in CFS, may be differentially diagnosed from primary depression by the absence of anhedonia, decreased motivation, and guilt; and the presence of somatic symptoms such as sore throat, swollen lymph nodes, and exercise intolerance with post exertional exacerbation of symptoms.[93]
## Management[edit]
Main article: Chronic fatigue syndrome treatment
There is no approved pharmacological treatment, therapy or cure for CFS[7][88] although various drugs have been or are being investigated.[97] A 2014 report prepared by the Agency for Healthcare Research and Quality stated that there are wide variations in patient management, that many receive a multifaceted approach to treatment, and that no medications have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ME/CFS, although several have been used off label. The report concluded that although counseling and graded exercise therapy (GET) have shown some benefits, these interventions have not been studied fully enough to recommend them for all persons affected. The report expressed concern that GET appears to be associated with worsening symptoms in some.[98] The CDC no longer recommends these interventions, and there is some evidence of patient harm.[99][100]
The CDC guide for the management of CFS states that while there is no cure, a number of methods might improve symptoms.[7] Treatment strategies for sleep problems, pain, (depression, stress, and anxiety) dizziness and lightheadedness (orthostatic Intolerance), and memory and concentration problems are enumerated. Other useful topics mentioned that patients and doctors might discuss include carefully monitoring and managing activity to avoid worsening of symptoms, counseling to cope with the impact the illness may have on quality of life, proper nutrition and nutritional supplements that may support better health, complementary therapies that might help increase energy or decrease pain.[7]
The United Kingdom's National Institute for Health and Clinical Excellence (NICE) 2007 guideline directed toward clinicians, specifies the need for shared decision-making between the patient and healthcare professionals, and acknowledges the reality and impact of the condition and the symptoms. The NICE guideline covers illness management aspects of diet, sleep and sleep disorders, rest, relaxation, and pacing. Referral to specialist care for cognitive behavioural therapy, graded exercise therapy and activity management (pacing) programmes are recommended to be offered as a choice to patients with mild or moderate CFS.[101] In 2017 NICE announced its guidance for CFS/ME needed to be updated,[102] and publication is expected in December 2020.[103]
Comorbid conditions can occur in CFS which may interact with and exacerbate the symptoms of CFS. Appropriate medical intervention for these conditions may be beneficial. The most commonly diagnosed include: fibromyalgia, irritable bowel syndrome, depression, anxiety, as well as allergies and chemical sensitivities.[104]
### Pacing[edit]
Pacing, or activity management, is an illness management strategy based on the observation that symptoms tend to increase following mental or physical exertion,[7] and was recommended for CFS in the 1980s.[105] It is now commonly used as a management strategy in chronic illnesses and in chronic pain.[106]
Its two forms are: symptom-contingent pacing, where the decision to stop (and rest or change an activity) is determined by a self awareness of an exacerbation of symptoms; and time-contingent pacing, which is determined by a set schedule of activities that a patient estimates he or she is able to complete without triggering postexertional malaise (PEM). Thus, the principle behind pacing for CFS is to avoid overexertion and an exacerbation of symptoms. It is not aimed at treating the illness as a whole. Those whose illness appears stable may gradually increase activity and exercise levels, but according to the principle of pacing, must rest if it becomes clear that they have exceeded their limits.[105] Use of a heart-rate monitor with pacing to monitor and manage activity levels is recommended by a number of patient groups and the UK's 2007 NICE guideline.[107][102][failed verification]
#### Energy envelope theory[edit]
Energy envelope theory is considered to be consistent with pacing, and is a management strategy suggested in the 2011 international consensus criteria for ME, which referred to using an "energy bank budget". Energy envelope theory was devised by psychologist Leonard Jason, a former sufferer of CFS.[108] Energy envelope theory states that patients should stay within the envelope of energy available to them, and avoid pushing through, which will reduce the postexertional malaise "payback" caused by overexerting and may help them make "modest gains" in physical functioning.[109][110] Several studies have found energy envelope theory to be a helpful management strategy, noting that it reduces symptoms and may increase the level of functioning in CFS.[111][112][110] Energy envelope theory does not recommend unilaterally increasing or decreasing activity and is not intended as a therapy or cure for CFS.[111] It has been promoted by various patient groups.[113][114] Some patient groups recommend using a heart rate monitor to increase awareness of exertion, and allow patients to stay within their aerobic threshold envelope.[115][116] Despite a number of studies showing positive results for energy envelope theory, randomized controlled trials are lacking.
### Exercise[edit]
Stretching, movement therapies, and toning exercises are recommended for pain in patients with CFS, and pain medication is also suggested. In many chronic illnesses, aerobic exercise is beneficial, but in chronic fatigue syndrome, the CDC does not recommend it. The CDC states:[7]
"Any activity or exercise plan for people with ME/CFS needs to be carefully designed with input from each patient. While vigorous aerobic exercise can be beneficial for many chronic illnesses, patients with ME/CFS do not tolerate such exercise routines. Standard exercise recommendations for healthy people can be harmful for patients with ME/CFS. However, it is important that patients with ME/CFS undertake activities that they can tolerate..."
### Counseling[edit]
The CDC states that counseling may help patients cope with pain caused by CFS, and that talking with a professional counselor or therapist may help people to more effectively manage the symptoms that affect their quality of daily life.[7]
### Nutrition[edit]
A proper diet is a significant contributor to the health of any individual. Medical consultation about diet and supplements are recommended for persons with CFS.[7] Persons with CFS may benefit from a balanced diet and properly supervised administration of nutritional support if deficiencies are detected by medical testing. Risks of nutritional supplements include interactions with prescribed medications.[117][7]
## Therapies[edit]
### Cognitive behavioral therapy[edit]
The CDC states that speaking with a therapist may help people cope with the illness.[7] A 2015 National Institutes of Health report concluded that while counseling and behavior therapies could produce benefits for some people, they may not yield improvement in quality of life, and because of this limitation such therapies should not be considered as a primary treatment, but rather should be used only as one component of a broader approach.[118] This same report stated that although counseling approaches have shown benefit in some measures of fatigue, function and overall improvement, these approaches have been inadequately studied in subgroups of the wider CFS patient population. Further concern was expressed that reporting of negative effects experienced by patients receiving counseling and behavior therapies had been poor.[98] A report by the Institute of Medicine published in 2015 states that it is unclear whether CBT helps to improve cognitive impairments experienced by patients.[2]:265 The rationale behind the use of CBT to change beliefs about the illness is disputed.[99]
A 2008 Cochrane Review concluded that CBT did reduce the symptom of fatigue, but noted that the benefits of CBT may diminish after the therapy is completed, and that due to study limitations "the significance of these findings should be interpreted with caution".[23] A 2014 systematic review reported that there was only limited evidence that patients increased levels of physical activity after receiving CBT. The authors concluded that, as this finding is contrary to the cognitive behavioural model of CFS, patients receiving CBT were adapting to the illness rather than recovering from it.[119]
Patient organisations have long criticised the use of CBT as a treatment for CFS, and the rationale behind the model is disputed.[100][120] In 2012 the ME Association (MEA) commenced an opinion survey of 493 patients who had received a CBT treatment in the UK. Based on the finding of this survey, in 2015 the MEA concluded that CBT in its current form should not be recommended as a primary intervention for people with CFS[121] In a letter published online in the Lancet in 2016, Dr Charles Shepherd, medical advisor to the MEA, expressed the view that the contention between patients and researchers lay in "a flawed model of causation that takes no account of the heterogeneity of both clinical presentations and disease pathways that come under the umbrella diagnosis of ME/CFS".[122] In 2019, a large UK survey of people with ME/CFS reported that CBT was ineffective for more than half of people, and Graded Exercise Therapy caused deterioration in most people.[123]
### Graded exercise therapy[edit]
Previously, a 2014 National Institutes of Health report concluded that while graded exercise therapy (GET) could produce benefits, it may not yield improvement in quality of life and because of this limitation, GET should not be considered as a primary treatment, but instead be used only as one component of a broader approach. The report also noted that a focus on exercise programs had discouraged patient participation in other types of physical activity, due to concerns of precipitating increased symptoms.[118] A July 2016 addendum to this report recommended that the Oxford criteria not be used when studying ME/CFS. If studies based on the Oxford criteria were excluded, there would be insufficient evidence of the effectiveness of GET on any outcome.[100]
A 2002 Cochrane review updated in 2019 stated that exercise therapy probably has a positive effect on fatigue in adults, and slightly improves sleep, but the long-term effects are unknown, and this has limited relevance to current definitions of ME/CFS.[124][8] Cochrane have announced that a new review to look at exercise therapies in chronic fatigue syndrome is to start in 2020.[8][125] As with CBT, patient organisations have long criticised the use of exercise therapy, most notably GET, as a treatment for CFS.[120] In 2012 the MEA commenced an opinion survey of patients who had received GET. Based on the findings of this survey, in 2015 the MEA concluded that GET in its current delivered form should not be recommended as a primary intervention for persons with CFS.[121]
### Adaptive pacing therapy[edit]
Adaptive pacing therapy (APT) was popularised by the PACE trial, a study that has caused much controversy among both patients and practitioners.[19][failed verification] APT, not to be confused with pacing,[126] is a therapy rather than a management strategy.[127] APT is based on the idea that CFS involves a person only having a limited amount of available energy, and using this energy wisely will mean the "limited energy will increase gradually".[127]:5 A large clinical trial known as the PACE trial found APT was no more effective than usual care or specialized medical care.[128] Unlike pacing, APT is based on the cognitive behavioral model of chronic fatigue syndrome and involves increasing activity levels, which it states may temporarily increase symptoms.[129] In APT, the patient first establishes a baseline level of activity, which can be carried out consistently without any postexertional malaise ("crashes"). APT states that persons should plan to increase their activity, as able. However, APT also requires patients to restrict their activity level to only 70% of what they feel able to do, while also warning against too much rest.[127] This has been described as contradictory, and Jason states that in comparison with pacing, this 70% limit restricts the activities that patients are capable of and results in a lower level of functioning.[126] Jason and Goudsmit, who first described pacing and the energy envelope theory for CFS, have both criticized APT for being inconsistent with the principles of pacing and highlighted significant differences.[126] APT was promoted by Action for ME, the patient charity involved in the PACE trial, until 2019.[129]
### Rintatolimod[edit]
Rintatolimod is a double-stranded RNA drug developed to modulate an antiviral immune reaction through activation of toll-like receptor 3. In several clinical trials of CFS, the treatment has shown a reduction in symptoms, but improvements were not sustained after discontinuation.[130] Evidence supporting the use of rintatolimod is deemed low to moderate.[19] The US FDA has denied commercial approval, called a new drug application, citing several deficiencies and gaps in safety data in the trials, and concluded that the available evidence is insufficient to demonstrate its safety or efficacy in CFS.[131][132] Rintatolimod has been approved for marketing and treatment for persons with CFS in Argentina,[133] and in 2019, FDA regulatory requirements were met for exportation of rintatolimod to the country.[134]
## Prognosis[edit]
A systematic review which looked at the course of CFS without systematic biological or psychological interventions found that "the median full recovery rate was 5% (range 0–31%) and the median proportion of patients who improved during follow-up was 39.5% (range 8–63%). Return to work at follow-up ranged from 8 to 30% in the three studies that considered this outcome." ... "In five studies, a worsening of symptoms during the period of follow-up was reported in between 5 and 20% of patients." A good outcome was associated with not attributing illness to a physical cause, and having a sense of control over symptoms. Other factors were occasionally, but not consistently, related to outcome, including age at onset, a longer duration of follow-up, and less fatigue severity at baseline. The review concludes that "irrespective of the biology of CFS, patients’ beliefs and attributions about the illness are intricately linked with the clinical presentation, the type of help sought and prognosis"[135] Another review found that children have a better prognosis than adults, with 54–94% having recovered by follow-up compared to less than 10% of adults returning to pre-illness levels of functioning.[136]
## Epidemiology[edit]
The prevalence rates for CFS/ME vary widely depending on "case definitions and diagnostic methods".[10] Based on the 1994 CDC diagnostic criteria, the global prevalence rate for CFS is 0.89%.[10] In comparison, the prevalence rate for the stricter criteria, such as the 1988 CDC "Holmes" criteria for CFS and the 2003 Canadian criteria for ME (both of which, for example, exclude patients with psychiatric diagnoses), produce an incidence rate of only 0.17%.[10] For an example of how these rates impact a nation: the CDC website states that "836,000 to 2.5 million Americans suffer from ME/CFS", but most remain undiagnosed.[1]
Females are diagnosed about 1.5 to 2.0 times more often with CFS than males.[10] An estimated 0.5% of children have CFS, and more adolescents are affected with the illness than younger children.[2]:182[21]
## History[edit]
Main article: History of chronic fatigue syndrome
### Myalgic encephalomyelitis[edit]
* From 1934 onwards, outbreaks of a previously unknown illness began to be recorded by doctors.[137][138] Initially considered to be occurrences of poliomyelitis, the illness was subsequently referred to as "epidemic neuromyasthenia".[138]
* In the 1950s, the term "benign myalgic encephalomyelitis" was used in relation to a comparable outbreak at the Royal Free Hospital in London.[139] The descriptions of each outbreak were varied, but included symptoms of malaise, tender lymph nodes, sore throat, pain, and signs of encephalomyelitis.[140] The cause of the condition was not identified, although it appeared to be infectious, and the term "benign myalgic encephalomyelitis" was chosen to reflect the lack of mortality, the severe muscular pains, symptoms suggesting damage to the nervous system, and to the presumed inflammatory nature of the disorder. Björn Sigurðsson disapproved of the name, stating that the illness is rarely benign, doesn't always cause muscle pain, and is possibly never encephalomyelitic.[137] The syndrome appeared in sporadic as well as epidemic cases.[141]
* In 1969, benign myalgic encephalomyelitis appeared as an entry to the International Classification of Diseases under Diseases of the nervous system.[142]
* In 1986, Ramsay published the first diagnostic criteria for ME, in which the condition was characterized by: 1) muscle fatiguability in which, even after minimal physical effort, 3 or more days elapse before full muscle power is restored; 2) extraordinary variability or fluctuation of symptoms, even in the course of one day; and 3) chronicity.[143]
* By 1988, the continued work of Ramsay had demonstrated that, although the disease rarely resulted in mortality, it was often severely disabling.[2]:28–29 Because of this, Ramsay proposed that the prefix "benign" be dropped.[139][144][145]
### Chronic fatigue syndrome[edit]
* In the mid-1980s, two large outbreaks of an illness that resembled mononucleosis drew national attention in the United States. Located in Nevada and New York, the outbreaks involved an illness characterized by "chronic or recurrent debilitating fatigue, and various combinations of other symptoms, including a sore throat, lymph node pain and tenderness, headache, myalgia, and arthralgias". An initial link to the Epstein-Barr virus had the illness acquire the name "chronic Epstein-Barr virus syndrome".[2]:29[87]
* In 1987, the CDC convened a working group to reach a consensus on the clinical features of the illness. The working group concluded that CFS was not new, and that the many different names given to it previously reflected widely differing concepts of the illness's cause and epidemiology.[146] The CDC working group chose "chronic fatigue syndrome" as a more neutral and inclusive name for the illness, but noted that "myalgic encephalomyelitis" was widely accepted in other parts of the world.[87]
* In 1988, the first definition of CFS was published. Although the cause of the illness remained unknown, several attempts were made to update this definition, most notably in 1994.[86]
* The most widely referenced diagnostic criteria and definition of CFS for research and clinical purposes were published in 1994 by the CDC.[59]
* In 2006, the CDC commenced a national program to educate the American public and health-care professionals about CFS.[147]
### Other medical terms[edit]
A range of both theorised and confirmed medical entities and naming conventions have appeared historically in the medical literature dealing with ME and CFS. These include:
* Epidemic neuromyasthenia was a term used for outbreaks with symptoms resembling poliomyelitis.[137][148]
* Iceland disease and Akureyri disease were synonymous terms used for an outbreak of fatigue symptoms in Iceland.[149]
* Low natural killer syndrome, a term used mainly in Japan, reflected research showing diminished in vitro activity of natural killer cells isolated from patients.[150][151]
* Neurasthenia has been proposed as an historical diagnosis that occupied a similar medical and cultural space to CFS.[152]
* Royal Free disease was named after the historically significant outbreak in 1955 at the Royal Free Hospital used as an informal synonym for "benign myalgic encephalomyelitis".[153]
* Tapanui flu was a term commonly used in New Zealand, deriving from the name of a town, Tapanui, where numerous people had the syndrome.[154]
## Society and culture[edit]
Presentation of a petition to the National Assembly for Wales relating to M.E. support in South East Wales.
### Naming[edit]
Many names have been proposed for the illness. Currently, the most commonly used are "chronic fatigue syndrome", "myalgic encephalomyelitis", and the umbrella term "ME/CFS". Reaching consensus on a name is challenging because the cause and pathology remain unknown.[2]:29–30
The term "chronic fatigue syndrome" has been criticized by some patients as being both stigmatizing and trivializing, and which in turn prevents the illness from being seen as a serious health problem that deserves appropriate research.[155] While many patients prefer "myalgic encephalomyelitis", which they believe better reflects the medical nature of the illness,[143][156] there is resistance amongst some clinicians toward the use of myalgic encephalomyelitis on the grounds that the inflammation of the central nervous system (myelitis) implied by the term has not been demonstrated.[157][158]
A 2015 report from the Institute of Medicine recommended the illness be renamed "systemic exertion intolerance disease", (SEID), and suggested new diagnostic criteria, proposing post-exertional malaise, (PEM), impaired function, and sleep problems are core symptoms of ME/CFS. Additionally, they described cognitive impairment and orthostatic intolerance as distinguishing symptoms from other fatiguing illnesses.[2][159][160][dead link]
### Economic impact[edit]
Reynolds et al. (2004)[161] estimated that the illness caused about $20,000 per person with CFS in lost productivity, which totals to $9.1 billion per year in the United States.[162] This is comparable to other chronic illnesses that extract some of the biggest medical and socioeconomic costs.[163] A 2008 study[164] calculated that the total annual cost burden of ME/CFS to society in the US was extensive, and could approach $24.0 billion.[165] A 2017 estimate for the annual economic burden in the United Kingdom from ME/CFS was 3.3 billion Pounds Sterling.[12]
### Awareness day[edit]
May 12 is designated as ME/CFS International Awareness Day.[166] The day is observed so that stakeholders have an occasion to improve the knowledge of "the public, policymakers, and health-care professionals about the symptoms, diagnosis, and treatment of ME/CFS, as well as the need for a better understanding of this complex illness."[167] It was chosen because it is the birthday of Florence Nightingale, who had an illness appearing similar to ME/CFS or fibromyalgia.[166][168]
### Doctor–patient relations[edit]
This section needs to be updated. Please update this article to reflect recent events or newly available information. (November 2020)
Some in the medical community do not recognize CFS as a real condition, nor does agreement exist on its prevalence.[169][170][171] There has been much disagreement over proposed causes, diagnosis, and treatment of the illness.[172][173][174][175][176] This uncertainty can significantly affect doctor-patient relations. A 2006 survey of GPs in southwest England found that despite more than two-thirds of them accepting CFS/ME as a recognizable clinical entity, nearly half did not feel confident with making the diagnosis and/or treating the disease. Three other key factors that were significantly, positively associated with GPs' attitudes were knowing someone socially with CFS/ME, being male, and seeing more patients with the condition in the last year.[177]
From the patient perspective, one 1997 study found that 77% of individuals with CFS reported negative experiences with health-care providers.[38] In a more recent metaanalysis of qualitative studies, a major theme identified in patient discourses was that they felt severely ill, yet were blamed and dismissed.[178] A study of themes in patient newsgroup postings noted key themes relating to denial of social recognition of suffering and feelings of being accused of "simply faking it". Another theme that emerged strongly was that achieving diagnosis and acknowledgement requires tremendous amounts of "hard work" by patients.[171][179]
### Blood donation[edit]
In 2010, several national blood banks adopted measures to discourage or prohibit individuals diagnosed with CFS from donating blood, based on concern following the 2009 claim of a link,[180] between CFS and a retrovirus which was subsequently shown to be unfounded. Organizations adopting these or similar measures included the Canadian Blood Services,[181] the New Zealand Blood Service,[182] the Australian Red Cross Blood Service[183] and the American Association of Blood Banks,[184] In November 2010, the UK National Blood Service introduced a permanent deferral of donation from ME/CFS patients based on the potential harm to those patients that may result from their giving blood.[185] Donation policy in the UK now states, "The condition is relapsing by nature and donation may make symptoms worse, or provoke a relapse in an affected individual."[186]
### Controversy[edit]
Main article: Controversies related to chronic fatigue syndrome
Much contention has arisen over the cause, pathophysiology,[50] nomenclature,[187] and diagnostic criteria of CFS.[172][173] Historically, many professionals within the medical community were unfamiliar with CFS, or did not recognize it as a real condition; nor did agreement exist on its prevalence or seriousness.[170][171][188] Some people with CFS reject any psychological component.[189]
Two British psychiatrists, in 1970, reviewed the case notes of 15 outbreaks of benign myalgic encephalomyelitis and concluded that it was caused by mass hysteria on the part of patients, or altered medical perception of the attending physicians.[190][191] Their conclusions were based on previous studies that found many normal physical test results, a lack of a discernible cause, and a higher prevalence of the illness in females. Consequently, the authors recommended that the disease should be renamed "myalgia nervosa". Despite strong refutation by Dr. Melvin Ramsay and other medical professionals, the proposed psychological hypothesis created great controversy, and convinced a generation of health professionals in the UK that this could be a plausible explanation for the condition, resulting in neglect by many medical specialties. The specialty that did take a major interest in the illness was psychiatry.[191]
Because of the controversy, sociologists hypothesized that stresses of modern living might be a cause of the illness, while some in the media used the term "Yuppie flu" and called it a disease of the middle class. People with disabilities from CFS were often not believed and called malingerers.[191] The November 1990 issue of Newsweek ran a cover story on CFS, which although supportive of an organic cause of the illness, also featured the term 'yuppie flu', reflecting the stereotype that CFS mainly affected yuppies. The implication was that CFS is a form of burnout. The term 'yuppie flu' is considered offensive by both patients and clinicians.[192][193]
In 2009, the journal Science[180] published a study that identified the XMRV retrovirus in a population of people with CFS. Other studies failed to reproduce this finding,[194][195][196] and in 2011, the editor of Science formally retracted its XMRV paper[197] while the Proceedings of the National Academy of Sciences similarly retracted a 2010 paper which had appeared to support the finding of a connection between XMRV and CFS.[198]
### Research funding[edit]
#### United Kingdom[edit]
The lack of research funding and the funding bias towards biopsychosocial studies and against biomedical studies has been highlighted a number of times by patient groups and a number of UK politicians.[199] A parliamentary inquiry by an ad hoc group of parliamentarians in the United Kingdom, set up and chaired by former MP, Dr Ian Gibson, called the Group on Scientific Research into CFS/ME,[102]:169–186[200] was addressed by a government minister claiming that few good biomedical research proposals have been submitted to the Medical Research Council (MRC) in contrast to those for psychosocial research. They were also told by other scientists of proposals that have been rejected, with claims of bias against biomedical research. The MRC confirmed to the group that from April 2003 to November 2006, it has turned down 10 biomedical applications relating to CFS/ME and funded five applications relating to CFS/ME, mostly in the psychiatric/psychosocial domain.
In 2008, the MRC set up an expert group to consider how the MRC might encourage new high-quality research into CFS/ME and partnerships between researchers already working on CFS/ME and those in associated areas. It currently lists CFS/ME with a highlight notice, inviting researchers to develop high-quality research proposals for funding.[201] In February 2010, the All-Party Parliamentary Group on ME (APPG on ME) produced a legacy paper, which welcomed the recent MRC initiative, but felt that far too much emphasis in the past had been on psychological research, with insufficient attention to biomedical research, and that further biomedical research must be undertaken to help discover a cause and more effective forms of management for this disease.[202]
Controversy surrounds psychologically oriented models of the disease and behavioral treatments conducted in the UK.[203]
#### United States[edit]
In 1998, $13 million for CFS research was found to have been redirected or improperly accounted for by the United States CDC, and officials at the agency misled Congress about the irregularities. The agency stated that they needed the funds to respond to other public-health emergencies. The director of a U.S. national patient advocacy group charged the CDC had a bias against studying the disease. The CDC pledged to improve their practices and to restore the $13 million to CFS research over three years.[204]
On 29 October 2015, the National Institutes of Health declared its intent to increase research on ME/CFS. The NIH Clinical Center was to study individuals with ME/CFS, and the National Institute of Neurological Disorders and Stroke would lead the Trans-NIH ME/CFS Research Working Group as part of a multi-institute research effort.[205]
### Notable cases[edit]
Main article: List of people with chronic fatigue syndrome
In 1989, The Golden Girls (1985–1992) featured chronic fatigue syndrome in a two-episode arc, "Sick and Tired: Part 1" and "Part 2," in which protagonist Dorothy Zbornak, portrayed by Bea Arthur, after a lengthy battle with her doctors in an effort to find a diagnosis for her symptoms, is finally diagnosed with CFS.[206] American author Ann Bannon had CFS.[207] Laura Hillenbrand, author of the popular book Seabiscuit, has struggled with CFS since age 19.[208][209]
## Research[edit]
The different case definitions used to research the illness influence the types of patients selected for studies,[82] and research also suggests subtypes of patients may exist within a heterogeneous population.[162][210][211][212] In one of the definitions, symptoms are accepted that may suggest a psychiatric disorder, while others specifically exclude primary psychiatric disorders.[85] The lack of a single, unifying case definition was criticized in the Institute of Medicine's 2015 report for "creating an unclear picture of the symptoms and signs of the disorder" and "complicating comparisons of the results" (study results).[2]:72
## References[edit]
1. ^ a b c d e f g h "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | CDC". www.cdc.gov. 2020-04-13. Retrieved 2020-05-20.
2. ^ a b c d e f g h i j k l m n o p q r s t u v Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of, Medicine (10 February 2015). Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness (PDF). PMID 25695122.
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* Data from Wikidata
* "CDC — Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)". Centers for Disease Control. Retrieved 2020-05-20.
Classification
D
* ICD-11: E849
* ICD-10: G93.3
* ICD-10-CM: G93.3, R53.82
* ICD-9-CM: 323.9 780.71
* MeSH: D015673
* DiseasesDB: 1645
External resources
* MedlinePlus: 001244
* eMedicine: med/3392 ped/2795
* Patient UK: Chronic fatigue syndrome
* v
* t
* e
Chronic fatigue syndrome
Medical issues
* Clinical descriptions
* Treatment
* Post-exertional malaise
Society and history
* History
* Controversies
* Notable patients
Organizations
* Solve ME/CFS Initiative
* Action for ME
* ME Association
* v
* t
* e
Diseases of the nervous system, primarily CNS
Inflammation
Brain
* Encephalitis
* Viral encephalitis
* Herpesviral encephalitis
* Limbic encephalitis
* Encephalitis lethargica
* Cavernous sinus thrombosis
* Brain abscess
* Amoebic
Brain and spinal cord
* Encephalomyelitis
* Acute disseminated
* Meningitis
* Meningoencephalitis
Brain/
encephalopathy
Degenerative
Extrapyramidal and
movement disorders
* Basal ganglia disease
* Parkinsonism
* PD
* Postencephalitic
* NMS
* PKAN
* Tauopathy
* PSP
* Striatonigral degeneration
* Hemiballismus
* HD
* OA
* Dyskinesia
* Dystonia
* Status dystonicus
* Spasmodic torticollis
* Meige's
* Blepharospasm
* Athetosis
* Chorea
* Choreoathetosis
* Myoclonus
* Myoclonic epilepsy
* Akathisia
* Tremor
* Essential tremor
* Intention tremor
* Restless legs
* Stiff-person
Dementia
* Tauopathy
* Alzheimer's
* Early-onset
* Primary progressive aphasia
* Frontotemporal dementia/Frontotemporal lobar degeneration
* Pick's
* Dementia with Lewy bodies
* Posterior cortical atrophy
* Vascular dementia
Mitochondrial disease
* Leigh syndrome
Demyelinating
* Autoimmune
* Inflammatory
* Multiple sclerosis
* For more detailed coverage, see Template:Demyelinating diseases of CNS
Episodic/
paroxysmal
Seizures and epilepsy
* Focal
* Generalised
* Status epilepticus
* For more detailed coverage, see Template:Epilepsy
Headache
* Migraine
* Cluster
* Tension
* For more detailed coverage, see Template:Headache
Cerebrovascular
* TIA
* Stroke
* For more detailed coverage, see Template:Cerebrovascular diseases
Other
* Sleep disorders
* For more detailed coverage, see Template:Sleep
CSF
* Intracranial hypertension
* Hydrocephalus
* Normal pressure hydrocephalus
* Choroid plexus papilloma
* Idiopathic intracranial hypertension
* Cerebral edema
* Intracranial hypotension
Other
* Brain herniation
* Reye syndrome
* Hepatic encephalopathy
* Toxic encephalopathy
* Hashimoto's encephalopathy
Both/either
Degenerative
SA
* Friedreich's ataxia
* Ataxia–telangiectasia
MND
* UMN only:
* Primary lateral sclerosis
* Pseudobulbar palsy
* Hereditary spastic paraplegia
* LMN only:
* Distal hereditary motor neuronopathies
* Spinal muscular atrophies
* SMA
* SMAX1
* SMAX2
* DSMA1
* Congenital DSMA
* Spinal muscular atrophy with lower extremity predominance (SMALED)
* SMALED1
* SMALED2A
* SMALED2B
* SMA-PCH
* SMA-PME
* Progressive muscular atrophy
* Progressive bulbar palsy
* Fazio–Londe
* Infantile progressive bulbar palsy
* both:
* Amyotrophic lateral sclerosis
Authority control
* LCCN: sh88006956
* NDL: 00577364
*[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 inhibitors
*[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
| Chronic fatigue syndrome | c0015674 | 4,814 | wikipedia | https://en.wikipedia.org/wiki/Chronic_fatigue_syndrome | 2021-01-18T18:50:42 | {"gard": ["7121"], "mesh": ["D015673"], "wikidata": ["Q209733"]} |
A number sign (#) is used with this entry because of evidence that metaphyseal dysplasia without hypotrichosis (MDWH) is caused by compound heterozygous mutation in the RMRP gene (157660) on chromosome 9p13.
Clinical Features
Verloes et al. (1990) presented a series of 6 patients with skeletal changes precisely like those of cartilage-hair hypoplasia (CHH; 250250), but without hypotrichosis or immunodeficiency. Two of the patients were sibs. Microscopic examination of the hair showed a reduction in the diameter of the hair shaft. Verloes et al. (1990) suggested that this may be a form of metaphyseal dysplasia allelic to CHH.
Molecular Genetics
In 2 unrelated boys with the cartilage-hair hypoplasia variant with only skeletal manifestations, Bonafe et al. (2002) identified compound heterozygous mutations (157660.0001; 157660.0009-157660.0011) in the RMRP gene that segregated with the disorder in both families. Bonafe et al. (2002) suggested that short stature and metaphyseal changes associated with cone-shaped epiphyses of the hands should raise the diagnostic possibility of a CHH-related disorder that can then be confirmed by mutation analysis.
INHERITANCE \- Autosomal recessive GROWTH Height \- Disproportionate dwarfism HEAD & NECK Face \- Normal facies SKELETAL \- Joint laxity, mild \- Metaphyseal dysplasia Spine \- Normal spine Pelvis \- Normal pelvis Limbs \- Limb shortening \- Short long bones \- Genu varus \- Metaphyseal irregularities (distal femora, proximal and distal tibiae, distal radii and ulnae) Hands \- Phalangeal cone-shaped epiphyses \- Short metacarpals \- Metacarpal/metaphyseal cupping SKIN, NAILS, & HAIR Hair \- Normal hair IMMUNOLOGY \- No immunodeficiency MISCELLANEOUS \- Allelic to cartilage-hair hypoplasia ( 250250 ) MOLECULAR BASIS \- Caused by mutation in the mitochondrial RNA-processing endoribonuclease gene (RMRP, 157660.0009 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[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
| METAPHYSEAL DYSPLASIA WITHOUT HYPOTRICHOSIS | c1834821 | 4,815 | omim | https://www.omim.org/entry/250460 | 2019-09-22T16:25:26 | {"mesh": ["C563574"], "omim": ["250460"], "orphanet": ["1838", "175"], "synonyms": ["Alternative titles", "CARTILAGE-HAIR HYPOPLASIA-LIKE SKELETAL DYSPLASIA WITHOUT HYPOTRICHOSIS OR IMMUNODEFICIENCY", "CARTILAGE-HAIR HYPOPLASIA VARIANT, SKELETAL MANIFESTATIONS ONLY"], "genereviews": ["NBK84550"]} |
Benign recurrent vertigo (BRV1) has been mapped to chromosome 6p.
Another locus for benign recurrent vertigo has been identified on chromosome 22q12 (BRV2; 613106).
Description
Benign recurrent vertigo (BRV), also known as benign paroxysmal positional vertigo (BPPV), is a common disorder affecting up to 2% of the adult population. The majority of individuals with chronic recurrent vertigo have no identifiable cause, no progression of the disorder, and no other neurologic or auditory signs. Many families have multiple affected individuals, suggesting familial transmission of the disorder with moderate to high penetrance (summary by Lee et al., 2006).
Clinical Features
Baloh et al. (1994) described 3 patients who presented with episodic vertigo followed by gait imbalance and oscillopsia and were found to have profound bilateral vestibular loss despite normal hearing. All had a parent with similar findings. The patients, their affected parent, and multiple other family members had a history of migraine headaches, although several of the family members with migraine had normal vestibular function. Acetazolamide stopped or markedly decreased the frequency of vertigo attacks in the 3 patients treated, but had little affect on the chronic vestibular loss. The syndrome, referred to as Dandy syndrome by Belal (1980) and described by Dandy (1941), is characterized by the features reported here. Although some ototoxins, such as streptomycin and gentamicin, are relatively specific for the vestibular system, other causes of Dandy syndrome also produce severe bilateral hearing loss.
Wilmot (1998) suggested that familial vestibulopathy may be the same as episodic ataxia type 2 (EA2; 108500) and spinocerebellar ataxia-6 (SCA6; 183086), both of which are due to mutations in the calcium channel gene CACNA1A (601011).
Inheritance
Benign paroxysmal positional vertigo (BPPV) is thought to be caused by dislodged otoconia from the utricular macula floating in the semicircular canals. At least half of BPPV cases are idiopathic. Experience with familial cases suggested to Gizzi et al. (1998) a genetic predisposition. They surveyed 120 successive BPPV patients and 120 successive dizzy patients without BPPV regarding the frequency of dizziness and BPPV (diagnosed by a physician) among family members. Patients in the BPPV group were 5 times as likely to have relatives with BPPV compared to the dizzy control group.
Oh et al. (2001) studied the families of 24 probands with benign recurrent vertigo who reported a family history of similar attacks of vertigo. The probands underwent a diagnostic evaluation to exclude identifiable causes. A questionnaire was sent to relatives of the probands. Of the 220 relatives responding, 37% reported benign recurrent vertigo, compared to 2% of unrelated spouses, and 50% met the criteria for migraine, compared to 23% of unrelated spouses. Of the first-degree relatives with benign recurrent vertigo, 73% were female. The authors concluded that the pedigrees were most consistent with autosomal dominant transmission of benign recurrent vertigo, with decreased penetrance in males.
Mapping
By genomewide linkage analysis on 4 families with bilateral vestibulopathy, 3 of whom were reported by Baloh et al. (1994), Jen et al. (2004) identified a 24-cM region on chromosome 6q suggestive of linkage to the disorder (maximum multipoint parametric lod score of 2.9 at marker D6S1556). A small Swedish family with vestibulopathy (Brantberg, 2003) did not show linkage to this region, suggesting genetic heterogeneity.
INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Vertigo, episodic \- Vestibulopathy, bilateral, progressive \- No hearing loss NEUROLOGIC Central Nervous System \- Vertigo, episodic (onset in second or third decade) \- Vestibulopathy, bilateral, progressive (onset in fourth or fifth decade) \- Gait imbalance \- Oscillopsia MISCELLANEOUS \- Slowly progressive disorder \- Acetazolamide may benefit attacks of vertigo ▲ 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 inhibitors
*[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
| VERTIGO, BENIGN RECURRENT | c0155502 | 4,816 | omim | https://www.omim.org/entry/193007 | 2019-09-22T16:31:59 | {"doid": ["13941"], "mesh": ["D065635"], "omim": ["193007"], "icd-9": ["386.11"], "synonyms": ["Alternative titles", "VERTIGO, BENIGN PAROXYSMAL POSITIONAL", "VESTIBULOPATHY, FAMILIAL"]} |
MERRF syndrome
Other namesFukuhara syndrome
"ragged red fibers" in MERRF syndrome
SpecialtyNeurology
MERRF syndrome (or myoclonic epilepsy with ragged red fibers) is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy.[1] MERRF syndrome affects different parts of the body, particularly the muscles and nervous system.[2] The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome are difficult to determine, but because it is a mitochondrial disorder, it can be caused by the mutation of nuclear DNA or mitochondrial DNA.[3] The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category. The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy,[3] and ragged red fibers (RRF) on muscle biopsy, leading to the disease's name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, or multiple lipomata. Mitochondrial disorders, including MERRFS, may present at any age.[4]
## Contents
* 1 Symptoms
* 2 Causes
* 3 Mechanism
* 4 Diagnosis
* 4.1 History and physical examination of the patient
* 5 Treatment
* 6 Recent studies
* 7 See also
* 8 References
* 9 External links
## Symptoms[edit]
An individual displaying MERRFs syndrome will manifest not only a single symptom, but patients regularly display more than one affected body part at a time. It has been observed that patients with MERRF syndrome will primarily display myoclonus as a first symptom. There may also be seizures, cerebellar ataxia and myopathy.[3] Secondary features can include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, multiple lipomata, and/or cardiomyopathy with Wolff Parkinson-White syndrome. Most patients will not exhibit all of these symptoms, but more than one of these symptoms will be present in a patient who has been diagnosed with MERRF disease. Mitochondrial disorders, including MERRF, may present at any age.[4] Due to the multiple symptoms presented by the individual, the severity of the syndrome is very difficult to evaluate.[5]
## Causes[edit]
Mitochondrial inheritance
The cause of MERRF disorder is due to mutations in the mitochondrial genome. This means that it is a pathological variant in mtDNA (mitochondrial DNA) and is transmitted by maternal inheritance. Four point mutations in the genome can be identified that are associated with MERRF: m.A8344G, m.T8356C, m.G8361A, and m.G8363A. The point mutation m.A8344G is mostly associated with MERRF,[6] in a study published by Paul Jose Lorenzoni from the Department of neurology at University of Panama[7] stated that 80% of the patients with MERRF disease exhibited this point mutation. This point mutation disrupts the mitochondrial gene for tRNA-Lys. This disrupts the synthesis of proteins. The remaining mutations only account for 10% of cases, and the remaining 10% of the patients with MERRF did not have an identifiable mutation in the mitochondrial DNA.[citation needed]
Many genes are involved.[8] These genes include:
* MT-TK[9]
* MT-TL1
* MT-TH[5]
* MT-TS1[10]
* MT-TS2
* MT-TF[11]
It involves the following characteristics:
* progressive myoclonic epilepsy
* "Ragged Red Fibers" - clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "Ragged Red Fibers" when muscle is stained with modified Gömöri trichrome stain.
There is currently no cure for MERRF.
## Mechanism[edit]
The mechanism by which MERRFs syndrome occur is not yet well understood. The human mitochondrial tRNA mutations are associated with a variety of diseases including mitochondrial myopathies.[12] However, it is understood that defects in the mitochondrial DNA (mtDNA) have been associated with these diseases, and studies have been able to assign biochemical defects.[13] One of these defects has to do with the decreased energy available for cell processes. As muscles are stained with Gömöri trichrome, characteristic ragged red fibers are visible under the microscope. This appearance is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber.[6] These may extend throughout the muscle fiber as the disease severity increases. The mitochondrial aggregates cause the contour of the muscle fiber to become irregular, leading to the "ragged" appearance.[3]
## Diagnosis[edit]
The diagnosis varies from individual to individual. Each is evaluated and diagnosed according to age, clinical phenotype, and pressed inheritance pattern.[14] If the individual has been experiencing myoclonus, the doctor will run a series of genetic studies to determine if it is a mitochondrial disorder.[citation needed]
The molecular genetic studies are run to identify the reason of for the mutations underlying the mitochondrial dysfunction. This approach will avoid the need for a muscle biopsy or an exhaustive metabolic evaluation. After sequencing the mitochondrial genomes, four points mutations in the genome can be identified which are associated with MERRF: A8344G, T8356C, G8361A, and G8363A. The point mutation[9] A8344G is mostly associated with MERRF,[6] in a study published by Paul Jose Lorenzoni from the Department of neurology at University of Panama[7] stated that 80% of the patients with MERRF disease exhibited this point mutation. The remaining mutations only account for 10% of cases, and the remaining 10% of the patients with MERRF did not have an identifiable mutation in the mitochondrial DNA.[12]
If a patient does not exhibit mitochondrial DNA mutations, there are other ways that they can be diagnosed with MERRF. They can go through computed tomography (CT) or magnetic resonance imaging (MRI).The classification for the severity of MERRF syndrome is difficult to distinguish since most individuals will exhibit multi-symptoms.[12] This is often necessary for children with complex neurologic or multi-system involvement, as described below.[4]
### History and physical examination of the patient[edit]
A detailed family history should be obtained from at least three generations, particularly if there have been any neonatal and childhood deaths. A family history may also indicate if any family members exhibit features of the multi-system disease, specifically if there has been maternal inheritance. This would show transmission of the disease only to females, or if there is a family member who experienced a multi-system involvement such as:[14] brain condition that a family member has been record to have such as seizures, dystonia, ataxia, or stroke-like episodes. There may also be optic atrophy, skeletal muscle with a history of myalgia, weakness, or ptosis. Family history may also include neuropathy and dysautonomia, or heart conditions such as cardiomyopathy. The patient's history might also exhibit kidney problems, such as proximal nephron dysfunction. There may also be endocrine conditions, such as diabetes or hypoparathyroidism. The patient might have also had a gastrointestinal condition which could have been due to liver disease, as well as episodes of nausea or vomiting. Multiple lipomas in the skin, sideroblastic anemia and pancytopenia in the metabolic system, or short stature might all be examples of patients with possible symptoms of MERRF disease.[citation needed]
## Treatment[edit]
Like many mitochondrial diseases, there is no cure for MERRF, no matter the means for diagnosis of the disease. The treatment is primarily symptomatic. High doses of Coenzyme Q10, B complex vitamins, and L-Carnitine are used for the altered metabolic processing that results in the disease.[9] There is very little success with these treatments as therapies in hopes of improving mitochondrial function.[15] The treatment only alleviates symptoms, and these do not prevent the disease from progressing. Patients with concomitant disease, such as diabetes, deafness, or cardiac disease, are treated in combination to manage symptoms.[citation needed]
## Recent studies[edit]
The Journal of Child Neurology published a paper that discusses possible new methods to test for MERRF and other mitochondrial diseases through a simple swabbing technique. This is a less invasive technique which allows for an analysis of buccal mitochondrial DNA, and showed significant amounts of the common 5 kb and 7.4 kb mitochondrial DNA deletions, which are also detectable in blood.[16] This study suggests that a buccal swab approach can be used to informatively examine mitochondrial dysfunction in children with seizures and may be applicable to screening mitochondrial disease with other clinical presentations.
Proceedings of the National Academy of Science of the United States of America published an article investigating the human mitochondrial tRNA (hmt-tRNA) mutations which are associated with mitochondrial myopathies. Since the current understanding of the precise molecular mechanisms of these mutations is limited, there is no efficient method to treat their associated mitochondrial diseases. All pathogenic mutants displayed pleiotropic phenotypes, with the exception of the G34A anticodon mutation, which solely affected aminoacylation.[12]
## See also[edit]
* Epilepsy
* Mitochondrial disease
* Myoclonus
* Ragged red fibers
## References[edit]
1. ^ Gene Reviews: MERRF
2. ^ DiMauro, Salvatore; Hirano, Michio (1993). "MERRF". In Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E.; Bean, Lora J.H.; Mefford, Heather C.; Stephens, Karen; Amemiya, Anne; Ledbetter, Nikki (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID 20301693.
3. ^ a b c d Chinnery, Patrick F. (1993). "Mitochondrial Disorders Overview". In Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E.; Bean, Lora J.H.; Mefford, Heather C.; Stephens, Karen; Amemiya, Anne; Ledbetter, Nikki (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID 20301403.
4. ^ a b c "Mitochondrial myopathies: Clinical features and diagnosis". www.uptodate.com. Retrieved 2017-11-07.
5. ^ a b Melone MA, Tessa A, Petrini S, et al. (February 2004). "Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERFF phenotype". Arch. Neurol. 61 (2): 269–72. doi:10.1001/archneur.61.2.269. PMID 14967777.[permanent dead link]
6. ^ a b c "Myoclonus Epilepsy Associated with Ragged-Red Fibers (MERRF) Diagnosis Discussed by Researchers - Mitochondrial Disease News". Mitochondrial Disease News. 2015-05-04. Retrieved 2017-11-08.
7. ^ a b Lorenzoni, Paulo José; Scola, Rosana Herminia; Kay, Cláudia Suemi Kamoi; Silvado, Carlos Eduardo S.; Werneck, Lineu Cesar; Lorenzoni, Paulo José; Scola, Rosana Herminia; Kay, Cláudia Suemi Kamoi; Silvado, Carlos Eduardo S. (October 2014). "When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?". Arquivos de Neuro-Psiquiatria. 72 (10): 803–811. doi:10.1590/0004-282x20140124. ISSN 0004-282X. PMID 25337734.
8. ^ Online Mendelian Inheritance in Man (OMIM): MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED FIBERS; MERRF - 545000
9. ^ a b c Zeviani M, Muntoni F, Savarese N, et al. (1993). "A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA(Lys) gene". Eur. J. Hum. Genet. 1 (1): 80–7. doi:10.1159/000472390. PMID 8069654.
10. ^ Nakamura M, Nakano S, Goto Y, et al. (September 1995). "A novel point mutation in the mitochondrial tRNA(Ser(UCN)) gene detected in a family with MERRF/MELAS overlap syndrome". Biochem. Biophys. Res. Commun. 214 (1): 86–93. doi:10.1006/bbrc.1995.2260. PMID 7669057.
11. ^ Mancuso M, Filosto M, Mootha VK, et al. (June 2004). "A novel mitochondrial tRNAPhe mutation causes MERRF syndrome". Neurology. 62 (11): 2119–21. doi:10.1212/01.wnl.0000127608.48406.f1. PMID 15184630.
12. ^ a b c d Ling, Jiqiang; Roy, Hervé; Qin, Daoming; Rubio, Mary Anne T.; Alfonzo, Juan D.; Fredrick, Kurt; Ibba, Michael (2007-09-25). "Pathogenic mechanism of a human mitochondrial tRNAPhe mutation associated with myoclonic epilepsy with ragged red fibers syndrome". Proceedings of the National Academy of Sciences of the United States of America. 104 (39): 15299–15304. doi:10.1073/pnas.0704441104. ISSN 0027-8424. PMC 2000536. PMID 17878308.
13. ^ McKenzie, Matthew; Liolitsa, Danae; Hanna, Michael G. (2004-03-01). "Mitochondrial Disease: Mutations and Mechanisms". Neurochemical Research. 29 (3): 589–600. doi:10.1023/B:NERE.0000014829.42364.dd. ISSN 0364-3190. PMID 15038606.
14. ^ a b "Mitochondrial myopathies: Clinical features and diagnosis". www.uptodate.com. Retrieved 2017-11-08.
15. ^ Gene reviews: MERRF: Management of patients
16. ^ Yorns, William R.; Valencia, Ignacio; Jayaraman, Aditya; Sheth, Sudip; Legido, Agustin; Goldenthal, Michael J. (2011-11-22). "Buccal Swab Analysis of Mitochondrial Enzyme Deficiency and DNA Defects in a Child With Suspected Myoclonic Epilepsy and Ragged Red Fibers (MERRF)". Journal of Child Neurology. 27 (3): 398–401. doi:10.1177/0883073811420870. PMID 22114216.
## External links[edit]
* MERRF+Syndrome at the US National Library of Medicine Medical Subject Headings (MeSH)
* merrf at NIH/UW GeneTests
Classification
D
* ICD-10: G31.8
* ICD-9-CM: 277.87
* OMIM: 545000
* MeSH: D017243
* DiseasesDB: 30794
External resources
* GeneReviews: MERRF
* Orphanet: 551
* v
* t
* e
Mitochondrial diseases
Carbohydrate metabolism
* PCD
* PDHA
Primarily nervous system
* Leigh disease
* LHON
* NARP
Myopathies
* KSS
* Mitochondrial encephalomyopathy
* MELAS
* MERRF
* PEO
No primary system
* DAD
* MNGIE
* Pearson syndrome
Chromosomal
* OPA1
* Kjer's optic neuropathy
* SARS2
* HUPRA syndrome
* TIMM8A
* Mohr–Tranebjærg syndrome
see also mitochondrial proteins
* v
* t
* e
Seizures and epilepsy
Basics
* Seizure types
* Aura (warning sign)
* Postictal state
* Epileptogenesis
* Neonatal seizure
* Epilepsy in children
Management
* Anticonvulsants
* Investigations
* Electroencephalography
* Epileptologist
Personal issues
* Epilepsy and driving
* Epilepsy and employment
Seizure types
Focal
Seizures
Simple partial
Complex partial
Gelastic seizure
Epilepsy
Temporal lobe epilepsy
Frontal lobe epilepsy
Rolandic epilepsy
Nocturnal epilepsy
Panayiotopoulos syndrome
Vertiginous epilepsy
Generalised
* Tonic–clonic
* Absence seizure
* Atonic seizure
* Automatism
* Benign familial neonatal seizures
* Lennox–Gastaut syndrome
* Myoclonic astatic epilepsy
* Epileptic spasms
Status epilepticus
* Epilepsia partialis continua
* Complex partial status epilepticus
Myoclonic epilepsy
* Progressive myoclonus epilepsy
* Dentatorubral–pallidoluysian atrophy
* Unverricht–Lundborg disease
* MERRF syndrome
* Lafora disease
* Juvenile myoclonic epilepsy
Non-epileptic seizure
* Febrile seizure
* Psychogenic non-epileptic seizure
Related disorders
* Sudden unexpected death in epilepsy
* Todd's paresis
* Landau–Kleffner syndrome
* Epilepsy in animals
Organizations
* Citizens United for Research in Epilepsy (US)
* Epilepsy Action (UK)
* Epilepsy Action Australia
* Epilepsy Foundation (US)
* Epilepsy Outlook (UK)
* Epilepsy Research UK
* Epilepsy Society (UK)
* v
* t
* e
Diseases of muscle, neuromuscular junction, and neuromuscular disease
Neuromuscular-
junction disease
* autoimmune
* Myasthenia gravis
* Lambert–Eaton myasthenic syndrome
* Neuromyotonia
Myopathy
Muscular dystrophy
(DAPC)
AD
* Limb-girdle muscular dystrophy 1
* Oculopharyngeal
* Facioscapulohumeral
* Myotonic
* Distal (most)
AR
* Calpainopathy
* Limb-girdle muscular dystrophy 2
* Congenital
* Fukuyama
* Ullrich
* Walker–Warburg
XR
* dystrophin
* Becker's
* Duchenne
* Emery–Dreifuss
Other structural
* collagen disease
* Bethlem myopathy
* PTP disease
* X-linked MTM
* adaptor protein disease
* BIN1-linked centronuclear myopathy
* cytoskeleton disease
* Nemaline myopathy
* Zaspopathy
Channelopathy
Myotonia
* Myotonia congenita
* Thomsen disease
* Neuromyotonia/Isaacs syndrome
* Paramyotonia congenita
Periodic paralysis
* Hypokalemic
* Thyrotoxic
* Hyperkalemic
Other
* Central core disease
Mitochondrial myopathy
* MELAS
* MERRF
* KSS
* PEO
General
* Inflammatory myopathy
* Congenital myopathy
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[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
| MERRF syndrome | c0162672 | 4,817 | wikipedia | https://en.wikipedia.org/wiki/MERRF_syndrome | 2021-01-18T18:39:52 | {"mesh": ["D017243"], "umls": ["C0162672"], "icd-9": ["277.87"], "orphanet": ["551"], "wikidata": ["Q1881388"]} |
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: "Sari cancer" – news · newspapers · books · scholar · JSTOR (January 2021) (Learn how and when to remove this template message)
Sari cancer
Sari tightened around the waist. A man wearing a dhoti is seen in the background.
SpecialtyDermatology
Sari cancer is a type of skin cancer that occurs along the waistline in females wearing the sari, caused by constant irritation which can result in scaling and changes in pigmentation of the skin. It is a rare type of cancer and generally found in the Indian subcontinent, where saris are commonly worn by girls and women throughout their lives.[1] It is similar to Marjolin's ulcer in cause, involving chronic inflammation.
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Management
* 4 History
* 5 References
* 6 External links
## Signs and symptoms[edit]
The foremost symptoms of sari cancer are the constant irritation with scaling and pigmentation change at the waistline; gradually these become chronic. The person may have non-healing ulcer or a hyper- or hypopigmented patch or a growth-like lesion over the waistline. The lesion may be associated with serous discharge with foul smell.[citation needed]
## Cause[edit]
The sari is common female attire in the Indian subcontinent. It is a piece of long (generally 5.5 metres or 18 feet) cloth which can be made of various materials: cotton, silk, nylon, chiffon or synthetic fabric. It is worn over an inner skirt (petticoat) which is tightened around the waist by a thick cotton cord. This is the traditional costume of most Indian women. The sari is attached to the waist throughout the day in the hot and humid climate. The waist is often soiled with dust and sweat and remains without proper cleaning. This causes changes in pigmentation and mild scaling over the waist. This, in turn, causes chronic irritation and gradually malignancy may develop in the skin at the waistline.[2]
## Management[edit]
Excision biopsy is required to confirm the diagnosis of sari cancer. In many cases local excision with skin grafting is considered the appropriate treatment.[1] Different ways of wearing the petticoat may help sari-wearers to prevent sari cancer. Some such strategies are:
* Loosening the petticoat
* Changing the usual rope-like belt to broader ones that reduce pressure on the area
* Continuously changing the level at which the petticoat is tied[1]
## History[edit]
In 1945 physicians Khanolkar and Suryabai described a new type of skin cancer with hypopigmented and thickened scars which were more likely to progress into malignant lesions. They termed it "dhoti cancer", the dhoti being a traditional male costume of India which like the sari is wrapped around the waist. The term "sari cancer" was first used by a group of doctors led by Dr. A. S. Patil from Bombay Hospital, India, in the Bombay Hospital Journal. The dermatological problem in the waist of Indian women wearing saris had been recognised before by some other researchers. This type of cancer is related to Marjolin's ulcer, the malignant degeneration of a chronic wound which was described by Jean-Nicolas Marjolin in 1828.[citation needed]
## References[edit]
1. ^ a b c Mathai, Kamini (30 January 2012). "Sari cancer poses threat to women: Doctors". Times of India. Retrieved 12 November 2012.
2. ^ Bakhshi GD, Borisa A, Tayade MB (November 2011). "Waist cancer: report of two cases". J Indian Med Assoc. 109 (11): 829, 831. PMID 22666941.
## External links[edit]
* Dhoti cancer: a waistline skin cancer with review of literature
*[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 inhibitors
*[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
| Sari cancer | None | 4,818 | wikipedia | https://en.wikipedia.org/wiki/Sari_cancer | 2021-01-18T18:36:43 | {"wikidata": ["Q2224895"]} |
Cantu et al. (1982) reported 4 unrelated girls with an apparently identical syndrome consisting of mild mental retardation, short stature, macrocranium, prominent forehead, hypertelorism, exophthalmos, cardiac anomalies, cutis laxa, wrinkled palms and soles, joint hyperextensibility, wide ribs, and small vertebral bodies. The cases were all sporadic. The parents were nonconsanguineous. The father's age in each case was advanced: 45, 55, 46, and 51. The authors suggested that these patients were the result of de novo autosomal dominant mutation. (Possibly X-linked dominant mutation is equally plausible.)
INHERITANCE \- ?Autosomal dominant GROWTH Height \- Short stature (below 3rd centile) HEAD & NECK Head \- Macrocephaly \- Dolicocephaly Face \- Prominent forehead \- Coarse face Ears \- Low-set ears Eyes \- Hypertelorism \- Exophthalmos \- Hypermetropia \- Horizontal nystagmus \- Exophoria and/or exotropia Nose \- Flat nasal bridge \- Short nose \- Anteverted nostrils Mouth \- Long philtrum Teeth \- Malocclusion \- Dental anomalies Neck \- Short neck CARDIOVASCULAR Heart \- Cardiomegaly \- Systolic murmur CHEST External Features \- Short and wide thorax Ribs Sternum Clavicles & Scapulae \- Pectus excavatum ABDOMEN External Features \- Prominent abdomen SKELETAL \- Joint hypermobility \- Delayed bone age Skull \- Malar bone hypoplasia \- J-shaped sella turcica Spine \- Small vertebral bodies Pelvis \- Hypoplastic pelvis Limbs \- Cubitus valgus \- Slender bones with thin corticals SKIN, NAILS, & HAIR Skin \- Wrinkled palms \- Wrinkled soles \- Cutis laxa \- Ecchymosis Hair \- Scanty, thin hair \- Hypopigmented hair NEUROLOGIC Central Nervous System \- Mental retardation (IQ 60-68) MISCELLANEOUS \- Based on one report of 4 unrelated sporadic 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 inhibitors
*[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
| CRANIOFACIOFRONTODIGITAL SYNDROME | c2676032 | 4,819 | omim | https://www.omim.org/entry/114620 | 2019-09-22T16:43:47 | {"mesh": ["C567298"], "omim": ["114620"], "orphanet": ["363705"], "synonyms": ["Alternative titles", "CANTU CRANIOFACIOFRONTODIGITAL SYNDROME"]} |
A rare T-cell non-Hodgkin lymphoma characterized by a neoplasm of intraepithelial T-cells mostly occurring in the jejunum or ileum in patients with celiac disease. The lesion may be multifocal and form ulcerating nodules, plaques, strictures, or an exophytic mass. The mesentery and mesenteric lymph nodes are commonly involved. Patients typically present with abdominal pain, malabsorption or diarrhea, anorexia, weight loss, fatigue, nausea, vomiting, and sometimes intestinal perforation or hemorrhage. Prognosis is generally poor.
*[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 inhibitors
*[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
| Enteropathy-associated T-cell lymphoma | c0456889 | 4,820 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86880 | 2021-01-23T19:03:02 | {"gard": ["9809"], "mesh": ["D058527"], "umls": ["C0456889"], "icd-10": ["C86.2"], "synonyms": ["EATL", "ETTL", "Enteropathy-type T-cell lymphoma", "Intestinal T-cell lymphoma"]} |
A number sign (#) is used with this entry because multiple genetic loci are involved in the causation of this complex trait.
One susceptibility locus for major depressive disorder (MDD1; 608520) has been mapped to chromosome 12q22-q23.2. Another susceptibility locus for major depressive disorder (MDD2; 608691) has been mapped to 15q25.3-q26.2.
Polymorphism in the FKBP5 gene (602623), which plays a role in the stress hormone-regulating hypothalamic-pituitary-adrenal axis, has been found to be related to a faster response to antidepressant drug treatment and to increased recurrence of depressive episodes.
A mutation in the tryptophan hydroxylase-2 gene (TPH2; 607478), which encodes the rate-limiting enzyme of neuronal serotonin synthesis and maps to 12q21, was found in individuals with unipolar major depression.
A polymorphism in the HTR2A gene (182135.0003), which encodes the serotonin 2A receptor, has been associated with citalopram treatment outcome in major depressive disorder.
Clinical Features
According to the DSM-IV-TR (American Psychiatric Association, 2000), major depressive disorder is characterized by one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes. A major depressive episode is characterized by at least 2 weeks during which there is a new onset or clear worsening of either depressed mood or loss of interest or pleasure in nearly all activities. Four additional symptoms must also be present including changes in appetite, weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. The episode must be accompanied by distress or impairment in social, occupational, or other important areas of functioning.
Major depressive disorder is commonly recurrent and can be lethal. Up to 15% of individuals with severe major depressive disorder die by suicide. There is a 4-fold increase in death rate of individuals with major depressive disorder over 55 years of age (American Psychiatric Association, 2000).
Other Features
In a brain imaging study of 131 individuals, 66 at high risk for depression, including those with a parental history of depression, and 65 at low risk, Peterson et al. (2009) found that high-risk individuals had large expanses of cortical thinning across the lateral surface of the right cerebral hemisphere compared to low-risk individuals. An average reduction of 28% in cortical thickness was observed in this area, which included the inferior and middle frontal gyri, somatosensory and motor cortices, the dorsal and inferior parietal regions, the inferior occipital gyrus, and the posterior temporal cortex. Although cortical thickness was not associated with a lifetime history of depression, thinning correlated with measures of current symptom severity, inattention, and visual memory for social and emotional stimuli. Peterson et al. (2009) suggested that cortical thinning in the right hemisphere is a familial trait and may produce disturbances in arousal, attention, and memory for social stimuli, which in turn may increase the risk of developing depressive illness.
In 209 patients with migraine without aura (MO) and 151 patients with migraine with aura (MA) and 617 controls, all of whom were from a genetically isolated Dutch population, Stam et al. (2010) found a significant association between migraine with aura and depression (p less than 0.001; OR, 1.70). Heritability estimates were significant for all migraine (0.56), MO (0.77), and MA (0.96) patients, and decreased somewhat after adjustment for depression, especially in MA. The findings indicated a bidirectional association between depression and migraine, in particular migraine with aura, which may be partly due to shared genetic factors.
Biochemical Features
Mathe et al. (1994) examined the concentration of calcitonin gene-related peptide (CALCA, or CGRP; 114130) immunoreactivity in the CSF of 63 patients with major depression with the concentration found in the CSF of 28 patients with schizophrenia (181500) and 20 controls. Patients with all forms of major depression had higher levels of this peptide in the spinal fluid than did patients with schizophrenia or controls. The authors suggested that the increased concentration of CGRP may be a marker trait of major depressive disorder.
Using whole-genome expression profiling of postmortem hippocampal tissue from 21 patients with major depressive disorder and 18 controls, Duric et al. (2010) found significantly increased expression of MKP1 (DUSP1; 600714) in patients with depression. There was 2.3-fold increase in the dentate gyrus and a 2.4-fold increase in the CA1 pyramidal cell layer. Similar results were found in a second cohort, with MDD patients having 31% and 16% increased MKP1 mRNA levels in the dentate gyrus and CA1 region, respectively, compared to controls. This increase was associated with downregulation of the neurotrophic factor-MAPK cascade and an inhibition of downstream ERK signaling. Studies in rats showed that chronic unpredictable stress was associated with increased Mkp1 expression in the hippocampus, and that injection of Mkp1 into hippocampus of wildtype rats induced depressive behavior. Finally, Mkp1-null rats were resistant to chronic stress-induced depressive behavior compared to controls. The findings implicated MKP1 as a key factor in the pathophysiology of MDD.
Population Genetics
Major depressive disorder is one of the most common psychiatric disorders (Murray and Lopez, 1996). According to the DSM-IV-TR (American Psychiatric Association, 2000), the rate of major depressive disorder is highest in the 25- to 44-year-old age group. The lifetime risk of major depressive disorder in community samples varies from 10 to 25% for women and 5 to 12% for men. Point prevalence varies from 5 to 9% for women and 2 to 3% for men. Prevalence rates appear to be unrelated to ethnicity, education, income, or marital status. Fifty to 60% of individuals who have had a single major depressive disorder episode can be expected to have a second episode. Those who have had 2 episodes stand a 70% chance of having a third episode, and those with 3 episodes have a 90% chance of having a fourth.
Inheritance
Although epidemiologic studies indicate an environmental component in the etiology of major depressive disorder, a genetic component has also been found. Twin studies estimate the heritability of major depressive disorder at 0.36 to 0.70 (Torgersen, 1986; McGuffin et al. (1991, 1996); Kendler et al. (1993, 2001); Bierut et al., 1999; Sullivan et al., 2000).
Several studies have found the risk of major depressive disorder in first-degree relatives of probands to be 2 to 4 times that of controls (Tsuang et al., 1994; Gershon et al., 1982; Weissman et al. (1984, 1993); Maier et al., 1993).
In a complex segregation analysis of 832 individuals from 50 multigenerational families ascertained through a proband with recurrent, early-onset major depressive disorder, Marazita et al. (1997) found the relative risk of the disorder to be 4 to 8 times greater in relatives of probands.
Levinson et al. (2003) described 838 affected individuals from 305 families containing 613 affected sib pairs with a mean age of onset of 18.5 years and a mean of 7.3 episodes of depression. They found that panic disorder was a more common comorbidity of affected women, whereas substance use was more common in affected men.
In a study of 2,287 Australian and 1,185 Dutch twins and sibs, Middeldorp et al. (2005) found a correlation of 0.20 for major depression, yielding an upper heritability estimate of 36%.
In a questionnaire-based study of 3,053 Australian twin individuals aged 50 to 94 years, including 654 monozygotic twin pairs, Mosing et al. (2009) found that genetic factors could explain 36%, 34%, and 46% of the variation in optimism, mental health, and self-rated health, respectively. Genetic variance accounted for 14 to 20% of covariance between these variables. The overall findings suggested that high optimism, which may be genetically determined, is related to good mental health and self-rated health. There was some evidence for possible sex differences.
Bartels and Boomsma (2009) used a questionnaire-based method to assess measurements of subjective well-being (SWB) as defined by 4 measures: quality of life in general, satisfaction with life, quality of life at the moment, and subjective happiness, in 5,024 individuals aged 12 to 23 years, including 770 monozygotic and 590 dizygotic twin pairs and nontwin sibs, from 2,157 families. The results indicated a broad-sense heritability for SWB between 40 and 50%, and implicated both additive and nonadditive genetic factors on the phenotype.
Cytogenetics
St Clair et al. (1990) studied a family with 23 cases of mental and/or behavioral disorders. Of the 77 family members available for cytogenetic analysis, 34 were found to carry a balanced translocation t(1;11)(q43;q21). Psychiatric diagnoses had been recorded for 16 of the 34 members with the translocation compared with only 5 of the 43 without it. Lod scores were greatest when the mental disorders in the phenotype were restricted to schizophrenia, schizoaffective disorder, recurrent major depression, and adolescent conduct and emotional disorders. St Clair et al. (1990) suggested that the 11q21-q22 region may be the site of a gene or genes predisposing to major mental illness.
Clinical Management
In a study of 38 female outpatients with depression to investigate the effect of antidepressant treatment on hippocampal volumes, Sheline et al. (2003) found that longer durations during which depressive episodes went untreated with antidepressant medication were associated with reductions in hippocampal volume. There was no significant relationship between hippocampal volume loss and time depressed while taking antidepressant medication or with lifetime exposure to antidepressants. Sheline et al. (2003) concluded that antidepressants may have a neuroprotective effect during depression.
Patients with major depressive disorder whose treatment is unsuccessful with one medication often have a response when treated with an antidepressant of a different chemical class. In a search for genetic predictors of treatment outcome in 1,953 patients with major depressive disorder who were treated with the antidepressant citalopram and were prospectively assessed, McMahon et al. (2006) found significant and reproducible association between treatment outcome and a marker in intron 2 of the HTR2A gene (182135.0003). Citalopram downregulates the serotonin 2A receptor, which is encoded by the HTR2A gene. The A allele was over 6 times more frequent in white than in black participants, and treatment was less effective among black participants. Participants who were homozygous for the A allele had an 18% reduction in absolute risk of having no response to treatment compared with those homozygous for the other allele. McMahon et al. (2006) concluded that the A allele of the intron 2 HTR2A polymorphism may contribute to racial differences in outcomes of antidepressant treatment.
Molecular Genetics
### Association with the MTHFR Gene on Chromosome 1p36
Bjelland et al. (2003) examined the association between folate, total homocysteine, vitamin B12, and the MTHFR 677C/T polymorphism (607093.0003) and anxiety and depression in a population-based study of 5,948 subjects, aged 46 to 49 years and 70 to 74 years, from the Hordaland Homocysteine Study cohort. Hyperhomocysteinemia (plasma total homocysteine level greater than or equal to 15.0 micromol/L) and the T/T genotype, but not low plasma folate or B12 levels, were significantly related to depression without comorbid anxiety disorder.
Lewis et al. (2006) genotyped the 677C/T polymorphism in 3,478 women in the British Women's Heart and Health Study to look for an association between genotype and 3 indicators of depression: ever diagnosed as depressed, currently taking antidepressants, and the EuroQol mood question. Subsequently, they performed a systematic review and metaanalysis of all published studies associated with this polymorphism. In the British Women's Heart and Health Study, they found an increased risk of having been diagnosed as depressed in TT compared to CC individuals (OR, 1.35; 95% CI, 1.01, 1.80). A metaanalysis of the other studies combined with this study yielded an OR of 1.36 (95% CI, 1.11, 1.67, p = 0.003), suggesting that folate or its derivatives may be causally related to risk of depression.
### Association with the CREB1 Gene on Chromosome 2q34
Zubenko et al. (2003) conducted a genomewide linkage survey for genetic loci that influence the development of unipolar mood disorders in 81 families identified through individuals with recurrent early-onset MDD (RE-MDD). Model-free linkage analysis was performed using genotypes for 389 highly informative simple sequence tandem repeat polymorphisms (SSTRPs) with an average spacing of 9 cM. In light of previous evidence suggesting that sex-specific susceptibility genes for mood disorders may be commonplace (Zubenko et al., 2002), as well as evidence implicating the region of chromosome 2q33-q35 that includes the CREB1 gene (123810) as a sex-limited susceptibility locus (Zubenko et al. (2002, 2002, 2002); Philibert et al., 2003), linkage analysis was also performed using a model with covariates to control for the effects of sex and linkage to CREB1. Simulations were performed to determine lod thresholds that corresponded to genomewide levels of significance for each phenotype/model. Nineteen chromosomal regions contained linkage peaks reaching genomewide statistical significance (genomewide adjusted p less than 0.05) and 10 of these were 'highly significant' (adjusted p less than 0.001). The findings indicated that these 19 loci (1) frequently have sex-specific effects, predominantly affecting the risk of depression in women; (2) often work together to influence risk; and (3) typically affect the risk of a spectrum of depressive disorders as well as alcoholism and other addictions. The highest multipoint lod score observed, 8.19 (adjusted p less than 0.0001), occurred for recurrent MDD at marker D2S2321 (205 cM), located 121 kb proximal to CREB1. In a previous linkage analysis that controlled only for sex, the multipoint lod score reached 6.89 at this location (Zubenko et al., 2002). Zubenko et al. (2003) detected sequence variations in the promoter and intron 8 of CREB1 that cosegregated with mood disorders, or their absence, in women from their collection of 81 RE-MDD families, identifying CREB1 as a likely sex-limited susceptibility gene for unipolar mood disorders, and implicating the cAMP signaling pathway in the pathophysiology of mood disorders and related conditions. Since these signaling pathways are used ubiquitously, not just by brain cells, Zubenko et al. (2003) suggested that the susceptibility genes for MDD may contribute directly to the development of systemic medical problems. Zubenko et al. (2001) noted that nearly half the deceased members of the 81 RE-MDD families studied died before reaching 65 years of age, typically of 'natural' causes.
Burcescu et al. (2005) investigated the association of CREB1 with childhood-onset mood disorder in a sample of 195 nuclear families (225 affected children) collected in Hungary and in a sample of 112 probands with mood disorders collected in the Pittsburgh area and matching controls. Genotyping for 2 DNA variants previously found to be associated, -656G/A and a C ins/del in intron 8, as well as for 3 additional polymorphisms spanning CREB1, revealed no evidence for association with early-onset mood disorder or for sex-specific relationship.
### Association with the FKBP5 Gene on Chromosome 6p21
The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. Binder et al. (2004) investigated the possible association between genes regulating the HPA axis and response to antidepressants and susceptibility to depression. By genotyping single-nucleotide polymorphisms (SNPs) in 8 of these genes in depressed individuals and matched controls, they found significant associations of response to antidepressants and the recurrence of depressive episodes with SNPs in FKBP5 (602623), a glucocorticoid receptor-regulation cochaperone of heat-shock 90-kD protein-1 (HSPCA; 140571), in 2 independent samples.
### Association with the CHRM2 Gene on Chromosome 7q35
Wang et al. (2004) examined 11 SNPs within and flanking CHRM2 gene (118493) in 262 families with alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (COGA). Three SNPs showed highly significant association with alcoholism (103780) (p = 0.004, 0.004, and 0.007, respectively). Two SNPs were significantly associated with major depressive syndrome (p = 0.004 and 0.017). Haplotype analyses revealed that the most common haplotype, T-T-T (rs1824024, rs2061174, and rs324650), was undertransmitted to affected individuals with alcohol dependence and major depressive syndrome.
In a large, adequately powered, clinical depression case-control sample (1,420 cases and 1,624 controls), Cohen-Woods et al. (2009) found no association between previously implicated SNPs in the CHRM2 gene and major depression.
### Association with the TOR1A Gene on Chromosome 9q34
Heiman et al. (2004) administered a standard psychiatric interview to 96 manifesting carriers of the torsin dystonia (DYT1; 128100) deletion mutation (605204.0001), 60 nonmanifesting carriers of the mutation, and 65 noncarriers. The risk for early-onset (before 30 years) recurrent major depression was increased in both manifesting mutation carriers (relative risk of 3.62) and nonmanifesting mutation carriers (relative risk of 4.95) compared to noncarriers. The severity of dystonia in manifesting carriers was not associated with the likelihood of major depression, and mutation carriers did not have an increased risk for other affective disorders. Heiman et al. (2004) concluded that early-onset recurrent major depression is a clinical expression of the DYT1 gene mutation that is independent of dystonia. In an accompanying commentary, Richard and McDonald (2004) noted that the DYT1 gene is likely involved in dopamine release or turnover and that the findings of Heiman et al. (2004) suggested a link between basal ganglia disease and depression. The authors noted that other basal ganglia diseases, including Parkinson disease (168600), Huntington disease (143100), and caudate stroke are associated with high rates of depression.
### Association with the DRD4 Gene on Chromosome 11p15
Lopez Leon et al. (2005) conducted a metaanalysis to reevaluate the role of the 48-bp repeat polymorphism in the dopamine D4 receptor (DRD4; 126452) gene on chromosome 11p15 in mood disorders. In 917 patients with unipolar or bipolar affective disorder and 1,164 control subjects from 12 samples, an association was found between the DRD4 2-repeat (2R) allele and unipolar depression (p less than 0.001) and unipolar and bipolar depression combined (p less than 0.001).
### Association with the TPH1 Gene on Chromosome 11p15
Nash et al. (2005) noted that genetic susceptibility to depression and anxiety is both overlapping and dimensional. To index this common genetic susceptibility, they created a quantitative phenotype from several depression and anxiety-related measures. They studied 119 sibships comprising 312 individuals from a community-based sample of 34,371 individuals, selected for extreme scores on this measure. A pathway-based candidate gene study examined 5 microsatellite markers located within or close to 5 serotonin system genes, i.e., HTR2C (312861), HTR1D (182133), HTR1B (182131), TPH1 (191060), and MAOB (309860). Statistical analysis using the quantitative TDT gave significant association with a microsatellite downstream of TPH1. When further analysis included a life-events composite as a covariable, a stronger association with TPH1 was observed.
Gizatullin et al. (2006) screened TPH1 SNPs spanning over 23 kb (promoter to exon 8) in 228 patients with major depression and 253 healthy control subjects. Several haplotypes were associated with depression, and the 6-SNP haplotypes that occurred in less than 5% of both groups were associated with the disease (31.6% vs 18.0% in controls, p less than 0.00005). A sliding window analysis attributed the strongest disease association to a 2-SNP haplotype comprising rs1799913 (A779C) and rs7933505 localized between intron 7 and 8 (p less than 0.00005). Gizatullin et al. (2006) concluded that the most common variants appear not to carry risk while some less frequent variants might contribute to major depression.
### Association with the TPH2 Gene on Chromosome 12q21
Zhang et al. (2005) identified a 1465G-A SNP (607478.0001) in the rate-limiting enzyme of neuronal serotonin synthesis, tryptophan hydroxylase-2 (TPH2; 607478). This functional SNP replaces the highly conserved arg441 with his (R441H) and resulted in about 80% loss of function in serotonin production when TPH2 was expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that 9 patients carried the mutant (1463A) allele, while among 219 controls, 3 subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in TPH2 suggested that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression. Garriock et al. (2005), however, found no evidence of the TPH2 1463G-A SNP by sequence analysis of 182 patients with unipolar depression (83 were treatment resistant), 186 nondepressed controls, and 8 bipolar patients. The ethnicity and gender distribution was similar to that studied by Zhang et al. (2005).
### Association with the SLC6A4 Gene on Chromosome 17q
Ogilvie et al. (1996) identified polymorphisms of the serotonin transporter gene (SLC6A4; 182138) and detected 3 novel alleles of the variable number tandem repeat (VNTR) region, containing 9, 10, or 12 copies of the VNTR element. They found a significant difference between a control and an affective disorder group, largely explained by an excess association of the 9-copy allele with risk of unipolar depression.
Caspi et al. (2003) tested why stressful experiences led to depression in some people but not in others. A functional polymorphism in the promoter region of the SLC6A4 gene (182138.0001) was found to moderate the influence of stressful life events on depression. Individuals with 1 or 2 copies of the short allele of the promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele.
In a study of 466 patients with major depressive disorder and 836 control subjects of German descent, Hoefgen et al. (2005) found that the short allele of the promoter polymorphism of the SLC6A4 gene was significantly more frequent in patients than in control subjects (45.5% vs 39.9%; p = 0.006; odds ratio = 1.26).
Taylor et al. (2005) studied the influence of serotonin transporter promoter polymorphisms on hippocampal volumes in late-life depression. They genotyped and performed brain MRIs on 72 individuals with early-onset depression, 63 with late-onset depression, and 83 healthy controls. Subjects with late-onset depression who were homozygous for the long allele (L/L) had significantly smaller right hippocampal volumes than did L/L individuals with early-onset depression (p = 0.046) or L/L control individuals (p = 0.01). Post hoc analysis also showed that later age of depression onset was associated with smaller hippocampal volumes in individuals with the L/L genotype, but earlier age of onset was associated with smaller hippocampal volumes in individuals who were homozygous for the short allele.
Willeit et al. (2003) genotyped 138 patients with seasonal affective disorder (SAD), which is usually a variant of major depressive disorder, and 146 healthy volunteers for the long/short promoter polymorphism of serotonin transporter. No difference between patients and controls was found for genotype distribution and allele frequency. However, genotype distribution and allele frequencies were strongly associated with DSM-IV depressive subtypes such that melancholic depression was associated with the long allele and atypical depression with the short allele (2-sided Fisher exact test: genotype distribution, p = 0.0038; allele frequencies, p = 0.007). Willeit et al. (2003) concluded that the findings support the notion that the promoter region of the serotonin transporter influences phenotypic expression of disease but does not cause the disease.
### Association with the BCR Gene on Chromosome 21q11
Hashimoto et al. (2005) genotyped 171 patients with bipolar disorder (125480), 329 patients with major depressive disorder, and 351 controls, all of whom were Japanese, for 11 SNPs in the breakpoint cluster region gene (BCR; 151410) on chromosome 22q11, and found significant association with major depression for 6 polymorphisms.
### Other Associations
Nash et al. (2004) sought to identify genetic variants associated with liability to depression and anxiety (607834) in a large community-based sample of 34,371 individuals. A composite index of liability (G) was constructed and used to select a smaller but statistically powerful sample for DNA collection (757 individuals, 297 sibships). These individuals were genotyped with more than 400 microsatellite markers. Linkage analysis revealed 2 potential quantitative trait loci (QTL): 1 on chromosome 1p (lod = 2.2) around 64 cM near D1S2892 and another on chromosome 6p (lod = 2.7) around 47 cM near D6S1610. The authors further noted that these QTLs might have sex-limited effects.
For a discussion of a possible association between seasonal affective disorder and variation in the PER3 gene, see 603427.0001 and FASPS3 (616882).
### Reviews
Kato (2007) reviewed molecular genetic findings on bipolar disorder and major depression from 2004 to 2006.
Animal Model
Malkesman et al. (2006) examined whether existing genetic animal models of depression in adult rats were also valid in prepubertal rats. Specifically they studied the Flinders Sensitivity Line and their controls (Sprague-Dawley); and the Wistar Kyoto line and their controls (Wistar) to test the hypothesis that male prepubertal animal models would show increased swim test immobility and different patterns of social play as well as different basal plasma levels of corticosteroid and ACTH compared to control rats. Prepubertal Flinders and Wistar Kyoto rats exhibited significantly longer duration of immobility than control rats in the swim test. Flinders rats demonstrated significantly higher levels of social play behaviors and lower levels of corticosterone and ACTH compared with controls, whereas Wistar Kyoto rats demonstrated significantly lower levels of social play behaviors and higher plasma levels of corticosterone and ACTH compound. Malkesman et al. (2006) suggested that prepubertal Flinders Sensitivity Line and Wistar Kyoto rats are both putative genetic animal models for childhood depression but exhibit separate patterns and symptoms of the disorder.
*[v]: View this template
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*[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 inhibitors
*[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
| MAJOR DEPRESSIVE DISORDER | c1269683 | 4,821 | omim | https://www.omim.org/entry/608516 | 2019-09-22T16:07:43 | {"doid": ["1595"], "mesh": ["D003865"], "omim": ["608516"], "icd-10": ["F32.9"], "synonyms": ["Alternative titles", "UNIPOLAR DEPRESSION"]} |
A number sign (#) is used with this entry because of evidence that immunodeficiency-37 (IMD37) is caused by homozygous mutation in the BCL10 gene (603517) on chromosome 1p22. One such patient has been reported.
Clinical Features
Torres et al. (2014) reported a boy, born of consanguineous parents from Ecuador, with a primary combined immunodeficiency disorder resulting in death at age 3 years. He presented at age 6 months with gastroenteritis, otitis, and respiratory infections. At age 8 months, he had severe viral influenza infection, respiratory syncytial virus (RSV) infection, and oral and diaper Candida infections. Later infections included Campylobacter jejuni, adenovirus, and Clostridium difficile. He also had 2 episodes of neurologic deterioration: the first presented as seizures and status epilepticus, but the second, believed to be an encephalitis, was fatal. Laboratory studies showed hypogammaglobulinemia without lymphopenia, but with profoundly reduced memory B cells and memory T cells and increased numbers of circulating naive lymphocytes. He had a sister who died of infection at age 6 months.
Inheritance
The transmission pattern of IMD37 in the family reported by Torres et al. (2014) was consistent with autosomal recessive inheritance.
Molecular Genetics
In a boy, born of consanguineous parents from Ecuador, with immunodeficiency-37, Torres et al. (2014) identified a homozygous mutation in the BCL10 gene (603517.0019), resulting in a complete loss of protein. The mutation was found by whole-exome sequencing. Patient fibroblasts showed impaired NFKB (see 164011) signaling via TLR4 (603030) compared to controls, and patient B and T cells showed impaired development and proliferation, respectively, in response to stimulus. Myeloid cells did not appear to be affected, and cytokine production was similar to controls. The effect of BCL10 deficiency was dependent on the signaling pathway and, for some pathways, the cell type affected.
Animal Model
Ruland et al. (2001) showed that one-third of Bcl10 -/- mouse embryos developed exencephaly, leading to embryonic lethality. Surprisingly, Bcl10 -/- cells retained susceptibility to various apoptotic stimuli in vivo and in vitro. However, surviving Bcl10 -/- mice were severely immunodeficient, and Bcl10 -/- lymphocytes were defective in antigen receptor or phorbol myristate acetate (PMA)/ionomycin-induced activation. Early tyrosine phosphorylation, mitogen-activated protein kinase (MAPK; see 604921) and activator protein-1 (AP1; 165160) activation, and calcium signaling were normal in mutant lymphocytes, but antigen receptor-induced NFKB activation was absent. Thus, the authors concluded that BCL10 functions as a positive regulator of lymphocyte proliferation that specifically connects antigen receptor signaling in B and T cells to NFKB activation.
By disrupting exon 3 of the Bcl10 gene, which encodes the CARD domain, Xue et al. (2003) generated healthy, fertile mice lacking Bcl10. Flow cytometric and immunohistochemical analyses demonstrated a reduction in the number of follicular, marginal zone, and B1 B cells. Follicular and marginal zone B cells were unable to proliferate, and marginal zone B cells were unable to activate Nfkb in response to lipopolysaccharide. Mutant mice did not survive infection with Streptococcus pneumoniae. Xue et al. (2003) concluded that BCL10 is essential for the development of all mature B-cell subsets.
INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Otitis, recurrent Mouth \- Candida infections RESPIRATORY \- Recurrent infections ABDOMEN Gastrointestinal \- Infectious diarrhea NEUROLOGIC Central Nervous System \- Encephalitis \- Seizures IMMUNOLOGY \- Immunodeficiency \- Recurrent bacterial and viral infections \- Hypogammaglobulinemia \- Decreased memory B cells \- Decreased memory T cells \- Increased percentage of naive B cells \- Increased percentage of naive T cells MISCELLANEOUS \- Onset in infancy \- One family has been reported (last curated November 2014) MOLECULAR BASIS \- Caused by mutation in the B-cell CLL/lymphoma 10 gene (BCL10, 603517.0019 ) ▲ 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 inhibitors
*[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
| IMMUNODEFICIENCY 37 | c4015195 | 4,822 | omim | https://www.omim.org/entry/616098 | 2019-09-22T15:49:58 | {"omim": ["616098"]} |
Involuntary urination while asleep
Nocturnal enuresis
Other namesNighttime urinary incontinence, sleepwetting, bedwetting
Urine mark on bedding caused by a nocturnal enuresis episode.
SpecialtyPediatrics, Psychiatry, Urology
Nocturnal enuresis, also called bedwetting, is involuntary urination while asleep after the age at which bladder control usually begins. Bedwetting in children and adults can result in emotional stress.[1] Complications can include urinary tract infections.[1]
Most bedwetting is a developmental delay—not an emotional problem or physical illness. Only a small percentage (5 to 10%) of bedwetting cases have a specific medical cause.[2] Bedwetting is commonly associated with a family history of the condition.[3] Nocturnal enuresis is considered primary (PNE) when a child has not yet had a prolonged period of being dry. Secondary nocturnal enuresis (SNE) is when a child or adult begins wetting again after having stayed dry.
Treatments range from behavioral therapy, such as bedwetting alarms, to medication, such as hormone replacement, and even surgery such as urethral dilatation. Since most bedwetting is simply a developmental delay, most treatment plans aim to protect or improve self-esteem.[2] Treatment guidelines recommend that the physician counsel the parents,[4] warning about psychological consequences caused by pressure, shaming, or punishment for a condition children cannot control.[2]
Bedwetting is the most common childhood complaint.[5][6][7]
## Contents
* 1 Impact
* 1.1 Self-esteem
* 1.2 Behavioral impact
* 1.3 Punishment for bedwetting
* 1.4 Families
* 1.5 Sociopathy
* 2 Causes
* 2.1 Unconfirmed
* 3 Mechanism
* 4 Diagnosis
* 4.1 Voiding diary
* 4.2 Physical examination
* 4.3 Classification
* 4.3.1 Primary nocturnal enuresis
* 4.3.2 Secondary nocturnal enuresis
* 4.3.3 Psychological definition
* 5 Management
* 5.1 Treatment approaches
* 5.2 Condition management
* 5.3 Unproven
* 6 Epidemiology
* 7 History
* 8 See also
* 9 References
* 10 External links
## Impact[edit]
A review of medical literature shows doctors consistently stressing that a bedwetting child is not at fault for the situation. Many medical studies state that the psychological impacts of bedwetting are more important than the physical considerations. "It is often the child's and family members' reaction to bedwetting that determines whether it is a problem or not."[8]
### Self-esteem[edit]
Whether bedwetting causes low self-esteem remains a subject of debate, but several studies have found that self-esteem improved with management of the condition.[9]
Children questioned in one study ranked bedwetting as the third most stressful life event, after "parental war of words", divorce and parental fighting. Adolescents in the same study ranked bedwetting as tied for second with parental fighting.[9]
Bedwetters face problems ranging from being teased by siblings, being punished by parents, the embarrassment of still having to wear diapers, and being afraid that friends will find out.
Psychologists report that the amount of psychological harm depends on whether the bedwetting harms self-esteem or development of social skills. Key factors are:[10][unreliable medical source?]
* How much the bedwetting limits social activities like sleep-overs and campouts
* The degree of the social ostracism by peers
* (Perceived) Anger, punishment, refusal and rejection by caregivers along with subsequent guilt
* The number of failed treatment attempts
* How long the child has been wetting
### Behavioral impact[edit]
Studies show that bedwetting children are more likely to have behavioral problems. For children who have developmental problems, the behavioral problems and the bedwetting are frequently part of/caused by the developmental issues. For bedwetting children without other developmental issues, these behavioral issues can result from self-esteem issues and stress caused by the wetting.[10][unreliable medical source?]
As mentioned below, current studies show that it is very rare for a child to intentionally wet the bed as a method of acting out.
### Punishment for bedwetting[edit]
Medical literature states, and studies show, that punishing or shaming a child for bedwetting will frequently make the situation worse. Doctors describe a downward cycle where a child punished for bedwetting feels shame and a loss of self-confidence. This can cause increased bedwetting incidents, leading to more punishment and shaming.[11]
In the United States, about 25% of enuretic children are punished for wetting the bed.[12] In Hong Kong, 57% of enuretic children are punished for wetting.[13] Parents with only a grade-school level education punish bedwetting children at twice the rate of high-school- and college-educated parents.[12]
### Families[edit]
Parents and family members are frequently stressed by a child's bedwetting. Soiled linens and clothing cause additional laundry. Wetting episodes can cause lost sleep if the child wakes and/or cries, waking the parents. A European study estimated that a family with a child who wets nightly will pay about $1,000 a year for additional laundry, extra sheets, disposable absorbent garments such as diapers, and mattress replacement.[9]
Despite these stressful effects, doctors emphasize that parents should react patiently and supportively.[14]
### Sociopathy[edit]
Bedwetting does not indicate a greater possibility of being a sociopath, as long as caregivers do not cause trauma by shaming or punishing a bedwetting child. Bedwetting was part of the Macdonald triad, a set of three behavioral characteristics described by John Macdonald in 1963.[15] The other two characteristics were firestarting and animal abuse. Macdonald suggested that there was an association between a person displaying all three characteristics, then later displaying sociopathic criminal behavior.
MacDonald (1963) observed in his most sadistic patients a triad of childhood cruelty to animals, firesetting and enuresis or frequent bed-wetting. Such maladaptive childhood behaviors often result from poorly developed coping mechanisms. This triad, although not intended to predict criminal behavior, provides the warning signs of a child under considerable stress. Children under substantial stress, particularly in their home environment, frequently engage in maladaptive behaviors, such as these, in order to alleviate the stress produced by their surroundings.
Up to 60% of multiple-murderers, according to some estimates, wet their beds post-adolescence.[16]
Enuresis is an "unconscious, involuntary, and nonviolent act and therefore linking it to violent crime is more problematic than doing so with animal cruelty or firesetting".[17]
Bedwetting can be connected to emotional or physical trauma. Trauma can trigger a return to bedwetting (secondary enuresis) in both children and adults. In addition, caregivers cause some level of emotional trauma when they punish or shame a bedwetting child.
This leads to a difficult distinction: it is not the bedwetting that increases the chance of criminal behavior, but the trauma.[18] For example, parental cruelty can result in "homicidal proneness".[19]
## Causes[edit]
The aetiology of NE is not fully understood, although there are three common causes: excessive urine volume, poor sleep arousal, and bladder contractions. Differentiation of cause is mainly based on patient history and fluid charts completed by the parent or carer to inform management options.[20][21]
Bedwetting has a strong genetic component. Children whose parents were not enuretic have only a 15% incidence of bedwetting. When one or both parents were bedwetters, the rates jump to 44% and 77% respectively.[22]
These first two items are the most common factors in bedwetting, but current medical technology offers no easy testing for either cause. There is no test to prove that bedwetting is only a developmental delay, and genetic testing offers little or no benefit.
As a result, other conditions should be ruled out. The following causes are less common, but are easier to prove and more clearly treated:
In some bed wetting children this increase in ADH production does not occur, while other children may produce an increased amount of ADH but their response is insufficient.[20][23]
* Attention deficit hyperactivity disorder patients are 2.7 times more likely to have bedwetting issues.[24]
* Caffeine increases urine production.[25]
* Chronic constipation can cause bed wetting.[26] When the bowels are full, it can put pressure on the bladder.[27] Often such children defecate normally, yet they retain a significant mass of material in the bowel which causes bed wetting.[28]
* Infections and disease are more strongly connected with secondary nocturnal enuresis and with daytime wetting. Less than 5% of all bedwetting cases are caused by infection or disease, the most common of which is a urinary tract infection.[24]
* Patients with more severe neurological-developmental issues have a higher rate of bedwetting problems. One study of seven-year-olds showed that "handicapped and intellectually disabled children" had a bedwetting rate almost three times higher than "non-handicapped children" (26.6% vs. 9.5%, respectively).[29]
* Psychological issues (e.g., death in the family, sexual abuse, extreme bullying) are established as a cause of secondary nocturnal enuresis (a return to bedwetting), but are very rarely a cause of PNE-type bedwetting.[22][30] Bedwetting can also be a symptom of a pediatric neuropsychological disorder called PANDAS.[31]
* Sleep apnea stemming from an upper airway obstruction has been associated with bedwetting. Snoring and enlarged tonsils or adenoids are a sign of potential sleep apnea problems.[22]
* Sleepwalking can lead to bedwetting. During sleepwalking, the sleepwalker may think he/she is in another room. When the sleepwalker urinates during a sleepwalking episode, he/she usually thinks they are in the bathroom, and therefore urinate where they think the toilet should be. Cases of this have included opening a closet and urinating in it; urinating on the sofa and simply urinating in the middle of the room.
* Stress is a cause of people who return to wetting the bed. Researchers find that moving to a new town, parent conflict or divorce, arrival of a new baby, or loss of a loved one or pet can cause insecurity, contributing to returning bedwetting.[8]
* Type 1 diabetes mellitus can first present as nocturnal enuresis could be the presenting symptom of. It is classically associated with polyuria, polydipsia, and polyphagia, and weight loss, lethargy, and diaper candidiasis may also be present in those with new-onset disease.
### Unconfirmed[edit]
* Food allergies may be part of the cause for some patients. This link is not well established, requiring further research.[32][33]
* Improper toilet training is another disputed cause of bedwetting. This theory was more widely supported in the last century and is still cited by some authors today. Some say bedwetting can be caused by improper toilet training,[34] either by starting the training when the child is too young or by being too forceful. Recent research has shown more mixed results and a connection to toilet training has not been proven or disproven.[35] According to the American Academy of Pediatrics, more child abuse occurs during potty training than in any other developmental stage.
* Dandelions are reputed to be a potent diuretic, and anecdotal reports and folk wisdom say children who handle them can end up wetting the bed.[36] English folk names for the plant are "peebeds" and "pissabeds".[37] In French the dandelion is called pissenlit, which means "piss in bed"; likewise "piscialletto", an Italian folkname, and "meacamas" in Spanish.[38]
## Mechanism[edit]
Two physical functions prevent bedwetting. The first is a hormone that reduces urine production at night. The second is the ability to wake up when the bladder is full. Children usually achieve nighttime dryness by developing one or both of these abilities. There appear to be some hereditary factors in how and when these develop.[citation needed]
The first ability is a hormone cycle that reduces the body's urine production. At about sunset each day, the body releases a minute burst of antidiuretic hormone (also known as arginine vasopressin or AVP). This hormone burst reduces the kidney's urine output well into the night so that the bladder does not get full until morning. This hormone cycle is not present at birth. Many children develop it between the ages of two and six years old, others between six and the end of puberty, and some not at all.[citation needed]
The second ability that helps people stay dry is waking when the bladder is full. This ability develops in the same age range as the vasopressin hormone, but is separate from that hormone cycle.
The typical development process begins with one- and two-year-old children developing larger bladders and beginning to sense bladder fullness. Two- and three-year-old children begin to stay dry during the day. Four- and five-year-olds develop an adult pattern of urinary control and begin to stay dry at night.[2]
## Diagnosis[edit]
Thorough history regarding frequency of bedwetting, any period of dryness in between, associated daytime symptoms, constipation, and encopresis should be sought.
### Voiding diary[edit]
* People are asked to observe, record and measure when and how much their child voids and drinks, as well as associated symptoms. A voiding diary in the form of frequency volume chart records voided volume along with time of each micturition for at least 24 hours. Frequency volume chart is enough for patients with complaint of nocturia and frequency only. If other symptoms are also present then a detailed bladder diary must be maintained. In a bladder diary, times of micturition and voided volume, incontinence episodes, pad usage and other information such as fluid intake, the degree of urgency and the degree of incontinence are recorded.[39]
### Physical examination[edit]
* Each child should be examined physically at least once at the beginning of treatment. A full paediatric and neurological exam is recommended.[40] Measurement of blood pressure is important to rule out any renal pathology. External genitalia and lumbosacral spine should be examined thoroughly. A spinal defect, such as a dimple, hair tuft, or skin discoloration, might be visible in approximately 50% of patients with an intraspinal lesion. Thorough neurologic examination of the lower extremities, including gait, muscle power, tone, sensation, reflexes, and plantar responses should be done during first visit.
### Classification[edit]
Nocturnal urinary continence is dependent on 3 factors: 1) nocturnal urine production, 2) nocturnal bladder function and 3) sleep and arousal mechanisms. Any child will suffer from nocturnal enuresis if more urine is produced than can be contained in the bladder or if the detrusor is hyperactive, provided that he or she is not awakened by the imminent bladder contraction.[41]
#### Primary nocturnal enuresis[edit]
Primary nocturnal enuresis (PNE) is the most common form of bedwetting. Bedwetting becomes a disorder when it persists after the age at which bladder control usually occurs (4–7 years), and is either resulting in an average of at least two wet nights a week with no long periods of dryness or not able to sleep dry without being taken to the toilet by another person.
New studies show that anti-psychotic drugs can have a side effect of causing enuresis.[42]
It has been shown that diet impacts enuresis in children. Constipation from a poor diet can result in impacted stool in the colon putting undue pressure on the bladder creating loss of bladder control (overflow incontinence).[43]
Some researchers, however, recommend a different starting age range. This guidance says that bedwetting can be considered a clinical problem if the child regularly wets the bed after turning 7 years old.[8]
#### Secondary nocturnal enuresis[edit]
Secondary enuresis occurs after a patient goes through an extended period of dryness at night (six months or more) and then reverts to night-time wetting. Secondary enuresis can be caused by emotional stress or a medical condition, such as a bladder infection.[44]
#### Psychological definition[edit]
Psychologists may use a definition from the DSM-IV, defining nocturnal enuresis as repeated urination into bed or clothes, occurring twice per week or more for at least three consecutive months in a child of at least 5 years of age and not due to either a drug side effect or a medical condition. Even if the case does not meet these criteria, the DSM-IV definition allows psychologists to diagnose nocturnal enuresis if the wetting causes the patient clinically significant distress.[45]
## Management[edit]
There are a number of management options for bedwetting. The following options apply when the bedwetting is not caused by a specifically identifiable medical condition such as a bladder abnormality or diabetes. Treatment is recommended when there is a specific medical condition such as bladder abnormalities, infection, or diabetes. It is also considered when bedwetting may harm the child's self-esteem or relationships with family/friends. Only a small percentage of bedwetting is caused by a specific medical condition, so most treatment is prompted by concern for the child's emotional welfare. Behavioral treatment of bedwetting overall tends to show increased self-esteem for children.[46]
Parents become concerned much earlier than doctors. A study in 1980 asked parents and physicians the age that children should stay dry at night. The average parent response was 2.75 years old, while the average physician response was 5.13 years old.[47]
Punishment is not effective and can interfere with treatment.
### Treatment approaches[edit]
Simple behavioral methods are recommended as initial treatment.[48] Other treatment methods include the following:
* Motivational therapy in nocturnal enuresis mainly involves parent and child education. Guilt should be allayed by providing facts. Fluids should be restricted 2 hours prior to bed. The child should be encouraged to empty the bladder completely prior to going to bed. Positive reinforcement can be initiated by setting up a diary or chart to monitor progress and establishing a system to reward the child for each night that he or she is dry. The child should participate in morning cleanup as a natural, nonpunitive consequence of wetting. This method is particularly helpful in younger children (<8 years) and will achieve dryness in 15-20% of the patients.[49][50]
* Waiting: Almost all children will outgrow bedwetting. For this reason, urologists and pediatricians frequently recommend delaying treatment until the child is at least six or seven years old. Physicians may begin treatment earlier if they perceive the condition is damaging the child's self-esteem and/or relationships with family/friends.
* Bedwetting alarms: Physicians also frequently suggest bedwetting alarms which sound a loud tone when they sense moisture. This can help condition the child to wake at the sensation of a full bladder.[51] These alarms are considered more effective than no treatment and may have a lower risk of adverse events than some medical therapies but it is still uncertain if alarms are more effective than other treatments.[52] There may be a 29% to 69% relapse rate, so the treatment may need to be repeated.[53]
* DDAVP (desmopressin) tablets are a synthetic replacement for antidiuretic hormone, the hormone that reduces urine production during sleep. Desmopressin is usually used in the form of desmopressin acetate, DDAVP. Patients taking DDAVP are 4.5 times more likely to stay dry than those taking a placebo.[53] The drug replaces the hormone for that night with no cumulative effect. US drug regulators have banned using desmopressin nasal sprays for treating bedwetting since the oral form is considered safer.
* DDAVP is most efficient in children with nocturnal polyuria (nocturnal urine production greater than 130% of expected bladder capacity for age) and normal bladder reservoir function (maximum voided volume greater than 70% of expected bladder capacity for age).[54][55] Other children who are likely candidates for desmopressin treatment are those in whom alarm therapy has failed or those considered unlikely to comply with alarm therapy. It can be very useful for summer camp and sleepovers to prevent enuresis.[49]
* Tricyclic antidepressants: Tricyclic antidepressant prescription drugs with anti-muscarinic properties have been proven successful in treating bedwetting, but also have an increased risk of side effects, including death from overdose.[56] These drugs include amitriptyline, imipramine and nortriptyline. Studies find that patients using these drugs are 4.2 times as likely to stay dry as those taking a placebo.[53] The relapse rates after stopping the medicines are close to 50%.
### Condition management[edit]
* Absorbent underwear: Absorbent underwear or diapers can reduce embarrassment for bedwetters and make cleanup easier for caregivers. These products are known as training pants or diapers when used for younger children, and as absorbent underwear or incontinence briefs when marketed for older children and adults. Some brands of diaper are marketed especially for people with bedwetting. A major benefit is the reduced stress on both the bedwetter and caregivers. Absorbent underwear can be especially beneficial for bedwetting children wishing to attend sleepovers or campouts, reducing emotional problems caused by social isolation and/or embarrassment in front of peers. Extended diaper usage may interfere with learning to stay dry at night, at least in adults with severe disabilities.[57]
Plastic pants suitable for nocturnal enuresis in larger child or small adult
* Waterproof mattress pads are used in some cases to ease clean-up of bedwetting incidents, however they only protect the mattress, and the sheets, bedding or sleeping partner may be soiled.
### Unproven[edit]
* Acupuncture: While acupuncture is safe in most adolescents,[58] studies done to assess its effectiveness for nocturnal enuresis are of low quality.[59]
* Dry bed training: Dry bed training consists of a strict schedule of waking the child at night, attempting to condition the child into waking by himself/herself.[60] [61]Studies show this training is ineffective by itself[62] and does not increase the success rate when used in conjunction with a bedwetting alarm.[53]
* Star chart: A star chart allows a child and parents to track dry nights, as a record and/or as part of a reward program. This can be done either alone or with other treatments. There is no research to show effectiveness, either in reducing bedwetting or in helping self-esteem.[53] Some psychologists, however, recommend star charts as a way to celebrate successes and help a child's self-esteem.[60]
## Epidemiology[edit]
Doctors frequently consider bedwetting as a self-limiting problem, since most children will outgrow it. Children 5 to 9 years old have a spontaneous cure rate of 14% per year. Adolescents 10 to 18 years old have a spontaneous cure rate of 16% per year.[63]
As can be seen from the numbers above, a portion of bedwetting children will not outgrow the problem. Adult rates of bedwetting show little change due to spontaneous cure. Persons who are still enuretic at age 18 are likely to deal with bedwetting throughout their lives.[63]
Studies of bedwetting in adults have found varying rates. The most quoted study in this area was done in the Netherlands. It found a 0.5% rate for 20- to 79-year-olds. A Hong Kong study, however, found a much higher rate. The Hong Kong researchers found a bedwetting rate of 2.3% in 16- to 40-year-olds.[63]
## History[edit]
An early psychological perspective on bedwetting was given in 1025 by Avicenna in The Canon of Medicine:[64]
"Urinating in bed is frequently predisposed by deep sleep: when urine begins to flow, its inner nature and hidden will (resembling the will to breathe) drives urine out before the child awakes. When children become stronger and more robust, their sleep is lighter and they stop urinating."
Psychological theory through the 1960s placed much greater focus on the possibility that a bedwetting child might be acting out, purposefully striking back against parents by soiling linens and bedding. However, more recent research and medical literature states that this is very rare.[65][66]
## See also[edit]
* Urinary incontinence
* Nocturnal emission
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## External links[edit]
Classification
D
* ICD-10: F98.0, R32
* ICD-9-CM: 307.6, 788.36
* MeSH: D053206
* DiseasesDB: 4326
External resources
* MedlinePlus: 003144
* eMedicine: ped/689
* 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
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Emotional and behavioral
* ADHD
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* Emotional and behavioral disorders
* Separation anxiety disorder
* Movement disorders
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* Selective mutism
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* Tic disorder
* Tourette syndrome
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* Lujan–Fryns syndrome
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(developmental disabilities)
* Pervasive
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* Erectile dysfunction
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* Hypersexuality
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* Brief reactive psychosis
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* Catatonia
Symptoms and uncategorized
* Impulse control disorder
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* v
* t
* e
Symptoms and signs relating to the urinary system
Pain
* Dysuria
* Renal colic
* Costovertebral angle tenderness
* Vesical tenesmus
Control
* Urinary incontinence
* Enuresis
* Diurnal enuresis
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* Nocturnal enuresis
* Post-void dribbling
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Volume
* Oliguria
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Other
* Lower urinary tract symptoms
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Eponymous
* Addis count
* Brewer infarcts
* Lloyd's sign
* Mathe's sign
Authority control
* NDL: 00574235
*[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 inhibitors
*[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
| Nocturnal enuresis | c0270327 | 4,823 | wikipedia | https://en.wikipedia.org/wiki/Nocturnal_enuresis | 2021-01-18T18:29:40 | {"mesh": ["D053206"], "umls": ["C0270327"], "icd-9": ["788.36", "307.6"], "icd-10": ["R32", "F98.0"], "wikidata": ["Q318005"]} |
A number sign (#) is used with this entry because autosomal recessive spastic paraplegia-64 (SPG64) is caused by homozygous mutation in the ENTPD1 gene (601752) on chromosome 10q24.
For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).
Clinical Features
Novarino et al. (2014) performed whole-exome sequencing network analysis to identify mutations in consanguineous families with hereditary spastic paraplegia. In 1 family with a complicated form of spastic paraplegia (family 1242), 2 brothers presented between 3 and 4 years of age with abnormal gait. When last examined, one brother, aged 12, was nonambulatory, and the other, aged 6, could walk with support. Both brothers had deep tendon reflexes, dysarthria, and spasticity. Neither had had an MRI, but both had borderline IQ, aggressiveness, delayed puberty, and microcephaly. In another family with a complicated form of spastic paraplegia (family 1800), a brother and sister presented at age 1 year with unsteady gait. When last examined, one at age 11 years and the other at age 21 years, they could still walk without support. Both sibs had dysarthria and spasticity; 1 had absent reflexes, and the other had normal reflexes. Both had mild white matter changes on brain MRI and moderate intellectual disability.
Molecular Genetics
In affected members of 2 consanguineous families segregating autosomal recessive spastic paraplegia, Novarino et al. (2014) identified homozygosity for a missense mutation (G217R; 601752.0001) and a nonsense mutation (E181X; 601752.0002).
INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly (family A) Eyes \- Congenital cataract (1 patient) SKELETAL Feet \- Pes equinovarus (1 patient) MUSCLE, SOFT TISSUES \- Amyotrophy NEUROLOGIC Central Nervous System \- Intellectual disability, moderate \- Dysarthria (in some patients) \- Can walk with support (some patients) \- Abnormal gait \- Spasticity (family A) Behavioral Psychiatric Manifestations \- Aggressiveness (family A) ENDOCRINE FEATURES \- Delayed puberty (family A) MISCELLANEOUS \- Two consanguineous families with 2 patients each have been reported (last curated August 2015) MOLECULAR BASIS \- Caused by mutation in the ectonucleoside triphosphate diphosphohydrolase 1 gene (ENTPD1, 601752.0001 ) ▲ 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 inhibitors
*[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
| SPASTIC PARAPLEGIA 64, AUTOSOMAL RECESSIVE | c3810289 | 4,824 | omim | https://www.omim.org/entry/615683 | 2019-09-22T15:51:18 | {"doid": ["0110815"], "omim": ["615683"], "orphanet": ["401810"], "synonyms": ["SPG64"]} |
Silver-Russell syndrome
Other namesSilver–Russell dwarfism
A somewhat triangular head and delicate facial features are typical characteristics of Silver-Russell syndrome.
SpecialtyMedical genetics
Silver–Russell syndrome (SRS), also called Silver–Russell dwarfism, is a rare congenital growth disorder. In the United States it is usually referred to as Russell–Silver syndrome (RSS), and Silver–Russell syndrome elsewhere. It is one of 200 types of dwarfism and one of five types of primordial dwarfism.
Silver–Russell syndrome occurs in approximately one out of every 50,000 to 100,000 births. Males and females seem to be affected with equal frequency.[1]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Diagnosis
* 4 Treatment
* 5 Eponym
* 6 References
* 7 External links
## Signs and symptoms[edit]
Although confirmation of a specific genetic marker is in a significant number of individuals, there are no tests to clearly determine if this is what a person has. As a syndrome, a diagnosis is typically given for children upon confirmation of the presence of several symptoms listed below.[2]
Symptoms are intrauterine growth restriction (IUGR) combined with some of the following:
* Often small for gestational age (SGA) at birth (birth weight less than 2.8 kg)
* Feeding problems: the baby is uninterested in feeding and takes only small amounts with difficulty
* Hypoglycemia
* Excessive sweating as a baby, especially at night, and a greyness or pallor of the skin. This may be a symptom of hypoglycemia
* Triangular face with a small jaw and a pointed chin that tends to lessen slightly with age. The mouth tends to curve down
* A blue tinge to the whites of the eyes in younger children
* Head circumference may be of normal size and disproportionate to a small body size
* Wide and late-closing fontanelle
* Clinodactyly
* Body asymmetry: one side of the body grows more slowly than the other
* Continued poor growth with no "catch up" into the normal centile lines on growth chart
* Precocious puberty (occasionally)
* Low muscle tone
* Gastroesophageal reflux disease
* A striking lack of subcutaneous fat
* Constipation (sometimes severe)
The average adult height for patients without growth hormone treatment is 4'11" for males and 4'7" for females.[3]
## Cause[edit]
Its exact cause is unknown, but present research points toward a genetic and epigenetic component, possibly following maternal genes on chromosomes 7 and 11.[4]
It is estimated that approximately 50% of Silver–Russell patients have hypomethylation of H19 and IGF2.[5] This is thought to lead to low expression of IGF2 and over-expression of the H19 gene.[6]
In 10% of the cases the syndrome is associated with maternal uniparental disomy (UPD) on chromosome 7.[4] This is an imprinting error where the person receives two copies of chromosome 7 from the mother (maternally inherited) rather than one from each parent.
Other genetic causes such as duplications, deletions and chromosomal aberrations have also linked to Silver–Russell syndrome.[6]
Interestingly, Silver–Russell patients have variable hypomethylation levels in different body tissues, suggesting a mosaic pattern and a postzygotic epigenetic modification issue. This could explain the body asymmetry of the SRS phenotype.[7]
Like other imprinting disorders (e.g. Prader–Willi syndrome, Angelman syndrome, and Beckwith–Wiedemann syndrome), Silver–Russell syndrome may be associated with the use of assisted reproductive technologies such as in vitro fertilization.[8]
## Diagnosis[edit]
For many years the diagnosis of Silver–Russell syndrome was clinical. However, this led to overlaps with syndromes with similar clinical features such as Temple syndrome and 12q14 microdeletion syndrome.[9] In 2017, an international consensus was published – detailing the steps clinicians should take to diagnose Silver–Russell syndrome.[10] It is now recommended to test for 11p15 loss of methylation and mUPD7 first. If they are negative, then testing for mUPD16, mUPD20 should take place. Testing for 14q32 should also be considered, to rule out Temple syndrome as a differential diagnosis. If these tests come back inconclusive, then a clinical diagnosis should be made.[10]
It is recommended that the Netchine-Harbison clinical scoring system (NH-CSS) is used to group the clinical features together in a point based score.[10]
## Treatment[edit]
The caloric intake of children with SRS must be carefully controlled in order to provide the best opportunity for growth.[2] If the child is unable to tolerate oral feeding, then enteral feeding may be used, such as the percutaneous endoscopic gastrostomy.
In children with limb-length differences or scoliosis, physiotherapy can alleviate the problems caused by these symptoms. In more severe cases, surgery to lengthen limbs may be required. To prevent aggravating posture difficulties children with leg length differences may require a raise in their shoe.[citation needed]
Growth hormone therapy is often prescribed as part of the treatment of SRS. The hormones are given by injection typically daily from the age of 2 years old through teenage years. It may be effective even when the patient does not have a growth hormone deficiency. Growth hormone therapy has been shown to increase the rate of growth in patients[11] and consequently prompts 'catch up' growth. This may enable the child to begin their education at a normal height, improving their self-esteem and interaction with other children. The effect of growth hormone therapy on mature and final height is as yet uncertain.[12] There are some theories suggesting that the therapy also assists with muscular development and managing hypoglycemia.
## Eponym[edit]
It is named for Henry Silver and Alexander Russell.[13][14][15]
## References[edit]
1. ^ Gilbert, Patricia (1996). "Silver-Russell Syndrome". The A-Z Reference Book of Syndromes and Inherited Disorders (second ed.). pp. 271–273. doi:10.1007/978-1-4899-6918-7_71. ISBN 978-0-412-64120-6.
2. ^ a b "Russell-Silver Syndrome". patient.info.
3. ^ Wollmann, H. A.; Kirchner, T; Enders, H; Preece, M. A.; Ranke, M. B. (1995). "Growth and symptoms in Silver-Russell syndrome: Review on the basis of 386 patients". European Journal of Pediatrics. 154 (12): 958–68. doi:10.1007/bf01958638. PMID 8801103. S2CID 21595433.
4. ^ a b "Silver-Russell Syndrome; SRS". OMIM.
5. ^ Bartholdi, D; Krajewska-Walasek, M; Ounap, K; Gaspar, H; Chrzanowska, K H; Ilyana, H; Kayserili, H; Lurie, I W; Schinzel, A; Baumer, A (2008). "Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): Results from a large cohort of patients with SRS and SRS-like phenotypes" (PDF). Journal of Medical Genetics. 46 (3): 192–7. doi:10.1136/jmg.2008.061820. PMID 19066168. S2CID 29211777.
6. ^ a b Eggermann, Thomas; Begemann, Matthias; Binder, Gerhard; Spengler, Sabrina (2010). "Silver-Russell syndrome: genetic basis and molecular genetic testing". Orphanet Journal of Rare Diseases. 5 (1): 19. doi:10.1186/1750-1172-5-19. ISSN 1750-1172. PMC 2907323. PMID 20573229.
7. ^ Ishida, Miho (April 2016). "New developments in Silver–Russell syndrome and implications for clinical practice". Epigenomics. 8 (4): 563–580. doi:10.2217/epi-2015-0010. ISSN 1750-1911. PMC 4928503. PMID 27066913.
8. ^ Butler, M. G. (2009). "Genomic imprinting disorders in humans: A mini-review". Journal of Assisted Reproduction and Genetics. 26 (9–10): 477–86. doi:10.1007/s10815-009-9353-3. PMC 2788689. PMID 19844787.
9. ^ Spengler, S.; Schonherr, N.; Binder, G.; Wollmann, H. A.; Fricke-Otto, S.; Muhlenberg, R.; Denecke, B.; Baudis, M.; Eggermann, T. (2009-09-16). "Submicroscopic chromosomal imbalances in idiopathic Silver-Russell syndrome (SRS): the SRS phenotype overlaps with the 12q14 microdeletion syndrome" (PDF). Journal of Medical Genetics. 47 (5): 356–360. doi:10.1136/jmg.2009.070052. ISSN 0022-2593. PMID 19762329. S2CID 30653418.
10. ^ a b c Wakeling, Emma L.; Brioude, Frédéric; Lokulo-Sodipe, Oluwakemi; O'Connell, Susan M.; Salem, Jennifer; Bliek, Jet; Canton, Ana P. M.; Chrzanowska, Krystyna H.; Davies, Justin H. (2016-09-02). "Diagnosis and management of Silver–Russell syndrome: first international consensus statement". Nature Reviews Endocrinology. 13 (2): 105–124. doi:10.1038/nrendo.2016.138. ISSN 1759-5029. PMID 27585961. S2CID 13729923.
11. ^ Rakover, Y.; Dietsch, S.; Ambler, G. R.; Chock, C.; Thomsett, M.; Cowell, C. T. (1996). "Growth hormone therapy in Silver Russell Syndrome: 5 years experience of the Australian and New Zealand Growth database (OZGROW)". European Journal of Pediatrics. 155 (10): 851–7. doi:10.1007/BF02282833. PMID 8891553. S2CID 11550940.
12. ^ Child Growth Foundation Russell Silver Syndrome
13. ^ synd/2892 at Who Named It?
14. ^ Russell, A (1954). "A syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples)". Proceedings of the Royal Society of Medicine. 47 (12): 1040–4. PMC 1919148. PMID 13237189.
15. ^ Silver, H. K.; Kiyasu, W; George, J; Deamer, W. C. (1953). "Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins". Pediatrics. 12 (4): 368–76. PMID 13099907.
## External links[edit]
Classification
D
* ICD-10: Q87.1 (ILDS Q87.114)
* ICD-9-CM: 759.89
* OMIM: 180860
* MeSH: D056730
* DiseasesDB: 11748
External resources
* MedlinePlus: 001209
* eMedicine: ped/2099
* GeneReviews: Russell-Silver Syndrome
* Orphanet: 813
* GeneReviews/NCBI/NIH/UW entry on Russell-Silver Syndrome
* v
* t
* e
Congenital abnormality syndromes
Craniofacial
* Acrocephalosyndactylia
* Apert syndrome
* Carpenter syndrome
* Pfeiffer syndrome
* Saethre–Chotzen syndrome
* Sakati–Nyhan–Tisdale syndrome
* Bonnet–Dechaume–Blanc syndrome
* Other
* Baller–Gerold syndrome
* Cyclopia
* Goldenhar syndrome
* Möbius syndrome
Short stature
* 1q21.1 deletion syndrome
* Aarskog–Scott syndrome
* Cockayne syndrome
* Cornelia de Lange syndrome
* Dubowitz syndrome
* Noonan syndrome
* Robinow syndrome
* Silver–Russell syndrome
* Seckel syndrome
* Smith–Lemli–Opitz syndrome
* Snyder–Robinson syndrome
* Turner syndrome
Limbs
* Adducted thumb syndrome
* Holt–Oram syndrome
* Klippel–Trénaunay–Weber syndrome
* Nail–patella syndrome
* Rubinstein–Taybi syndrome
* Gastrulation/mesoderm:
* Caudal regression syndrome
* Ectromelia
* Sirenomelia
* VACTERL association
Overgrowth syndromes
* Beckwith–Wiedemann syndrome
* Proteus syndrome
* Perlman syndrome
* Sotos syndrome
* Weaver syndrome
* Klippel–Trénaunay–Weber syndrome
* Benign symmetric lipomatosis
* Bannayan–Riley–Ruvalcaba syndrome
* Neurofibromatosis type I
Laurence–Moon–Bardet–Biedl
* Bardet–Biedl syndrome
* Laurence–Moon syndrome
Combined/other,
known locus
* 2 (Feingold syndrome)
* 3 (Zimmermann–Laband syndrome)
* 4/13 (Fraser syndrome)
* 8 (Branchio-oto-renal syndrome, CHARGE syndrome)
* 12 (Keutel syndrome, Timothy syndrome)
* 15 (Marfan syndrome)
* 19 (Donohue syndrome)
* Multiple
* Fryns syndrome
* v
* t
* e
Disorders due to genomic imprinting
Chromosome 15
* Angelman syndrome ♀ / Prader-Willi syndrome ♂
Chromosome 11
* Beckwith–Wiedemann syndrome ♀ / Silver–Russell syndrome ♂
* Myoclonic dystonia
Chromosome 20
* Pseudohypoparathyroidism ♀ / Pseudopseudohypoparathyroidism ♂
Chromosome 6
* Transient neonatal diabetes mellitus
*[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 inhibitors
*[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
| Silver–Russell syndrome | c0175693 | 4,825 | wikipedia | https://en.wikipedia.org/wiki/Silver%E2%80%93Russell_syndrome | 2021-01-18T19:00:13 | {"gard": ["4870"], "mesh": ["D056730"], "umls": ["C0175693"], "icd-9": ["759.89"], "orphanet": ["813"], "wikidata": ["Q2142496"]} |
Not to be confused with Scleroderma.
Scleredema
Other namesBuschke disease, Scleredema of Buschke, and Scleredema adultorum[1][2]
SpecialtyRheumatology, pediatrics
Scleredema, is a rare, self-limiting skin condition defined by progressive thickening and hardening of the skin, usually on the areas of the upper back, neck, shoulders and face.[3] The skin may also change color to red or orange. The disease was discovered by Abraham Buschke. Although the cause of scleredema is unknown, it is usually associated with a disease, usually diabetes,[4] a viral illness or strep throat.[5] It is usually not fatal, but it may cause death if the disease spreads to the internal organs.[3] It may also cause an infection.[5]
## Contents
* 1 Diagnosis
* 2 Treatment
* 3 See also
* 4 References
* 5 External links
## Diagnosis[edit]
The scleredema is usually proposed as a diagnosis based on the appearance of the skin and the patient's medical history. To confirm the diagnosis, the doctor performs a skin biopsy, in which hematoxylin and eosin staining will show a thick reticular dermis with thick collagen bundles separated by clear spaces.[6] The patient's blood may be examined for diseases that may appear after the onset of symptoms, such as multiple myeloma.[5]
## Treatment[edit]
Although many types of medications have been tried as treatments, none of them have been proven effective in treating scleredema. Those treatments, such as corticosteroids, may benefit the patient, but will not cure their condition. If the affected area is infected, it is usually treated immediately. The symptoms of the condition usually resolve within six months to two years after onset. However, patients whose condition was associated to diabetes may suffer for longer periods of time.[5]
Myocarditis resulting as a complication from the disease has been successfully treated with penicillin and steroids.[7]
## See also[edit]
* Necrobiosis lipoidica
## References[edit]
1. ^ Turchin I, Adams SP, Enta T (September 2003). "Dermacase. Scleredema adultorum, or Bushke disease". Can Fam Physician. 49: 1089, 1093. PMC 2214291. PMID 14526859.
2. ^ Pegum JS (June 1972). "Scleredema of Buschke". Proc. R. Soc. Med. 65 (6): 528. PMC 1643957. PMID 5044976.
3. ^ a b "Scleredema". Retrieved 2009-05-18.
4. ^ Meguerditchian, C; Jacquet P; Béliard S; et al. (November 2006). "Scleredema adultorum of Buschke: an under recognized skin complication of diabetes". Diabetes and Metabolism. 32 (5): 481–484. doi:10.1016/S1262-3636(07)70307-5. PMID 17110904.
5. ^ a b c d "Scleredema". Retrieved 2009-05-18.
6. ^ Schmults CA (October 2003). "Scleredema". Dermatol. Online J. 9 (4): 11. PMID 14594584.
7. ^ Erlichman, Matityahu; Glaser, Joram (1983). "Buschke's Sclerema with right-sided heart failure". Cardiology. 70 (6): 344–348. doi:10.1159/000173618. PMID 6673828.
## External links[edit]
Classification
D
* ICD-10: M34.8, P83.0
* MeSH: D012592
* DiseasesDB: 31361
External resources
* eMedicine: article/1066175
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*[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 inhibitors
*[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
| Scleredema | c0036413 | 4,826 | wikipedia | https://en.wikipedia.org/wiki/Scleredema | 2021-01-18T19:03:07 | {"gard": ["5975"], "mesh": ["D012592"], "umls": ["C0036413"], "icd-10": ["M34.8"], "orphanet": ["352763"], "wikidata": ["Q7434137"]} |
A number sign (#) is used with this entry because isobutyryl-CoA dehydrogenase deficiency (IBDD) is caused by homozygous or compound heterozygous mutation in the ACAD8 gene (604773) on chromosome 11q25.
Clinical Features
The first patient with isobutyryl-CoA dehydrogenase deficiency was described by Roe et al. (1998) and presented at age 12 months with dilated cardiomyopathy, anemia, and carnitine deficiency. An elevated C4-acylcarnitine was noted in a plasma acylcarnitine profile, but a subsequent urine organic acid analysis was normal. Treatment with oral L-carnitine supplementation led to catch-up growth and normalization of the cardiac status. Oglesbee et al. (2007) reported that the patient remained carnitine-dependent at almost 11 years of age.
Eight additional patients with IBD deficiency were reported by Koeberl et al. (2003), Sass et al. (2004), and Pedersen et al. (2006). All were identified by newborn screening when isolated elevation of C4-acylcarnitine prompted further diagnostic investigations. There was clinical information available on 6 of the 9 patients. Two patients remained asymptomatic for more than 1 year without treatment. One patient was noted to have muscle hypotonia and mild developmental delay at 8 months of age. Two patients were treated for speech delay at 5 years and 2 years of age, respectively, but had normal growth and development; and 1 patient was incidentally noted at 1 year of age to have mild branch peripheral pulmonary stenosis, which was detected by echocardiography to rule out a cardiomyopathy.
Oglesbee et al. (2007) reported an additional 13 patients with IBD deficiency who were identified by newborn screening due to an elevation of C4-acylcarnitine in dried blood spots. At the time of their report, 10 of the 13 remained asymptomatic, 2 were lost to follow-up, and 1 had required frequent hospitalizations due to emesis and dehydration during the first 2 years of life but was developing normally at 5 years of age.
Diagnosis
Oglesbee et al. (2007) described an algorithm for the diagnosis of IBD deficiency identified by elevated C4-acylcarnitine on newborn screening. They noted that urine acylcarnitine analysis appeared to be a practical tool for diagnosing IBD deficiency.
Molecular Genetics
Nguyen et al. (2002) found a homozygous mutation in the ACAD8 gene (R302Q; 604773.0005) in the original patient with IBD deficiency described by Roe et al. (1998).
Oglesbee et al. (2007) found 10 different mutations in the ACAD8 gene in 9 individuals with IBD deficiency (see, e.g., 604773.0001-604773.0004). Six infants were compound heterozygotes, and 3 were homozygotes. Three infants of European descent carried the same allele (M130T; 604773.0001). Another allele was common to 3 additional infants (G355S; 604773.0002). In 1 of the infants carrying the G355S allele, no alteration was found on the other ACAD8 allele.
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*[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 inhibitors
*[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
| ISOBUTYRYL-CoA DEHYDROGENASE DEFICIENCY | c1969809 | 4,827 | omim | https://www.omim.org/entry/611283 | 2019-09-22T16:03:24 | {"mesh": ["C535541"], "omim": ["611283"], "orphanet": ["79159"], "synonyms": ["Alternative titles", "IBD DEFICIENCY", "ACYL-CoA DEHYDROGENASE FAMILY, MEMBER 8, DEFICIENCY OF", "ACAD8 DEFICIENCY"]} |
Dystrophic epidermolysis bullosa pruriginosa is a rare subtype of dystrophic epidermolysis bullosa (DEB, see this term) characterized by generalized or localized skin lesions associated with severe, if not intractable, pruritus.
## Epidemiology
Prevalence is unknown. Approximately 100 families or sporadic cases have been reported to date.
## Clinical description
While skin fragility and blistering lesions usually manifest in infancy, which heal with atrophic scarring and milia formation, the onset of intense pruritus is frequently delayed until the adolescence or even adulthood. At the onset of pruritus, the clinical picture generally worsens with the development of papules, nodules, lichenoid and hypertrophic lesions in a linear distribution, preferentially in the extensor surfaces of the limbs. Nail dystrophy is usually present.
## Etiology
DEB pruriginosa is caused by mutations within the type VII collagen gene (COL7A1). Mutations in this gene lead to an alteration in function or to reduced amounts of collagen VII. This impairs its assembly into anchoring fibrils that anchor the basement membrane to the underlying dermis.
## Genetic counseling
Transmission is autosomal dominant (DDEB pruriginosa) or autosomal recessive (RDEB pruriginosa).
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*[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 inhibitors
*[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
| Dystrophic epidermolysis bullosa pruriginosa | c1275114 | 4,828 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=89843 | 2021-01-23T18:58:11 | {"mesh": ["C563192"], "omim": ["604129"], "umls": ["C1275114"], "icd-10": ["Q81.2"], "synonyms": ["DEB, pruriginosa", "DEB-Pr", "Pruriginous dystrophic epidermolysis bullosa"]} |
Monothematic delusion
SpecialtyPsychiatry
A monothematic delusion is a delusional state that concerns only one particular topic. This is contrasted by what is sometimes called multi-thematic or polythematic delusions where the person has a range of delusions (typically the case of schizophrenia). These disorders can occur within the context of schizophrenia or dementia or they can occur without any other signs of mental illness. When these disorders are found outside the context of mental illness, they are often caused by organic dysfunction as a result of traumatic brain injury, stroke, or neurological illness.
People who experience these delusions as a result of organic dysfunction often do not have any obvious intellectual deficiency nor do they have any other symptoms. Additionally, a few of these people even have some awareness that their beliefs are bizarre, yet they cannot be persuaded that their beliefs are false.[citation needed]
## Contents
* 1 Types
* 2 Causes
* 3 See also
* 4 References
* 5 External links
## Types[edit]
Some delusions that fall under this category are:
* Capgras delusion: the belief that (usually) a close relative or spouse has been replaced by an identical-looking impostor.
* Fregoli delusion: the belief that various people whom the believer meets are actually the same person in disguise.
* Intermetamorphosis: the belief that people in one's environment swap identities with each other while maintaining the same appearance.
* Subjective doubles: a person believes there is a doppelgänger or double of him- or herself carrying out independent actions.
* Cotard delusion: the belief that oneself is dead or does not exist; sometimes coupled with the belief that one is putrefying or missing internal organs.
* Mirrored-self misidentification: the belief that one's reflection in a mirror is some other person.
* Reduplicative paramnesia: the belief that a familiar person, place, object, or body part has been duplicated. For example, a person may believe that they are, in fact, not in the hospital to which they were admitted, but in an identical-looking hospital in a different part of the country.
* Somatoparaphrenia: the delusion where one denies ownership of a limb or an entire side of one's body (often connected with stroke).
Note that some of these delusions are sometimes grouped under the umbrella term of delusional misidentification syndrome.
## Causes[edit]
Current cognitive neuropsychology research points toward a two-factor approach to the cause of monothematic delusions.[1] The first factor being the anomalous experience—often a neurological defect—which leads to the delusion, and the second factor being an impairment of the belief formation cognitive process.
As an example of one of these first factors, several studies point toward Capgras delusion being the result of a disorder of the affect component of face perception. As a result, while the person can recognize their spouse (or other close relation) they do not feel the typical emotional reaction, and thus the spouse does not seem like the person they once knew.
As studies have shown, these neurological defects are not enough on their own to cause delusional thinking.[citation needed] An additional second factor—a bias or impairment of the belief formation cognitive process—is required to solidify and maintain the delusion. Since we do not currently have a solid cognitive model of the belief formation process, this second factor is still somewhat of an unknown.[citation needed]
Some research has shown that delusional people are more prone to jumping to conclusions,[2][3][4] and thus they would be more likely to take their anomalous experience as veridical and make snap judgments based on these experiences. Additionally, studies[4] have shown that they are more prone to making errors due to matching bias—indicative of a tendency to try and confirm the rule. These two judgment biases help explain how delusion-prone people could grasp onto extreme delusions and be very resistant to change.
Researchers claim this is enough to explain the delusional thinking. However, other researchers still argue that these biases are not enough to explain why they remain completely impervious to evidence over time. They believe that there must be some additional unknown neurological defect in the patient's belief system (probably in the right hemisphere).[citation needed]
## See also[edit]
* Belief
* Cognitive neuropsychiatry
* Cognitive neuropsychology
* Cognitive neuroscience
* Delusion
* Face perception
* Neurocognitive
* Neuropsychology
* Philosophy of mind
## References[edit]
1. ^ Davies, M., Coltheart, M., Langdon, R., Breen, N. (2001). "Monothematic delusions: Towards a two-factor account" (PDF). Philosophy, Psychiatry and Psychology. 8 (2): 133–158. doi:10.1353/ppp.2001.0007. Archived from the original (PDF) on 2011-03-02.CS1 maint: multiple names: authors list (link)
2. ^ Sellen, J., Oaksford, M., Langdon, R., Gray, N. (2005). "Schizotypy and Conditional Reasoning". Schizophrenia Bulletin. 31 (1): 105–116. doi:10.1093/schbul/sbi012.CS1 maint: multiple names: authors list (link)
3. ^ Dudley RE, John CH, Young AW, Over DE (May 1997). "Normal and abnormal reasoning in people with delusions". Br J Clin Psychol. 36 (Pt 2): 243–58. doi:10.1111/j.2044-8260.1997.tb01410.x. PMID 9167864.
4. ^ a b Stone, T. (2005). "Delusions and Belief Formation" (Powerpoint).[dead link]
* Stone, T. (2005). "Face Recognition and Delusions" (Powerpoint).[dead link]
## External links[edit]
* The Belief Formation Project a project of the Macquarie Centre for Cognitive Science, which uses research on delusions with the aim of developing a cognitive model of beliefs (link accessed on February 1, 2016)
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*[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 inhibitors
*[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
| Monothematic delusion | None | 4,829 | wikipedia | https://en.wikipedia.org/wiki/Monothematic_delusion | 2021-01-18T19:09:49 | {"wikidata": ["Q3043350"]} |
Non-distal monosomy 12q is a partial autosomal monosomy characterized by variable combination of developmental delay, intellectual disability, ectodermal, genitourinary and minor cardiac anomalies, and specific dysmorphic features (prominent forehead and low-set ears). Specific combination depends on the size and breakpoints of deleted regions.
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*[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 inhibitors
*[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
| Non-distal monosomy 12q | None | 4,830 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96160 | 2021-01-23T17:48:47 | {"icd-10": ["Q93.5"], "synonyms": ["Non-distal deletion 12q", "Non-telomeric monosomy 12q"]} |
A spondylodysplasic dysplasia clinically characterized by postnatal progressive vertebral fusions frequently manifesting as block vertebrae, contributing to an shortened trunk and hence disproportionate short stature, scoliosis, lordosis, carpal and tarsal synostosis and infrequently, club feet.
## Epidemiology
Spondylocarpotarsal synostosis (SCT) is very rare. To date, less than 40 cases have been reported in the medical literature.
## Clinical description
While the clinical onset is postnatal, the diagnosis becomes clinically evident in early in childhood. Primary clinical characteristics of SCT syndrome include progressive vertebral fusions manifesting as block vertebrae leading to a shortened trunk resulting in disproportionate short stature that becomes apparent with physical growth. Scoliosis, lordosis, carpal and tarsal synostosis are frequent with club feet being observed in a minority of cases. A mild facial dysmorphism with a round face with frontal bossing and anteverted nostrils can be evident. Midline cleft palate, conductive hearing loss, joint laxity and dental enamel hypoplasia are uncommonly reported.
## Etiology
SCT syndrome is due to biallelic mutations in FLNB (localized to 3p14.3) that encodes cytoskeletal protein filamin B. A very similar condition is caused by either monoallelic or biallelic mutations in MYH3.
## Diagnostic methods
Diagnosis is confirmed by skeletal x-rays and genetic testing. Radiographs demonstrate progressive vertebral fusions and lumbar spine, carpal and tarsal synostosis without rib anomalies. Occasionally, delayed ossification of epiphyses and bilateral epiphyseal femur dysplasia are reported.
## Differential diagnosis
Differential diagnosis may include isolated Klippel-Feil syndrome and other vertebral dysplasias, such as autosomal dominant spondylocostal dysplasia and multiple synostoses syndrome.
## Genetic counseling
SCT syndrome follows an autosomal recessive inheritance (FLNB, MYH3) or occasionally autosomal dominant inheritance (MYH3). Genetic counseling should be proposed to at risk couples informing them that there is 25% (autosomal recessive) or 50% (autosomal dominant) risk of tranmitting the disease to offspring.
## Management and treatment
Management involves ophthalmologic, audiologic and spine assessments. Scoliosis is treated medically; no effective surgical intervention has been described. The cervical spine should be evaluated for features of instability prior to general anesthesia. Pain management is indispensable as patients suffer from much continuing physical pain due to the spinal deformities and fused block vertebrae.
## Prognosis
It has not been formally evaluated if SCT syndrome affects life expectancy.
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*[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 inhibitors
*[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
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| Spondylocarpotarsal synostosis | c1848934 | 4,831 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3275 | 2021-01-23T16:59:17 | {"gard": ["4974"], "mesh": ["C535780"], "omim": ["272460"], "umls": ["C1848934"], "icd-10": ["Q76.4"], "synonyms": ["Synspondylism"]} |
Chronic focal seizure disorder
Temporal lobe epilepsy
Lobes of the brain. Temporal lobe in green
SpecialtyPsychiatry, Neurology
Temporal lobe epilepsy (TLE) is a chronic disorder of the nervous system characterized by recurrent, unprovoked focal seizures that originate in the temporal lobe of the brain and last about one or two minutes. TLE is the most common form of epilepsy with focal seizures.[1] A focal seizure in the temporal lobe may spread to other areas in the brain when it may become a focal to bilateral seizure.
TLE is diagnosed by taking a medical history, blood tests, and brain imaging. It can have a number of causes such as head injury, stroke, brain infections, structural lesions in the brain, or brain tumors, or it can be of unknown onset. The first line of treatment is through anticonvulsants. Surgery may be an option, especially when there is an observable abnormality in the brain. Another treatment option is electrical stimulation of the brain through an implanted device called the vagus nerve stimulator (VNS).[1]
## Contents
* 1 Types
* 2 Signs and symptoms
* 2.1 Focal seizures
* 2.1.1 Focal aware seizures
* 2.1.2 Focal impaired awareness seizures
* 2.1.3 Focal to bilateral seizures or generalized seizures
* 2.2 Postictal period
* 2.3 Complications
* 2.3.1 Depression
* 2.3.2 Memory
* 2.3.3 Childhood onset
* 2.3.4 Personality
* 3 Causes
* 3.1 Febrile seizures
* 3.2 Human herpes virus 6
* 3.3 Reelin
* 4 Pathophysiology
* 4.1 Neuronal loss
* 4.2 GABA reversal
* 4.3 Granule cell dispersion in the dentate gyrus
* 4.4 Aberrant mossy fiber sprouting
* 5 Diagnosis
* 5.1 Differential diagnosis
* 6 Treatments
* 6.1 Anticonvulsants
* 6.2 Surgical interventions
* 6.3 Other treatments
* 7 Effects on society
* 8 References
* 9 External links
## Types[edit]
Over forty types of epilepsy are recognized and these are divided into two main groups: focal seizures and generalized seizures.[2] Focal seizures account for approximately sixty percent of all adult cases.[3] Temporal lobe epilepsy (TLE) is the single most common form of focal seizure.[4]
The International League Against Epilepsy (ILAE) recognizes two main types of temporal lobe epilepsy: mesial temporal lobe epilepsy (MTLE), arising in the hippocampus, the parahippocampal gyrus and the amygdala which are located in the inner (medial) aspect of the temporal lobe and lateral temporal lobe epilepsy (LTLE), the rarer type, arising in the neocortex at the outer (lateral) surface of the temporal lobe.[3] The seizures of LTLE are characterized by auditory or visual features. Autosomal dominant lateral temporal lobe epilepsy (ADLTLE) is a rare hereditary condition, often associated with mutations in the LGI1 gene.[5]
## Signs and symptoms[edit]
When a seizure begins in the temporal lobe, its effects depend on the precise location of its point of origin, its locus. In 1981, the ILAE recognized three types of seizures occurring in temporal lobe epilepsy. The classification was based on EEG findings.[6] However, as of 2017 the general classification of seizures has been revised.[7] The newer classification uses three key features: where the seizures begin, the level of awareness during a seizure, and other features.[7]
### Focal seizures[edit]
MRI Location amygdala
Focal seizures in the temporal lobe involve small areas of the lobe such as the amygdala and hippocampus.[citation needed]
The newer classification gives two types of focal onset seizures, as focal aware and focal impaired awareness.[2]
#### Focal aware seizures[edit]
Focal aware means that the level of consciousness is not altered during the seizure.[2] In temporal lobe epilepsy, a focal seizure usually causes abnormal sensations only.
These may be:
* Sensations such as déjà vu (a feeling of familiarity), jamais vu (a feeling of unfamiliarity)
* Amnesia of a single memory or set of memories
* A sudden sense of unprovoked fear and anxiety
* Nausea
* Auditory, visual, olfactory, gustatory, or tactile hallucinations.
* Visual distortions such as macropsia and micropsia
* Dissociation or derealisation
* Synesthesia (stimulation of one sense experienced in a second sense) may transpire.[8]
* Dysphoric or euphoric feelings, fear, anger, and other emotions may also occur. Often, the patient cannot describe the sensations.[9]
Olfactory hallucinations often seem indescribable to patients beyond "pleasant" or "unpleasant".[10]
Focal aware seizures are often called "auras" when they serve as a warning sign of a subsequent seizure. Regardless, an aura is actually a seizure itself, and such a focal seizure may or may not progress to a focal impaired awareness seizure.[11] People who experience only focal aware seizures may not recognize what they are, nor seek medical care.[citation needed]
#### Focal impaired awareness seizures[edit]
Focal impaired awareness seizures are seizures which impair consciousness to some extent:[2] they alter the person's ability to interact normally with their environment. They usually begin with a focal aware seizure, then spread to a larger portion of the temporal lobe, resulting in impaired consciousness. They may include autonomic and psychic features present in focal aware seizures.[citation needed]
Signs may include:[12]
* Motionless staring
* Automatic movements of the hands or mouth
* Confusion and disorientation
* Altered ability to respond to others, unusual speech
* Transient aphasia (losing ability to speak, read, or comprehend spoken word)
These seizures tend to have a warning or aura before they occur, and when they occur they generally tend to last only 1–2 minutes. It is not uncommon for an individual to be tired or confused for up to 15 minutes after a seizure has occurred, although postictal confusion can last for hours or even days. Though they may not seem harmful, due to the fact that the individual does not normally seize, they can be extremely harmful if the individual is left alone around dangerous objects. For example, if a person with complex partial seizures is driving alone, this can cause them to run into the ditch, or worse, cause an accident involving multiple people. With this type, some people do not even realize they are having a seizure and most of the time their memory from right before or after the seizure is wiped. First-aid is only required if there has been an injury or if this is the first time a person has had a seizure.[citation needed]
#### Focal to bilateral seizures or generalized seizures[edit]
Seizures which begin in the temporal lobe, and then spread to involve both sides of the brain are termed focal to bilateral. Where both sides of the brain or the whole brain are involved from the onset, these seizures are known as generalized seizures and may be tonic clonic.[7] The arms, trunk, and legs stiffen (the tonic phase), in either a flexed or extended position, and then jerk (the clonic phase). These were previously known as grand mal seizures.[12] The word grand mal comes from the French term, meaning major affliction.[citation needed]
### Postictal period[edit]
There is some period of recovery in which neurological function is altered after each of these seizure types. This is the postictal state. The degree and length of postictal impairment directly correlates with the severity of the seizure type. Focal aware seizures often last less than sixty seconds; focal with impaired awareness seizures may last up to two minutes; and generalized tonic clonic seizures may last up to three minutes.[citation needed] The postictal state in seizures other than focal aware may last much longer than the seizure itself.
Because a major function of the temporal lobe is short-term memory, a focal with impaired awareness seizure, and a focal to bilateral seizure can cause amnesia for the period of the seizure, meaning that the seizure may not be remembered.[citation needed]
### Complications[edit]
#### Depression[edit]
Individuals with temporal lobe epilepsy have a higher prevalence of depression than the general population. Although the psychosocial impacts of epilepsy may be causative, there are also links in the phenomenology and neurobiology of TLE and depression.[13]
#### Memory[edit]
Hippocampus
The temporal lobe and particularly the hippocampus play an important role in memory processing. Declarative memory (memories which can be consciously recalled) is formed in the area of the hippocampus called the dentate gyrus.[citation needed]
Temporal lobe epilepsy is associated with memory disorders and loss of memory. Animal models and clinical studies show that memory loss correlates with temporal lobe neuronal loss in temporal lobe epilepsy. Verbal memory deficit correlates with pyramidal cell loss in TLE. This is more so on the left in verbal memory loss. Neuronal loss on the right is more prominent in non-verbal (visuospatial memory loss).[14][15][16][17][18]
#### Childhood onset[edit]
After childhood onset, one third will "grow out" of TLE, finding a lasting remission up to an average of 20 years. The finding of a lesion such as hippocampal sclerosis (a scar in the hippocampus), tumour, or dysplasia, on magnetic resonance imaging (MRI) predicts the intractability of seizures.[19]
#### Personality[edit]
Main article: Geschwind syndrome
The effect of temporal lobe epilepsy on personality is a historical observation dating to the 1800s. Personality and behavioural change in temporal lobe epilepsy is seen as a chronic condition when it persists for more than three months.[20]
Geschwind syndrome is a set of behavioural phenomena seen in some people with TLE. Documented by Norman Geschwind, signs include: hypergraphia (compulsion to write (or draw) excessively), hyperreligiosity (intense religious or philosophical experiences or interests), hyposexuality (reduced sexual interest or drive), circumstantiality (result of a non-linear thought pattern, talks at length about irrelevant and trivial details).[21] The personality changes generally vary by hemisphere.[21]
The existence of a "temporal lobe epileptic personality" and of Geschwind syndrome have been disputed and research is inconclusive.[21]
## Causes[edit]
The causes of TLE include mesial temporal sclerosis, traumatic brain injury, brain infections, such as encephalitis and meningitis, hypoxic brain injury, stroke, cerebral tumours, and genetic syndromes. Temporal lobe epilepsy is not the result of psychiatric illness or fragility of the personality.[12]
### Febrile seizures[edit]
Although the theory is controversial, there is a link between febrile seizures (seizures coinciding with episodes of fever in young children) and subsequent temporal lobe epilepsy, at least epidemiologically.[22][23][24][25]
### Human herpes virus 6[edit]
Reelin
In the mid 1980s, human herpesvirus 6 (HHV-6) was suggested as a possible causal link between febrile convulsions and mesial temporal lobe epilepsy. However, although the virus is found in temporal lobe tissue at surgery for TLE, it has not been recognised as a major factor in febrile seizures or TLE.[26][27][28]
### Reelin[edit]
Dispersion of the granule cell layer in the hippocampal dentate gyrus is occasionally seen in temporal lobe epilepsy and has been linked to the downregulation of reelin, a protein that normally keeps the layer compact by containing neuronal migration. It is unknown whether changes in reelin expression play a role in epilepsy.[29][30]
## Pathophysiology[edit]
### Neuronal loss[edit]
In TLE, there is loss of neurons in region CA1 and CA3 of the hippocampus.[31][32] There is also damage to mossy cells and inhibitory interneurons in the hilar region of the hippocampus (region IV) and to the granule cells of the dentate gyrus. In animal models, neuronal loss occurs during seizures but in humans, neuronal loss predates the first seizure and does not necessarily continue with seizure activity.[33][34][35][36][37] The loss of the GABA-mediated inhibitory interneurons may increase the hyperexcitability of neurons of the hippocampus leading to recurrent seizures.[38] According to the "dormant basket cell" hypothesis, mossy cells normally excite basket cells which in turn, inhibit granule cells. Loss of mossy cells lowers the threshold of action potentials of the granule cells.[39]
### GABA reversal[edit]
In certain patients with temporal lobe epilepsy it has been found that the subiculum could generate epileptic activity. It has been found that GABA reversal potential is depolarising[40] in the subpopulation of the pyramidal cells due to the lack of KCC2 co-transporter. It has been shown that it is theoretically possible to generate seizures in the neural networks due to down-regulation of KCC2,[41] consistent with the chloride measurements during the transition to seizure[42] and KCC2 blockade experiments.[43]
### Granule cell dispersion in the dentate gyrus[edit]
Granule cell dispersion is a type of developmental migration and a pathological change found in the TLE brain which was first described in 1990.[44][45] The granule cells of the dentate gyrus are tightly packed forming a uniform, laminated layer with no monosynaptic connections.[46] This structure provides a filter for the excitability of neurons.[46]
In TLE, granule cells are lost, the structure is no longer closely packed and there are changes in the orientation of dendrites.[45][47] These changes may or may not be epileptogenic. For instance, if the dendrites of granule cells reconnect, it may be in a way (through the laminar planes) that allows hyperexcitability.[34] However, not all patients have granule cell dispersion.[31](p387–389)
### Aberrant mossy fiber sprouting[edit]
Mossy fibers are the axons of granule cells. They project into the hilus of the dentate gyrus and stratum lucidum in the CA3 region giving inputs to both excitatory and inhibitory neurons.[46][48][49]
In the TLE brain, where granule cells are damaged or lost, axons, the mossy fibres, 'sprout' in order to reconnect to other granule cell dendrites. This is an example of synaptic reorganization. This was noted in human tissue in 1974 and in animal models in 1985. In TLE, the sprouting mossy fibres are larger than in the normal brain and their connections may be aberrant. Mossy fibre sprouting continues from one week to two months after injury.[31](p416–431)[46][50][51][52]
Aberrant mossy fibre sprouting may create excitatory feedback circuits that lead to temporal lobe seizures. This is evident in intracellular recordings.[53] Stimulation of aberrant mossy fibre areas increases the excitatory postsynaptic potential response.[54][55]
However, aberrant mossy fiber sprouting may inhibit excitatory transmission by synapsing with basket cells which are inhibitory neurons and by releasing GABA and neuropeptide Y which are inhibitory neurotransmitters. Also, in animal models, granule cell hyper-excitability is recorded before aberrant mossy fibre sprouting has occurred.[56][57][58][59]
## Diagnosis[edit]
Epileptic spike and wave discharges monitored with EEG
The diagnosis of temporal lobe epilepsy can include the following methods:[60] Magnetic resonance imaging (MRI), CT scans, positron emission tomography (PET), EEG, and magnetoencephalography.
### Differential diagnosis[edit]
Other medical conditions with similar symptoms include panic attacks, psychosis spectrum disorders, tardive dyskinesia, and occipital lobe epilepsy.[61]
## Treatments[edit]
### Anticonvulsants[edit]
Many anticonvulsant oral medications are available for the management of temporal lobe seizures. Most anticonvulsants function by decreasing the excitation of neurons, for example, by blocking fast or slow sodium channels or by modulating calcium channels; or by enhancing the inhibition of neurons, for example by potentiating the effects of inhibitory neurotransmitters like GABA.[citation needed]
In TLE, the most commonly used older medications are phenytoin, carbamazepine, primidone, valproate, and phenobarbital. Newer drugs, such as gabapentin, topiramate, levetiracetam, lamotrigine, pregabalin, tiagabine, lacosamide, and zonisamide promise similar effectiveness, with possibly fewer side-effects. Felbamate and vigabatrin are newer, but can have serious adverse effects so they are not considered as first-line treatments.[citation needed]
Up to one third of patients with medial temporal lobe epilepsy will not have adequate seizure control with medication alone. For patients with medial TLE whose seizures remain uncontrolled after trials of several types of anticonvulsants (that is, the epilepsy is intractable), surgical excision of the affected temporal lobe may be considered.[62]
### Surgical interventions[edit]
Epilepsy surgery has been performed since the 1860s and doctors have observed that it is highly effective in producing freedom from seizures. However, it was not until 2001 that a scientifically sound study was carried out to examine the effectiveness of temporal lobectomy.[63]
Temporal lobe surgery can be complicated by decreased cognitive function. However, after temporal lobectomy, memory function is supported by the opposite temporal lobe; and recruitment of the frontal lobe.[64][65] Cognitive rehabilitation may also help.[66]
### Other treatments[edit]
Where surgery is not recommended, further management options include new (including experimental) anticonvulsants, and vagus nerve stimulation. The ketogenic diet is also recommended for children, and some adults.[67] Other options include brain cortex responsive neural stimulators, deep brain stimulation, stereotactic radiosurgery, such as the gamma knife, and laser ablation.[68]
## Effects on society[edit]
This section needs more medical references for verification or relies too heavily on primary sources, specifically: Use of primary and unreliable medical sources. Problems obvious in Ramachandran paragraph. 3d para assembled from primary + synth. 1st para is also poorly written, the szrs are abnormal.. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed.
Find sources: "Temporal lobe epilepsy" – news · newspapers · books · scholar · JSTOR (August 2017)
The first to record and catalog the abnormal symptoms and signs of TLE was Norman Geschwind. He found a constellation of symptoms that included hypergraphia, hyperreligiosity, collapse, and pedantism, now called Geschwind syndrome.
Vilayanur S. Ramachandran explored the neural basis of the hyperreligiosity seen in TLE using the galvanic skin response (GSR), which correlates with emotional arousal, to determine whether the hyperreligiosity seen in TLE was due to an overall heightened emotional state or was specific to religious stimuli. Ramachandran presented two subjects with neutral, sexually arousing and religious words while measuring GSR. Ramachandran was able to show that patients with TLE showed enhanced emotional responses to the religious words, diminished responses to the sexually charged words, and normal responses to the neutral words. This study was presented as an abstract at a neuroscience conference and referenced in Ramachandran's book, Phantoms in the Brain,[69] but it has never been published in the peer-reviewed scientific press.[70]
A study in 2015, reported that intrinsic religiosity and religiosity outside of organized religion were higher in patients with epilepsy than in controls.[71] Lower education level, abnormal background EEG activity, and hippocampal sclerosis have been found to be contributing factors for religiosity in TLE.[72]
TLE has been suggested as a materialistic explanation for the revelatory experiences of prominent religious figures such as Abraham, Moses, Jesus, Mohammed, Saint Paul, Joan of Arc,[73] Saint Teresa of Ávila, and Joseph Smith. These experiences are described (in possibly unreliable accounts) as complex interactions with their visions; but lack the stereotypy, amnestic periods, and automatisms or generalized motor events, which are characteristic of TLE. Psychiatric conditions with psychotic spectrum symptoms might be more plausible physical explanation of these experiences.[74] It has been suggested that Pope Pius IX's doctrine of the immaculate conception was influenced by his forensically-diagnosed partial epilepsy.[75]
In 2016, a case history found that a male temporal lobe epileptic patient experienced a vision of God following a temporal lobe seizure, while undergoing EEG monitoring. The patient reported that God had sent him to the world to "bring redemption to the people of Israel".[76] The purported link between TLE and religiosity has inspired work by Michael Persinger and other researchers in the field of neurotheology. Others have questioned the evidence for a link between temporal lobe epilepsy and religiosity.[70][77]
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43. ^ Sivakumaran, Sudhir; Cardarelli, Ross A.; Maguire, Jamie; Kelley, Matt R.; Silayeva, Liliya; Morrow, Danielle H.; Mukherjee, Jayanta; Moore, Yvonne E.; Mather, Robert J. (27 May 2015). "Selective Inhibition of KCC2 Leads to Hyperexcitability and Epileptiform Discharges in Hippocampal Slices and In Vivo". Journal of Neuroscience. 35 (21): 8291–8296. doi:10.1523/JNEUROSCI.5205-14.2015. ISSN 0270-6474. PMC 4444547. PMID 26019342.
44. ^ Thom M, et al. (2005). "Cell proliferation and granule cell dispersion in human hippocampal sclerosis". J Neuropathol Exp Neurol. 64 (3): 194–201. doi:10.1093/jnen/64.3.194. PMID 15804050.
45. ^ a b Houser C. R. (1990). "Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy". Brain Research. 535 (2): 195–204. doi:10.1016/0006-8993(90)91601-c. PMID 1705855. S2CID 7510030.
46. ^ a b c d Nadler J. V. (2003). "The recurrent mossy fiber pathway of the epileptic brain". Neurochemical Research. 28 (11): 1649–1658. doi:10.1023/a:1026004904199. PMID 14584819. S2CID 2566342.
47. ^ Freimanr T. M.; et al. (2011). "Granule cell dispersion in temporal lobe epilepsy is associated with changes in dendritic orientation and spine distribution". Experimental Neurology. 229 (2): 332–338. doi:10.1016/j.expneurol.2011.02.017. PMID 21376037. S2CID 6207296.
48. ^ Lim C, et al. (1997). "Connections of the hippocampal formation in humans: I. The mossy fiber pathway". Journal of Comparative Neurology. 385 (3): 325–351. doi:10.1002/(sici)1096-9861(19970901)385:3<325::aid-cne1>3.0.co;2-5. PMID 9300763.
49. ^ Henze D. A.; et al. (2000). "The multifarious hippocampal mossy fiber pathway: a review". Neuroscience. 98 (3): 407–427. doi:10.1016/s0306-4522(00)00146-9. PMID 10869836. S2CID 11663807.
50. ^ Scheibel P, et al. (1974). "The hippocampal-dentate complex in temporal lobe epilepsy". Epilepsia. 15 (1): 55–80. doi:10.1111/j.1528-1157.1974.tb03997.x. PMID 4523024.
51. ^ Steward O (1992). "Lesion-induced synapse reorganization in the hippocampus of cats: sprouting of entorhinal, commissural/associational, and mossy fiber projections after unilateral entorhinal cortex lesions, with comments on the normal organization of these pathways". Hippocampus. 2 (3): 247–68. doi:10.1002/hipo.450020305. PMID 1284974.
52. ^ Babb T. L.; et al. (1991). "Synaptic reorganization by mossy fibers in human epileptic fascia dentata". Neuroscience. 42 (2): 351–363. doi:10.1016/0306-4522(91)90380-7. PMID 1716744. S2CID 34237315.
53. ^ Buckmaster P, et al. (2002). "Axon sprouting in a model of temporal lobe epilepsy creates a predominantly excitatory feedback circuit". Journal of Neuroscience. 22 (15): 6650–6658. doi:10.1523/JNEUROSCI.22-15-06650.2002. PMC 6758164. PMID 12151544.
54. ^ Nadler J. V.; et al. (1985). "Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats". Journal of Neuroscience. 5 (4): 1016–1022. doi:10.1523/JNEUROSCI.05-04-01016.1985. PMC 6565006. PMID 3981241.
55. ^ Scharfman H. E.; et al. (2003). "Electrophysiological evidence of monosynaptic excitatory transmission between granule cells after seizure-induced mossy fiber sprouting". Journal of Neurophysiology. 90 (4): 2536–2547. CiteSeerX 10.1.1.326.233. doi:10.1152/jn.00251.2003. PMID 14534276.
56. ^ Sloviter R. S.; et al. (2006). "Kainic acid-induced recurrent mossy fiber innervation of dentate gyrus inhibitory interneurons: possible anatomical substrate of granule cell hyperinhibition in chronically epileptic rats". Journal of Comparative Neurology. 494 (6): 944–60. doi:10.1002/cne.20850. PMC 2597112. PMID 16385488.
57. ^ Sloviter R. S.; et al. (2003). "Dormant basket cell hypothesis revisited: relative vulnerabilities of dentate gyrus mossy cells and inhibitory interneurons after hippocampal status epilepticus in the rat". Journal of Comparative Neurology. 459 (1): 44–76. doi:10.1002/cne.10630. PMID 12629666. S2CID 36798455.
58. ^ Tu B, et al. (2005). "Spontaneous release of neuropeptide Y tonically inhibits recurrent mossy fiber synaptic transmission in epileptic brain". Journal of Neuroscience. 25 (7): 1718–1729. doi:10.1523/JNEUROSCI.4835-04.2005. PMC 6725947. PMID 15716408.
59. ^ Schwarzer C.; Sperk G. (1995). "Hippocampal granule cells express glutamic acid decarboxylase-67 after limbic seizures in the rat". Neuroscience. 69 (3): 705–709. doi:10.1016/0306-4522(95)00348-m. PMID 8596641. S2CID 2947533.
60. ^ "Temporal Lobe Epilepsy Workup: Approach Considerations, Computed Tomography Scanning, Magnetic Resonance Imaging". emedicine.medscape.com. Archived from the original on 23 August 2016. Retrieved 24 August 2016.
61. ^ "Temporal Lobe Epilepsy; TLE medical Information Page | Patient". Patient. Archived from the original on 29 August 2016. Retrieved 24 August 2016.
62. ^ Kwan P (2000). "Early identification of refractory epilepsy". NEJM. 342 (5): 314–319. doi:10.1056/NEJM200002033420503. PMID 10660394.
63. ^ Wiebe S, et al. (2001). "A randomized, controlled trial of surgery for temporal lobe epilepsy". NEJM. 345 (5): 311–318. doi:10.1056/NEJM200108023450501. PMID 11484687.
64. ^ Cheung; et al. (2009). "Pre- and postoperative fMRI and clinical memory performance in temporal lobe epilepsy". J Neurol Neurosurg Psychiatry. 80 (10): 1099–1106. doi:10.1136/jnnp.2009.173161. hdl:10397/33373. PMID 19389718. S2CID 5602939.
65. ^ Maccotta L, et al. (2007). "Changing frontal contributions to memory before and after medial temporal lobectomy". Cereb Cortex. 17 (2): 443–456. doi:10.1093/cercor/bhj161. PMID 16547345.
66. ^ Helmstaedter C, et al. (2008). "The effects of cognitive rehabilitation on memory outcome after temporal lobe epilepsy surgery". Epilepsy Behav. 12 (3): 402–409. doi:10.1016/j.yebeh.2007.11.010. PMID 18155965. S2CID 29690584.
67. ^ Freeman, JM; Kossoff, EH; Hartman, AL (March 2007). "The ketogenic diet: one decade later". Pediatrics. 119 (3): 535–43. doi:10.1542/peds.2006-2447. PMID 17332207. S2CID 26629499.
68. ^ Curry, Daniel J.; Gowda, Ashok; McNichols, Roger J.; Wilfong, Angus A. (2012). "MR-guided stereotactic laser ablation of epileptogenic foci in children". Epilepsy & Behavior. 24 (4): 408–414. doi:10.1016/j.yebeh.2012.04.135. PMID 22687387. S2CID 531323.
69. ^ Ramachandran, V. and Blakeslee (1998). Phantoms in the Brain.
70. ^ a b Craig Aaen-Stockdale (2012). "Neuroscience for the Soul". The Psychologist. 25 (7): 520–523. Archived from the original on 26 October 2015.
71. ^ Tedrus, Glória Maria Almeida Souza; Fonseca, Lineu Corrêa; Fagundes, Tatiane Mariani; da Silva, Gabriela Leopoldino (2015). "Religiosity aspects in patients with epilepsy". Epilepsy & Behavior. 50: 67–70. doi:10.1016/j.yebeh.2015.06.003. PMID 26133113. S2CID 22703938.
72. ^ Tedrus, Glória Maria Almeida Souza; Fonseca, Lineu Corrêa; Höehr, Gabriela Chaves (2013). "Spirituality aspects in patients with epilepsy". Seizure. 23 (1): 25–8. doi:10.1016/j.seizure.2013.09.005. PMID 24094727. "Patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) had significantly higher SSRS scores than those with other epileptic syndromes and, than in individuals of the CG (control Group)"
73. ^ d'Orsi, Giuseppe; Tinuper, Paolo (2006). ""I heard voices...": from semiology, a historical review, and a new hypothesis on the presumed epilepsy of Joan of Arc". Epilepsy & Behavior. 9 (1): 152–157. doi:10.1016/j.yebeh.2006.04.020. PMID 16750938. S2CID 24961015.
74. ^ Murray E. D.; et al. (2012). "The role of psychotic disorders in religious history considered". The Journal of Neuropsychiatry and Clinical Neurosciences. 24 (4): 410–426. doi:10.1176/appi.neuropsych.11090214. PMID 23224447. S2CID 207654711.
75. ^ Sirven, Joseph I; Drazkowski, Joseph F; Noe, Katherine H (2007). "Seizures among public figures: lessons learned from the epilepsy of Pope Pius IX". Mayo Clinic Proceedings. 82 (12): 1535–1540. doi:10.1016/S0025-6196(11)61100-2. PMID 18053463.
76. ^ Arzy, Shahar; Schurr, Roey (2016). ""God has sent me to you": Right temporal epilepsy, left prefrontal psychosis". Epilepsy & Behavior. 60: 7–10. doi:10.1016/j.yebeh.2016.04.022. PMID 27176877. Lay summary. "In this patient, a messianic revelation experience occurred several hours after a complex partial seizure of temporal origin, compatible with postictal psychosis (PIP)"
77. ^ Benson, D.F. & Hermann, B.P. (1998) Personality disorders. In J. Engel Jr. & T.A. Pedley (Eds.) Epilepsy: A comprehensive textbook. Vol. II (pp. 2065–2070). Philadelphia: Lippincott–Raven.
## External links[edit]
Classification
D
* ICD-10: G40.1-G40.2
* ICD-9-CM: 345.4
* MeSH: D004833
* DiseasesDB: 29433
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* MedlinePlus: 001399
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*[v]: View this template
*[t]: Discuss this template
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*[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
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*[MAOIs]: Monoamine oxidase inhibitors
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*[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
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*[Rate]: ICU-care cases per confirmed cases in each category
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| Temporal lobe epilepsy | c0014556 | 4,832 | wikipedia | https://en.wikipedia.org/wiki/Temporal_lobe_epilepsy | 2021-01-18T18:39:25 | {"mesh": ["D004833"], "umls": ["C0014556"], "icd-9": ["345.4"], "icd-10": ["G40.2", "G40.1"], "wikidata": ["Q616667"]} |
Epigastric hernia
Abdominal ultrasound of a midline epigastric hernia.
SpecialtyGeneral surgery
An epigastric hernia is a type of hernia that causes fat to push through a weakened area in the walls of the abdomen. It may develop in the epigastrium (upper, central part of the abdomen). Epigastric hernias are more common in adults and usually appear above the umbilical region of the abdomen. It is a common condition that is usually asymptomatic although sometimes their unusual clinical presentation can present a diagnostic dilemma for the clinician. Unlike the benign diastasis recti, epigastric hernia may trap fat and other tissues inside the opening of the hernia, causing pain and tissue damage.[1] It is usually present at birth and may appear and disappear only when the patient is doing an activity that creates abdominal pressure, pushing to have bowel movements, or crying.
## Contents
* 1 Symptoms
* 2 Causes
* 3 Diagnosis
* 4 Treatment
* 5 Prognosis
* 6 See also
* 7 References
## Symptoms[edit]
* Pain
* tenderness[2]
* redness
* Impulse on cough
## Causes[edit]
* Obesity
* Pregnancy.[1]
* Frequent heavy lifting
* Genetic defects
* Aging
* Severe vomiting
## Diagnosis[edit]
Computed tomography scans of the suspected areas with intravenous contrast can assist in diagnosis.[3] Doctors are also able to identify whether it is a suspected hernia by palpating the affected area.[4]
Ultrasonography is also used for diagnostic purposes.[citation needed]
## Treatment[edit]
Symptomatic epigastric hernias are repaired with surgery.[1] Even if they are asymptomatic, they can be surgically corrected for cosmetic reasons. In general, cosmetic surgery on infants is delayed until the infant is older and better able to tolerate anesthesia. If the size of the hernia is greater than 4 cm, then a hernioplasty or herniorraphy surgery is required.[5]
## Prognosis[edit]
Epigastric hernia becomes a problem when the hernia becomes incarcerated or loses blood supply to that area. This can be life-threatening.[citation needed]
## See also[edit]
* Diastasis recti
## References[edit]
1. ^ a b c Norton, Jeffrey A. (2003). Essential practice of surgery: basic science and clinical evidence. Berlin: Springer. pp. 350. ISBN 0-387-95510-0.
2. ^ "Epigastric hernia: Causes, repair, and recovery". Medical News Today. Retrieved 2019-05-14.
3. ^ Toms, A. P.; Dixon, A. K.; Murphy, J. M.; Jamieson, N. V. (October 1999). "Illustrated review of new imaging techniques in the diagnosis of abdominal wall hernias". The British Journal of Surgery. 86 (10): 1243–1249. doi:10.1046/j.1365-2168.1999.01211.x. ISSN 0007-1323. PMID 10540124. S2CID 43879390.
4. ^ "Abdominal Wall Hernias | Michigan Medicine". www.uofmhealth.org. Retrieved 2019-05-14.
5. ^ Sallam, Raouf Mahmoud; El-sayed, Ahmed Mohamed; Abdou, Abdou Mahmoud (2018-10-05). "Comparative Study between Drained and Drainless Sub-rectal Mesh Hernioplasty in Paraumbilical Hernia". Egyptian Journal of Hospital Medicine. 73 (4): 6417–6422.
This article about a disease, disorder, or medical condition is a stub. You can help Wikipedia by expanding it.
* v
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* 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 inhibitors
*[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
| Epigastric hernia | c0019287 | 4,833 | wikipedia | https://en.wikipedia.org/wiki/Epigastric_hernia | 2021-01-18T18:37:42 | {"umls": ["C0019287"], "wikidata": ["Q779898"]} |
A number sign (#) is used with this entry because of evidence that microphthalmia and/or coloboma, with or without rhizomelic skeletal dysplasia, is caused by heterozygous mutation in the MAB21L2 gene (604357) on chromosome 4q31. One family with a homozygous mutation has also been reported.
Clinical Features
Rainger et al. (2014) described 8 patients from 5 unrelated families with mutations in the MAB21L2 gene who had microphthalmia with coloboma or clinical anophthalmia, with or without rhizomelic skeletal dysplasia. In 1 family (family 1463), there were 9 affected individuals spanning 3 generations; all but 1 had isolated microphthalmia and coloboma. The 13-year-old male proband also exhibited skeletal involvement, with bowing of both legs noted in infancy; he had joint contractures of the knees and hips bilaterally and bilateral hypoplastic femoral condyles and pes cavus as well as hypospadias and wasting of the calf muscles. A 10-year-old Norwegian girl (family 676) and an unrelated 24-year-old man (family 4480), both with clinical anophthalmia, had severe bilateral rhizomelia as well as contractures of all large joints; additional findings in the girl included macrocephaly and precocious puberty at age 7 years, and in the man, hypoplastic femoral condyles. Both had moderate intellectual disability, and the girl also exhibited features of autistic spectrum disorder. A 39-year-old man (family 131) with bilateral microphthalmia, coloboma, and microcornea had fairly good vision until 11 years of age, after which he became blind over a period of 2 years. There was no evidence of retinal detachment; no retinal electrophysiology was available. He exhibited minor skeletal dysmorphism, with recurrent dislocations of the patella and soft tissue syndactyly of fingers 3 and 4 and toes 2 and 3; he also had bilateral undescended testes. Two brothers, aged 3 and 5 years, who were born of consanguineous parents (family 4468), had bilateral coloboma, but only the younger brother had microphthalmia, which was unilateral. They both exhibited facial dysmorphism, including prominent forehead, periorbital fullness, long eyelashes, epicanthus, and long and prominent philtrum, and both had unilateral strabismus. The younger brother had mild shortening of the long bones with decreased tubulation, but the older brother exhibited no skeletal changes. Their unaffected first-cousin parents had normal vision, and examination revealed no evidence of an asymptomatic structural eye malformation. Horn et al. (2015) provided additional clinical details on the probands of families 676 and 4480.
Deml et al. (2015) reported a 3-generation family in which a 32-year-old man and his sister, brother, and 2 nephews had coloboma, microcornea, cataracts, and skeletal dysplasia. The proband had bilateral microcornea, iris and chorioretinal coloboma, corectopia, nystagmus, and cataract, and also exhibited rhizomelic shortening of the upper and lower limbs, and mild contractures of the knees and elbows. Ultrasound measurements of the proband's eyes revealed axial lengths to be within the normal range; axial lengths of other affected family members were not reported.
Molecular Genetics
In 3 independent exome-sequencing projects, Rainger et al. (2014) identified 4 different missense mutations in the MAB21L2 gene (604357) in 8 patients from 5 unrelated families with bilateral microphthalmia and coloboma or clinical anophthalmia with or without rhizomelic skeletal dysplasia. The mutations segregated with disease in each family and were not found in public databases, including those of the 1000 Genomes Project and the NHLBI Exome Variant server. In 4 of the families, the mutations were heterozygous and located near each other, involving R51 in 3 families (R51H, 604357.0001; R51C, 604357.0002) and E49 (E49K; 604357.0003); however, 2 brothers, born of consanguineous parents, were homozygous for an R247Q mutation (604357.0004) for which their unaffected parents were both heterozygous. Rainger et al. (2014) stated that the restricted repertoire of mutations in the monoallelic cases strongly suggested an unusual genetic mechanism beyond simple loss of function, and further noted that the 2 patients with homozygous mutations were the least severely affected.
In a 3-generation family with coloboma, microcornea, cataracts, and skeletal dysplasia, Deml et al. (2015) identified heterozygosity for a missense mutation in the MAB21L2 gene (R51G; 604357.0005) that segregated with disease and was not found in public variant databases. The proband's unaffected mother appeared to have low-level mosaicism for the mutation. Analysis of whole-exome data from 276 patients with developmental ocular conditions revealed no additional mutations in MAB21L2. In 125 patients derived from the UK10K Rare Coloboma project, the R51H mutation was detected in 2 patients; the authors noted that these 2 patients were members of the family (family 1463) previously studied by Rainger et al. (2014) in which the R51H mutation had been identified.
INHERITANCE \- Autosomal dominant \- Autosomal recessive (1 family) HEAD & NECK Head \- Macrocephaly (rare) Face \- Prominent forehead (in 2 brothers with homozygous mutation) \- Long prominent philtrum (in 2 brothers with homozygous mutation) Eyes \- Microphthalmia or clinical anophthalmia \- Coloboma \- Microcornea \- Corectopia \- Cataract \- Nystagmus \- Strabismus (in 2 brothers with homozygous mutation) \- Periorbital fullness (in 2 brothers with homozygous mutation) \- Epicanthal folds (in 2 brothers with homozygous mutation) \- Long eyelashes (in 2 brothers with homozygous mutation) \- Sclerocornea (rare) GENITOURINARY External Genitalia (Male) \- Hypospadias (rare) Internal Genitalia (Male) \- Undescended testicles (rare) SKELETAL Skull \- Macrocephaly (rare) Limbs \- Contractures of large joints (in some patients) \- Hypoplastic femoral condyles (in some patients) \- Rhizomelia (in some patients) \- Shortness of long bones, mild (in some patients) \- Decreased tubulation of long bones (rare) \- Patellar dislocations, recurrent (rare) Hands \- Cutaneous syndactyly of fingers 3 and 4 (rare) Feet \- Cutaneous syndactyly of toes 2 and 3 (rare) \- Pes planus (rare) MUSCLE, SOFT TISSUES \- Wasting of calf muscles (rare) NEUROLOGIC Central Nervous System \- Intellectual disability, moderate (in some patients) Behavioral Psychiatric Manifestations \- Autistic spectrum disorder (rare) ENDOCRINE FEATURES \- Precocious puberty (rare) MISCELLANEOUS \- Homozygous mutation reported in 1 family, in which heterozygous parents had normal vision and ocular examination MOLECULAR BASIS \- Caused by mutation in the mab-21 like 2 gene (MAB21L2, 604357.0001 ) ▲ 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 inhibitors
*[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
| MICROPHTHALMIA/COLOBOMA AND SKELETAL DYSPLASIA SYNDROME | c4014540 | 4,834 | omim | https://www.omim.org/entry/615877 | 2019-09-22T15:50:46 | {"omim": ["615877"], "orphanet": ["424099"], "synonyms": ["Alternative titles", "MICROPHTHALMIA AND/OR COLOBOMA WITH OR WITHOUT RHIZOMELIC SKELETAL DYSPLASIA", "Microphthalmia-coloboma-rhizomelic skeletal dysplasia", "MICROPHTHALMIA, SYNDROMIC 14"]} |
A woman urinating into the mouth of a man; an example of golden showers.
Salirophilia is a sexual fetish or paraphilia that involves deriving erotic pleasure from soiling or disheveling the object of one's desire, usually an attractive person. It may involve tearing or damaging their clothing, covering them in mud or filth, or messing their hair or makeup. The fetish does not involve harming or injuring the subject, only their appearance.
It is related to wet and messy fetishism, bukkake (ejaculating semen on someone), cum shot, gokkun (drinking semen of someone), facial, omorashi (preventing urination), mysophilia (ex. fetishism of used underwear), urolagnia (urinating on someone), and coprophilia, etc. Salirophilia also extends to other areas such as forcing the partner to wear torn or poorly fitting clothing and other actions which would render them normally unattractive.
The fetish sometimes manifests itself in the defacing of statues or pictures of attractive people, especially celebrities or fictional characters. It is common to refer to the practice involving ejaculating on a photo as "facepainting". This may be done with a physical photograph or the screen of a phone, tablet, or computer. The fetishist finds this sexually exciting, rather than mere vandalism and they sometimes form collections of defaced art, either created by themselves or in collaboration with others, for future enjoyment. A video of the fetishist ejaculating on a picture of someone or a photo depicting the result is known colloquially as a "tribute".
The term comes from the French for soiling, salir. In cases where the fetish is obsessive it is called saliromania. It is frequently confused with salophilia, an attraction to salt or salty things (especially body sweat) that derives from the Latin for salt, sal.
## Mysophilia[edit]
Mysophilia relates to soiled or dirty material or people.[1] Mysophiliacs may find dirt, soiled underwear, feces, or vomit to be sexually arousing.[2]
It is possible for people with mysophilia to be aroused by unclean locales, such as an alleyway, or a dirty room/bathroom; wearing the same clothing for many days at a time; or not bathing, from mere days to several weeks.[citation needed] Helen Memel, a teen-aged protagonist in Charlotte Roche's 2008 novel Wetlands and David Wnendt's 2013 similarly titled film based on the book, would be considered a mysophiliac, insofar as she sought out the dirtiest of public toilets and rubbed her vulva around the rim of the toilet. She also went for long periods of time without washing her vulva, deriving pleasure form its scents and secretions.
## See also[edit]
* BDSM
* Edgeplay
* Erotic humiliation
## References[edit]
1. ^ Butcher, Nancy (2003). The Strange Case of the Walking Corpse: A Chronicle of Medical Mysteries, Curious Remedies, and Bizarre but True Healing Folklore. New York: Avery. p. 133. ISBN 1-58333-160-3. OCLC 52107453.
2. ^ Holmes, Ronald M. Sex Crimes: Patterns and Behavior. Thousand Oaks: Sage Publications. p. 79. ISBN 0-7619-2417-5. OCLC 48883594.
* v
* t
* e
Paraphilias
List
* Abasiophilia
* Acrotomophilia
* Agalmatophilia
* Algolagnia
* Apotemnophilia
* Autassassinophilia
* Biastophilia
* Capnolagnia
* Chremastistophilia
* Chronophilia
* Coprophagia
* Coprophilia
* Crurophilia
* Crush fetish
* Dacryphilia
* Dendrophilia
* Emetophilia
* Eproctophilia
* Erotic asphyxiation
* Erotic hypnosis
* Erotophonophilia
* Exhibitionism
* Formicophilia
* Frotteurism
* Gerontophilia
* Homeovestism
* Hybristophilia
* Infantophilia
* Kleptolagnia
* Klismaphilia
* Lactaphilia
* Macrophilia
* Masochism
* Mechanophilia
* Microphilia
* Narratophilia
* Nasophilia
* Necrophilia
* Object sexuality
* Odaxelagnia
* Olfactophilia
* Omorashi
* Paraphilic infantilism
* Partialism
* Pedophilia
* Podophilia
* Plushophilia
* Pyrophilia
* Sadism
* Salirophilia
* Scopophilia
* Somnophilia
* Sthenolagnia
* Tamakeri
* Telephone scatologia
* Transvestic fetishism
* Trichophilia
* Troilism
* Urolagnia
* Urophagia
* Vorarephilia
* Voyeurism
* Zoophilia
* Zoosadism
See also
* Other specified paraphilic disorder
* Erotic target location error
* Courtship disorder
* Polymorphous perversity
* Sexual fetishism
* Human sexual activity
* Perversion
* Sexology
* Book
* Category
This sexuality-related 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 inhibitors
*[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
| Salirophilia | None | 4,835 | wikipedia | https://en.wikipedia.org/wiki/Salirophilia | 2021-01-18T18:58:57 | {"wikidata": ["Q1266211"]} |
A rare low-grade astrocytoma characterized by a benign, slowly growing lesion typically arising in the wall of the lateral ventricles, composed of large ganglioid astrocytes. The tumor corresponds to WHO grade I and typically occurs during the first two decades of life in patients with tuberous sclerosis complex. Most patients present with worsening of epilepsy or symptoms of increased 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 inhibitors
*[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
| Subependymal giant cell astrocytoma | c0205768 | 4,836 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251618 | 2021-01-23T17:15:06 | {"gard": ["10632"], "mesh": ["D001254"], "umls": ["C0205768"], "icd-10": ["D43.2"], "synonyms": ["SEGA"]} |
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. (May 2018) (Learn how and when to remove this template message)
HDN due to anti-Rhc alloimmunization
SpecialtyHematology
Hemolytic disease of the newborn (anti-Rhc) can range from a mild to a severe disease. It is the third most common cause of severe HDN. Rh disease is the most common and hemolytic disease of the newborn (anti-Kell) is the second most common cause of severe HDN. It occurs more commonly in women who are Rh D negative.[citation needed]
## Contents
* 1 Presentation
* 1.1 Complications
* 1.1.1 Transfusion reactions
* 2 Causes
* 3 Diagnosis
* 3.1 Mother
* 3.2 Father
* 3.3 Fetus
* 4 Prevention
* 5 Treatment
* 5.1 Early pregnancy
* 5.2 Mid to late pregnancy
* 6 After Birth
* 6.1 Testing
* 7 Treatment
* 8 History
* 9 See also
* 10 References
* 11 Further reading
* 12 External links
## Presentation[edit]
### Complications[edit]
* High at birth or rapidly rising bilirubin[1]
* Prolonged hyperbilirubinemia[1]
* Bilirubin Induced Neurological Dysfunction[2]
* Cerebral Palsy[3]
* Kernicterus[4]
* Neutropenia[5][6]
* Thrombocytopenia[5]
* Hemolytic Anemia - MUST NOT be treated with iron[7]
* Late onset anemia - Must NOT be treated with iron. Can persist up to 12 weeks after birth.[8][9][10]
#### Transfusion reactions[edit]
Once a woman has antibodies, she is at high risk for a transfusion reaction.[11] For this reason, she must carry a medical alert card at all times and inform all doctors of her antibody status.[citation needed]
"Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures."[12]
## Causes[edit]
A Rhc negative mother can become sensitised by red blood cell (RBC) Rhc antigens by her first pregnancy with a Rhc positive fetus. The mother can make IgG anti-Rhc antibodies, which are able to pass through the placenta and enter the fetal circulation. If the fetus is Rhc positive alloimmune hemolysis can occur leading to HDN. This is similar as for Rh disease, which is usually caused when a RhD negative mother is sensitised by her first pregnancy with a RhD positive fetus.[citation needed]
Sensitization to Rhc antigens can also be caused by blood transfusion.[citation needed]
## Diagnosis[edit]
Testing for HDN involves blood work from both mother and father, and may also include assessment with amniocentesis and Middle Cerebral Artery scans.[citation needed]
Anti-C and anti-c can both show a negative DAT but still have a severely affected infant.[13][14] An indirect coombs must also be run.
In the case of anti-c, the woman should be checked around 28 weeks to see if she has developed anti-E as well.[citation needed]
### Mother[edit]
Blood testing for the mother is called an Indirect Coombs Test (ICT) or an Indirect Agglutination Test (IAT). This test tells whether there are antibodies in the maternal plasma. If positive, the antibody is identified and given a titer. Critical titers are associated with significant risk of fetal anemia and hydrops.[15] Titers of 1:8 or higher is considered critical for Kell. Titers of 1:16 or higher are considered critical for all other antibodies. After critical titer is reached, care is based on MCA scans. If antibodies are low and have a sudden jump later in pregnancy, an MCA scan is warranted. If the titer undergoes a 4 fold increase, it should be considered significant regardless of if the critical value has been reached. Maternal titers are not useful in predicting fetal anemia after the first affected gestation and should not be used for the basis of care.[16] Titers are tested monthly until 24 weeks, after which they are done every 2 weeks.[17]
"In only 2 situations are patients not monitored identically to patients who are Rh sensitized. The first is that of alloimmunization to the c, E, or, C antigens. Some concern exists that hemolysis may occur in these patients with a lower than 1:16 titer. Thus, if the initial titer is 1:4 and stable but increases at 26 weeks' gestation to 1:8, assessment with MCA Doppler velocity at that point is reasonable. However, if the patient presents in the first trimester with a 1:8 titer that remains stable at 1:8 throughout the second trimester, continued serial antibody titers are appropriate. The second situation in which patients should not be treated identically to patients who are Rh D sensitized is that of Kell isoimmunization because several cases of severe fetal hemolysis with anti-Kell antibodies have occurred in the setting of low titers."[15]
In the case of a positive ICT, the woman must carry a medical alert card or bracelet for life because of the risk of a transfusion reaction.[18]
### Father[edit]
Blood is generally drawn from the father to help determine fetal antigen status.[19] If he is homozygous for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen and at risk for HDN. If he is heterozygous, there is a 50% chance of offspring to be positive for the antigen.[20] This test can help with knowledge for the current baby, as well as aid in the decision about future pregnancies. With RhD, the test is called the RhD genotype. With RhCE, and Kell antigen it is called an antigen phenotype.[21]
### Fetus[edit]
There are 3 possible ways to test the fetal antigen status. Free Cell DNA, Amniocentesis, and Chorionic Villus Sampling (CVS). Of the three, CVS is no longer used due to risk of worsening the maternal antibody response. Once antigen status has been determined, assessment may be done with MCA scans.[citation needed]
* Cell-free DNA can be run on certain antigens. Blood is taken from the mother, and using PCR, can detect the K, C, c, D, and E alleles of fetal DNA. This blood test is non-invasive to the fetus and is an easy way of checking antigen status and risk of HDN. Testing has proven very accurate and is routinely done in the UK at the International Blood Group Reference Laboratory in Bristol.[22] Sanequin laboratory in Amsterdam, Netherlands also performs this test. For US patients, blood may be sent to either of the labs. In the US, Sensigene is done by Sequenome to determine fetal D status. Sequenome does not accept insurance in the US, but US and Canadian patients have had insurance cover the testing done overseas.[citation needed]
* Amniocentesis is another recommended method for testing antigen status and risk for HDN. Fetal antigen status can be tested as early as 15 weeks by PCR of fetal cells.[17]
* CVS is possible as well to test fetal antigen status but is not recommended. CVS carries a higher risk of fetal maternal hemorrhage and can raise antibody titers, potentially worsening the antibody effect.[17]
MCA scans: Middle cerebral artery - peak systolic velocity is changing the way sensitized pregnancies are managed.[23] This test is done noninvasively with ultrasound. By measuring the peak velocity of blood flow in the middle cerebral artery, a MoM (multiple of the median) score can be calculated. MoM of 1.5 or greater indicates severe anemia and should be treated with IUT.[24][23]
## Prevention[edit]
It has been suggested that women of child-bearing age or young girls should not be given a transfusion with Rhc positive blood (or Kell 1 positive blood for similar reasons). This would require a lot of extra work in blood transfusion departments and it is considered not economical to do the blood group screening at the present time.[citation needed]
It is theoretically likely that IgG anti-Rhc antibody injections would prevent sensitization to RBC surface Rhc antigens in a similar way that IgG anti-D antibodies (Rho(D) immune globulin) are used to prevent Rh disease, but the methods for IgG anti-Rhc antibodies have not been developed at the present time.[citation needed]
## Treatment[edit]
There are several intervention options available in early, mid and late pregnancies.
### Early pregnancy[edit]
* IVIG - IVIG stands for Intravenous Immunoglobulin. It is used in cases of previous loss, high maternal titers, known aggressive antibodies, and in cases where religion prevents blood transfusion. Ivig can be more effective than IUT alone [25] Fetal mortality was reduced by 36% in the IVIG and IUT group than in the IUT alone group. IVIG and plasmapheresis together can reduce or eliminate the need for an IUT.[26]
* Plasmapheresis - Plasmapheresis aims to decrease the maternal titer by direct plasma replacement.[27] Plasmapheresis and IVIG together can even be used on women with previously hydropic fetuses and losses.[28][29]
### Mid to late pregnancy[edit]
* IUT - Intrauterine transfusion (IUT) is done either by intraperitoneal transfusion (IPT) or intravenous transfusion (IVT).[30] IVT is preferred over IPT.[15] IUTs are only done until 35 weeks. After that, the risk of an IUT is greater than the risk from post birth transfusion.[31]
* Steroids - Steroids are sometimes given to the mother before IUTs and early delivery to mature the fetal lungs.[31][16]
* Phenobarbital - Phenobarbital is sometimes given to the mother to help mature the fetal liver and reduce hyperbilirubinemia.[16][32]
* Early Delivery - Delivery can occur anytime after the age of viability.[15] Emergency delivery due to failed IUT is possible, along with induction of labor at 35–38 weeks.[31][33]
## After Birth[edit]
### Testing[edit]
* Coombs - after birth baby will have a direct coombs test run to confirm antibodies attached to the infant's red blood cells. This test is run from cord blood.[1]
In some cases, the direct coombs will be negative but severe, even fatal HDN can occur.[13] An indirect coombs needs to be run in cases of anti-C,[14] anti-c,[14] and anti-M. Anti-M also recommends antigen testing to rule out the presence of HDN.[27]
* Hgb - the infant's hemoglobin should be tested from cord blood.[1]
* Reticulocyte count - Reticulocytes are elevated when the infant is producing more blood to combat anemia.[1] A rise in the retic count can mean that an infant may not need additional transfusions.[34] Low retic is observed in infants treated with IUT and in those with HDN from anti-Kell.[14]
* Neutrophils - as Neutropenia is one of the complications of HDN, the neutrophil count should be checked.[5][6]
* Thrombocytes - as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.[5]
* Bilirubin should be tested from cord blood.[1]
* Ferritin - because most infants affected by HDN have iron overload, a ferritin must be run before giving the infant any additional iron.[7]
* Newborn Screening Tests - Transfusion with donor blood during pregnancy or shortly after birth can affect the results of the Newborn Screening Tests. It is recommended to wait and retest 10–12 months after last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions.[citation needed]
## Treatment[edit]
* Phototherapy - Phototherapy is used for cord bilirubin of 3 or higher. Some doctors use it at lower levels while awaiting lab results.[35]
* IVIG - IVIG has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well.[36] IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy.[37] The AAP recommends "In isoimmune hemolytic disease, administration of intravenousγ-globulin (0.5-1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34-51 μmol/L) of the exchange level . If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms). Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease."[35]
* Exchange transfusion - Exchange transfusion is used when bilirubin reaches either the high or medium risk lines on the nonogram provided by the American Academy of Pediatrics (Figure 4).[35] Cord bilirubin >4 is also indicative of the need for exchange transfusion.[38]
## History[edit]
Hemolytic disease of the fetus and newborn (HDN) is a condition where the passage of maternal antibodies results in the hemolysis of fetal/neonatal red cells. The antibodies can be naturally occurring such as anti-A, and anti-B, or immune antibodies developed following a sensitizing event.[39] Isoimmunization occurs when the maternal immune system is sensitized to red blood cell surface antigens. The most common causes of isoimmunization are blood transfusion, and fetal-maternal hemorrhage.[17] The hemolytic process can result in anemia, hyperbilirubinemia, neonatal thrombocytopenia, and neonatal neutropenia.[5] With the use of RhD Immunoprophylaxis, (commonly called Rhogam), the incidence of anti-D has decreased dramatically and other alloantibodies are now a major cause of HDN.[39]
## See also[edit]
* Hemolytic anemia
* Hemolytic disease of the newborn
* Rh blood group system
## References[edit]
1. ^ a b c d e f Murray, N. A; Roberts, I. A G (2007). "Haemolytic disease of the newborn". Archives of Disease in Childhood: Fetal and Neonatal Edition. 92 (2): F83–8. doi:10.1136/adc.2005.076794. PMC 2675453. PMID 17337672.
2. ^ Shapiro, Steven M (2004). "Definition of the Clinical Spectrum of Kernicterus and Bilirubin-Induced Neurologic Dysfunction (BIND)". Journal of Perinatology. 25 (1): 54–9. doi:10.1038/sj.jp.7211157. PMID 15578034. S2CID 19663259.
3. ^ Blair, Eve; Watson, Linda (2006). "Epidemiology of cerebral palsy". Seminars in Fetal and Neonatal Medicine. 11 (2): 117–25. doi:10.1016/j.siny.2005.10.010. PMID 16338186.
4. ^ Lande, Lottie (1948). "Clinical signs and development of survivors of kernicterus due to Rh sensitization". The Journal of Pediatrics. 32 (6): 693–705. doi:10.1016/S0022-3476(48)80225-8. PMID 18866937.
5. ^ a b c d e Koenig, J. M.; Christensen, R. D. (1989). "Neutropenia and thrombocytopenia in infants with Rh hemolytic disease". The Journal of Pediatrics. 114 (4 Pt 1): 625–31. doi:10.1016/s0022-3476(89)80709-7. PMID 2494315.
6. ^ a b Lalezari, P; Nussbaum, M; Gelman, S; Spaet, T. H. (1960). "Neonatal neutropenia due to maternal isoimmunization". Blood. 15 (2): 236–43. doi:10.1182/blood.V15.2.236.236. PMID 14413526.[permanent dead link]
7. ^ a b Rath, M. E. A.; Smits-Wintjens, V. E. H. J.; Oepkes, D.; Walther, F. J.; Lopriore, E. (2013). "Iron status in infants with alloimmune haemolytic disease in the first three months of life". Vox Sanguinis. 105 (4): 328–33. doi:10.1111/vox.12061. PMID 23802744.
8. ^ Mitchell, S; James, A (1999). "Severe late anemia of hemolytic disease of the newborn". Paediatrics & Child Health. 4 (3): 201–3. doi:10.1093/pch/4.3.201. PMC 2828194. PMID 20212966.
9. ^ Al-Alaiyan, S.; Al Omran, A. (1999). "Late hyporegenerative anemia in neonates with rhesus hemolytic disease". Journal of Perinatal Medicine. 27 (2): 112–5. doi:10.1515/JPM.1999.014. PMID 10379500. S2CID 32155893.
10. ^ Jadala, Hareesh; v., Pooja; k., Raghavendra; m., Prithvish; b., Srinivas (2016). "Late onset severe anemia due to rhesus isoimmunization". International Journal of Contemporary Pediatrics: 1472–3. doi:10.18203/2349-3291.ijcp20163704.
11. ^ Strobel, Erwin (2008). "Hemolytic Transfusion Reactions". Transfusion Medicine and Hemotherapy. 35 (5): 346–353. doi:10.1159/000154811. PMC 3076326. PMID 21512623.
12. ^ Transfusion Reactions at eMedicine
13. ^ a b Heddle, N. M.; Wentworth, P.; Anderson, D. R.; Emmerson, D.; Kelton, J. G.; Blajchman, M. A. (1995). "Three examples of Rh haemolytic disease of the newborn with a negative direct antiglobulin test". Transfusion Medicine. 5 (2): 113–6. doi:10.1111/j.1365-3148.1995.tb00197.x. PMID 7655573.
14. ^ a b c d Hemolytic Disease of Newborn~workup at eMedicine
15. ^ a b c d Erythrocyte Alloimmunization and Pregnancy at eMedicine
16. ^ a b c Hemolytic Disease of Newborn~treatment at eMedicine
17. ^ a b c d Cacciatore, A; Rapiti, S; Carrara, S; Cavaliere, A; Ermito, S; Dinatale, A; Imbruglia, L; Recupero, S; La Galia, T; Pappalardo, E. M.; Accardi, M. C. (2009). "Obstetric management in Rh alloimmunizated pregnancy". Journal of Prenatal Medicine. 3 (2): 25–7. PMC 3279102. PMID 22439037.
18. ^ Strobel, Erwin (2008). "Hemolytic Transfusion Reactions". Transfusion Medicine and Hemotherapy. 35: 346–353. doi:10.1159/000154811. PMID 21512623.
19. ^ Scheffer, PG; Van Der Schoot, CE; Page-Christiaens, Gcml; De Haas, M (2011). "Noninvasive fetal blood group genotyping of rhesus D, c, E and of K in alloimmunised pregnant women: Evaluation of a 7-year clinical experience". BJOG: An International Journal of Obstetrics & Gynaecology. 118 (11): 1340–8. doi:10.1111/j.1471-0528.2011.03028.x. PMID 21668766.
20. ^ Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects ISBN 978-0-12-397788-5[page needed][full citation needed]
21. ^ https://www.aacc.org/publications/cln/articles/2015/march/molecular-typing-for-red-blood-cell-antigens[full citation needed]
22. ^ Finning, Kirstin; Martin, Peter; Summers, Joanna; Daniels, Geoff (2007). "Fetal genotyping for the K (Kell) and Rh C, c, and E blood groups on cell-free fetal DNA in maternal plasma". Transfusion. 47 (11): 2126–33. doi:10.1111/j.1537-2995.2007.01437.x. PMID 17958542.
23. ^ a b Mari, Giancarlo; Deter, Russell L.; Carpenter, Robert L.; Rahman, Feryal; Zimmerman, Roland; Moise, Kenneth J.; Dorman, Karen F.; Ludomirsky, Avi; Gonzalez, Rogelio; Gomez, Ricardo; Oz, Utku; Detti, Laura; Copel, Joshua A.; Bahado-Singh, Ray; Berry, Stanley; Martinez-Poyer, Juan; Blackwell, Sean C. (2000). "Noninvasive Diagnosis by Doppler Ultrasonography of Fetal Anemia Due to Maternal Red-Cell Alloimmunization". New England Journal of Medicine. 342 (1): 9–14. doi:10.1056/NEJM200001063420102. PMID 10620643.
24. ^ Mari, G. (2005). "Middle cerebral artery peak systolic velocity for the diagnosis of fetal anemia: The untold story". Ultrasound in Obstetrics and Gynecology. 25 (4): 323–30. doi:10.1002/uog.1882. PMID 15789353.
25. ^ Voto, L. S.; Mathet, E. R.; Zapaterio, J. L.; Orti, J; Lede, R. L.; Margulies, M (1997). "High-dose gammaglobulin (IVIG) followed by intrauterine transfusions (IUTs): A new alternative for the treatment of severe fetal hemolytic disease". Journal of Perinatal Medicine. 25 (1): 85–8. doi:10.1515/jpme.1997.25.1.85. PMID 9085208. S2CID 22822621.
26. ^ Novak, Deborah J.; Tyler, Lisa N.; Reddy, Ramakrishna L.; Barsoom, Michael J. (2008). "Plasmapheresis and intravenous immune globulin for the treatment of D alloimmunization in pregnancy". Journal of Clinical Apheresis. 23 (6): 183–5. doi:10.1002/jca.20180. PMID 19003884.
27. ^ a b Arora, Satyam; Doda, Veena; Maria, Arti; Kotwal, Urvershi; Goyal, Saurabh (2015). "Maternal anti-M induced hemolytic disease of newborn followed by prolonged anemia in newborn twins". Asian Journal of Transfusion Science. 9 (1): 98–101. doi:10.4103/0973-6247.150968. PMC 4339947. PMID 25722586.
28. ^ Palfi, Miodrag; Hildén, Jan-Olof; Matthiesen, Leif; Selbing, Anders; Berlin, Gösta (2006). "A case of severe Rh (D) alloimmunization treated by intensive plasma exchange and high-dose intravenous immunoglobulin". Transfusion and Apheresis Science. 35 (2): 131–6. doi:10.1016/j.transci.2006.07.002. PMID 17045529.
29. ^ Ruma, Michael S.; Moise, Kenneth J.; Kim, Eunhee; Murtha, Amy P.; Prutsman, Wendy J.; Hassan, Sonia S.; Lubarsky, Suzanne L. (2007). "Combined plasmapheresis and intravenous immune globulin for the treatment of severe maternal red cell alloimmunization". American Journal of Obstetrics and Gynecology. 196 (2): 138.e1–6. doi:10.1016/j.ajog.2006.10.890. PMID 17306655.
30. ^ Deka, Dipika (2016). "Intrauterine Transfusion". Journal of Fetal Medicine. 27 (3): 13–17. doi:10.1007/s40556-016-0072-4. PMID 26811110. S2CID 42005756.
31. ^ a b c http://www.uptodate.com/contents/intrauterine-fetal-transfusion-of-red-cells[full citation needed]
32. ^ https://www.mombaby.org/wp-content/uploads/2016/03/UNC-Isoimmunization-Detection-Prevention.pdf[full citation needed][permanent dead link]
33. ^ Rimon, E.; Peltz, R.; Gamzu, R.; Yagel, S.; Feldman, B.; Chayen, B.; Achiron, R.; Lipitz, S. (2006). "Management of Kell isoimmunization — evaluation of a Doppler-guided approach". Ultrasound in Obstetrics and Gynecology. 28 (6): 814–20. doi:10.1002/uog.2837. PMID 16941575.
34. ^ https://www.ucsfbenioffchildrens.org/pdf/manuals/42_Hemol.pdf[full citation needed]
35. ^ a b c American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. (2004). "Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation". Pediatrics. 114 (1): 297–316. doi:10.1542/peds.114.1.297. PMID 15231951.
36. ^ Onesimo, Roberta; Rizzo, Daniela; Ruggiero, Antonio; Valentini, Piero (2010). "Intravenous Immunoglobulin therapy for anti-E hemolytic disease in the newborn". The Journal of Maternal-Fetal & Neonatal Medicine. 23 (9): 1059–61. doi:10.3109/14767050903544751. PMID 20092394. S2CID 25144401.
37. ^ Gottstein, R; Cooke, R. W. (2003). "Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn". Archives of Disease in Childhood: Fetal and Neonatal Edition. 88 (1): F6–10. doi:10.1136/fn.88.1.F6. PMC 1755998. PMID 12496219.
38. ^ Hemolytic Disease of Newborn~followup at eMedicine
39. ^ a b Basu, Sabita; Kaur, Ravneet; Kaur, Gagandeep (2011). "Hemolytic disease of the fetus and newborn: Current trends and perspectives". Asian Journal of Transfusion Science. 5 (1): 3–7. doi:10.4103/0973-6247.75963. PMC 3082712. PMID 21572705.
## Further reading[edit]
* Antenatal & neonatal screening (second edition). Chapter 12: Rhesus and other haemolytic diseases, by E.A. Letsky, I. Leck, J.M. Bowman. 2000. Oxford University Press. ISBN 0-19-262826-7.
* Mollison PL, Engelfriet CP and Contreras M. Blood Transfusion in Clinical Medicine. 1997. 10th edition. Blackwell Science, Oxford, UK.
## External links[edit]
Classification
D
* ICD-10: P55.8
* ICD-9-CM: 773.2
* v
* t
* e
Conditions originating in the perinatal period / fetal disease
Maternal factors
complicating pregnancy,
labour or delivery
placenta
* Placenta praevia
* Placental insufficiency
* Twin-to-twin transfusion syndrome
chorion/amnion
* Chorioamnionitis
umbilical cord
* Umbilical cord prolapse
* Nuchal cord
* Single umbilical artery
presentation
* Breech birth
* Asynclitism
* Shoulder presentation
Growth
* Small for gestational age / Large for gestational age
* Preterm birth / Postterm pregnancy
* Intrauterine growth restriction
Birth trauma
* scalp
* Cephalohematoma
* Chignon
* Caput succedaneum
* Subgaleal hemorrhage
* Brachial plexus injury
* Erb's palsy
* Klumpke paralysis
Affected systems
Respiratory
* Intrauterine hypoxia
* Infant respiratory distress syndrome
* Transient tachypnea of the newborn
* Meconium aspiration syndrome
* Pleural disease
* Pneumothorax
* Pneumomediastinum
* Wilson–Mikity syndrome
* Bronchopulmonary dysplasia
Cardiovascular
* Pneumopericardium
* Persistent fetal circulation
Bleeding and
hematologic disease
* Vitamin K deficiency bleeding
* HDN
* ABO
* Anti-Kell
* Rh c
* Rh D
* Rh E
* Hydrops fetalis
* Hyperbilirubinemia
* Kernicterus
* Neonatal jaundice
* Velamentous cord insertion
* Intraventricular hemorrhage
* Germinal matrix hemorrhage
* Anemia of prematurity
Gastrointestinal
* Ileus
* Necrotizing enterocolitis
* Meconium peritonitis
Integument and
thermoregulation
* Erythema toxicum
* Sclerema neonatorum
Nervous system
* Perinatal asphyxia
* Periventricular leukomalacia
Musculoskeletal
* Gray baby syndrome
* muscle tone
* Congenital hypertonia
* Congenital hypotonia
Infections
* Vertically transmitted infection
* Neonatal infection
* rubella
* herpes simplex
* mycoplasma hominis
* ureaplasma urealyticum
* Omphalitis
* Neonatal sepsis
* Group B streptococcal infection
* Neonatal conjunctivitis
Other
* Miscarriage
* Perinatal mortality
* Stillbirth
* Infant mortality
* Neonatal withdrawal
*[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 inhibitors
*[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
| Hemolytic disease of the newborn (anti-Rhc) | None | 4,837 | wikipedia | https://en.wikipedia.org/wiki/Hemolytic_disease_of_the_newborn_(anti-Rhc) | 2021-01-18T18:55:25 | {"icd-9": ["773.2"], "icd-10": ["P55.8"], "wikidata": ["Q5712513"]} |
Lymphoepithelial-like carcinoma is a rare, malignant epithelial tumor, composed of undifferentiated epithelial cells with dense lymphoid stroma, mimicking lymphoepithelioma. It often shows association with Epstein-Barr virus infection and can develop in various organs, such as the nasopharynx, stomach, skin, breast and lungs, among others. The presenting symptoms, as well as the radiologic features, are usually nonspecific and depend on the affected site and organ.
*[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 inhibitors
*[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
| Lymphoepithelial-like carcinoma | c0334254 | 4,838 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=289682 | 2021-01-23T17:27:02 | {} |
For the Australian music group, see The Blackwater Fever.
Blackwater fever
SpecialtyInfectious disease
Blackwater fever is a complication of malaria infection in which red blood cells burst in the bloodstream (hemolysis), releasing hemoglobin directly into the blood vessels and into the urine, frequently leading to kidney failure. The disease was first linked to malaria by the Sierra Leonean physician Dr John Farrell Easmon in his 1884 pamphlet entitled The Nature and Treatment of Blackwater Fever. Easmon coined the name "blackwater fever" and was the first to successfully treat such cases following the publication of his pamphlet.
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Treatment
* 4 Prominent victims
* 5 Cultural references
* 6 References
* 7 External links
## Signs and symptoms[edit]
Within a few days of onset there are chills, with rigor, high fever, jaundice, vomiting, rapidly progressive anemia, and dark red or black urine.
## Causes[edit]
The cause of hemolytic crises in this disease is unknown (mainly due to intravascular haemolysis). There is rapid and massive destruction of red blood cells resulting in hemoglobinemia (hemoglobin in the blood, but outside the red blood cells), hemoglobinuria (hemoglobin in urine), intense jaundice, anuria (passing less than 50 milliliters of urine in a day), and finally death in the majority of cases.[citation needed]
The most probable explanation for blackwater fever is an autoimmune reaction apparently caused by the interaction of the malaria parasite and the use of quinine. Blackwater fever is caused by heavy parasitization of red blood cells with Plasmodium falciparum. However, there have been other cases attributed to Plasmodium vivax,[1] Plasmodium malariae,[2] Plasmodium knowlesi.[3]
Blackwater fever is a serious complication of malaria, but cerebral malaria has a higher mortality rate. Blackwater fever is much less common today than it was before 1950.[4] It may be that quinine plays a role in triggering the condition,[5] and this drug is no longer commonly used for malaria prophylaxis. Quinine remains important for treatment of malaria.[citation needed]
## Treatment[edit]
The treatment is antimalarial chemotherapy, intravenous fluid and sometimes supportive care such as intensive care and dialysis.
## Prominent victims[edit]
* Prior to his photography career, Henri Cartier-Bresson[6] contracted blackwater fever while hunting in Western Africa. Expecting to die, he sent instructions to his family on his wishes for a funeral. He made a full recovery.
* Zoologist John Samuel Budgett died from the disease in 1904, after returning from a collecting trip to West Africa, in search of specimens of the fish Polypterus.[7]
* Missionary and explorer George Grenfell died after a bad attack of blackwater fever at Basoko on 1 July 1906.[citation needed]
* Jesse Brand, a missionary to the Chat Mountains in India, died of blackwater fever in 1928.[citation needed]
* Actor Don Adams, best known as Maxwell Smart from the popular sitcom Get Smart and as the title character in Inspector Gadget, contracted blackwater fever after being shot in combat at Guadalcanal during World War II. Adams was evacuated from his United States Marine Corps unit to a hospital in New Zealand where he ultimately made a full recovery.[citation needed]
* Humanitarian and MMA fighter Justin Wren contracted malaria, which devolved into blackwater fever, while drilling water-wells for Congo Pygmies in 2013. The affliction nearly claimed Wren's life. He was misdiagnosed four times and required airlift to Uganda, where he narrowly recovered from severe symptoms.[8]
* Aeneas, Jeannie Gunn's husband, is described as having died from Blackwater Fever or Malarial Dysentry at Elsey Station in the Northern Territory in 1903.[citation needed] She later authored the classic account We of the Never Never.
* Bernard Deacon
* Peter Cameron Scott, a Scottish-American missionary and founder of Africa Inland Mission, died from the disease in December 1896.
## Cultural references[edit]
* Out of Africa, a 1985 film based on the experiences of author Isak Dinesen
* The Power of One, a 1992 film based on the book of the same name
* The Bridge on the River Kwai, a 1957 film about prisoners of war in a jungle environment
* At Play in the Fields of the Lord, a 1965 novel by Peter Matthiessen
* West with the Night (1942), African memoir by aviator Beryl Markham
* Burmese Days, a 1934 novel by George Orwell; several associates of Flory are noted to have died of blackwater fever in chapter 5
* Showdown, a 1946 novel by Errol Flynn
* The Heart of the Matter, a 1948 novel by Graham Greene
* Green Hills of Africa, a 1935 novel by Ernest Hemingway
* The Book of Secrets, a 1994 novel by M. G. Vassanji
* The Blackwater Fever, a blues band out of Australia
* An Ice-Cream War, a 1982 novel by William Boyd set during the First World War in German East Africa
* Liberia as I know it, a 1929 novel by medical missionary Clinton Caldwell Boone
* Showa: A History of Japan|Showa 1944–1953 A History of Japan, a 2014 four-part autobiographical graphic novel of the Showa period in Japanese history Shigeru Mizuki
* Stand on Zanzibar, a 1968 science-fiction novel by John Brunner quotes a line from the sea chanty "The Bight of Benin": "The bight of Benin, the bight of Benin! Blackwater fever and pounds of quinine!" [9]
## References[edit]
1. ^ Katongole-Mbidde E, Banura C, Kizito A (1988-03-19). "Blackwater fever caused by Plasmodium vivax infection in the acquired immune deficiency syndrome". Br Med J (Clin Res Ed). 296 (6625): 827. doi:10.1136/bmj.296.6625.827. PMC 2545111. PMID 3130932.
2. ^ Madhuri, M. S.; Elavarasan, K.; Benjamin, V. P.; Sridhar, M. S.; Natarajan, S.; Chiranjeevi, V. (2018-10-01). "Falciparum malaria complicated by black water fever". Journal of Clinical and Scientific Research. 7 (4): 187. doi:10.4103/JCSR.JCSR_14_19. ISSN 2277-5706.
3. ^ Barber, Bridget E.; Grigg, Matthew J.; William, Timothy; Yeo, Tsin W.; Anstey, Nicholas M. (2016-09-09). "Intravascular haemolysis with haemoglobinuria in a splenectomized patient with severe Plasmodium knowlesi malaria". Malaria Journal. 15 (1): 462. doi:10.1186/s12936-016-1514-0. ISSN 1475-2875. PMC 5017000. PMID 27613607.
4. ^ Bruneel, F.; B. Gacho; M. Wolff; et al. (2002). "Blackwater fever" (in French). 31 (28). Presse médicale (Paris, France: 1983): 1329–34. PMID 12355996. Cite journal requires `|journal=` (help)
5. ^ Brunee, Fabrice; Gachot, Bertrand; Wolff, Michel; Régnier, Bernard; Danis, Martin; Vachon, François (2001-04-15). "Resurgence of Blackwater Fever in Long-Term European Expatriates in Africa: Report of 21 Cases and Review". Clinical Infectious Diseases. 32 (8): 1133–1140. doi:10.1086/319743. ISSN 1058-4838.
6. ^ "10 things to know about HenriCartier-Bresson | Christie's'". Retrieved 2017-09-16.
7. ^ "John Samuel Budgett(1872–1904): In Pursuit of Polypterus" BioScience May 2001 / Vol. 51 No. 5
8. ^ "Wren back in MMA to 'Fight for the Forgotten'". 27 August 2015.
9. ^ Brunner, John (1969). Stand on Zanzibar. New York: Ballantine. ISBN 978-0345027580."Stand on Zanzibar, a 1968 science-fiction novel by John Brunner quotes a line from the sea chanty "The Bight of Benin": "The bight of Benin, the bight of Benin! Blackwater fever and pounds of quinine!""
## External links[edit]
Classification
D
* ICD-10: B50
* ICD-9-CM: 084.8
* MeSH: D001742
* DiseasesDB: 7751
* v
* t
* e
Malaria
Biology
* Malaria
* Cerebral
* Quartan fever
* Blackwater fever
* Pregnancy-associated
* Plasmodium
* biology
* life cycle
* vivax
* falciparum
* ovale
* malariae
* knowlesi
* Anopheles mosquito
* Lifecycle
* Schizont
* Merozoite
* Hypnozoite
* Gametocyte
Control and prevention
* Public health
* DDT
* Mosquito net
* Malaria prophylaxis
* Mosquito control
* Sterile insect technique
* Genetic resistance
* Duffy antigen
* Sickle-cell anaemia
* Thalassemia
* G6PDH deficiency
* Malaria vaccine
* RTS,S
Diagnosis and treatment
* Diagnosis of malaria
* Malaria culture
* Blood film
* Malaria antigen detection tests
* Antimalarials
* Artemisinin
* Mefloquine
* Proguanil
Society and malaria
* Diseases of poverty
* Millennium Development Goals
* History of malaria
* Roman fever
* National Malaria Eradication Program
* World Malaria Day
* Epidemiology
* Malaria and the Caribbean
* Malaria Atlas Project
Organisations
* Malaria Consortium
* Against Malaria Foundation
* Bill & Melinda Gates Foundation
* Imagine No Malaria
* Malaria No More
* Africa Fighting Malaria
* African Malaria Network Trust
* South African Malaria Initiative
* African Leaders Malaria Alliance
* Amazon Malaria Initiative
* The Global Fund to Fight AIDS, Tuberculosis and Malaria
* Medicines for Malaria Venture
Category
* 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
*[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 inhibitors
*[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
| Blackwater fever | c0005681 | 4,839 | wikipedia | https://en.wikipedia.org/wiki/Blackwater_fever | 2021-01-18T19:09:15 | {"mesh": ["D001742"], "umls": ["C0005681"], "icd-10": ["B50"], "wikidata": ["Q265420"]} |
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder characterised by early-onset cerebellar ataxia with spasticity, a pyramidal syndrome and peripheral neuropathy.
## Epidemiology
It was initially described in the Charlevoix-Saguenay region of Quebec where incidence of ARSACS at birth has been estimated at 1 in 1,932. The incidence and prevalence worldwide remain unknown but ARSACS is very rare in other countries with cases described from Turkey, Japan, The Netherlands, Italy, Belgium, France and Spain.
## Clinical description
The age of onset in non-Quebec patients is variable (ranging from late infantile, juvenile to early-adult onset) but in individuals from Quebec, onset occurs between 12 and 18 months of age with gait disturbance and walking difficulties. Other early signs of cerebellar ataxia include dysarthria and nystagmus. The spasticity is progressive and eventually dominates the clinical picture. The pyramidal syndrome is characterised by brisk patellar tendon reflexes and the Babinski sign. Onset of the peripheral neuropathy generally occurs later and leads to absence of the Achilles tendon reflex, distal amyotrophy and deep sensory disturbances (impaired vibration sense). Retinal hypermyelination (without vision loss) is a constant feature in ARSACS patients from Quebec but may be absent in patients from other countries. Lack of leg spasticity has been reported in some Japanese families and intellectual deficit may be a feature in some non-Quebec patients. Other manifestations may include mitral valve prolapse, pes cavus, and bladder dysfunction.
## Etiology
ARSACS is caused by autosomal recessive mutations in the SACS gene (13q11), which encodes a large protein of unknown function named sacsin.
## Diagnostic methods
Clinical diagnosis relies on the results of neuroimaging studies (MRI and CT scans revealing atrophy of the upper cerebellar vermis and cervical spinal cord) and neurophysiological data (signs of both axonal and demyelinating neuropathy, with nerve conduction studies revealing loss of sensory nerve conduction and reduced motor conduction velocities). Retinal examination may also be useful for diagnosis. Diagnosis can be confirmed by detection of SACS mutations.
## Differential diagnosis
Differential diagnoses include other autosomal recessive ataxias, such as Friedreich ataxia and ataxia with vitamin E deficiency (AVED), and hereditary forms of spastic paraplegia (see these terms), in particular spastic paraplegia 20 (SPG20-Troyer syndrome).
## Antenatal diagnosis
Prenatal diagnosis is possible when the disease-causing mutation has been identified and genetic counselling should be offered to affected families.
## Management and treatment
Treatment is symptomatic aiming towards controlling the spasticity and should include physiotherapy, pharmacotherapy and use of ankle-foot orthoses.
## Prognosis
Most patients become wheelchair-bound by the 5th decade of life. Death generally occurs during the sixth decade but survival into the seventies has been reported.
*[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 inhibitors
*[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
| Autosomal recessive spastic ataxia of Charlevoix-Saguenay | c1849140 | 4,840 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98 | 2021-01-23T17:18:16 | {"gard": ["4910"], "mesh": ["C536787"], "omim": ["270550"], "umls": ["C1849140"], "icd-10": ["G11.1"], "synonyms": ["ARSACS", "Autosomal recessive spastic ataxia type 6", "SPAX6"]} |
A number sign (#) is used with this entry because this form of transient neonatal diabetes mellitus is caused by mutation in the ABCC8 gene (600509).
For a phenotypic description and a discussion of genetic heterogeneity of transient neonatal diabetes mellitus, see 601410.
From a group of 73 patients with neonatal diabetes, Babenko et al. (2006) screened the ABCC8 gene in 34 who did not have alterations in chromosome 6q (see 601410) or mutations in the KCNJ11 (600937) or GCK (138079) genes. They identified heterozygosity for 5 different mutations (see, e.g., 600509.0019 and 600509.0020) in 7 patients with transient neonatal diabetes mellitus. They also identified heterozygosity for mutations (600509.0017 and 600509.0018) in 2 patients with permanent neonatal diabetes (606176). Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had markedly higher activity than did wildtype channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. The mutation-positive fathers of 5 of the probands with TNDM developed type II diabetes mellitus (125853) in adulthood; Babenko et al. (2006) proposed that mutations of the ABCC8 gene may give rise to a monogenic form of type II diabetes with variable expression and age at onset. The authors noted that dominant mutations in ABCC8 accounted for 12% of cases of neonatal diabetes in the study group.
*[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 inhibitors
*[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
| DIABETES MELLITUS, TRANSIENT NEONATAL, 2 | c1832386 | 4,841 | omim | https://www.omim.org/entry/610374 | 2019-09-22T16:04:40 | {"doid": ["0060334"], "mesh": ["C563322"], "omim": ["610374"], "orphanet": ["99886"], "synonyms": ["Alternative titles", "TNDM2"]} |
Aromatic alpha-keto acid reductase catalyzes the reduction of phenylpyruvic and p-OH-phenylpyruvic acids to their corresponding lactate derivatives in the presence of NADH2. By study of human-Chinese hamster somatic cell hybrids, Donald (1982) concluded that the gene for KAR is on chromosome 12. Interestingly, KAR's substrate specificity overlaps that of lactate dehydrogenase which, in one of its isozymic forms, is also determined by a gene on chromosome 12. However, the enzymes are distinctly different in electrophoretic mobility and subunit composition. In a single person, Donald (1982) found an unusual phenotype of KAR following electrophoresis in starch gel and interpreted this to represent a genetic variant. Friedrich and Ferrell (1985) found no variants in a starch gel electrophoresis of 509 persons from many different racial groups and none in a survey by thin-layer isoelectric focusing in polyacrylamide gel involving 232 persons. Friedrich et al. (1987, 1988) presented evidence from several nonhuman species and from humans that alpha-ketoacid reductase and cytoplasmic malate dehydrogenase (MDH1; 154200) are identical. In starch-gel electrophoresis the 2 enzyme functions comigrated in all species studied except some marine species. Inhibition with malate, the end-product of the MDH reaction, substantially reduced or totally eliminated KAR activity. Genetically determined electrophoretic variants of MDH1 seen in fresh water bony fish and in the amphibian Rana pipiens exhibited identical variation of KAR, and the 2 traits cosegregated in the offspring from 1 R. pipiens heterozygote studied. Both enzymes comigrated with no electrophoretic variation among several inbred strains of mice. Antisera raised against purified chicken MDH1 totally inhibited both MDH1 and KAR activity in chicken liver homogenates. In all species examined, KAR activity was associated only with cytoplasmic MDH, not with mitochondrial MDH (MDH2; 154100). MDH1 in man maps to 2p23. Friedrich et al. (1988) called into question the assignment of KAR to chromosome 12 in somatic cell hybrids because interspecific hybrid bands of both MDH1 and LDH appeared with slightly different mobility approximately midway between the human and hamster controls in somatic cell hybrid studies. Friedrich et al. (1988) concluded that the bulk of KAR activity in human blood is due to MDH1, with a minor fraction catalyzed by LDH, as is the case in most other species studied.
*[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 inhibitors
*[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
| AROMATIC ALPHA-KETO ACID REDUCTASE | c1862520 | 4,842 | omim | https://www.omim.org/entry/107920 | 2019-09-22T16:44:46 | {"omim": ["107920"], "synonyms": ["Alternative titles", "ALPHA-KETO ACID REDUCTASE"]} |
Adrenal tumor
Incidences and prognoses of adrenal tumors.[1]
SpecialtyOncology
An adrenal tumor or adrenal mass[2] is any benign or malignant neoplasms of the adrenal gland, several of which are notable for their tendency to overproduce endocrine hormones. Adrenal cancer is the presence of malignant adrenal tumors, and includes neuroblastoma, adrenocortical carcinoma and some adrenal pheochromocytomas. Most adrenal pheochromocytomas and all adrenocortical adenomas are benign tumors, which do not metastasize or invade nearby tissues, but may cause significant health problems by unbalancing hormones.
## Contents
* 1 Metastasis to the adrenals
* 2 Tumors of the adrenal cortex
* 2.1 Adrenocortical adenoma
* 2.2 Adrenocortical carcinoma
* 3 Tumors of the Adrenal Medulla
* 3.1 Neuroblastoma
* 3.2 Pheochromocytoma
* 4 Incidentalomas
* 5 References
* 6 Further reading
* 7 External links
## Metastasis to the adrenals[edit]
Main sites of metastases for some common cancer types. Primary cancers are denoted by "...cancer" and their main metastasis sites are denoted by "...metastases".[3] Lung cancer metastasis to the adrenal glands are mentioned with red arrows.
Metastasis to one or both adrenal glands is the most common form of malignant adrenal lesion, and the second most common adrenal tumor after benign adenomas.[4] Primary tumors in such cases are most commonly from lung cancer (39%), breast cancer (35%), malignant melanoma, gastrointestinal tract cancer, pancreas cancer, and renal cancer.[4]
## Tumors of the adrenal cortex[edit]
The adrenal cortex is composed of three distinct layers of endocrine cells which produce critical steroid hormones. These include the glucocorticoids which are critical for regulation of blood sugar and the immune system, as well as response to physiological stress, the mineralcorticoid aldosterone, which regulates blood pressure and kidney function, and certain sex hormones. Both benign and malignant tumors of the adrenal cortex may produce steroid hormones, with important clinical consequences.[citation needed]
### Adrenocortical adenoma[edit]
Main article: Adrenocortical adenoma
Adrenocortical adenomas are benign tumors of the adrenal cortex which are extremely common (present in 1-10% of persons at autopsy). They should not be confused with adrenocortical "nodules", which are not true neoplasms. Adrenocortical adenomas are uncommon in patients younger than 30 years old, and have equal incidence in both sexes.[citation needed] The clinical significance of these neoplasms is twofold. First, they have been detected as incidental findings with increasing frequency in recent years, due to the increasing use of CT scans and magnetic resonance imaging in a variety of medical settings. This can result in expensive additional testing and invasive procedures to rule out the slight possibility of an early adrenocortical carcinoma. Second, a minority (about 15%) of adrenocortical adenomas are "functional", meaning that they produce glucocorticoids, mineralcorticoids, and/or sex steroids, resulting in endocrine disorders such as Cushing's syndrome, Conn's syndrome (hyperaldosteronism), virilization of females, or feminization of males. Functional adrenocortical adenomas are surgically curable.[citation needed]
Most of the adrenocortical adenomas are less than 2 cm in greatest dimension and less than 50 gram in weight. However, size and weight of the adrenal cortical tumors are no longer considered to be a reliable sign of benignity or malignancy. Grossly, adrenocortical adenomas are encapsulated, well-circumscribed, solitary tumors with solid, homogeneous yellow-cut surface. Necrosis and hemorrhage are rare findings.[citation needed]
### Adrenocortical carcinoma[edit]
Main article: Adrenocortical carcinoma
Adrenocortical carcinoma (ACC) is a rare, highly aggressive cancer of adrenal cortical cells, which may occur in children or adults. ACCs may be "functional", producing steroid hormones and consequent endocrine dysfunction similar to that seen in many adrenocortical adenomas, but many are not. Due to their location deep in the retroperitoneum, most adrenocortical carcinomas are not diagnosed until they have grown quite large. They frequently invade large vessels, such as the renal vein and inferior vena cava, as well as metastasizing via the lymphatics and through the blood to the lungs and other organs. The most effective treatment is surgery, although this is not feasible for many patients, and the overall prognosis of the disease is poor. Chemotherapy, radiation therapy, and hormonal therapy may also be employed in the treatment of this disease.[citation needed]
## Tumors of the Adrenal Medulla[edit]
The adrenal medulla is located anatomically at the center of each adrenal gland, and is composed of neuroendocrine (chromaffin) cells which produce and release epinephrine (adrenaline) into the bloodstream in response to activation of the sympathetic nervous system. Neuroblastoma and pheochromocytoma are the two most important tumors which arise from the adrenal medulla. Both tumors may also arise from extra-adrenal sites, specifically, in the paraganglia of the sympathetic chain.[citation needed]
### Neuroblastoma[edit]
Main article: Neuroblastoma
Neuroblastoma is an aggressive cancer of immature neuroblastic cells (precursors of neurons), and is one of the most common pediatric cancers, with a median age at diagnosis of two years. Adrenal neuroblastoma typically presents with a rapidly enlarging abdominal mass. Although the tumor has often spread to distant parts of the body at the time of diagnosis, this cancer is unusual in that many cases are highly curable when the spread is limited to the liver, skin, and/or bone marrow (stage IVS). Related, but less aggressive tumors composed of more mature neural cells include ganglioneuroblastoma and ganglioneuroma. Neuroblastic tumors often produce elevated levels of catecholamine hormone metabolites, such as vanillylmandelic acid (VMA) and homovanillic acid, and may produce severe watery diarrhea through production of vasoactive intestinal peptide. Treatment of neuroblastoma includes surgery and radiation therapy for localized disease, and chemotherapy for metastatic disease.[5]
### Pheochromocytoma[edit]
Main article: Pheochromocytoma
Pheochromocytoma is a neoplasm composed of cells similar to the chromaffin cells of the mature adrenal medulla. Pheochromocytomas occur in patients of all ages, and may be sporadic, or associated with a hereditary cancer syndrome, such as multiple endocrine neoplasia (MEN) types IIA and IIB, neurofibromatosis type I, or von Hippel-Lindau syndrome. Only 10% of adrenal pheochromocytomas are malignant, while the rest are benign tumors. The most clinically important feature of pheochromocytomas is their tendency to produce large amounts of the catecholamine hormones epinephrine (adrenaline) and norepinephrine. This may lead to potentially life-threatening high blood pressure, or cardiac arrythmias, and numerous symptoms such as headache, palpitations, anxiety attacks, sweating, weight loss, and tremor. Diagnosis is most easily confirmed through urinary measurement of catecholamine metabolites such as VMA and metanephrines. Most pheochromocytomas are initially treated with anti-adrenergic drugs to protect against catecholamine overload, with surgery employed to remove the tumor once the patient is medically stable.[citation needed]
## Incidentalomas[edit]
An adrenal incidentaloma is an adrenal tumor found by coincidence without clinical symptoms or suspicion. It is one of the more common unexpected findings revealed by computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography.[6]
In these cases, a dexamethasone suppression test is often used to detect cortisol excess, and metanephrines or catecholamines for excess of these hormones. Tumors under 3 cm are generally considered benign and are only treated if there are grounds for a diagnosis of Cushing's syndrome or pheochromocytoma.[7] Radiodensity gives a clue in estimating malignancy risk, wherein a tumor with 10 Hounsfield units or less on an unenhanced CT is probably a lipid-rich adenoma.[8] Hormonal evaluation includes:[9]
* 1-mg overnight dexamethasone suppression test
* 24-hour urinary specimen for measurement of fractionated metanephrines and catecholamines
* Blood plasma aldosterone concentration and plasma renin activity, if hypertension is present
On CT scan, benign adenomas typically are of low radiographic density (due to fat content) and show rapid washout of contrast medium (50% or more of the contrast medium washes out at 10 minutes). If the hormonal evaluation is negative and imaging suggests benign, followup should be considered with imaging at 6, 12, and 24 months and repeat hormonal evaluation yearly for 4 years[9]
## References[edit]
1. ^ Data and references for pie chart are located at file description page in Wikimedia Commons.
2. ^ Perappadan, Bindu Shajan. "Doctors remove 'world's largest adrenal tumour'". The Hindu. Retrieved 2017-02-23.
3. ^ List of included entries and references is found on main image page in Commons: File:Metastasis sites for common cancers.svg
4. ^ a b Shashank R. Cingam; Harsha Karanchi. "Cancer, Adrenal Metastasis". StatPearls at National Center for Biotechnology Information. Last Update: January 20, 2019.
5. ^ Saab ST. and MacLennan GT. "Adrenal Cortical Neoplasms: Perspectives in Pediatric Patients" in "Adrenal Glands: From Pathophysiology to Clinical Evidence" Nova Science Publishers, New York, NY - 2015
6. ^ Arnold DT, Reed JB, Burt K (January 2003). "Evaluation and management of the incidental adrenal mass". Proc (Bayl Univ Med Cent). 16 (1): 7–12. doi:10.1080/08998280.2003.11927882. PMC 1200803. PMID 16278716.
7. ^ Grumbach MM, Biller BM, Braunstein GD, et al. (2003). "Management of the clinically inapparent adrenal mass ("incidentaloma")". Ann. Intern. Med. 138 (5): 424–9. doi:10.7326/0003-4819-138-5-200303040-00013. PMID 12614096. S2CID 23454526.
8. ^ Jonathon M. Willatt & Isaac R. Francis (2010). "Radiologic Evaluation of Incidentally Discovered Adrenal Masses". Am Fam Physician. 81 (11).
9. ^ a b Young WF (2007). "Clinical practice. The incidentally discovered adrenal mass". N. Engl. J. Med. 356 (6): 601–10. doi:10.1056/NEJMcp065470. PMID 17287480.
## Further reading[edit]
* Adrenal Glands: From Pathophysiology to Clinical Evidence. New York, NY: Nova Science. 2015. ISBN 978-1-63483-570-1.
* Ramzi Cotran; Vinay Kumar; Tucker Collins (1999). Robbins Pathologic Basis of Disease (Sixth ed.). W.B. Saunders. ISBN 978-0-7216-7335-6.
* Richard Cote; Saul Suster; Lawrence Weiss (2003). Noel Weidner (ed.). Modern Surgical Pathology (2 Volume Set). London: W B Saunders. ISBN 978-0-7216-7253-3.
## External links[edit]
Classification
D
* ICD-10: C74
* MeSH: D000310
* v
* t
* e
Tumours of endocrine glands
Pancreas
* Pancreatic cancer
* Pancreatic neuroendocrine tumor
* α: Glucagonoma
* β: Insulinoma
* δ: Somatostatinoma
* G: Gastrinoma
* VIPoma
Pituitary
* Pituitary adenoma: Prolactinoma
* ACTH-secreting pituitary adenoma
* GH-secreting pituitary adenoma
* Craniopharyngioma
* Pituicytoma
Thyroid
* Thyroid cancer (malignant): epithelial-cell carcinoma
* Papillary
* Follicular/Hurthle cell
* Parafollicular cell
* Medullary
* Anaplastic
* Lymphoma
* Squamous-cell carcinoma
* Benign
* Thyroid adenoma
* Struma ovarii
Adrenal tumor
* Cortex
* Adrenocortical adenoma
* Adrenocortical carcinoma
* Medulla
* Pheochromocytoma
* Neuroblastoma
* Paraganglioma
Parathyroid
* Parathyroid neoplasm
* Adenoma
* Carcinoma
Pineal gland
* Pinealoma
* Pinealoblastoma
* Pineocytoma
MEN
* 1
* 2A
* 2B
*[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 inhibitors
*[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
| Adrenal tumor | c0001624 | 4,843 | wikipedia | https://en.wikipedia.org/wiki/Adrenal_tumor | 2021-01-18T19:10:24 | {"mesh": ["D000310"], "umls": ["C0001624"], "icd-10": ["C74"], "wikidata": ["Q4684715"]} |
Gait abnormality
Foot drop
Shown here, the right foot drops due to paralysis of the tibialis anterior muscle, while the left foot demonstrates normal lifting abilities.
SpecialtyNeurology
Play media
A patient recovering from surgery to treat foot drop, with limited plantar and dorsiflexion.
Foot drop is a gait abnormality in which the dropping of the forefoot happens due to weakness, irritation or damage to the common fibular nerve including the sciatic nerve, or paralysis of the muscles in the anterior portion of the lower leg. It is usually a symptom of a greater problem, not a disease in itself. Foot drop is characterized by inability or impaired ability to raise the toes or raise the foot from the ankle (dorsiflexion). Foot drop may be temporary or permanent, depending on the extent of muscle weakness or paralysis and it can occur in one or both feet. In walking, the raised leg is slightly bent at the knee to prevent the foot from dragging along the ground.
Foot drop can be caused by nerve damage alone or by muscle or spinal cord trauma, abnormal anatomy, atoxins, or disease. Toxins include organophosphate compounds which have been used as pesticides and as chemical agents in warfare. The poison can lead to further damage to the body such as a neurodegenerative disorder called organophosphorus induced delayed polyneuropathy. This disorder causes loss of function of the motor and sensory neural pathways. In this case, foot drop could be the result of paralysis due to neurological dysfunction. Diseases that can cause foot drop include trauma to the posterolateral neck of fibula, stroke, amyotrophic lateral sclerosis, muscular dystrophy, poliomyelitis, Charcot Marie Tooth disease, multiple sclerosis, cerebral palsy, hereditary spastic paraplegia, Guillain–Barré syndrome, Welander distal myopathy, and Friedreich's ataxia. It may also occur as a result of hip replacement surgery or knee ligament reconstruction surgery.
## Contents
* 1 Signs and symptoms
* 2 Pathophysiology
* 2.1 Gait cycle
* 3 Diagnosis
* 4 Treatment
* 5 See also
* 6 References
* 7 Further reading
## Signs and symptoms[edit]
Play media
Mild steppage gait after treatment for foot drop
Foot drop is characterized by steppage gait.[1] While walking, people suffering the condition drag their toes along the ground or bend their knees to lift their foot higher than usual to avoid the dragging.[2] This serves to raise the foot high enough to prevent the toe from dragging and prevents the slapping.[3][4] To accommodate the toe drop, the patient may use a characteristic tiptoe walk on the opposite leg, raising the thigh excessively, as if walking upstairs, while letting the toe drop. Other gaits such as a wide outward leg swing (to avoid lifting the thigh excessively or to turn corners in the opposite direction of the affected limb) may also indicate foot drop.[5]
Patients with painful disorders of sensation (dysesthesia) of the soles of the feet may have a similar gait but do not have foot drop. Because of the extreme pain evoked by even the slightest pressure on the feet, the patient walks as if walking barefoot on hot sand.
Human lower leg anatomy
## Pathophysiology[edit]
The causes of foot drop, as for all causes of neurological lesions, should be approached using a localization-focused approach before etiologies are considered. Most of the time, foot drop is the result of neurological disorder; only rarely is the muscle diseased or nonfunctional. The source for the neurological impairment can be central (spinal cord or brain) or peripheral (nerves located connecting from the spinal cord to an end-site muscle or sensory receptor).
Foot drop is rarely the result of a pathology involving the muscles or bones that make up the lower leg. The anterior tibialis is the muscle that picks up the foot. Although the anterior tibialis plays a major role in dorsiflexion, it is assisted by the fibularis tertius, extensor digitorum longus and the extensor hallucis longus. If the drop foot is caused by neurological disorder all of these muscles could be affected because they are all innervated by the deep fibular (peroneal) nerve, which branches from the sciatic nerve. The sciatic nerve exits the lumbar plexus with its root arising from the fifth lumbar nerve space.
Occasionally, spasticity in the muscles opposite the anterior tibialis, the gastrocnemius and soleus, exists in the presence of foot drop, making the pathology much more complex than foot drop. Isolated foot drop is usually a flaccid condition. There are gradations of weakness that can be seen with foot drop, as follows according to MRC:
* 0 = complete paralysis,
* 1 = flicker of contraction,
* 2 = contraction with gravity eliminated alone,
* 3 = contraction against gravity alone,
* 4 = contraction against gravity and some resistance, and
* 5 = contraction against powerful resistance (normal power).
Foot drop is different from foot slap, which is the audible slapping of the foot to the floor with each step that occurs when the foot first hits the floor on each step, although they often are concurrent.
Treated systematically, possible lesion sites causing foot drop include (going from peripheral to central):
1. Neuromuscular disease;
2. Peroneal nerve (common, i.e., frequent) —chemical, mechanical, disease;
3. Sciatic nerve—direct trauma, iatrogenic;
4. Lumbosacral plexus;
5. L5 nerve root (common, especially in association with pain in back radiating down leg);
6. Cauda equina syndrome, which is cause by impingement of the nerve roots within the spinal canal distal to the end of the spinal cord;
7. Spinal cord (rarely causes isolated foot drop) —poliomyelitis, tumor;
8. Brain (uncommon, but often overlooked) —stroke, TIA, tumor;
9. Genetic (as in Charcot-Marie-Tooth Disease and hereditary neuropathy with liability to pressure palsies);
10. Nonorganic causes, e.g. as part of a functional neurological symptom disorder.
If the L5 nerve root is involved, the most common cause is a herniated disc. Other causes of foot drop are diabetes (due to generalized peripheral neuropathy), trauma, motor neuron disease (MND), adverse reaction to a drug or alcohol, and multiple sclerosis.
### Gait cycle[edit]
Drop foot and foot drop are interchangeable terms that describe an abnormal neuromuscular disorder that affects the patient's ability to raise their foot at the ankle. Drop foot is further characterized by an inability to point the toes toward the body (dorsiflexion) or move the foot at the ankle inward or outward. Therefore, the normal gait cycle is affected by the drop foot syndrome.
The normal gait cycle is as follows:
* Swing phase (SW): The period of time when the foot is not in contact with the ground. In those cases where the foot never leaves the ground (foot drag), it can be defined as the phase when all portions of the foot are in forward motion.
* Initial contact (IC): The point in the gait cycle when the foot initially makes contact with the ground; this represents the beginning of the stance phase. It is suggested that heel strike not be a term used in clinical gait analysis as in many circumstances initial contact is not made with the heel. Suggestion: Should use foot strike.
* Terminal contact (TC): The point in the gait cycle when the foot leaves the ground: this represents the end of the stance phase or beginning of the swing phase. Also referred to as foot off. Toe-off should not be used in situations where the toe is not the last part of the foot to leave the ground.
The drop foot gait cycle requires more exaggerated phases.
* Drop foot SW: If the foot in motion happens to be the affected foot, there will be greater flexion at the knee to accommodate the inability to dorsiflex. This increase in knee flexion will cause a stair-climbing movement.
* Drop foot IC: Initial contact of the foot that is in motion will not have normal heel-toe foot strike. Instead, the foot may either slap the ground or the entire foot may be planted on the ground all at once.
* Drop foot TC: Terminal contact that is observed in patients that have drop foot is quite different. Since patients tend to have weakness in the affected foot, they may not have the ability to support their body weight. Often, a walker or cane will be used to assist in this aspect.
Drop Foot is the inability to dorsiflex, evert, or invert the foot. So when looking at the Gait cycle, the part of the gait cycle that involves most dorsiflexion action would be Heel Contact of the foot at 10% of Gait Cycle, and the entire swing phase, or 60-100% of the Gait Cycle. This is also known as Gait Abnormalities.
## Diagnosis[edit]
Initial diagnosis often is made during routine physical examination. Such diagnosis can be confirmed by a medical professional such as a physiatrist, neurologist, orthopedic surgeon or neurosurgeon. A person with foot drop will have difficulty walking on his or her heels because he will be unable to lift the front of the foot (balls and toes) off the ground. Therefore, a simple test of asking the patient to dorsiflex may determine diagnosis of the problem. This is measured on a 0-5 scale that observes mobility. The lowest point, 0, will determine complete paralysis and the highest point, 5, will determine complete mobility.
There are other tests that may help determine the underlying etiology for this diagnosis. Such tests may include MRI, MRN, or EMG to assess the surrounding areas of damaged nerves and the damaged nerves themselves, respectively. The nerve that communicates to the muscles that lift the foot is the peroneal nerve. This nerve innervates the anterior muscles of the leg that are used during dorsi flexion of the ankle. The muscles that are used in plantar flexion are innervated by the tibial nerve and often develop tightness in the presence of foot drop. The muscles that keep the ankle from supination (as from an ankle sprain) are also innervated by the peroneal nerve, and it is not uncommon to find weakness in this area as well. Paraesthesia in the lower leg, particularly on the top of the foot and ankle, also can accompany foot drop, although it is not in all instances.
A common yoga kneeling exercise, the Varjrasana has, under the name "yoga foot drop," been linked to foot drop.[6][7]
## Treatment[edit]
AFO (Ankle Foot Orthosis) brace is a type of orthotic used to support the foot and ankle.
The underlying disorder must be treated. For example, if a spinal disc herniation in the low back is impinging on the nerve that goes to the leg and causing symptoms of foot drop, then the herniated disc should be treated. If the foot drop is the result of a peripheral nerve injury, a window for recovery of 18 months to 2 years is often advised. If it is apparent that no recovery of nerve function takes place, surgical intervention to repair or graft the nerve can be considered, although results from this type of intervention are mixed.
Non-surgical treatments for spinal stenosis include a suitable exercise program developed by a physical therapist, activity modification (avoiding activities that cause advanced symptoms of spinal stenosis), epidural injections, and anti-inflammatory medications like ibuprofen or aspirin. If necessary, a decompression surgery that is minimally destructive of normal structures may be used to treat spinal stenosis.
Non-surgical treatments for this condition are very similar to the non-surgical methods described above for spinal stenosis. Spinal fusion surgery may be required to treat this condition, with many patients improving their function and experiencing less pain.
Nearly half of all vertebral fractures occur without any significant back pain. If pain medication, progressive activity, or a brace or support does not help with the fracture, two minimally invasive procedures - vertebroplasty or kyphoplasty \- may be options.
Dynamic advanced orthosis for drop foot
Ankles can be stabilized by lightweight orthoses, available in molded plastics as well as softer materials that use elastic properties to prevent foot drop. Additionally, shoes can be fitted with traditional spring-loaded braces to prevent foot drop while walking. Regular exercise is usually prescribed.
Functional electrical stimulation (FES) is a technique that uses electrical currents to activate nerves innervating extremities affected by paralysis resulting from spinal cord injury (SCI), head injury, stroke and other neurological disorders. FES is primarily used to restore function in people with disabilities. It is sometimes referred to as Neuromuscular electrical stimulation (NMES) The latest treatments include stimulation of the peroneal nerve, which lifts the foot when you step. Many stroke and multiple sclerosis patients with foot drop have had success with it. Often, individuals with foot drop prefer to use a compensatory technique like steppage gait or hip hiking as opposed to a brace or splint.
Treatment for some can be as easy as an underside "L" shaped foot-up ankle support (ankle-foot orthoses). Another method uses a cuff placed around the patient's ankle, and a topside spring and hook installed under the shoelaces. The hook connects to the ankle cuff and lifts the shoe up when the patient walks.
## See also[edit]
* Yoga foot drop
* Toe walking
* Polymyositis
* inclusion body myositis
## References[edit]
1. ^ "Definition of Steppage gait". MedicineNet, Inc. Archived from the original on 7 August 2012. Retrieved 23 March 2013.
2. ^ "Walking abnormalities". MedlinePlus. Archived from the original on 23 March 2013. Retrieved 23 March 2013.
3. ^ "high stepping gait". GPnotebook. Archived from the original on 12 February 2012. Retrieved 23 March 2013.
4. ^ Mayo Clinic staff. "Foot drop". Mayo Clinic. Archived from the original on 7 March 2013. Retrieved 23 March 2013.
5. ^ http://www.painontopoffoottalk.com Archived 2014-02-25 at the Wayback Machine
6. ^ Joseph Chusid (August 9, 1971). "Yoga Foot Drop". JAMA: The Journal of the American Medical Association. 271 (6): 827–828. doi:10.1001/jama.1971.03190060065025.
7. ^ William J. Broad (January 5, 2012). "How Yoga Can Wreck Your Body". The New York Times Magazine. Archived from the original on August 22, 2012. Retrieved August 29, 2012.
## Further reading[edit]
* Agency for Healthcare Research and Quality (2011). Healthcare Cost and Utilization Project.
* Balali-Mood, Mahdi (January 2008). "Neurotoxic disorders of organophosphorus compounds and their managements". Arch Iran Med. 11(1):65–89. PMID 18154426.
* Jokanovic, Milan, Melita Kosanovic, Dejan Brkic, and Predrag Vukomanovic (2011). "Organophosphate Induced Delayed Polyneuropathy in Man: An Overview". Clinical Neurology and Neurosurgery 113.1: 7–10. PMID 20880629. doi:10.1016/j.clineuro.2010.08.015.
* Mayo Clinic. "Foot Drop".
* Pritchett, James W., MD (June 21, 2018). "Foot Drop". Vinod K Panchbhavi, MD, FACS (ed.).
* Saladin, Kenneth (2015). Anatomy & Physiology: A Unity of Form & Function. 7th ed. New York: McGraw-Hill Education. Print.
*[v]: View this template
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*[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 inhibitors
*[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
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*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
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*[CAN]: Canada
| Foot drop | c0085684 | 4,844 | wikipedia | https://en.wikipedia.org/wiki/Foot_drop | 2021-01-18T18:37:02 | {"mesh": ["D020427"], "icd-9": ["736.79"], "icd-10": ["M21.3"], "wikidata": ["Q1942814"]} |
A number sign (#) is used with this entry because of evidence that Crohn disease (IBD19) is associated with variation in the IRGM gene (608212) on chromosome 5q33.
For a general description and a discussion of genetic heterogeneity of inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), see IBD1 (266600).
Mapping
In a panel of 1,182 individuals with Crohn disease and 2,024 controls, Parkes et al. (2007) analyzed 37 SNPs from 31 distinct loci that were associated at p values of less than 10(-5) in the Wellcome Trust Case Control Consortium (2007) dataset and obtained replication for 2 SNPs flanking the IRGM gene (608212) on chromosome 5q33.1 (replication p = 6.6 x 10(-4), combined p = 2.1 x 10(-10)). Parkes et al. (2007) sequenced the coding exon of the IRGM gene and 4 small putative downstream exons in 48 affected individuals homozygous or heterozygous for risk alleles and identified 2 new SNPs and an exonic synonymous SNP (rs10065172, 313T-C, 608212.0001). Genotyping in 769 unselected affected individuals and 705 controls showed that only the 313T-C silent variant, which was in near-perfect linkage disequilibrium with the SNP rs13361189, was associated with CD (p = 0.008). Parkes et al. (2007) stated that their results suggested that the causal variants do not change the amino acid sequence of IGRM and may lie in regulatory sequences in linkage disequilibrium with the associated SNPs. The authors also replicated linkage with rs6887695 in the IL12B gene on chromosome 5q33.3 (combined p = 9.21 x 10(-6); odds ratio, 1.26).
Using an array custom-made for the Wellcome Trust Case Control Consortium (2007) and a staged experimental design, Fisher et al. (2008) genotyped a total of 3,133 unrelated patients with ulcerative colitis and 4,494 controls but found no association between the SNPs flanking the IRGM gene and ulcerative colitis; an association was found with UC at rs6556416 in IL12B, which the authors stated was used as a proxy for 10045431 (combined p = 6.8 x 10(-4)).
Franke et al. (2008) investigated 50 previously reported susceptibility loci in a German sample of 1,850 CD patients, 1,103 UC patients, and 1,817 controls, and replicated the association with CD at 2 SNPs (rs4958847 and rs4958427) flanking IRGM. Fine mapping supported a lack of association of the IRGM gene region with UC and strengthened the evidence for an exclusive association with CD. Significant association with CD was also replicated at rs6556416 in the IL12B gene on chromosome 5q33.3 (corrected p = 7.99 x 10(-6); odds ratio, 1.36). The authors stated that they could not rule out involvement of neighboring gene ZNF300 (612429) on 5q33, obtaining significant association with CD (p = 5.24 x 10(-7)) for rs4958427 in intron 3 of ZNF300, a marker in strong LD with rs4858847 near IRGM.
McCarroll et al. (2008) identified a common 20-kb insertion/deletion polymorphism located immediately upstream of the IRGM gene that causes IRGM to segregate in the population with 2 distinct upstream sequences and that is in perfect linkage disequilibrium with rs13361189, a SNP previously identified by the Wellcome Trust Case Control Consortium (2007) as strongly associated (p = 2.1 x 10(-10)) with Crohn disease risk. McCarroll et al. (2008) genotyped the polymorphism in a North American IBD case-control collection that included 172 CD patients and 171 UC patients and found an elevated frequency of the polymorphism in IBD patients, with association to both Crohn disease (allele frequency 15%, odds ratio 1.6, p less than 0.01) and ulcerative colitis (allele frequency 14%, odds ratio 1.4, p less than 0.05). The IRGM variant and reference haplotypes showed distinct expression patterns in different cell types, and manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in Crohn disease. McCarroll et al. (2008) suggested that Crohn disease association at the IRGM locus arises from an alteration in IRGM regulation that affects the efficacy of autophagy and that this common indel polymorphism upstream of IRGM is a likely causal variant.
In a metaanalysis of data from 3 studies of Crohn disease involving a total of 3,230 cases and 4,829 controls (Rioux et al., 2007, the Wellcome Trust Case Control Consortium, 2007, and Libioulle et al., 2007) with replication in 3,664 independent cases, Barrett et al. (2008) identified significant association with rs11747270 (combined p = 3.40 x 10(-16); case-control odds ratio, 1.33) and with rs10045431 (combined p = 3.86 x 10(-13); case-control odds ratio, 1.11), both on chromosome 5q33.
In a case-control study involving 289 pediatric cases of Crohn disease and 290 controls, Amre et al. (2009) found no significant association between CD and the exonic synonymous SNP rs10065172 in the IRGM gene previously found to be associated with CD by Parkes et al. (2007).
In a study involving 2,731 Dutch and Belgian IBD patients, including 1,656 CD patients and 1,075 UC patients, as well as 1,086 controls, Weersma et al. (2009) replicated association at rs13361189 and rs4958847 for CD (corrected p = 1.34 x 10(-4) and 9.04 x 10(-4), respectively), but did not find significant association with UC.
The Wellcome Trust Case Control Consortium (2010) undertook a large direct genomewide study of association between copy number variants (CNVs) and 8 common human diseases involving approximately 19,000 individuals. Association testing and follow-up replication analyses confirmed involvement of copy number variation at the IRGM locus with Crohn disease.
Prescott et al. (2010) reported that small insertion/deletion polymorphisms in the promoter and 5-prime untranslated region of IRGM were (together with an upstream CNV) strongly associated with Crohn disease (CD), and that the CNV and the 5-prime untranslated region variant -308(GTTT)5 contributed independently to CD susceptibility. The CD risk haplotype was associated with a significant decrease in IRGM expression in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case-control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. The authors suggested that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene-gene or gene-environment interactions which are absent in Asian populations, or that none of the variants analyzed are causal, and that the true causal variants arose after the European-Asian split.
Molecular Genetics
Brest et al. (2011) demonstrated that the miRNA196 family of microRNAs (see 608632) is overexpressed in the inflammatory intestinal epithelium of individuals with Crohn disease and downregulates the protective C allele of the common IRGM exonic synonymous SNP 313C-T (608212.0001), but not the risk-associated T allele. The authors showed that the subsequent loss of tight regulation of IRGM expression compromises control of intracellular replication of the CD-associated adherent invasive E. coli (AIEC) by autophagy. Brest et al. (2011) hypothesized that AIEC infection in individuals with miRNA196-dysregulated IRGM expression (313T carriers) leads to altered antibacterial activity of intestinal epithelial cells and abnormal persistence of Crohn disease-associated intracellular bacteria, with a substantial impact on the outcome of intestinal inflammation.
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*[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 inhibitors
*[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
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*[BEL]: Belgium
*[CAN]: Canada
| INFLAMMATORY BOWEL DISEASE (CROHN DISEASE) 19 | c2677079 | 4,845 | omim | https://www.omim.org/entry/612278 | 2019-09-22T16:02:00 | {"mesh": ["C567372"], "omim": ["612278"]} |
For a phenotypic description and a discussion of genetic heterogeneity of psoriasis, see PSORS1 (177900).
Mapping
Zhang et al. (2002) performed a genomewide scan with 2-point and multipoint parametric and nonparametric linkage analyses in 61 multiplex Han families residing in east and southeast China, comprising 189 affected and 166 unaffected individuals. They detected evidence for linkage at 6p21 (PSORS1). Zhang et al. (2002) could not confirm the PSORS3 locus on distal chromosome 4q (601454); however, a region of highly suggestive linkage was identified proximal to this proposed locus. Multipoint nonparametric analysis demonstrated nonparametric linkage scores greater than 3 throughout a region between 152.5 cM and 165.1 cM (from pter) with a maximum peak of 3.69 (p = 0.00033) at 157.9 cM, which locates D4S413. A maximum multipoint heterogeneity lod score of 2.31 (alpha = 46%) was reached at 163.1 cM. With 2-point parametric linkage analysis, Zhang et al. (2002) observed the highest lod score of 2.43 and heterogeneity lod score of 3.94 (alpha = 77%) at marker D4S1597. These results demonstrated that chromosomes 6p and 4q may contain genes involved in the susceptibility to psoriasis vulgaris in a Chinese Han population.
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*[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 inhibitors
*[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
| PSORIASIS 9, SUSCEPTIBILITY TO | c1842897 | 4,846 | omim | https://www.omim.org/entry/607857 | 2019-09-22T16:08:39 | {"omim": ["607857"]} |
Osteogenesis imperfecta type I is a mild type of osteogenesis imperfecta (OI; see this term), a genetic disorder characterized by increased bone fragility, low bone mass and susceptibility to bone fractures.
## Epidemiology
The overall prevalence of OI is estimated at between 1/10,000 and 1/20,000 but the prevalence of type I is unknown.
## Clinical description
OI type I is nondeforming with normal height or mild short stature, blue sclera, and no dentinogenesis imperfecta (DI; see this term).
## Etiology
OI type I is caused by mutations in the COL1A1 and COL1A2 genes (17q21.31-q22 and 7q22.1 respectively).
## Genetic counseling
Transmission is autosomal dominant.
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*[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 inhibitors
*[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
| Osteogenesis imperfecta type 1 | c0023931 | 4,847 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=216796 | 2021-01-23T18:26:57 | {"gard": ["8694"], "mesh": ["D010013"], "omim": ["166200", "166230"], "icd-10": ["Q78.0"], "synonyms": ["Adair-Dighton syndrome", "Mild osteogenesis imperfecta", "Non-deforming osteogenesis imperfecta", "OI type 1", "Van der Hoeve syndrome"]} |
A number sign (#) is used with this entry because hyperlipoproteinemia type III is caused by homozygous, compound heterozygous, or heterozygous mutation in the APOE gene (107741) on chromosome 19q13.
Description
Hyperlipoproteinemia type III, also called dysbetalipoproteinemia, is characterized by hyperlipidemia due to accumulation of remnants of the triglyceride (TG)-rich lipoproteins (TGRL), very low density lipoproteins (VLDL), and chylomicrons (CM), in response to dysfunctional genetic variants of apolipoprotein E or absence of apoE (summary by Blum, 2016).
Clinical Features
In normal individuals, chylomicron remnants and very low density lipoprotein remnants are rapidly removed from the circulation by receptor-mediated endocytosis in the liver. In familial dysbetalipoproteinemia, or type III hyperlipoproteinemia, increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants because of a defect in apolipoprotein E. Accumulation of the remnants can result in xanthomatosis and premature coronary and/or peripheral vascular disease. Hyperlipoproteinemia III can either be due to primary heritable defects in apolipoprotein metabolism or secondary to other conditions such as hypothyroidism, systemic lupus erythematosus, or diabetic ketoacidosis. Most patients with familial dysbetalipoproteinemia are homozygous for the E2 isoform (Breslow et al., 1982). Only rarely does the disorder occur with the heterozygous phenotypes E3E2 or E4E2. The E2 isoform shows defective binding of remnants to hepatic lipoprotein receptors (Schneider et al., 1981; Rall et al., 1982) and delayed clearance from plasma (Gregg et al., 1981). Additional genetic and/or environmental factors must be required for development of the disorder, however, because only 1-4% of E2E2 homozygotes develop familial dysbetalipoproteinemia. Since the defect in this disorder involves the exogenous cholesterol transport system, the degree of hypercholesterolemia is sensitive to the level of cholesterol in the diet (Brown et al., 1981). Even on a normal diet, the patient may show increased plasma cholesterol and the presence of an abnormal lipoprotein called beta-VLDL. VLDL in general is markedly increased while LDL is reduced. Carbohydrate induces or exacerbates the hyperlipidemia, resulting in marked variability in plasma levels and ready therapy through dietary means. Often tuberous and planar and sometimes tendon xanthomas occur as well as precocious atherosclerosis and abnormal glucose tolerance. Tuberous and tuberoeruptive xanthomas are particularly characteristic. Development of the phenotype is age dependent, being rarely evident before the third decade. Subsequent description of specific biochemical alterations in apolipoprotein structure and metabolism has proven this phenotype to be genetically heterogeneous. In the first application of apoprotein immunoassay to this group of disorders, Kushwaha et al. (1977) found that apolipoprotein E (arginine-rich lipoprotein) is high in the VLD lipoproteins of type III. They also found that exogenous estrogen, which stimulates triglyceride production in normal women and those with endogenous hypertriglyceridemia, exerted a paradoxical hypotriglyceridemic effect in this disorder (Kushwaha et al., 1977). The abnormal pattern of apoE by isoelectric focusing (IEF), specifically, the absence of apoE3, is the most characteristic biochemical feature of HLP III. Gregg et al. (1981) showed that apoE isolated from subjects with type III HLP had a decreased fractional catabolic rate in vivo in both type III HLP patients and normal persons.
Ghiselli et al. (1981) studied a black kindred with type III HLP due to deficiency of apolipoprotein E. No plasma apolipoprotein E could be detected. Other families with type III HLP have had increased amounts of an abnormal apoE. In addition, the patients of Ghiselli et al. (1981) had only mild hypertriglyceridemia, increased LDL cholesterol, and a much higher ratio of VLDL cholesterol to plasma triglyceride than reported in other type III HLP families. The proband was a 60-year-old woman with a 10-year history of tuberoeruptive xanthomas of the elbows and knees, a 3-year history of angina pectoris, and 80% narrowing of the first diagonal coronary artery by arteriography. Her father had xanthomas and died at age 62 of myocardial infarction. Her mother was alive and well at age 86. Three of 7 sibs also had xanthomas; her 2 offspring had no xanthomas. The evidence suggests that apoE is important for the catabolism of chylomicron fragments. The affected persons in the family studied by Ghiselli et al. (1981) had plasma levels of apoE less than 0.05 mg/dl by radioimmunoassay, and no structural variants of apoE were detected by immunoblot of plasma or VLDL separated by 2-dimensional gel electrophoresis. Anchors et al. (1986) reported that the apoE gene was present in the apoE-deficient patient and that there were no major insertions or deletions in the gene by Southern blot analysis. Blood monocyte-macrophages isolated from a patient contained levels of apoE mRNA 1 to 3% of that present in monocyte-macrophages isolated from normal subjects. The mRNA from the patient appeared to be of normal size. Anchors et al. (1986) suggested that the decreased apoE mRNA might be due to a defect in transcription or processing of the primary transcript or to instability of the apoE mRNA. The decreased plasma level of apoE resulted in delayed clearance of remnants of triglyceride-rich lipoproteins, hyperlipidemia, and the phenotype of type III HLP.
Although nearly every type III hyperlipoproteinemic person has the E2/E2 phenotype, 95 to 99% of persons with this phenotype do not have type III HLP nor do they have elevated plasma cholesterol levels. Rall et al. (1983) showed that apoE2 of hypo-, normo-, and hypercholesterolemic subjects showed the same severe functional abnormalities. Thus, factors in addition to the defective receptor binding activity of the apoE2 are necessary for manifestation of type III HLP. A variety of factors exacerbate or modulate type III. In women, it most often occurs after menopause and in such patients is particularly sensitive to estrogen therapy. Hypothyroidism exacerbates type III and thyroid hormone is known to enhance receptor-mediated lipoprotein metabolism. Obesity, diabetes, and age are associated with increased hepatic synthesis of VLDL and/or cholesterol; occurrence of type III in E2/E2 persons with these factors may be explained thereby. Furthermore, the defect in familial combined HLP (144250), which is, it seems, combined with E2/E2 in the production of type III (Utermann et al., 1979; Hazzard et al., 1981), may be hepatic overproduction of cholesterol and VLDL. As pointed out by Brown and Goldstein (1983), familial hypercholesterolemia (FH; 143890) is a genetic defect of the LDL receptor (LDLR; 606945), whereas familial dysbetalipoproteinemia is a genetic defect in a ligand. The puzzle that all apoE2/2 homozygotes do not have extremely high plasma levels of IDL and chylomicron remnants (apoE-containing lipoproteins) may be solved by the observation that the lipoprotein levels in these patients are exquisitely sensitive to factors that reduce hepatic LDL receptors, e.g., age, decreased levels of thyroid hormone and estrogen, and the genetic defect of FH. Presumably, high levels of hepatic LDL receptors can compensate for the genetic binding defect of E2 homozygotes.
Bersot et al. (1983) studied atypical dysbetalipoproteinemia characterized by severe hypercholesterolemia and hypertriglyceridemia, xanthomatosis, premature vascular disease, the apoE3/3 phenotype (rather than the classic E2/2 phenotype), and a preponderance of beta-VLDL. They showed that the beta-VLDL from these subjects stimulated cholesteryl ester accumulation in mouse peritoneal macrophages. They suggested that the accelerated vascular disease results from this uptake by macrophages which are converted into the foam cells of atherosclerotic lesions.
Schaefer et al. (1986) described a unique American black kindred with premature cardiovascular disease, tuberoeruptive xanthomas, and type III HLP associated with familial apolipoprotein E deficiency. Four homozygotes had marked increases in cholesterol-rich, very low density lipoproteins and intermediate density lipoproteins (IDL). Homozygotes had only trace amounts of plasma apoE, and accumulations of apoB-48 (107730) and apoA-4 (107690) in VLDL, IDL, and low density lipoproteins. Obligate heterozygotes generally had normal plasma lipids and mean plasma apoE concentrations that were 42% of normal. The findings indicated that apoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. It had been shown that cultured peripheral blood monocytes synthesized low amounts of 2 aberrant forms of apoE mRNA but produced no immunoprecipitable forms of apoE. The expression studies were done comparing the normal and abnormal APOE genes transfected into mouse cells in combination with the mouse metallothionein I promoter.
Boerwinkle and Utermann (1988) studied the simultaneous effect of apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism. Since both apoB and apoE bind to the LDL receptor and since the different isoforms show different binding affinity, these effects are not unexpected.
In a case-control study of 338 centenarians compared with adults aged 20 to 70 years of age, Schachter et al. (1994) found that the E4 allele of apoE, which promotes premature atherosclerosis, was significantly less frequent in centenarians than in controls (p = less than 0.001), while the frequency of the E2 allele, associated previously with types III and IV hyperlipidemia, was significantly increased (p = less than 0.01).
Feussner et al. (1996) reported a 20-year-old man with a combination of type III hyperlipoproteinemia and heterozygous familial hypercholesterolemia (FH; 143890). Multiple xanthomas were evident on the elbows, interphalangeal joints and interdigital webs of the hands. Lipid-lowering therapy caused significant decrease of cholesterol and triglycerides as well as regression of the xanthomas. Flat xanthomas of the interdigital webs were also described in 3 out of 4 previously reported patients with combination of these disorders of lipoprotein metabolism. Feussner et al. (1996) stated that these xanthomas may indicate compound heterozygosity (actually double heterozygosity) for type III hyperlipoproteinemia and FH.
Clinical Management
Among 1,383 Scottish adult patients with diabetes taking statin medication to reduce serum LDL cholesterol levels, Donnelly et al. (2008) found an association of APOE genotype with both baseline and treatment responses. E2 homozygotes achieved significantly lower LDL levels compared to E4 homozygotes (mean 0.6 versus 1.7 mmol/L; p = 2.96 x 10(-12)). All E2 homozygotes reached the target serum LDL level, compared to 32% of E4 homozygotes who did not (p = 5.3 x 10(-5)). The findings indicated that APOE genotype may be an important marker for clinical responses to statin drugs.
Molecular Genetics
Most patients with familial dysbetalipoproteinemia type III are homozygous for the E2 isoform arg258-to-cys mutation (R258C; 107741.0001) (Breslow et al., 1982).
In the kindred with apolipoprotein E deficiency studied by Ghiselli et al. (1981), the defect was shown by Cladaras et al. (1987) to involve an acceptor splice site mutation in intron 3 of the APOE gene (107741.0005).
Smit et al. (1987) described 3 out of 41 Dutch dysbetalipoproteinemic patients who were apparent E3/E2 heterozygotes rather than the usual E2/E2 homozygotes. All 3 genetically unrelated patients showed an uncommon E2 allele that contained only 1 cysteine residue. The uncommon allele cosegregated with familial dysbetalipoproteinemia which in these families seemed to behave as a dominant. Smit et al. (1990) showed that these 3 unrelated patients were heterozygous for E2(K146Q; 107741.0011).
### Susceptibility to Coronary Artery Disease
Eto et al. (1989) presented data from Japan indicating that both the E2 allele and the E4 allele are associated with an increased risk of ischemic heart disease as compared with the E3 allele.
In 5 of 19 Australian men, aged 30 to 50, who were referred for coronary angioplasty (26%), van Bockxmeer and Mamotte (1992) observed homozygosity for E4. This represented a 16-fold increase compared with controls. Payne et al. (1992), O'Malley and Illingworth (1992), and de Knijff et al. (1992) expressed doubts concerning a relationship between E4 and atherosclerosis.
Frikke-Schmidt et al. (2007) presented evidence that combinations of SNPs in APOE and LPL (609708) identify subgroups of individuals at substantially increased risk of ischemic heart disease beyond that associated with smoking, diabetes, and hypertension.
Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9 SNPs, including rs4420638 of APOE, had previously been associated with elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the associations with each SNP and created a genotype score on the basis of the number of unfavorable alleles. With increasing genotype scores, the level of LDL cholesterol increased, whereas the level of HDL cholesterol decreased. At 10-year follow-up, the genotype score was found to be an independent risk factor for incident cardiovascular disease (myocardial infarction, ischemic stroke, or death from coronary heart disease); the score did not improve risk discrimination but modestly improved clinical risk reclassification for individual subjects beyond standard clinical factors.
History
The nosography of the type III hyperlipoproteinemia phenotype up to 1977 was reviewed by Levy and Morganroth (1977).
*[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 inhibitors
*[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
| HYPERLIPOPROTEINEMIA, TYPE III | c0020479 | 4,848 | omim | https://www.omim.org/entry/617347 | 2019-09-22T15:46:03 | {"doid": ["3145"], "mesh": ["D006952"], "omim": ["617347"], "orphanet": ["412"], "synonyms": ["Alternative titles", "APOLIPOPROTEIN E, DEFICIENCY OR DEFECT OF", "DYSBETALIPOPROTEINEMIA DUE TO DEFECT IN APOLIPOPROTEIN E-d", "FAMILIAL HYPERBETA- AND PREBETALIPOPROTEINEMIA", "FAMILIAL HYPERCHOLESTEROLEMIA WITH HYPERLIPEMIA", "HYPERLIPEMIA WITH FAMILIAL HYPERCHOLESTEROLEMIC XANTHOMATOSIS", "BROAD-BETALIPOPROTEINEMIA", "FLOATING-BETALIPOPROTEINEMIA"]} |
Progressive nodular histiocytoma
SpecialtyDermatology
Progressive nodular histiocytoma is a cutaneous condition characterized by generalized, discrete yellow papules and nodules with prominent facial involvement.[1]
## See also[edit]
* Generalized eruptive histiocytoma
* List of cutaneous conditions
## References[edit]
1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
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 inhibitors
*[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
| Progressive nodular histiocytoma | None | 4,849 | wikipedia | https://en.wikipedia.org/wiki/Progressive_nodular_histiocytoma | 2021-01-18T18:54:03 | {"wikidata": ["Q7248851"]} |
## Summary
### Clinical characteristics.
Oral-facial-digital syndrome type I (OFD1) is usually male lethal during gestation and predominantly affects females. OFD1 is characterized by the following features:
* Oral (lobulated tongue, tongue nodules, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities)
* Facial (widely spaced eyes or telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft upper lip, micrognathia)
* Digital (brachydactyly, syndactyly, clinodactyly of the fifth finger; duplicated hallux [great toe])
* Kidney (polycystic kidney disease)
* Brain (e.g., intracerebral cysts, agenesis of the corpus callosum, cerebellar agenesis with or without Dandy-Walker malformation)
* Intellectual disability (in ~50% of individuals)
### Diagnosis/testing.
The diagnosis of OFD1 is established in a proband by identification of an OFD1 pathogenic variant on molecular genetic testing.
### Management.
Treatment of manifestations: Surgery for cleft lip/palate, tongue nodules, accessory frenulae, and syndactyly; removal of accessory teeth and orthodontia for malocclusion; routine treatment for renal disease and seizures. Speech therapy and special education may be warranted.
Surveillance: Annual audiology evaluation and assessment of speech development in children if cleft lip and/or cleft palate is present. Individuals age ten years and older: annual blood pressure examination, serum creatinine, annual ultrasound examination for renal, hepatic, pancreatic, and ovarian cystic disease.
### Genetic counseling.
OFD1 is inherited in an X-linked manner. Approximately 75% of affected individuals represent simplex cases (i.e., with no family history of OFD1). A female proband with OFD1 may have the disorder as the result of a de novo pathogenic variant; the proportion of cases caused by de novo pathogenic variants is unknown. The risk that the unaffected mother of an affected female who is a simplex case will give birth to another female with OFD1 is less than 1%. At conception, the risk to the offspring of females with OFD1 of inheriting the pathogenic variant is 50%; however, most male conceptuses with the pathogenic variant miscarry. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known. Prenatal ultrasound examination may detect structural brain malformations and/or duplication of the hallux.
## Diagnosis
### Suggestive Findings
Oral-facial-digital syndrome type I (OFD1) should be suspected in females with typical oral-facial-digital findings, milia, and/or polycystic kidney disease. The oral-facial-digital findings are also found in other OFDs. OFD1 is characterized by renal cystic disease in approximately 50% of individuals and by the X-linked inheritance pattern in familial cases; see Table 1 (pdf). Almost all individuals with OFD1 are female; however, a few affected males have been reported. In most cases, these males are described as malformed fetuses delivered by an affected female.
#### Clinical Features
Oral
* Tongue anomalies (e.g., lobulated, nodules, ankyloglossia)
* Cleft palate
* Alveolar clefts and accessory gingival frenulae
* Dental anomalies (e.g., missing teeth, extra teeth)
Facial
* Widely spaced eyes, telecanthus, downslanting palpebral fissures
* Hypoplasia of the alae nasi
* Median cleft lip, pseudocleft upper lip
* Micrognathia
Digital
* Brachydactyly, syndactyly
* Clinodactyly of the fifth finger
* Radial or ulnar deviation of the other fingers, particularly the third
* Unilateral duplicated hallux (great toe)
Other
* Milia
* Polycystic kidney disease (50%)
* Intellectual disability
* X-linked dominant inheritance pattern in familial cases
#### Radiographic Features
Hand x-rays often demonstrate fine reticular radiolucencies, described as irregular mineralization of the bone, with or without spicule formation of the phalanges.
Renal ultrasound examination shows renal cysts in at least 50% of individuals.
Brain MRI most commonly shows intracerebral cysts, agenesis of the corpus callosum, and cerebellar agenesis with or without Dandy-Walker malformation.
### Establishing the Diagnosis
No formal diagnostic criteria are available. Because of the extensive genetic heterogeneity observed in OFD syndromes, OFD1 molecular genetic testing is recommended to establish the diagnosis [Franco & Thauvin-Robinet 2016].
* Female proband. The diagnosis of OFD1 is established by identification of a heterozygous pathogenic variant in OFD1 by molecular genetic testing (see Table 2).
* Male proband. The diagnosis of OFD1 is established by identification of a hemizygous pathogenic variant in OFD1 by molecular genetic testing (see Table 2).
Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
* Single-gene testing. Sequence analysis of OFD1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
* A multigene panel that includes OFD1 and other genes of interest (see Differential Diagnosis) is recommended if no pathogenic variant is identified on single-gene testing. 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 is recommended if single-gene testing (and/or use of a multigene panel that includes OFD1) fails to confirm a diagnosis in an individual with features of OFD1. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes 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 2.
Molecular Genetic Testing Used in Oral-Facial-Digital Syndrome Type I
View in own window
Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
OFD1Sequence analysis 3, 480% 5
Gene-targeted deletion/duplication analysis 65% 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\.
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\.
A variety of pathogenic variants have been identified, the majority of which predict premature protein truncation. The reported detection rate with sequence analysis is about 80% [Nowaczyk et al 2003, Thauvin-Robinet et al 2006, Prattichizzo et al 2008].
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\.
One study found that six of 131 individuals with OFD1 had a deletion ranging in size from one to 14 exons. None had the same deletion. Within this group, 23% of those who did not have a pathogenic variant identified on gene sequencing were found on qPCR to have an exon or multiexon deletion [Thauvin-Robinet et al 2009].
## Clinical Characteristics
### Clinical Description
The diagnosis of oral-facial-digital syndrome type I (OFD1) is established at birth in some infants on the basis of characteristic oral, facial, and digital anomalies; in other instances, the diagnosis is suspected only after polycystic kidney disease is identified in later childhood or adulthood. Almost all affected individuals with OFD1 are female; however, a few affected males have been reported. In most cases, these males are described as malformed fetuses delivered by a female with OFD1.
Oral manifestations. The tongue is lobulated. Tongue nodules, which are usually hamartomas or lipomas, also occur in at least one third of individuals with OFD1. Ankyloglossia attributable to a short lingual frenulum is common. Cleft hard or soft palate, submucous cleft palate, or highly arched palate occurs in more than 50% of affected individuals. Trifurcation of the soft palate has been reported [al-Qattan 1998]. Alveolar clefts and accessory gingival frenulae are common. These fibrous bands are hyperplastic frenulae extending from the buccal mucous membrane to the alveolar ridge, resulting in notching of the alveolar ridges. Dental abnormalities include missing teeth (most common), extra teeth, enamel dysplasia, and malocclusion.
Facial features. Widely spaced eyes or telecanthus occurs in at least 33% of affected individuals. Hypoplasia of the alae nasi, median cleft lip, or pseudocleft upper lip is common. Micrognathia and downslanting palpebral fissures are common.
Digital anomalies. Brachydactyly, syndactyly of varying degrees, and clinodactyly of the fifth finger are common. The other fingers, particularly the third (i.e., middle finger) may show variable radial or ulnar deviation. Duplicated hallux (great toe) occurs in fewer than 50% of affected individuals, and if present is usually unilateral. Preaxial or postaxial polydactyly of the hands occurs in 1%-2% of affected individuals.
Radiographs of the hands often demonstrate fine reticular radiolucencies, described as irregular mineralization of the bone, with or without spicule formation of the phalanges [al-Qattan & Hassanain 1997].
Milia, small keratinizing cysts, occur in at least 10%, and likely more, most often appearing on the scalp, ear pinnae, face, and dorsa of the hands. Milia are usually present in infancy and then resolve, but can leave pitting scars.
Kidney. Renal cysts can develop from both tubules and glomeruli. The age of onset is most often in adulthood, but renal cysts in children as young as age two years have been described. Although renal cysts have been reported as a prenatal finding [Nishimura et al 1999], the diagnosis is doubtful in these cases. The risk for significant renal disease appears to be higher than 60% after age 18 years [Prattichizzo et al 2008, Saal et al 2010]. End-stage renal disease has been reported in affected girls and women ranging in age from 11 to 70 years.
Intellectual disability. It is estimated that as many as 50% of individuals with OFD1 have some degree of intellectual disability or learning disability. Intellectual disability depends in part on the presence of brain abnormalities, but no consistent correlation exists. When present, intellectual disability is usually mild. Severe intellectual disability in the absence of brain malformations appears to be rare [Del Giudice et al 2014].
Brain malformations. Structural brain abnormalities may occur in as many as 65% of individuals with OFD1 [Thauvin-Robinet et al 2006, Macca & Franco 2009, Bisschoff et al 2013, Del Giudice et al 2014]. Anomalies most commonly include intracerebral cysts, agenesis of the corpus callosum, and cerebellar agenesis with or without Dandy-Walker malformation. Other reported anomalies include type 2 porencephaly (schizencephalic porencephaly), pachygyria and heterotopias, hydrocephalus, cerebral or cerebellar atrophy, hypothalamic hamartomas, and berry aneurysms, each of which has been described in a few affected individuals.
Structural brain abnormalities may be accompanied by seizures and ataxia, especially in those with cerebellar atrophy.
Other
Hearing loss from recurrent otitis media, usually associated with cleft palate, has been reported. On occasion, speech and mastication can be affected.
The hair is often described as dry, coarse, and brittle. Alopecia, usually partial, is an occasional finding. Alopecia following the lines of Blaschko has been described [Boente et al 1999].
Liver, pancreatic, and ovarian cysts may be observed, but only in those who have renal cysts as well.
Short stature, choanal atresia, and tibial pseudarthrosis have been reported.
Phenotypic variability is often seen in affected females, possibly as a result of random X-chromosome inactivation [Morleo & Franco 2008].
### Genotype-Phenotype Correlations
No convincing genotype-phenotype correlations have been reported. The majority of OFD1 pathogenic variants are localized within exon 16 of the OFD1 transcript.
### Penetrance
OFD1 appears to be highly penetrant, although highly variable in expression. In some reports, renal cysts are the only apparent manifestation in affected females [McLaughlin et al 2000].
### Nomenclature
OFD1 was previously called Papillon-Léage-Psaume syndrome.
### Prevalence
Prevalence estimates range from 1:250,000 to 1:50,000.
## Differential Diagnosis
The differential diagnosis includes the other oral-facial-digital syndromes and disorders, including cystic renal disease.
Oral-facial-digital (OFD) syndromes. See also Table 1 (pdf).
* OFD2 (Mohr syndrome; OMIM 252100) is primarily distinguished by polydactyly. Other manifestations include bifid nasal tip. Affected individuals do not have milia or polycystic kidney disease.
* OFD3 (OMIM 258850) is characterized by seesaw winking (alternate winking of the eyes) and polydactyly. Myoclonic jerks, profound intellectual disability, bulbous nose, and apparently low-set ears also occur.
* OFD4 (OMIM 258860) has tibial involvement and polydactyly as the primary manifestations. Other findings include pectus excavatum and short stature.
* OFD5 (OMIM 174300) includes polydactyly and median cleft lip only. Hyperplastic frenula have been reported in one affected individual.
* OFD6 (OMIM 277170) is distinguished by polydactyly (particularly central) and cerebellar malformations. Renal agenesis and dysplasia have been described. Brain MRI may show a molar tooth sign leading some to consider OFD6 a Joubert syndrome-related disorder.
* OFD8 (OMIM 300484), apparently inherited as an X-linked trait, is characterized by the combination of polydactyly, tibial and radial defects, and epiglottal abnormalities, none of which are seen in the classic form of OFD1.
* OFD9 (OMIM 258865) includes retinal abnormalities and non-median cleft lip.
* OFD10 (OMIM 165590) includes short limbs with bilateral radial shortening and fibular agenesis.
* OFD11 (OMIM 612913) includes odontoid and vertebral abnormalities.
* OFD12 is described in only one individual with brain malformations, myelomeningocele, short tibiae and central Y-shaped metacarpal [Gurrieri et al 2007].
* OFD13 is described in only one individual with neuropsychiatric disturbances and leukokaraiosis [Gurrieri et al 2007].
* OFD14 (OMIM 615948) includes severe microcephaly and intellectual disability. Brain MRI shows vermis hypoplasia and molar tooth sign.
Cystic renal disease
* Autosomal dominant polycystic kidney disease (ADPKD). The diagnosis of ADPKD has been made in some individuals who later were found to have OFD1 [Scolari et al 1997]. In ADPKD, cysts develop from tubules, whereas in OFD1 cysts develop from both tubules and glomeruli; however, imaging studies cannot always distinguish the renal cystic disease of OFD1 from that of ADPKD and other cystic renal disorders. The cysts are said to be smaller and more uniform in size in OFD1 than in ADPKD, and the kidneys are not as enlarged or malformed in OFD1. Hepatic cysts and berry aneurysms have been observed in OFD1. Other distinguishing features are mode of inheritance and the absence of oral, facial, digital, or brain abnormalities in ADPKD. The two genes in which pathogenic variants are known to cause ADPKD are PKD1 and PKD2.
* Meckel-Gruber syndrome is characterized by CNS malformation (posterior encephalocele, cerebral and cerebellar hypoplasia), polycystic or hypoplastic kidneys, preaxial or postaxial polydactyly, and early demise. Additional findings include cleft lip and palate, ambiguous genitalia, microcephaly, and microphthalmia. Ocular histopathology reveals retinal dysplasia, coloboma, cataract, and corneal dysgenesis. Inheritance is autosomal recessive. See Meckel Syndrome: OMIM Phenotypic Series for associated genes.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with oral-facial-digital syndrome type I (OFD1), the following evaluations are recommended:
* Examination of the face, especially the mouth, and the hands for characteristic anomalies
* Formal, age-appropriate assessment of development and behavior
* Evaluation of CNS involvement
* Blood pressure and serum creatinine concentration
* Urinalysis, serum chemistries, and ultrasound examination of the kidneys, liver, ovary and pancreas for cysts if the individual is age ten years or older
* Audiology evaluation if cleft palate is present
* Consultation with a clinical geneticist and/or genetic counselor
### Treatment of Manifestations
The following are appropriate:
* Cosmetic or reconstructive surgery for clefts of the lip and/or palate, tongue nodules, and accessory frenulae; treatment as for isolated cleft palate, including speech therapy and assessment for and aggressive treatment of otitis media
* Removal of accessory teeth
* Orthodontia for malocclusion
* Surgery to repair syndactyly, if present
* Routine management of renal disease, which may require hemodialysis or peritoneal dialysis and renal transplantation
* Routine management of seizures
* Special educational evaluation and input to address learning disabilities and other cognitive impairments
### Surveillance
Surveillance includes the following:
* Annual audiology evaluation and assessment of speech development and frequency of ear infections in children if cleft lip and/or cleft palate is present
* Annual blood pressure examination and serum creatinine concentration to monitor renal function in individuals age ten years or older
* Annual ultrasound examination for renal, hepatic, pancreatic, and ovarian cystic disease in individuals age ten years and older
### Evaluation of Relatives at Risk
If an OFD1 pathogenic variant has been identified in an affected family member, it is appropriate to evaluate apparently asymptomatic female relatives (even in the absence of oral, facial, and digital anomalies) to determine if they are at risk for renal disease.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Pregnancy Management
Affected pregnant women should undergo careful monitoring of their blood pressure and renal function during pregnancy.
### 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.
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*[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 inhibitors
*[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
| Oral-Facial-Digital Syndrome Type I | c1510460 | 4,850 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1188/ | 2021-01-18T21:06:30 | {"mesh": ["D009958"], "synonyms": ["OFD1", "Orofaciodigital Syndrome I"]} |
## Description
Microtia-anotia (M-A) can occur either as an isolated defect or in association with other defects. Only in a minority of cases has a genetic or environmental cause been found; in these cases, M-A is usually part of a specific pattern of multiple congenital anomalies. For instance, M-A is an essential component of isotretinoin embryopathy (243440), is an important manifestation of thalidomide embryopathy, and can be part of the prenatal alcohol syndrome and maternal diabetes embryopathy. M-A occurs with a number of single gene disorders, such as Treacher Collins syndrome (154500), branchiotorenal/branchiootic syndromes (see 113650 and 602588), oculoauricular syndrome (612109), microtia with hearing impairment and cleft palate (612290), or chromosomal syndromes, such as trisomy 18. M-A also occurs as part of seemingly nonrandom patterns of multiple defects, such as Goldenhar syndrome (164210) (Mastroiacovo et al., 1995).
Alasti and Van Camp (2009) reviewed the genetics of microtia and microtia-associated syndromes and discussed their clinical aspects in relation to the causative genes. They stated that the estimated prevalence of microtia is 0.8 to 4.2 per 10,000 births, that it is more common in males, and that it can have a genetic or environmental predisposition.
Inheritance
Mastroiacovo et al. (1995) studied the epidemiology and genetics of microtia-anotia (M-A) using data collected from the Italian Multicenter Birth Defects Registry (IPIMC) from 1983 to 1992. Among 1,173,794 births, they identified 172 with M-A, a rate of 1.46/10,000; 38 of the 172 infants (22.1%) had anotia. Of the 172 infants, 114 (66.2%) had an isolated defect, 48 (27.9%) were multimalformed infants (MMI) with M-A, and 10 (5.8%) had a well defined syndrome. The frequency of bilateral defects among nonsyndromic cases was 12% compared to 50% of syndromic cases. Among the MMI, only holoprosencephaly was preferentially associated with M-A; 4 cases were observed versus 0.7 expected (p = 0.005). No geographic variation in the prevalence of nonsyndromic cases was observed nor was there evidence of time trends. Mothers with parity 1 had a higher risk of giving birth to an MMI with M-A. Mothers with insulin-dependent diabetes were at significantly higher risk for having a child with M-A. Mastroiacovo et al. (1995) suggested autosomal dominant inheritance with variable expression and incomplete penetrance 'in a proportion of cases,' or multifactorial etiology. Three cases had consanguineous parents, but there were no other affected sibs to support recessive inheritance.
Hussain et al. (2004) reported a pair of monozygotic male twins, both of whom had right microtia with an atretic external ear and an absent external auditory canal, without evidence of facial asymmetry or other dysmorphic features or abnormalities. The left pinna was normal in both.
Artunduaga et al. (2009) ascertained 13 monozygotic and 22 dizygotic twin pairs in which at least 1 sib had severe nonsyndromic microtia requiring surgical repair. The concordance rate for all auricular malformations was higher in monozygotic than in dizygotic twins (61.5% and 4.5%, respectively; odds ratio, 33.4 and p = 0.003), as was concordance for microtia (38.5% and 4.5%, respectively; OR, 12.6 and p = 0.029). Combining their data with 37 twin pairs with microtia reported in the literature, the 72 sets of twins showed significant differences in the concordance rate for monozygotic (26.3%) and dizygotic (2.9%) twins (OR, 11.5; p = 0.023). Artunduaga et al. (2009) concluded that there is a strong genetic contribution to malformations of the external ear, and that the data are consistent with either an incompletely penetrant germline mutation or somatic mutation with epigenetic events occurring early in embryogenesis.
Inheritance \- Autosomal dominant vs. multifactorial Misc \- Association with holoprosencephaly \- Higher risk for mothers with insulin-dependent diabetes Ears \- Microtia-anotia (M-A) ▲ Close
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*[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 inhibitors
*[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
| MICROTIA-ANOTIA | c0702139 | 4,851 | omim | https://www.omim.org/entry/600674 | 2019-09-22T16:15:57 | {"mesh": ["D065817"], "omim": ["600674"], "orphanet": ["93976", "83463"]} |
Bronchorrhea is the production of more than 100 mL per day of watery sputum.[1] Chronic bronchitis is a common cause, but it may also be caused by asthma,[2] pulmonary contusion,[3] bronchiectasis, tuberculosis, cancer, scorpion stings, severe hypothermia and poisoning by organophosphates and other poisons. Massive bronchorrhea may occur in either bronchioloalveolar carcinoma, or in metastatic cancer that is growing in a bronchioloalveolar pattern.[1][4][5] It commonly occurs in the setting of chest wall trauma, in which setting it can cause lobar atelectasis.[6]
## Contents
* 1 Diagnosis
* 2 Treatment
* 3 References
## Diagnosis[edit]
This section is empty. You can help by adding to it. (September 2017)
## Treatment[edit]
Treatment options for bronchorrhea vary depending on the inciting cause; they include:
* gefitinib \- epidermal growth factor receptor tyrosine kinase inhibitor[7][8][9][10][11]
* indomethacin[12][13][14]
* corticosteroids[15]
* octreotide[16]
* radiation therapy[17]
* bronchoscopy as is often done in the post traumatic setting.[6]
## References[edit]
1. ^ a b Lembo T, Donnelly T (1995). "A case of pancreatic carcinoma causing massive bronchial fluid production and electrolyte abnormalities". Chest. 108 (4): 1161–3. doi:10.1378/chest.108.4.1161. PMID 7555132.
2. ^ Shimura S, Sasaki T, Sasaki H, Takishima T (1988). "Chemical properties of bronchorrhea sputum in bronchial asthma". Chest. 94 (6): 1211–5. doi:10.1378/chest.94.6.1211. PMID 2903819.
3. ^ Gavelli G, Canini R, Bertaccini P, Battista G, Bnà C, Fattori R (June 2002). "Traumatic injuries: imaging of thoracic injuries". European Radiology. 12 (6): 1273–1294. doi:10.1007/s00330-002-1439-6. PMID 12042932.
4. ^ Shimura S, Takishima T (1994). "Bronchorrhea from diffuse lymphangitic metastasis of colon carcinoma to the lung". Chest. 105 (1): 308–10. doi:10.1378/chest.105.1.308. PMID 8275762.
5. ^ Mito K, Yamakami Y, Kashima K, Mizunoe S, Tokimatsu I, Ichimiya T, Hiramatsu K, Nagai H, Kadota J, Nasu M (2002). "[A case of suspected lung metastasis of pancreatic carcinoma with bronchorrhea similar to bronchioloalveolar carcinoma]". Nihon Kokyuki Gakkai Zasshi. 40 (8): 666–70. PMID 12428395.
6. ^ a b Abbott, Mark S. Parker, Melissa L. Rosado de Christenson, Gerald F. (2005). Teaching atlas of chest imaging. New York: Thieme. ISBN 978-1588902306.
7. ^ Kitazaki T, Soda H, Doi S, Nakano H, Nakamura Y, Kohno S (2005). "Gefitinib inhibits MUC5AC synthesis in mucin-secreting non-small cell lung cancer cells". Lung Cancer. 50 (1): 19–24. doi:10.1016/j.lungcan.2005.05.005. PMID 16009452.
8. ^ Kitazaki T, Fukuda M, Soda H, Kohno S (2005). "Novel effects of gefitinib on mucin production in bronchioloalveolar carcinoma; two case reports". Lung Cancer. 49 (1): 125–8. doi:10.1016/j.lungcan.2004.11.027. PMID 15949598.
9. ^ Milton D, Kris M, Gomez J, Feinstein M (2005). "Prompt control of bronchorrhea in patients with bronchioloalveolar carcinoma treated with gefitinib (Iressa)". Support Care Cancer. 13 (1): 70–2. doi:10.1007/s00520-004-0717-z. PMID 15558327.
10. ^ Takao, Motoshi; Inoue, K; Watanabe, F; Onoda, K; Shimono, T; Shimpo, H; Yada, I (2003). "Successful treatment of persistent bronchorrhea by gefitinib in a case with Recurrent Bronchioloalveolar Carcinoma: a case report". World J Surg Oncol. 1 (1): 8. doi:10.1186/1477-7819-1-8. PMC 183862. PMID 12917017.
11. ^ Yano S, Kanematsu T, Miki T, Aono Y, Azuma M, Yamamoto A, Uehara H, Sone S (2003). "A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 ("I[res]sa")". Cancer Science. 94 (5): 453–8. doi:10.1111/j.1349-7006.2003.tb01464.x. PMID 12824893.
12. ^ Tamaoki J, Kohri K, Isono K, Nagai A (2000). "Inhaled indomethacin in bronchorrhea in bronchioloalveolar carcinoma: role of cyclooxygenase". Chest. 117 (4): 1213–4. doi:10.1378/chest.117.4.1213. PMID 10767270.
13. ^ Homma S, Kawabata M, Kishi K, Tsuboi E, Narui K, Nakatani T, Nakata K (1999). "Successful treatment of refractory bronchorrhea by inhaled indomethacin in two patients with bronchioloalveolar carcinoma". Chest. 115 (5): 1465–8. doi:10.1378/chest.115.5.1465. PMID 10334175.
14. ^ Tamaoki J, Chiyotani A, Kobayashi K, Sakai N, Kanemura T, Takizawa T (1992). "Effect of indomethacin on bronchorrhea in patients with chronic bronchitis, diffuse panbronchiolitis, or bronchiectasis". Am Rev Respir Dis. 145 (3): 548–52. doi:10.1164/ajrccm/145.3.548. PMID 1546834.
15. ^ Nakajima T, Terashima T, Nishida J, Onoda M, Koide O (2002). "Treatment of bronchorrhea by corticosteroids in a case of bronchioloalveolar carcinoma producing CA19-9". Intern Med. 41 (3): 225–8. doi:10.2169/internalmedicine.41.225. PMID 11929186.
16. ^ Hudson E, Lester J, Attanoos R, Linnane S, Byrne A (2006). "Successful treatment of bronchorrhea with octreotide in a patient with adenocarcinoma of the lung". J Pain Symptom Manage. 32 (3): 200–2. doi:10.1016/j.jpainsymman.2006.05.003. PMID 16939841.
17. ^ Krawtz S, Mehta A, Vijayakumar S, Stoller J (1988). "Palliation of massive bronchorrhea". Chest. 94 (6): 1313–4. doi:10.1378/chest.94.6.1313-b. PMID 2461277.
This article about a medical condition affecting the respiratory system is a stub. You can help Wikipedia by expanding it.
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* e
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*[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 inhibitors
*[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
| Bronchorrhea | c0235568 | 4,852 | wikipedia | https://en.wikipedia.org/wiki/Bronchorrhea | 2021-01-18T18:44:58 | {"umls": ["C0235568"], "wikidata": ["Q600754"]} |
Global Acute Malnutrition (GAM) is a measurement of the nutritional status of a population that is often used in protracted refugee situations. Along with the Crude Mortality Rate, it is one of the basic indicators for assessing the severity of a humanitarian crisis.[1]
## Contents
* 1 Definition
* 2 Interpretation
* 3 Objectives and results
* 4 References
* 5 External links
## Definition[edit]
Countries showing percentage of population suffering from undernourishment, 2006.
To evaluate levels of GAM, workers in an emergency measure the weight and height of children between 6 and 59 months. They then use the results as a proxy for the health of the population as a whole. The weight to height index is compared to the same index for a reference population that has no shortage of nutrition. All children with weight less than 80% of the median weight of children with the same height in the reference population, and/or suffering from Oedema, are classified as GAM.[1] The World Health Organization describes Moderate Acute Malnutrition (MAM) as GAM in the 79% - 70% range, and Severe Acute Malnutrition (SAM) as GAM below 70%.[2]
An alternative definition is that a child suffers from GAM if their weight to height ratio is less than the value at -2 Standard Deviations on the Z-Score for the same measurement in the reference population. SAM is defined as a weight to height ratio less than -3 Standard Deviations on the Z-score for the reference population. In practice, since the distribution of weight to height ratios is much the same in all populations, the two definitions are equivalent.[1] Weight for height is chosen rather than weight for age since the latter may indicate long-term stunting rather than acute malnutrition.[3]
The World Health Organization also defines other measures of malnutrition including the Mid-upper arm circumference, Marasmus and Kwashiorkor.[2] Mid-upper arm circumference (MUAC) measurement, if conducted by well-trained staff, can give a quick assessment of new arrivals at a camp. It is based on the observation that this measurement does not change much in children between 6 months and five years old, so comparison to a "normal" measurement is useful. Based on analysis of field results, MUAC < 125mm corresponds to GAM and MUAC < 110mm with or without Oedema corresponds to SAM.[3]
## Interpretation[edit]
If 10% or more of children are classified as suffering from GAM, there is generally considered to be a serious emergency, and with over 15% the emergency is considered critical.[1] According to the Integrated Food Security Phase Classification (IPC), a famine is declared if three conditions exist. First, at least 20% of households face extreme food shortages with limited ability to cope. Second, GAM prevalence exceeds 30%. Third, crude death rates exceed two persons per 10,000 per day. In 2011 the conditions in some parts of the Horn of Africa met all three criteria.[4]
## Objectives and results[edit]
The U.S. State Department has set a target that less than 10% of children under five should suffer from Global Acute Malnutrition in complex humanitarian emergencies. In 2005, this objective was not met in 7% of targeted sites. GAM rates exceeded 10% in eleven camps in Chad, seven camps in Ethiopia, and one camp in the Central African Republic.[5] A study by the UNHCR published in January 2006 found unacceptable GAM levels in UNHCR/WFP supported protracted refugee situations including Chad (up to 18%), Eritrea (18.9%), Ethiopia (up to 19.6%), Kenya (up to 20.6%), Sierra Leone (16%) and South Sudan (16%). The report questioned why GAM rates were so high despite all efforts to bring them down, and why camps in Africa had rates consistently over 15% while camps in Asia were usually below 12% GAM.[6]
## References[edit]
1. ^ a b c d "Glossary: Global Acute Malnutrition (GAM)". Complex Emergency Database. Retrieved 2011-08-08.
2. ^ a b "Acute Malnutrition Summary Sheet" (PDF). Save the Children. Retrieved 2011-08-08.
3. ^ a b Cameron Lockie (2000). Travel medicine and migrant health. Elsevier Health Sciences. ISBN 0-443-06242-0.
4. ^ "Ten FAQ for famine in southern Somalia". UNICEF. Archived from the original on 2011-09-26. Retrieved 2011-08-08.
5. ^ "FY 2005 Performance and Accountability Report". U.S. State Department. November 2005. Retrieved 2011-08-08.
6. ^ Mary Corbett, Allison Oman (January 2006). "Acute Malnutrition in Protracted Refugee Situations: A Global Strategy" (PDF). UNHCR/WFP. Retrieved 2011-08-08.
## External links[edit]
* "WEST AFRICA - Global Acute Malnutrition (GAM) Prevalence" (PDF). ReliefWeb. 28 May 2009. Retrieved 2011-08-08.
* "Global Acute Malnutrition Prevalence (Z-score NCHS reference) – DRC" (PDF). ReliefWeb. April 2011. Retrieved 2011-08-08.
* "Complex Emergency Database (CE-DAT) - the international repository of health indicators, including GAM, from crisis settings". CRED. September 2012. Retrieved 2012-09-14.
*[v]: View this template
*[t]: Discuss this template
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*[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 inhibitors
*[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
| Global Acute Malnutrition | None | 4,853 | wikipedia | https://en.wikipedia.org/wiki/Global_Acute_Malnutrition | 2021-01-18T18:46:55 | {"wikidata": ["Q17017329"]} |
A rare form of autoimmune bullous skin disease characterized by polyformative skin lesions, typically beginning on the oral mucus membranes, and generally associated with lymphoma or chronic lymphoid leukemia.
## Epidemiology
The prevalence of this form of pemphigus is unknown. About 500 cases of paraneoplastic pemphigus have been reported worldwide in the literature. This form accounts for 3-5% of all pemphigus cases.
## Clinical description
Paraneoplastic pemphigus occurs in a background of suspected or proven neoplasia. The associated cancers are mostly lymphomas, chronic lymphoid leukaemia and in some cases, Kaposi sarcoma, Castelman's disease, thymomas, carcinomas, and poorly differentiated sarcomas. The disease almost always begins with severe diffuse blisters in the mouth, on the lips and on the oesophagus. Eyes are frequently involved. Skin lesions vary and can be misleading, presenting as bullous lichenoid lesions, evocative of urticaria or polymorphous erythema. Lungs can also be involved (in 30% to 40% of cases), as well as the gastrointestinal tract.
## Etiology
The etiology and pathogenesis of paraneoplastic pemphigus are poorly understood.
## Diagnostic methods
Histopathological analysis shows intra-epidermal acantholysis with the presence of necrotic keratinocyte cells, vacuolisation of the basal layer and dermic lichenoid inflammatory infiltrate. Direct immunofluorescence test usually shows granular-linear IgG and/or C3 deposits in the epidermal intracellular spaces, and/or at the dermo-epidermal junction (basement membrane zone). IgA and IgM can also be detected. Anti-plakine antibodies can be present (desmoplakin, periplakin, envoplakin), as well as anti-plectin, anti-desmoglein 1 and 3 antibodies, anti-BP180, and anti-BP230 antibodies.
## Differential diagnosis
Differential diagnosis includes some forms of bullous pemphigoid, pemphigus vulgaris, drug-induced rash (toxic epidermal necrolysis, Stevens-Johnson syndrom), erythema multiforme, Graft Versus Host Disease (GVHD), lichen planus, or major aphthous stomatitis.
## Management and treatment
The progression of paraneoplastic pemphigus rarely parallels neoplastic progression. The most commonly used treatment is systemic corticosteroids, but immunosuppressant drugs are often required. Some patients have been treated with intravenous immunoglobulin, plasmapheresis, and monoclonal antibodies. However, the efficacy of treatment varies depending on the underlying malignancy.
## Prognosis
Paraneoplastic pemphigus is often fatal (in 90% of cases), however, the prognosis depends on the nature of the underlying malignancy and is improved when the associated tumor is benign. The high mortality rate is explained by the occurrence of severe infections (sometimes due to immunosuppressive drugs), the evolution of the underlying malignancy, or bronchiolitis obliterans which is related to the autoimmune response in paraneoplastic pemphigus.
* European Reference Network
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*[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 inhibitors
*[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
| Paraneoplastic pemphigus | c1112570 | 4,854 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=63455 | 2021-01-23T17:59:21 | {"umls": ["C1112570"], "icd-10": ["L10.8"]} |
A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 5 (MC1DN5) is caused by homozygous or compound heterozygous mutation in the NDUFS1 gene (157655) on chromosome 2q33.
For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.
Clinical Features
Benit et al. (2001) described patients with mitochondrial complex I deficiency and mutation in the NDUFS1 gene. One proband had unrelated healthy parents and was normal until age 4 months, when he developed psychomotor retardation with hypotonia. At age 7 months, he presented with nystagmus and bilateral optic atrophy. Leukodystrophy, lactic acidosis, and hyperlactatorachia were noted. He died at age 10 months. An older sister with similar findings died at age 7 months, and an older brother developed 2 episodes of ataxia and mild psychomotor retardation at age 2 years. In another family the proband, offspring of healthy unrelated parents, was normal until age 2 months, when he presented with growth retardation, axial hypotonia, hepatomegaly, and persistent hyperlactatemia. Magnetic resonance imaging showed hyperintensity of basal ganglia. The child later developed macrocytic anemia and dystonia. He died suddenly at age 5 months. His older sister presented with growth retardation, macrocytic anemia, and metabolic acidosis at age 3 months and died shortly thereafter in an acute episode of hyperlactatemia.
Martin et al. (2005) reported a Spanish child with complex I deficiency and features of Leigh syndrome (see 256000) with mutation in the NDUFS1 gene. At 8.5 months of age, she was hospitalized for recurrent vomiting, hypotonia, and growth retardation. Other findings included irritability, horizontal nystagmus, hyperreflexia, and bilateral lesions in the substantia nigra and midbrain. There was increased lactic acid in serum and CSF. Her status worsened and she died at age 14 months. A younger brother with a similar clinical picture died at age 8 months. Biochemical studies showed that skeletal muscle complex I activity was reduced to 25% normal values.
Hoefs et al. (2010) reported 4 patients from 3 families with severe mitochondrial complex I deficiency and very low complex I activity (less than 30% of normal) who had biallelic mutations in the NDUFS1 gene. All patients had a severe, progressive disease course resulting in death in childhood due to neurologic disability. Brain MRI performed in 2 patients showed severe and progressive white matter abnormalities. Hoefs et al. (2010) suggested that patients with very low complex I deficiency should specifically be screened for NDUFS1 mutations.
Ferreira et al. (2011) reported 2 sibs, born of consanguineous parents, with complex I deficiency due to mutation in the NDUFS1 gene. The patients had a neurodegenerative disorder of the white matter beginning around the first year of life. One showed loss of early developmental milestones and the other showed early delayed psychomotor development and irritability. Both had dystonic posturing, difficulty swallowing, and increased lactate in bodily fluids. Although there were episodes of deterioration, there was also some improvement in symptoms with age. Brain MRI showed progressive cavitating leukoencephalopathy with multiple cystic lesions in the white matter. Muscle biopsy of 1 sib showed significantly decreased complex I activity (45% of controls) and a decreased amount of complex I subunits. Reduced fully assembled complex I was seen in mitochondria isolated from fibroblasts from the other sib, but only under stress conditions. Modeling of the mutation in yeast showed that reduced complex I activity was due mainly to decreased accumulation of fully assembled active complex I in the membrane and not to diminished activity of the mutant enzyme.
Molecular Genetics
In 3 of 36 patients with isolated mitochondrial complex I deficiency, Benit et al. (2001) identified 5 different point mutations and 1 large-scale deletion in the NDUFS1 gene (see, e.g., 157655.0001-157655.0003).
Martin et al. (2005) reported a Spanish child with complex I deficiency and features of Leigh syndrome caused by a homozygous mutation in the NDUFS1 gene (L231V; 157655.0004).
In 4 patients from 3 families with severe mitochondrial complex I deficiency and very low complex I activity (less than 30% of normal), Hoefs et al. (2010) identified 5 different biallelic mutations in the NDUFS1 gene (see, e.g., 157655.0006-157655.0008). Patient cells also showed decreased amounts of assembled complex I and accumulation of subcomplexes, indicating disturbance in the assembly or stability of complex I. Hoefs et al. (2010) suggested that patients with very low complex I deficiency should be specifically screened for NDUFS1 mutations.
Ferreira et al. (2011) reported 2 sibs, born of consanguineous parents, with complex I deficiency due to a homozygous mutation in the NDUFS1 gene (T595A; 157655.0005).
INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Head \- Microcephaly, progressive (in some patients) Eyes \- Optic atrophy \- Nystagmus \- Ptosis \- Strabismus \- Ophthalmoplegia RESPIRATORY \- Respiratory insufficiency \- Apnea ABDOMEN \- Dysphagia \- Vomiting MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Global developmental delay \- Developmental regression \- Impaired intellectual development \- Poor speech \- Ataxia \- Seizures (in some patients) \- Lethargy \- Irritability \- Pyramidal syndrome \- Hyperreflexia \- Extensor plantar responses \- Dystonia \- Leukodystrophy \- Leukoencephalopathy \- White matter abnormalities consistent with Leigh syndrome seen on brain imaging \- Cerebellar atrophy \- Brain atrophy \- Brainstem abnormalities \- Cystic brain lesions METABOLIC FEATURES \- Lactic acidosis LABORATORY ABNORMALITIES \- Increased serum and CSF lactate \- Mitochondrial respiratory complex I deficiency in various tissues MISCELLANEOUS \- Onset in infancy \- Symptoms may be exacerbated by concurrent infection \- Episodic deterioration \- Progressive disorder \- Variable phenotype \- Early death may occur MOLECULAR BASIS \- Caused by mutation in the NADH-ubiquinone oxidoreductase core subunit S1 gene (NDUFS1, 157655.0001 ) ▲ Close
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*[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 inhibitors
*[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
| MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 5 | c2936907 | 4,855 | omim | https://www.omim.org/entry/618226 | 2019-09-22T15:43:03 | {"mesh": ["C537475"], "omim": ["618226"], "orphanet": ["2609", "255241"]} |
Pectus carinatum refers to a chest wall abnormality in which the breastbone is pushed outward. It generally presents during childhood and worsens through adolescence. If the condition occurs in isolation, it is often not associated with any additional signs or symptoms. Rarely, affected people report shortness of breath during exercise, frequent respiratory infections, and/or asthma. The underlying cause of isolated pectus carinatum is unknown. Pectus carinatum can also be associated with a variety of genetic disorders and syndromes, including Marfan syndrome, Noonan syndrome, Morquio syndrome, homocystinuria, osteogenesis imperfecta, Coffin-Lowery syndrome, cardiofaciocutaneous syndrome, and certain chromosome abnormalities. In these cases, the condition has an underlying genetic cause and is associated with additional features that are characteristic of the genetic disease. Pectus carinatum is primarily a cosmetic concern and treatment, therefore, depends on the severity of the condition and the interests of the affected person and their family. In those who choose to pursue treatment, bracing and/or surgery may be an option.
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*[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 inhibitors
*[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
| Pectus carinatum | c0158731 | 4,856 | gard | https://rarediseases.info.nih.gov/diseases/9656/pectus-carinatum | 2021-01-18T17:58:24 | {"mesh": ["D066166"], "umls": ["C0158731"], "synonyms": ["Carinatum deformity of the chest"]} |
## Clinical Features
Zubenko et al. (1987) and Zubenko and Teply (1988) concluded that increased platelet membrane fluidity is a stable, familial characteristic that affects approximately half of the first-degree relatives of persons with Alzheimer disease (104300). The index of membrane fluidity used in this work is the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) in labeled platelet membranes.
Zubenko et al. (1999) showed that electron spin resonance spectroscopy using 12-doxylstearate (12-DS) as probe to evaluate platelet membrane fluidity was sensitive in detecting greater fluidity in deeper regions of membranes in 6 first-degree relatives of persons with AD. These results provided independent validation of the biophysical alterations of platelet membranes that are manifest by a subgroup of patients with AD and their first-degree relatives.
Inheritance
Chakravarti et al. (1989) performed complex segregation analysis of this continuous variable on 95 members of 14 pedigrees identified through probands who had autopsy-confirmed or clinically diagnosed Alzheimer disease. The results suggested that platelet membrane fluidity is controlled by a single genetic locus, PMF, with 2 alleles that have additive effects. The PMF locus appeared to explain approximately 80% of the total variation in platelet membrane fluidity within families of patients with Alzheimer disease.
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*[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 inhibitors
*[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
| PLATELET MEMBRANE FLUIDITY | c1868201 | 4,857 | omim | https://www.omim.org/entry/173560 | 2019-09-22T16:36:14 | {"omim": ["173560"]} |
Infectious tropical disease
Buruli ulcer
Other namesBairnsdale ulcer, Daintree ulcer, Mossman ulcer, Kumasi ulcer, Searls ulcer
Buruli ulcer lesions. Top-left, an early ulcer. Top-right, a larger ulcer across the lower arm and wrist. Bottom, a large ulcer on the thigh.
SpecialtyInfectious disease
SymptomsArea of swelling that becomes an ulcer
CausesMycobacterium ulcerans
TreatmentRifampicin and clarithromycin
Frequency2,713 cases reported to WHO in 2018[1]
Buruli ulcer is an infectious disease characterized by the development of painless open wounds. The disease is limited to certain areas of the world, most cases occurring in Sub-Saharan Africa and Australia. The first sign of infection is a small painless nodule or area of swelling, typically on the arms or legs. The nodule grows larger over days to weeks, eventually forming an open ulcer. Deep ulcers can cause scarring of muscles and tendons, resulting in permanent disability.
Buruli ulcer is caused by skin infection with bacteria called Mycobacterium ulcerans. The mechanism by which M. ulcerans is transmitted from the environment to humans is not known, but may involve the bite of an aquatic insect or the infection of open wounds. Once in the skin M. ulcerans grows and releases the toxin mycolactone, which blocks the normal function of cells, resulting in tissue death and immune suppression at the site of the ulcer.
The World Health Organization (WHO) recommends treating Buruli ulcer with a combination of the antibiotics rifampicin and clarithromycin. With antibiotic administration and proper wound care, small ulcers typically heal within six months. Deep ulcers and those on sensitive body sites may require surgery to remove dead tissue or repair scarred muscles or joints. Even with proper treatment, Buruli ulcer can take months to heal. Regular cleaning and dressing of wounds aids healing and prevents secondary infections.
In 2018, WHO received 2,713 reports of Buruli ulcer globally.[1] Buruli ulcer occurs in rural areas near slow-moving or stagnant water. The first written description of Buruli ulcer is credited to Albert Ruskin Cook in 1897 at Mengo Hospital in Uganda. Fifty years later, the causative bacterium was isolated and identified by a group at Melbourne University. In 1998, WHO established the Global Buruli Ulcer Initiative to coordinate global efforts to eliminate Buruli ulcer. WHO considers Buruli ulcer a neglected tropical disease.
## Contents
* 1 Signs and symptoms
* 2 Cause
* 2.1 Transmission
* 2.2 Genetic susceptibility
* 3 Diagnosis
* 4 Treatment
* 5 Prevention
* 6 Epidemiology
* 7 Other animals
* 8 Society and culture
* 9 History
* 10 Research
* 11 References
* 11.1 Citations
* 11.2 Works cited
* 12 External links
## Signs and symptoms[edit]
Early signs of Buruli ulcer in Cameroon. Top, painless swollen bumps. Bottom-left, a "plaque". Bottom-right, widespread swelling of the lower arm.
The first sign of Buruli ulcer is a painless swollen bump on the arm or leg, often similar in appearance to an insect bite.[1][2] Sometimes the swollen area instead appears as a patch of firm, raised skin about three centimeters across called a "plaque"; or a more widespread swelling under the skin.[1][2] Over the course of a few weeks, the original swollen area expands to form an irregularly shaped patch of raised skin.[2][3] After about four weeks, the affected skin sloughs off leaving a painless ulcer.[1] Buruli ulcers typically have "undermined edges", the ulcer being a few centimeters wider underneath the skin than the wound itself.[3] In some people, the ulcer may heal on its own or remain small but linger unhealed for years.[3][4] In others, it continues to grow wider and sometimes deeper, with skin at the margin dying and sloughing off. Large ulcers may extend deep into underlying tissue, causing bone infection and exposing muscle, tendon, and bone to the air.[3] When ulcers extend into muscles and tendons, parts of these tissues can be replaced by scar tissue, immobilizing the body part and resulting in permanent disability.[3] Exposed ulcers can be infected by other bacteria, causing the wound to become reddened, painful, and foul smelling.[5][3] Symptoms are typically limited to those caused by the wound; the disease rarely affects other parts of the body.[6]
Buruli ulcers can appear anywhere on the body, but are typically on the limbs. Ulcers are most common on the lower limbs (roughly 62% of ulcers globally) and upper limbs (24%), but can also be found on the trunk (9%), head or neck (3%), or genitals (less than 1%).[7] The World Health Organization classifies Buruli ulcer into three categories depending on the severity of its symptoms. Category I describes a single small ulcer that is less than 5 centimetres (2.0 inches). Category II describes a larger ulcer, up to 15 centimetres (5.9 in), as well as plaques and broader swollen areas that have not yet opened into ulcers. Category III is for an ulcer larger than 15 centimeters, multiple ulcers, or ulcers that have spread to include particularly sensitive sites such as the eyes, bones, joints, or genitals.[3]
## Cause[edit]
Buruli ulcer is caused by infection of the skin with the bacterium Mycobacterium ulcerans.[1] M. ulcerans is a mycobacterium, closely related to Mycobacterium marinum which infects aquatic animals and, rarely, humans.[8] It is more distantly related to other slow-growing mycobacteria that infect humans, such as Mycobacterium tuberculosis, which causes tuberculosis, and Mycobacterium leprae, which causes leprosy.[9] Buruli ulcer typically occurs near slow-moving or stagnant bodies of water, where M. ulcerans is found in aquatic insects, mollusks, fish, and the water itself.[10] How M. ulcerans is transmitted to humans remains unclear, but somehow bacteria enter the skin and begin to grow. Ulceration is primarily caused by the bacterial toxin mycolactone.[11] As the bacteria grow, they release mycolactone into the surrounding tissue. Mycolactone diffuses into host cells and blocks the action of Sec61, the molecular channel that serves as a gateway to the endoplasmic reticulum.[12] When Sec61 is blocked, proteins that would normally enter the endoplasmic reticulum are mistargeted to the cytosol, causing a pathological stress response that leads to cell death by apoptosis.[12] This results in tissue death at the site of infection, causing the open ulcer characteristic of the disease.[12] At the same time, Sec61 inhibition prevents cells from signaling to activate the immune system, leaving ulcers largely free of immune cells.[12] Immune cells that do reach the ulcer are killed by mycolactone, and tissue examinations of the ulcer show a core of growing bacteria surrounded by debris from dead and dying neutrophils (the most common immune cell).[13]
### Transmission[edit]
A riverine site in Ghana endemic for Buruli ulcer
It is not known how M. ulcerans is introduced to humans.[1] Buruli ulcer does not spread from one person to another.[10] In areas endemic for Buruli ulcer, disease occurs near stagnant bodies of water, leading to the long-standing hypothesis that M. ulcerans is somehow transmitted to humans from aquatic environments.[14] M. ulcerans is widespread in these environments, where it can survive as free-living or in association with other aquatic organisms.[7] Live M. ulcerans has been isolated from aquatic insects, mosses, and animal feces; and its DNA has been found in water, soil, mats of bacteria and algae, fish, crayfish, aquatic insects, and other animals that live in or near water.[14] A role for biting insects in transmission has been investigated, with particular focus on mosquitoes, giant water bugs, and Naucoridae. M. ulcerans is occasionally found in these insects, and they can sometimes transmit the bacteria in laboratory settings.[7] Whether these insects are regularly involved in transmission remains unclear.[10][14] Pre-existing wounds have been implicated in disease transmission, and people who immediately wash and bandage open wounds are less likely to acquire Buruli ulcer.[15] Wearing pants and long-sleeved shirts is associated with a lower risk of Buruli ulcer, possibly by preventing insect bites or protecting wounds.[10][15]
### Genetic susceptibility[edit]
While Buruli ulcer is not contagious, susceptibility sometimes runs in families, suggesting genetics could play a role in who develops disease. Severe Buruli ulcer in a Beninese family was attributed to a loss of 37 kilobases of chromosome 8 in a region that included a long non-coding RNA and was near the genes for beta-defensins, which are antimicrobial peptides involved in immunity and wound healing.[16][17] Broader studies have focused on genes involved in susceptibility to other mycobacterial infections, finding susceptibility to Buruli ulcer may be linked to variants in six immunity-related genes: SLC11A1, PRKN, NOD2, ATG16L1, iNOS, and IFNG, as well as in two long non-coding RNAs.[16] A genome-wide association study linked resistance to Buruli ulcer to a variant of ATG16L1 associated with susceptibility to Crohn's disease.[16]
## Diagnosis[edit]
Photomicrographs of a punch biopsy from a Buruli ulcer plaque lesion. In the left image, the tissue sample has been stained with hematoxylin and eosin, a common stain for histopathology examination. In the right image, it has been stained with Ziehl-Neelsen stain, which helps to visualize mycobacteria. The inset shows red-staining (acid-fast) bacilli, suggestive of mycobacteria.
As Buruli ulcer most commonly occurs in low-resource settings, treatment is often initiated by a clinician based on signs and symptoms alone.[18] Where available, diagnosis may then be confirmed by polymerase chain reaction (PCR) to detect M. ulcerans DNA or microscopy to detect mycobacteria.[19] The gold standard test is real-time PCR to detect a DNA sequence termed IS2404 that is unique to M. ulcerans.[20] This method detects M. ulcerans in 54–84% of infected people, and is highly specific to M. ulcerans.[21] In wealthier healthcare settings, diagnosis is routinely based on PCR results.[19] In low-resource settings, PCR is often unavailable, or can only be performed later at a centralized diagnostic laboratory.[19] For microscopy, fluid is typically taken from the ulcer's edge by fine-needle aspiration or by swabbing the edge of the ulcer. The fluid is then stained with the Ziehl-Neelsen stain which makes mycobacteria visible.[19] In practice microscopy detects M. ulcerans in just 30–40% of infected people, making it a relatively insensitive diagnostic test.[21] For many bacterial infections, the gold standard for diagnosis is isolating and growing the infective organism in laboratory media. M. ulcerans can be grown in laboratory media, but its extremely slow growth rate prevents this from being used diagnostically; even under optimal growth conditions, the bacteria must grow for 9 to 12 weeks before they can be easily detected and identified.[21] Another method of diagnosis is to take a tissue sample from the ulcer and examine it under histological stains. This requires more invasive sampling and review by a trained pathologist, and is rarely used in places where Buruli ulcer is endemic.[22]
Other ulcerative diseases can appear similar to Buruli ulcer at its various stages. The nodule that appears early in the disease can resemble a bug bite, sebaceous cyst, lipoma, onchocerciasis, other mycobacterial skin infections, or an enlarged lymph node.[3] Skin ulcers can resemble those caused by leishmaniasis, yaws, squamous cell carcinoma, Haemophilus ducreyi infection, and tissue death due to poor circulation.[3] More diffuse lesions can resemble cellulitis and fungal infections of the skin.[3]
## Treatment[edit]
Healed Buruli ulcer lesions in a Ghanaian woman
Buruli ulcer is treated through a combination of antibiotics to kill the bacteria, and wound care or surgery to support the healing of the ulcer. The most widely used antibiotic regimen is once daily oral rifampicin plus twice daily oral clarithromycin, recommended by the World Health Organization.[23][24] Several other antibiotics are sometimes used in combination with rifampicin, namely ciprofloxacin, moxifloxacin, ethambutol, amikacin, azithromycin, and levofloxacin.[24] A 2018 Cochrane review suggested that the many antibiotic combinations being used are effective treatments, but there is insufficient evidence to determine if any combination is the most effective.[25] Approximately 1 in 5 people with Buruli ulcer experience a temporary worsening of symptoms 3 to 12 weeks after they begin taking antibiotics.[26] This syndrome, called a paradoxical reaction, is more common in those with larger ulcers and ulcers on the trunk, and occurs more frequently in adults than in children.[26] The paradoxical reaction in Buruli ulcer is thought to be due to the immune system responding to the wound as bacteria die and the immune-suppressing mycolactone dissipates.[26]
Small or medium-sized ulcers (WHO categories I and II) typically heal within six months of antibiotic treatment,[5] whereas larger ulcers can take over two years to fully heal.[27] Given the long healing times, wound care is a major part of treating Buruli ulcer. The World Health Organization recommends standard wound care practices: cover the ulcer to keep it moist and protected from further damage; regularly change wound dressings to keep the ulcer clean, remove excess fluid, and help prevent infection.[28] Treatment sometimes includes surgery to speed healing by removing necrotic ulcer tissue, grafting healthy skin over the wound, or removing scar tissue that can deform muscles and joints.[26][28] Specialized wound dressings developed for non-infectious causes of ulcer are occasionally used for treating Buruli ulcer, but can be prohibitively expensive for low-resource settings.[24]
## Prevention[edit]
Buruli ulcer can be prevented by avoiding contact with aquatic environments in endemic areas although this may not be possible for people living in these areas.[24] The risk of acquiring Buruli ulcer can be reduced by wearing long sleeves and pants, using insect repellent, and cleaning and covering any wounds as soon as they are noticed.[10] There is no specific vaccine for preventing Buruli ulcer.[1] The BCG vaccine typically given to children to protect against tuberculosis offers temporary partial protection from Buruli ulcer.[26][29]
## Epidemiology[edit]
Cases of Buruli ulcer reported to the World Health Organization in 2018. Color indicates case number: yellow, (1–150) Dem. Rep. Congo, Gabon, Guinea, Togo; orange (151–300), Benin, Cameroon, Côte d'Ivoire; light red (301–450), Liberia, Nigeria; dark red (451+), Ghana. Not shown are Australia (358), Papua New Guinea (12) and Japan (3).
Buruli ulcer is relatively rare, with 2,713 cases reported to the World Health Organization in 2018.[1] Most countries do not report data on Buruli ulcer to the World Health Organization, and the extent of Buruli ulcer's spread is unknown.[30][31] In many endemic countries, health systems likely do not record each case due to insufficient reach and resources, and so the reported numbers likely underestimate the true disease prevalence.[32]
Buruli ulcer is concentrated in West Africa and coastal Australia, with occasional cases in Japan, Papua New Guinea and the Americas. In West Africa, disease is predominantly reported from remote, rural communities in Benin, Côte d'Ivoire, Cameroon, and Ghana.[33] Other countries in the region also have Buruli ulcer to some degree; a 2019 systematic review of prevalence studies found a clear consensus that Buruli ulcer is present in Democratic Republic of Congo, Gabon, Liberia, Nigeria, Togo, and South Sudan, as well as "strong" or "very strong" evidence of the disease in Republic of Congo, Sierra Leone, Central African Republic, Guinea, and Uganda.[31] Buruli ulcer is regularly reported from Australia, where it occurs in coastal clusters—two in Queensland (near Rockhampton and north of Cairns) and two in Victoria (near Bairnsdale and Melbourne).[34] It is more rarely reported from Japan, Papua New Guinea, and the Americas. Japan reports a few locally acquired cases per year scattered across the main island.[35] Papua New Guinea sporadically reports Buruli ulcer cases to the World Health Organization, typically less than a dozen per year.[36] In the Americas, most Buruli ulcer is reported from French Guiana, with few cases described in surrounding countries.[37] A 2019 review found "strong" evidence for the presence of Buruli ulcer in French Guiana and Peru, and "moderate" evidence in Brazil, Mexico and Suriname.[38]
Within affected countries, Buruli ulcer tends to occur in rural areas near slow-moving or stagnant water.[10] In particular, the disease tends to appear near water that has experienced human intervention, such as the building of dams or irrigation systems, flooding, or deforestation.[10] Within endemic communities, few characteristics predict who will acquire Buruli ulcer. Males and females are equally likely to be infected.[10] Ulcers can appear in people of all ages, although infections are most common among children between 5 and 15 years in West Africa, and adults over 40 in Australia and Japan.[32]
## Other animals[edit]
A common ringtail possum with an ulcer caused by M. ulcerans.
M. ulcerans infection can cause Buruli ulcer-like lesions in some non-human animals. Natural non-human infections have only been described in coastal Victoria, near Melbourne. There, M. ulcerans-positive lesions have been described in koalas, common ringtail possums, and common brushtail possums, with lesions typically on the face, limbs, and tail.[39] Ulcers have also been reported on domesticated animals, namely dogs, horses, alpacas, and a cat.[39] In laboratories several species of animals have been infected with M. ulcerans in an attempt to model the course of Buruli ulcer. Injection of M. ulcerans can cause ulcers in several rodents (mice, guinea pigs, greater cane rats and common African rats), larger mammals (nine-banded armadillos, common brushtail possums, pigs, and Cynomolgus monkeys), and anole lizards.[40]
## Society and culture[edit]
In endemic areas, particularly rural communities in Africa, people may be aware of Buruli ulcer's association with the environment, yet simultaneously associate it with witchcraft or other supernatural causes.[41] This dual understanding of disease—combined with poor access to conventional medicine—drives many to seek traditional healers for primary care.[41] Traditional healers often treat Buruli ulcer with two simultaneous approaches: herbs and sometimes burning or bleeding to treat the physical wound; and confession, ritual purification, and prohibitions on food, interpersonal contact, or sex to treat the spiritual component of the disease.[42] Those with Buruli ulcer report feeling shame and experiencing social stigma that could affect their relationships, school attendance, and marriage prospects.[43]
Buruli ulcer is known by several other names in different parts of the world. In southeastern Australia, it was originally called "Searls' ulcer" after the physician J. R. Searls who saw the first Australian patients at the Bairnsdale Clinic and sent material to Peter MacCallum's group for further examination.[44] The disease later became more generally known as "Bairnsdale ulcer" after the district where it was described.[45] In northeastern Australia, north of Cairns, the disease is called "Daintree ulcer" or "Mossman ulcer" after the nearby Daintree River and the town of Mossman.[46][47] In Papua New Guinea, the disease is called "Kumusi ulcer" after the Kumusi River along which villages with Buruli ulcer were originally described.[48]
## History[edit]
Albert R. Cook (center) at Mengo Hospital in 1897. Cook was the first to describe Buruli ulcer.
The first written description of Buruli ulcer is credited to a British missionary doctor, Albert R. Cook.[49][50] In 1897, at Mengo Hospital in Uganda, Cook noted several patients with slow-healing ulcers.[45][51] The cause of these slow-healing ulcers was identified 50 years later in 1948, when Peter MacCallum, Jean Tolhurst, Glen Buckle, and H. A. Sissons at Melbourne University described a series of cases from Bairnsdale, Victoria, isolated the causative mycobacterium, and showed it could cause ulcers in laboratory rats.[10][52] Over the following decades, more cases were described in Africa. A particularly high prevalence in Uganda's Buruli County led to the disease becoming more widely known as "Buruli ulcer".[45] In 1998, the World Health Organization started the Global Buruli Ulcer Initiative with the aim of coordinating global efforts to control the disease.[45] This was followed in 2004 by World Health Organization Resolution WHA57.1 calling upon member countries to support the Global Buruli Ulcer Initiative and increase research on Buruli ulcer diagnostics and treatment.[53][54] Interest in Buruli ulcer has been encouraged by its branding as a "neglected tropical disease", first in a 2005 PLOS Medicine article, and later by both the World Health Organization and PLOS Neglected Tropical Diseases.[55]
From the time the disease was described, Buruli ulcer was treated with surgery to remove all affected tissue, followed by prolonged wound care.[24] This treatment regimen was expensive, sometimes disfiguring, and often ineffective, ulcers recurring in up to a third of cases.[56] Treatment dramatically improved in 2004, when the World Health Organization recommended an eight-week course of daily oral rifampicin and injected streptomycin.[24] The introduction of antibiotics reduced the rate of ulcer recurrence to fewer than 2% of cases.[56] However, streptomycin can be toxic to the ears and kidneys, and administering daily injections is challenging in low-resource settings.[56] In 2017, the World Health Organization updated its recommendation to replace streptomycin with the oral antibiotic clarithromycin.[57]
## Research[edit]
Buruli ulcer has been the subject of scientific research since the description of M. ulcerans in 1948, and the demonstration that the bacteria could cause ulcers in laboratory animals.[10][52] While several animals are susceptible to M. ulcerans ulcers, mice (particularly BALB/c and C57BL/6 mice) are most commonly used to model Buruli ulcer in modern laboratories.[58] Since M. ulcerans can only grow in relatively cool temperatures, mice are typically infected in furless parts of the body: the ear, tail, or footpad.[58] After injection into the mouse, bacteria double every three to four days, and the first signs of skin disease appear after three to four weeks.[59] This mouse model of Buruli ulcer has primarily been used to test antibiotics. The antibiotic combinations, dose frequencies, and treatment durations currently in use were first tested in laboratory-infected mice.[60] Some vaccine platforms have been tested in M. ulcerans-infected mice, mostly based on the Mycobacterium bovis strain used in the BCG vaccine.[61] The BCG vaccine and versions of the vaccine that also express M. ulcerans antigens prolong the survival of mice after M. ulcerans infection. As of 2019, no vaccine tested completely protects mice from infection.[61]
M. ulcerans can be grown in laboratory media, although its slow growth makes it challenging to study.[62] Bacteria plated on laboratory media can take up to three months to form visible colonies.[62] Strains of M. ulcerans used in laboratories are less standardized than the mice they infect; different laboratories use different strains based on convenience and accessibility.[63] Three M. ulcerans strains are particularly common, each isolated from an infected person: "Cu001" from Adzopé, Côte d'Ivoire in 1996; "Mu1615" from Malaysia in the 1960s; and "S1013" from Cameroon in 2010.[63]
## References[edit]
### Citations[edit]
1. ^ a b c d e f g h i "Buruli ulcer (Mycobacterium ulcerans infection)". World Health Organization. 21 May 2019. Archived from the original on 17 October 2019. Retrieved 31 October 2019.
2. ^ a b c Yotsu et al. 2015, p. 1034.
3. ^ a b c d e f g h i j Guarner 2018, pp. 3–4.
4. ^ Röltgen & Pluschke 2020, p. 9.
5. ^ a b Kpeli & Yeboah-Manu 2019, pp. 227–228.
6. ^ Bravo 2019, p. 118.
7. ^ a b c Zingue et al. 2018, pp. 10–13.
8. ^ Demangel, Stinear & Cole 2009, p. 52.
9. ^ Tortoli 2014, p. 739, Figure 7.
10. ^ a b c d e f g h i j Guarner 2018, pp. 1–2.
11. ^ Yotsu et al. 2018, pp. 247–248.
12. ^ a b c d Yotsu et al. 2018, p. 251.
13. ^ Röltgen & Pluschke 2020, pp. 7–8.
14. ^ a b c Yotsu et al. 2018, p. 250.
15. ^ a b Jacobsen & Padgett 2010, pp. e678–e679.
16. ^ a b c Manry 2020, p. 3.
17. ^ Vincent et al. 2018, pp. 1–17.
18. ^ Röltgen et al. 2019, pp. 190–191.
19. ^ a b c d Röltgen et al. 2019, pp. 185–186.
20. ^ Röltgen et al. 2019, pp. 186–187.
21. ^ a b c Guarner 2018, pp. 4–6.
22. ^ Röltgen et al. 2019, pp. 189–190.
23. ^ "Buruli ulcer (Mycobacterium ulcerans infection) – Treatment". World Health Organization. Archived from the original on 10 September 2020. Retrieved 19 June 2020.
24. ^ a b c d e f Yotsu et al. 2018, pp. 251–252.
25. ^ Yotsu, Richardson & Ishii 2018, p. 3.
26. ^ a b c d e Guarner 2018, pp. 6–7.
27. ^ Kpeli & Yeboah-Manu 2019, pp. 235–236.
28. ^ a b World Health Organization 2012, pp. 6–9.
29. ^ Zimmerman, Finn & Curtis 2018, pp. 682–684.
30. ^ Simpson et al. 2019, pp. e912–e913.
31. ^ a b Simpson et al. 2019, pp. e917–e918.
32. ^ a b Yotsu et al. 2015, pp. 1033–1034.
33. ^ Tabah et al. 2019, pp. 51–54.
34. ^ Johnson 2019, pp. 62–63.
35. ^ Suzuki et al. 2019, pp. 87–88.
36. ^ Yotsu et al. 2018, p. 249.
37. ^ Couppié et al. 2019, pp. 77–78.
38. ^ Simpson et al. 2019, pp. e918.
39. ^ a b Bolz & Ruf 2019, p. 159.
40. ^ Bolz & Ruf 2019, pp. 160, 168–173.
41. ^ a b Tabah et al. 2019, p. 44.
42. ^ Nichter 2019, p. 258.
43. ^ Nichter 2019, pp. 256–258.
44. ^ Meyers 2007, p. 1.
45. ^ a b c d Röltgen & Pluschke 2019, pp. 1–2.
46. ^ O'Brien et al. 2014, p. 267.
47. ^ Johnson 2019, p. 64.
48. ^ Igo & Murthy 1988, p. 391.
49. ^ Zingue et al. 2018, pp. 4–8.
50. ^ van der Werf et al. 2005, p. 2.
51. ^ "Mengo Hospital medical notes – 1897". British Library. 2017. Retrieved 5 June 2020.
52. ^ a b MacCallum et al. 1948, pp. 95–98, 103, 117–118.
53. ^ Working to overcome the global impact of neglected tropical diseases: First WHO report on neglected tropical diseases. World Health Organization. 2010. p. 62. ISBN 9789241564090.
54. ^ "WHA57.1 – Surveillance and control of Mycobacterium ulcerans disease (Buruli ulcer)" (PDF). World Health Organization. May 2004. Retrieved 14 June 2020.
55. ^ Hotez et al. 2020, pp. 1–3.
56. ^ a b c Yotsu, Richardson & Ishii 2018, pp. 6–7.
57. ^ Tabah et al. 2019, p. 50.
58. ^ a b Bolz & Ruf 2019, pp. 160–161.
59. ^ Bolz & Ruf 2019, pp. 163–165.
60. ^ Bolz & Ruf 2019, p. 165.
61. ^ a b Bolz & Ruf 2019, pp. 166–167.
62. ^ a b Bolz & Ruf 2019, p. 163.
63. ^ a b Bolz & Ruf 2019, pp. 162–163.
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* Bolz M, Ruf MT (April 2019). "Buruli ulcer in animals and experimental infection models". In Pluschke G, Röltgen K (eds.). Buruli ulcer: Mycobacterium ulcerans disease. Cham, Switzerland: Springer. pp. 159–181. doi:10.1007/978-3-030-11114-4_9. ISBN 978-3-030-11114-4. PMID 32091701.
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* Couppié P, Blaizot R, Velvin CJ, Douine M, Combe M, Nacher M, Gozlan RE (April 2019). "Mycobacterium ulcerans infection in French Guiana; current state of knowledge". In Pluschke G, Röltgen K (eds.). Buruli ulcer: Mycobacterium ulcerans disease. Cham, Switzerland: Springer. pp. 77–85. doi:10.1007/978-3-030-11114-4_4. ISBN 978-3-030-11114-4. PMID 32091708.
* Demangel C, Stinear TP, Cole ST (January 2009). "Buruli ulcer: reductive evolution enhances pathogenicity of Mycobacterium ulcerans". Nature Reviews Microbiology. 7: 50–60. doi:10.1038/nrmicro2077.
* Guarner J (April 2018). "Buruli Ulcer: Review of a Neglected Skin Mycobacterial Disease". Journal of Clinical Microbiology. 56 (4): e01507-17. doi:10.1128/JCM.01507-17. PMC 5869816. PMID 29343539.
* Hotez PJ, Aksoy S, Brindley PJ, Kamhawi S (January 2020). "What constitutes a neglected tropical disease". PLOS Neglected Tropical Diseases. 14 (1): e0008001. doi:10.1371/journal.pntd.0008001. PMC 6991948. PMID 31999732.
* Igo JD, Murthy DP (1988). "Mycobacterium ulcerans infections in Papua New Guinea: Correlation of clinical, histological, and microbiologic features". American Journal of Tropical Medicine and Hygiene. 38 (2): 391–392. doi:10.4269/ajtmh.1988.38.391. PMID 2451445.
* Jacobsen KH, Padgett JJ (August 2010). "Risk factors for Mycobacterium ulcerans infection". International Journal of Infectious Diseases. 14 (8): e677–e681. doi:10.1016/j.ijid.2009.11.013. PMID 20185351.
* Johnson PD (April 2019). "Buruli ulcer in Australia". In Pluschke G, Röltgen K (eds.). Buruli ulcer: Mycobacterium ulcerans disease. Cham, Switzerland: Springer. pp. 61–76. doi:10.1007/978-3-030-11114-4_3. ISBN 978-3-030-11114-4. PMID 32091705.
* Kpeli GS, Yeboah-Manu D (April 2019). "Secondary infection of Buruli ulcer lesions". In Pluschke G, Röltgen K (eds.). Buruli ulcer: Mycobacterium ulcerans disease. Cham, Switzerland: Springer. pp. 227–239. doi:10.1007/978-3-030-11114-4_13. ISBN 978-3-030-11114-4. PMID 32091699.
* MacCallum P, Tolhurst JC, Buckle G, Sissons HA (January 1948). "A new mycobacterial infection in man". Journal of Pathology and Bacteriology. 60 (1): 93–122. doi:10.1002/path.1700600111. PMID 18876541.
* Manry J (April 2020). "Human genetics of Buruli ulcer". Human Genetics. 139 (6–7): 847–853. doi:10.1007/s00439-020-02163-1. PMID 32266523. S2CID 215405517.
* Meyers DH (July 2007). "Mycobacterium ulcerans infection: an eponymous ulcer". Medical Journal of Australia. 187 (1): 63. doi:10.5694/j.1326-5377.2007.tb01136.x. PMID 17605723. S2CID 20007397.
* Nichter M (April 2019). "Social Science Contributions to BU-Focused Health Service Research in West Africa". In Pluschke G, Röltgen K (eds.). Buruli ulcer: Mycobacterium ulcerans disease. Cham, Switzerland: Springer. pp. 249–272. doi:10.1007/978-3-030-11114-4_15. ISBN 978-3-030-11114-4. PMID 32091698.
* O'Brien D, Jenkin G, Buntine J, Steffen CM, McDonald A, Horne S, Friedman ND, Athan E, Huges A, Callan PP, Johnson PD (March 2014). "Treatment and prevention of Mycobacterium ulcerans infection (Buruli ulcer) in Australia: guideline update". The Medical Journal of Australia. 200 (5): 267–270. doi:10.5694/mja13.11331. PMID 24641151.
* Röltgen K, Cruz I, Ndung'u JM, Pluschke G (April 2019). "Laboratory Diagnosis of Buruli Ulcer: Challenges and Future Perspectives" (PDF). In Pluschke G, Röltgen K (eds.). Buruli ulcer: Mycobacterium ulcerans disease. Cham, Switzerland: Springer. pp. 183–202. doi:10.1007/978-3-030-11114-4_10. ISBN 978-3-030-11114-4. PMID 32091709. Retrieved 3 November 2020.
* Röltgen K, Pluschke G (April 2019). "Buruli ulcer: history and disease burden". In Pluschke G, Röltgen K (eds.). Buruli ulcer: Mycobacterium ulcerans disease. Cham, Switzerland: Springer. pp. 1–41. doi:10.1007/978-3-030-11114-4_1. ISBN 978-3-030-11114-4. PMID 32091710.
* Röltgen K, Pluschke G (May 2020). "Buruli ulcer: the efficacy of innate immune defense may be a key determinant for the outcome of infection with Mycobacterium ulcerans". Frontiers in Microbiology. 11: 1018. doi:10.3389/fmicb.2020.01018. PMC 7261859. PMID 32523571.
* Simpson H, Deribe K, Tabah EN, Peters A, Maman I, Frimpong M, Ampadu E, Phillips R, Sanderson P, Pullan RL, Cano J (July 2019). "Mapping the global distribution of Buruli ulcer: a systematic review with evidence consensus". Lancet Global Health. 7 (7): e912–e922. doi:10.1016/S2214-109X(19)30171-8. PMC 6614043. PMID 31200890.
* Suzuki K, Luo Y, Miyamoto Y, Murase C, Mikami-Sugawara M, Yotsu RR, Ishii N (April 2019). "Buruli ulcer in Japan". In Pluschke G, Röltgen K (eds.). Buruli ulcer: Mycobacterium ulcerans disease. Cham, Switzerland: Springer. pp. 87–105. doi:10.1007/978-3-030-11114-4_5. ISBN 978-3-030-11114-4. PMID 32091702.
* Tabah EN, Johnson CR, Degnonvi H, Pluschke G, Röltgen K (April 2019). "Buruli ulcer in Africa". In Pluschke G, Röltgen K (eds.). Buruli ulcer: Mycobacterium ulcerans disease. Cham, Switzerland: Springer. pp. 43–60. doi:10.1007/978-3-030-11114-4_2. ISBN 978-3-030-11114-4. PMID 32091704.
* Tortoli E (October 2014). "Microbiological features and clinical relevance of new species of the genus Mycobacterium". Clinical Microbiology Reviews. 27 (4): 727–752. doi:10.1128/CMR.00035-14.
* Vincent QB, Belkadi A, Fayard C, Marion E, Adeye A, Ardant MF, et al. (April 2018). "Microdeletion on chromosome 8p23.1 in a familial form of severe Buruli ulcer". PLOS Neglected Tropical Diseases. 12 (4): e0006429. doi:10.1371/journal.pntd.0006429. PMC 5945055. PMID 29708969.
* van der Werf TS, Stienstra Y, Johnson RC, Phillips R, Adjei O, Fleischer B, Wansbrough-Jones MW, Johnson PD, Portaels F, van der Graaf WT, Asiedu K (October 2005). "Mycobacterium ulcerans disease". Bulletin of the World Health Organization. 83 (10): 785–791. PMC 2626418. PMID 16283056.
* World Health Organization (2012). Treatment of Mycobacterium ulcernas Disease (Buruli Ulcer): Guidance for Health Workers (PDF). World Health Organization. ISBN 9789241503402. Retrieved 20 December 2020.
* Yotsu RR, Murase C, Sugawara M, Suzuki K, Nakanaga K, Ishii N, Asiedu K (September 2015). "Revisiting Buruli Ulcer". The Journal of Dermatology. 42 (11): 1033–41. doi:10.1111/1346-8138.13049. PMID 26332541.
* Yotsu RR, Suzuki K, Simmonds RE, Bedimo R, Ablordey A, Yeboah-Manu D, Phillips R, Asiedu K (September 2018). "Buruli Ulcer: a Review of the Current Knowledge". Current Tropical Medicine Reports. 5 (4): 247–256. doi:10.1007/s40475-018-0166-2. PMC 6223704. PMID 30460172.
* Yotsu RR, Richardson M, Ishii M (August 2018). "Drugs for treating Buruli ulcer (Mycobacterium ulcerans disease)". Cochrane Database of Systematic Reviews. 8 (8): CD012118. doi:10.1002/14651858.CD012118.pub2. PMC 6513118. PMID 30136733.
* Zimmerman P, Finn A, Curtis N (July 2018). "Does BCG vaccination protect against nontuberculous mycobacterial infection? A systematic review and meta-analysis". Journal of Infectious Disease. 218 (5): 679–687. doi:10.1093/infdis/jiy207. PMID 29635431.
* Zingue D, Bouam A, Tian RB, Drancourt M (January 2018). "Buruli Ulcer, a Prototype for Ecosystem-Related Infection, Caused by Mycobacterium ulcerans". Clinical Microbiology Reviews. 31 (1): e0004-17. doi:10.1128/CMR.00045-17. PMC 5740976. PMID 29237707.
## External links[edit]
* Media related to Buruli ulcer at Wikimedia Commons
Classification
D
* ICD-10: A31.1 (ILDS A31.120)
* ICD-9-CM: 031.1
* MeSH: D054312
* DiseasesDB: 8568
External resources
* Patient UK: Buruli ulcer
* v
* t
* e
Gram-positive bacterial infection: Actinobacteria
Actinomycineae
Actinomycetaceae
* Actinomyces israelii
* Actinomycosis
* Cutaneous actinomycosis
* Tropheryma whipplei
* Whipple's disease
* Arcanobacterium haemolyticum
* Arcanobacterium haemolyticum infection
* Actinomyces gerencseriae
Propionibacteriaceae
* Propionibacterium acnes
Corynebacterineae
Mycobacteriaceae
M. tuberculosis/
M. bovis
* Tuberculosis: Ghon focus/Ghon's complex
* Pott disease
* brain
* Meningitis
* Rich focus
* Tuberculous lymphadenitis
* Tuberculous cervical lymphadenitis
* cutaneous
* Scrofuloderma
* Erythema induratum
* Lupus vulgaris
* Prosector's wart
* Tuberculosis cutis orificialis
* Tuberculous cellulitis
* Tuberculous gumma
* Lichen scrofulosorum
* Tuberculid
* Papulonecrotic tuberculid
* Primary inoculation tuberculosis
* Miliary
* Tuberculous pericarditis
* Urogenital tuberculosis
* Multi-drug-resistant tuberculosis
* Extensively drug-resistant tuberculosis
M. leprae
* Leprosy: Tuberculoid leprosy
* Borderline tuberculoid leprosy
* Borderline leprosy
* Borderline lepromatous leprosy
* Lepromatous leprosy
* Histoid leprosy
Nontuberculous
R1:
* M. kansasii
* M. marinum
* Aquarium granuloma
R2:
* M. gordonae
R3:
* M. avium complex/Mycobacterium avium/Mycobacterium intracellulare/MAP
* MAI infection
* M. ulcerans
* Buruli ulcer
* M. haemophilum
R4/RG:
* M. fortuitum
* M. chelonae
* M. abscessus
Nocardiaceae
* Nocardia asteroides/Nocardia brasiliensis/Nocardia farcinica
* Nocardiosis
* Rhodococcus equi
Corynebacteriaceae
* Corynebacterium diphtheriae
* Diphtheria
* Corynebacterium minutissimum
* Erythrasma
* Corynebacterium jeikeium
* Group JK corynebacterium sepsis
Bifidobacteriaceae
* Gardnerella vaginalis
*[v]: View this template
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*[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 inhibitors
*[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
| Buruli ulcer | c0085568 | 4,858 | wikipedia | https://en.wikipedia.org/wiki/Buruli_ulcer | 2021-01-18T18:47:37 | {"gard": ["9520"], "mesh": ["D054312"], "umls": ["C0085568"], "icd-9": ["031.1"], "wikidata": ["Q1017169"]} |
Marfan syndrome is a disorder of the connective tissue. Connective tissue provides strength and flexibility to structures throughout the body such as bones, ligaments, muscles, walls of blood vessels, and heart valves. Marfan syndrome affects most organs and tissues, especially the skeleton, lungs, eyes, heart, and the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). It is caused by mutations in the FBN1 gene, which provides instructions for making a protein called fibrillin-1. Marfan syndrome is inherited in an autosomal dominant pattern. At least 25% of cases are due to a new (de novo) mutation. Treatment is based on the signs and symptoms in each person.
*[v]: View this template
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*[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 inhibitors
*[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
| Marfan syndrome | c0024796 | 4,859 | gard | https://rarediseases.info.nih.gov/diseases/6975/marfan-syndrome | 2021-01-18T17:59:15 | {"mesh": ["D008382"], "omim": ["154700"], "orphanet": ["558"], "synonyms": ["Contractural arachnodactyly"]} |
Lysinuric protein intolerance (LPI) is a very rare inherited multisystem condition caused by distrubance in amino acid metabolism.
## Epidemiology
It is mainly found in Italy and Finland where prevalence is 1/60,000.
## Clinical description
The metabolic disturbance in LPI causes increased renal excretion and reduced absorption from intestine of cationic amino acids, and orotic aciduria. Patients affected by LPI may present with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, bone marrow abnormalities, osteopenia, episodes of hyperammoniaemic coma, mental retardation, altered immune response, chronic renal disease, and lung involvement (mostly pulmonary alveolar proteinosis - PAP - and, to a lesser extent, interstitial lung disease).
## Etiology
It is caused by defective cationic amino acid transport at the basolateral membrane of epithelial cells in the kidney and intestine. LPI is caused by mutations of solute carrier family 7A member 7 (SLC7A7) located at chromosome 14q11.2.
## Diagnostic methods
Diagnosis requires amino acid assays in plasma and urine where increased urinary excretion and low plasma concentration of lysine, arginine, and ornithine indicate positive diagnosis.
## Genetic counseling
LPI is inherited according to autosomal recessive modality.
## Management and treatment
Treatment revolves around protein-restricted diet and supplement of lysine, ornithine, and citrulline. The complication of pulmonary alveolar proteinosis has been reported to be successfully treated by whole lung lavage.
## Prognosis
Prognosis varies depending on pulmonary complications.Pulmonary involvement represents a major cause of impaired clinical course and fatal outcome.
*[v]: View this template
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*[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 inhibitors
*[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
| Lysinuric protein intolerance | c0268647 | 4,860 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=470 | 2021-01-23T17:31:12 | {"gard": ["3335"], "mesh": ["C562687"], "omim": ["222700"], "umls": ["C0268647"], "icd-10": ["E72.0"], "synonyms": ["Hyperdibasic aminoaciduria", "LPI"]} |
A number sign (#) is used with this entry because hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase can be caused by compound heterozygous mutation in the AHCY gene (180960) on chromosome 20q11.
Clinical Features
In 3 daughters of Tunisian parents who were not known to be related but came from the same village in Tunisia, Labrune et al. (1990) described hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy. Hepatic S-adenosylhomocysteine hydrolase activity was decreased by 80% in the 3 children. Neonatal cholestasis was also a feature. A fourth daughter, who died of hepatic failure at the age of 9 months, was probably also affected. The disorder was presumably autosomal recessive.
Baric et al. (2004) reported a Croatian boy with hypermethioninemia and deficiency of S-adenosylhomocysteine hydrolase. The patient's psychomotor development was slow until his fifth month when stagnation and regression were noted. The main problems were hypotonia, sluggishness, lack of interest, and very poor head control. Electron microscopy of muscle showed numerous abnormal myelin figures; liver biopsy showed mild hepatitis with sparse rough endoplasmic reticulum. At age 12 months, brain MRI showed white matter atrophy and abnormally slow myelination. Hypermethioninemia was present in the initial metabolic study at age 8 months, and persisted without tyrosine elevation. Plasma total homocysteine was slightly elevated; in plasma, S-adenosylmethionine was 30-fold and S-adenosylhomocysteine 150-fold elevated. Activity of S-adenosylhomocysteine hydrolase was approximately 3% of control values in liver and was 5 to 10% of control values in red blood cells and cultured fibroblasts. Leukocyte DNA was hypermethylated.
Other causes of hypermethioninemia include hereditary tyrosinemia (276700), cystathionine beta-synthase deficiency (236200), and methionine adenosyltransferase deficiency (250850).
Inheritance
Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive disorder (Baric et al., 2004).
Pathogenesis
In discussing the basis of the pathologic effects of S-adenosylhomocysteine hydrolase deficiency, Baric et al. (2004) pointed to the numerous S-adenosylmethionine-dependent methyltransferases, which are inhibited to a greater or lesser extent by S-adenosylhomocysteine. They pointed out that changes in DNA methylation patterns are heritable and could negatively affect tissue-specific gene expression during embryogenesis and after birth. Because the silencing of genes by inappropriate methylation is the functional equivalent of somatic mutations, the heritability of DNA methylation patterns suggests that restoration of 'normal' genomic methylation patterns may not occur.
Molecular Genetics
In a Croatian boy with S-adenosylhomocysteine hydrolase deficiency, Baric et al. (2004) identified compound heterozygosity for 2 mutations in the AHCY gene (180960.0001 and 180960.0002).
Hair \- Abnormal hair Growth \- Failure to thrive Neuro \- Mental and motor retardation Facies \- Facial dysmorphism Teeth \- Abnormal teeth Cardiac \- Myocardiopathy Inheritance \- Autosomal recessive Lab \- Placental S-adenosylhomocysteine hydrolase deficiency \- Hypermethioninemia ▲ 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 inhibitors
*[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
| HYPERMETHIONINEMIA WITH S-ADENOSYLHOMOCYSTEINE HYDROLASE DEFICIENCY | c3151058 | 4,861 | omim | https://www.omim.org/entry/613752 | 2019-09-22T15:57:47 | {"doid": ["0111039"], "mesh": ["C564683"], "omim": ["613752"], "orphanet": ["88618"]} |
A number sign (#) is used with this entry because pseudohypoaldosteronism type IIB (PHA2B) is caused by heterozygous mutation in the WNK4 gene (601844) on chromosome 17q21.
For a phenotypic description and a discussion of genetic heterogeneity of pseudohypoaldosteronism type II, see PHA2A (145260).
Clinical Features
Farfel et al. (1978, 1978) described an Ashkenazi Jewish family in which some members had hyperkalemia (6-7 mEq/L) evident in childhood and hypertension that developed later in life. The patients had mild acidosis of the proximal renal tubular acidosis type. Chlorothiazide administration promptly corrected all features. The syndrome affected 7 members of 3 generations with instances of male-to-male transmission, thus indicating autosomal dominant inheritance. Investigations showed normal renal and adrenal function. Aldosterone concentrations were normal, but probably inappropriately low for the level of hyperkalemia. Renin was low. A low-salt diet reduced blood pressure and urinary sodium (in contrast to the salt loss that occurs in pseudohypoaldosteronism) but serum potassium did not change. Aldosterone administration caused the expected decrease in urinary sodium but no increase in urinary potassium, supporting a mechanism of resistance to aldosterone regarding potassium but not sodium transport. Infusion of insulin produced hypoglycemia but no substantial reduction in serum potassium in 3 patients studied. Farfel et al. (1978) suggested the existence of a generalized cellular defect in transmembrane potassium transport (in which the kidneys, of course, participate) rather than an isolated renal tubular abnormality.
In the family reported by Lee et al. (1979) and Lee and Morgan (1980), 2 generations were affected.
Clinical Management
Thiazide diuretics correct abnormalities in virtually all PHAII subjects (Boyden et al., 2012).
Mapping
By linkage analysis, Mansfield et al. (1997) demonstrated linkage of PHAII both to 1q31-q42 (PHA2A) and 17p11-q21 (PHA2B). Analysis of both chromosome regions together yielded a lod score of 8.1 for linkage of all families to either chromosome 1 (68% of families) or chromosome 17 (32% of families), with odds of 130 million:1 favoring linkage to 2 loci over the null hypothesis of no linkage. The chromosome 17 locus overlapped with the syntenic segment of rat chromosome 10 that contains a blood pressure quantitative trait locus (QTL).
Molecular Genetics
Wilson et al. (2001) identified the WNK4 gene (601844) between D17S250 and D17S579, within the minimum genetic interval containing the PHA2B locus. They identified 4 missense mutations in PHAII kindreds that had previously been linked to chromosome 17.
Boyden et al. (2012) studied a cohort of 52 PHAII kindreds including 126 affected subjects with renal hyperkalemia and otherwise normal renal function; hypertension and acidosis were present in 71% and 82%, respectively. The authors identified 5 kindreds with mutations in WNK4. There were 15 affected individuals diagnosed or referred at age 28 +/- 18 years with a mean potassium of 6.4 +/- 0.7; a mean bicarbonate 20.8 +/- 2.3, and only 10% had hypertension diagnosed at an age of less than or equal to 18 years.
### Exclusion Studies
Mansfield et al. (1997) analyzed all exons of the AE1 gene (109270), which lies in the chromosome 17 region to which the PHA2B locus was assigned and encodes an ion exchanger, by SSCP in 15 PHAII index cases. They identified no novel variants altering the encoded protein.
Genotype/Phenotype Correlations
Boyden et al. (2012) observed that families with PHAII due to mutation in the WNK1 gene (PHA2C; 614492) are significantly less severely affected than those with mutation in WNK4 (PHA2B) or dominant or recessive mutation in the KLHL3 gene (PHA2D), and all are less severely affected than those with dominant mutation in the CUL3 gene (603136; PHA2E, 614496).
INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Hypertension METABOLIC FEATURES \- Hyperchloremic metabolic acidosis, mild (HCO3 20.8 +/- 2.3 mM) LABORATORY ABNORMALITIES \- Hyperkalemia (6.4 +/- 0.7 mM) \- Hyperchloremia (mean 111 mM) MISCELLANEOUS \- 15 patients from 5 kindreds reported (as of February 2012) \- Age at diagnosis 28 +/- 18 years \- Only 10% develop hypertension at 18 years of age or less \- Responsive to thiazide diuretics MOLECULAR BASIS \- Caused by mutation in the WNK lysine deficient protein kinase 4 gene (WNK4, 601844.0001 ) ▲ Close
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*[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 inhibitors
*[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
| PSEUDOHYPOALDOSTERONISM, TYPE IIB | c1449844 | 4,862 | omim | https://www.omim.org/entry/614491 | 2019-09-22T15:55:06 | {"mesh": ["D011546"], "omim": ["614491"], "orphanet": ["757", "88939"], "genereviews": ["NBK65707"]} |
Sussman et al. (1970) described a 28-year-old woman with chronically elevated lactic and pyruvic acids and increased lactate-to-pyruvate ratio. Alcohol ingestion and moderate exercise increased lactate levels. As in glycogen storage disease, hyperuricemia was present and uric acid clearance was apparently depressed. The mother and 3 of the mother's sibs also showed abnormal lactate response to the combination of alcohol ingestion and exercise.
Inheritance \- Autosomal dominant Misc \- Worsened by alcohol ingestion and moderate exercise Lab \- Elevated lactic and pyruvic acids \- Increased lactate-to-pyruvate ratio \- Hyperuricemia \- Depressed uric acid clearance Metabolic \- Chronic adult lactic acidosis ▲ Close
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*[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 inhibitors
*[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
| LACTIC ACIDOSIS, CHRONIC ADULT FORM | c1835591 | 4,863 | omim | https://www.omim.org/entry/150170 | 2019-09-22T16:39:06 | {"mesh": ["C563640"], "omim": ["150170"]} |
Pyruvate dehydrogenase deficiency (PDHD) is a rare neurometabolic disorder characterized by a wide range of clinical signs with metabolic and neurological components of varying severity. Manifestations range from often fatal, severe, neonatal lactic acidosis to later-onset neurological disorders. Six subtypes related to the affected subunit of the PDH complex have been recognized with significant clinical overlap: PDHD due to E1-alpha, E1-beta, E2 and E3 deficiency, PDHD due to E3-binding protein deficiency, and PDH phosphatase deficiency (see these terms).
## Epidemiology
Exact prevalence is unknown but hundreds of cases have been reported.
## Clinical description
PDHD may affect fetal development, with poor fetal weight gain and low birth weight being noted. Characteristic facial dysmorphism has only been described in some patients (narrow head, frontal bossing, wide nasal bridge, long philtrum and flared nostrils). Structural brain lesions are commonly observed, especially in females. Other patients develop symptoms soon after birth. Some have a primarily metabolic-type picture (potentially fatal lactic acidosis, occasionally with hyperammonemia, poor feeding, lethargy, tachypnea) and few neurological signs, while others have mainly neurological signs (developmental delay, growth retardation, poor acquisition or loss of motor milestones, hypotonia, seizures, ataxia and dystonia). Symptoms may occur in periods of stress or illness in the less severe, later-onset cases. Many patients have the characteristic clinical presentation, disease course and neuropathological changes of Leigh syndrome (see this term).
## Etiology
PDHD is caused by a deficiency of one of the components of the PDH complex. The most common cause are mutations in the PDHA1 gene (Xp22.1), which encodes the E1-alpha subunit. Mutations in the genes for the other subunits have been described, but are far less frequent: E1-beta and E2 subunits (PDHB, DLAT); E3 binding protein (PDHX gene); and E3 and PDH phosphatase (DLD andPDP1).
## Diagnostic methods
PDHD should be considered in cases of early-onset neurological disease and unexplained lactic acidosis, particularly if there are structural cerebral abnormalities. In many cases, lactate concentration in cerebrospinal fluid (CSF) is disproportionately increased compared to blood lactate. Definitive diagnosis is made by demonstrating abnormal enzyme function and immunochemical demonstration of a specific subunit deficiency.
## Differential diagnosis
Differential diagnosis includes other causes of primary lactic acidosis (pyruvate carboxylase deficiency, defects of gluconeogenesis and a wide range of mitochondrial diseases). In patients presenting as Leigh syndrome, the differential diagnosis includes various forms of Complex I deficiency (see this term), cytochrome oxidase deficiency due to mutation in the SURF1 gene and a number of mitochondrial DNA mutations.
## Antenatal diagnosis
Due to the severity of PDHD, prenatal diagnosis is requested in affected families (chorionic villi or amniocyte testing).
## Genetic counseling
Most cases are due to mutations in the PDHA1 gene and are thus inherited as an X-linked dominant trait. As patients almost always have severe symptoms and greatly reduced life expectancy, most new cases are sporadic. Inheritance of all other forms of PDHD is autosomal recessive.
## Management and treatment
Treatment is generally aimed at stimulating the PDH complex or providing an alternative energy source for the brain. Cofactor supplementation with thiamine, carnitine, and lipoic acid has been recommended. A very small number of patients with mutations in the PDHA1 gene are thiamine-responsive. A ketogenic diet may be indicated especially for those presenting with a dystonic disorder. Dichloroacetate has been used but significant side effects, such as peripheral neuropathy, may limit effectiveness. No treatment has an effect on preventing prenatal development of structural central nervous system anomalies.
## Prognosis
Prognosis is variable but is generally poor (in terms of impact on development and life expectancy).
*[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 inhibitors
*[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
| Pyruvate dehydrogenase deficiency | c0034345 | 4,864 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=765 | 2021-01-23T17:19:53 | {"gard": ["7513"], "mesh": ["C536257", "D015325"], "omim": ["245348", "245349", "246900", "312170", "608782", "614111"], "umls": ["C0034345", "C2936911"], "icd-10": ["E74.4"], "synonyms": ["PDH", "PDHC", "Pyruvate dehydrogenase complex deficiency"]} |
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: "Skin infection" – news · newspapers · books · scholar · JSTOR (September 2019) (Learn how and when to remove this template message)
A skin infection is an infection of the skin in humans and other animals, that can also affect the associated soft tissues such as loose connective tissue and mucous membranes.[citation needed] They comprise a category of infections termed skin and skin structure infections (SSSIs), or skin and soft tissue infections (SSTIs),[1] and acute bacterial SSSIs (ABSSSIs).[2] They are distinguished from dermatitis (inflammation of the skin).[3][4] although skin infections can result in skin inflammation.[citation needed][5]
## Contents
* 1 Causes
* 1.1 Bacterial
* 1.2 Fungal
* 1.3 Parasitic
* 1.4 Viral
* 2 References
## Causes[edit]
### Bacterial[edit]
This section has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages)
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. (September 2019) (Learn how and when to remove this template message)
This section needs expansion with: a more comprehensive, secondary source-based description of the infection type and recent data on numbers effected, with comparable numbers of the most prevalent examples given for each. You can help by adding to it. (September 2019)
(Learn how and when to remove this template message)
Example of cellulitis showing 3+ edema of left leg
Main article: Skin and skin structure infection
Further information: List of cutaneous conditions § Bacterium-related
Bacterial skin infections affected about 155 million people and cellulitis occurred in about 600 million people in 2013.[6] Bacterial skin infections include:
* Cellulitis, a diffuse inflammation of connective tissue with severe inflammation of dermal and subcutaneous layers of the skin[7]
* Erysipelas, an acute infection of the deep epidermis often with lymphatic spread, almost exclusively caused by beta-hemolytic streptococcus bacteria [8] [9][verification needed]
* Folliculitis, an infection of the hair follicle[clarification needed] [8]
* Impetigo, a highly contagious ABSSSI (acute bacterial skin and skin structure infection) common among pre-school children, primarily associated with the pathogens S. aureus and S. pyogenes[10][11]
### Fungal[edit]
Further information: List of cutaneous conditions § Mycosis-related
Fungal skin infections may present as either a superficial or deep infection of the skin, hair, and/or nails. Mycetoma are a broad group of fungal infections that characteristically originate in the skin and subcutaneous tissues of the foot.[12] If not treated appropriately and in a timely fashion mycetoma infections can extend to deeper tissues like bones and joints causing osteomyelitis.[13] Extensive osteomyelitis can necessitate surgical bone resections and even lower limb amputation.[13] As of 2010, they affect about one billion people globally.[14]
### Parasitic[edit]
Further information: List of cutaneous conditions § Parasitic infestations, stings, and bites
Parasitic infestations of the skin are caused by several phyla of organisms, including Annelida, Arthropoda, Bryozoa, Chordata, Cnidaria, Cyanobacteria, Echinodermata, Nemathelminthes, Platyhelminthes, and Protozoa.[15]
### Viral[edit]
Further information: List of cutaneous conditions § Virus-related
Virus-related cutaneous conditions caused by these obligate intracellular agents derive from both DNA and RNA viruses.[16]
## References[edit]
1. ^ Stevens, D. L.; Bisno, A. L.; Chambers, H. F.; Dellinger, E. P.; Goldstein, E. J. C.; Gorbach, S. L.; Hirschmann, J. V.; Kaplan, S. L.; Montoya, J. G.; Wade, J. C. (18 June 2014). "Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America". Clinical Infectious Diseases. 59 (2): e10–e52. doi:10.1093/cid/ciu296. PMID 24947530.
2. ^ "Guidance Compliance Regulatory Information" (PDF). www.fda.gov. Retrieved 2019-09-15.
3. ^ "International Statistical Classification of Diseases and Related Health Problems 10th Revision". apps.who.int. Retrieved 2019-09-15.
4. ^ In the WHO classification, it is noted that the infection classification "Excludes:... infective dermatitis...". See the WHO classification, op. cit.
5. ^ Skin inflammation due to skin infection is called "infective dermatitis". See the WHO classifications, op. cit.
6. ^ Global Burden of Disease Study 2013 Collaborators (22 August 2015). "Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 386 (9995): 743–800. doi:10.1016/s0140-6736(15)60692-4. PMC 4561509. PMID 26063472.
7. ^ Raff, Adam B.; Kroshinsky, Daniela (2016-07-19). "Cellulitis: A Review". JAMA. 316 (3): 325–337. doi:10.1001/jama.2016.8825. ISSN 0098-7484. PMID 27434444.
8. ^ a b Stulberg, Daniel L.; Penrod, Marc A.; Blatny, Richard A. (2002-07-01). "Common Bacterial Skin Infections". American Family Physician. 66 (1): 119–24. ISSN 0002-838X. PMID 12126026.
9. ^ "erysipelas" at Dorland's Medical Dictionary[full citation needed]
10. ^ "Impetigo". nhs.uk. October 19, 2017.
11. ^ Kumar, V., Abbas, A.K., Fausto, N. & Mitchell, R.N. (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. p. 843. ISBN 978-1-4160-2973-1.CS1 maint: multiple names: authors list (link)
12. ^ Verma, P.; Jha, A. (March 2019). "Mycetoma: reviewing a neglected disease". Clinical and Experimental Dermatology. 44 (2): 123–129. doi:10.1111/ced.13642. PMID 29808607. S2CID 44123860.
13. ^ a b EL-Sobky, Tamer Ahmed; Haleem, John Fathy; Samir, Shady (21 September 2015). "Eumycetoma Osteomyelitis of the Calcaneus in a Child: A Radiologic-Pathologic Correlation following Total Calcanectomy". Case Reports in Pathology. 2015: 129020. doi:10.1155/2015/129020. PMC 4592886. PMID 26483983. S2CID 15644051.
14. ^ Vos, T (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.
15. ^ Diaz, JH (January 2010). "Mite-transmitted dermatoses and infectious diseases in returning travelers". Journal of Travel Medicine. 17 (1): 21–31. doi:10.1111/j.1708-8305.2009.00352.x. PMID 20074098.
16. ^ Lebwohl MG, Rosen T, Stockfleth E (November 2010). "The role of human papillomavirus in common skin conditions: current viewpoints and therapeutic options". Cutis. 86 (5): suppl 1–11, quiz suppl 12. PMID 21214125.
* 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]: 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 inhibitors
*[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
| Skin infection | c0037278 | 4,865 | wikipedia | https://en.wikipedia.org/wiki/Skin_infection | 2021-01-18T18:28:50 | {"mesh": ["D012874"], "umls": ["C0037278"], "wikidata": ["Q2458539"]} |
Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations is a rare cancer-predisposing syndrome, associated with the D1 subgroup of Fanconi anemia (FA), characterized by progressive bone marrow failure, cardiac, brain, intestinal or skeletal abnormalities and predisposition to various malignancies. Bone marrow suppression and the incidence of developmental abnormalities are less frequent than in other FA, but cancer risk is very high with the spectrum of childhood cancers including Wilms tumor, brain tumor (often medulloblastoma) and ALL/AML.
*[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 inhibitors
*[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
| Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations | c1838457 | 4,866 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319462 | 2021-01-23T17:45:43 | {"mesh": ["C563980"], "omim": ["605724"]} |
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-81 (RP81) is caused by homozygous mutation in the IFT43 gene (614068) on chromosome 14q24. One such family has been reported.
For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Clinical Features
Biswas et al. (2017) studied a large consanguineous Pakistani family (PKRD272) in which 9 members exhibited early-onset retinal degeneration. The 4 affected sibs (patients III:1, III:2, III:7, and III:8) who underwent clinical analysis all reported noticeable night vision abnormalities before age 5 years. Funduscopy in 2 of the sibs (III:1 and III:8) at ages 30 and 23 years, respectively, showed optic nerve pallor, retinal vessel attenuation, and bone spicule pigmentary changes anterior to the arcades and in the nasal retina. Both sibs showed atrophy of the retinal pigment epithelium and choroid in the macula, which was more extensive in the older sib. Full-field electroretinography (ERG) responses were undetectable to all stimulus conditions in all 4 sibs at ages ranging from 28 to 46 years, whereas an unaffected sib showed normal cone and rod responses at age 30 years. The affected sibs had normal physical development and body mass index, and exhibited no features of Sensenbrenner syndrome (see CED3, 614099) such as polydactyly, short ribs, or micromelia.
Mapping
In 4 affected and 2 unaffected individuals from a large consanguineous Pakistani family (PKRD272) with early-onset retinal degeneration, Biswas et al. (2017) performed homozygosity mapping and identified an 18-Mb homozygous region on chromosome 14 (chr14:59,000,001-77,000,000) that was shared by the 4 affected sibs. The interval contained 3 known retinal disease-associated genes (RDH11, 607849; RDH12, 608830; TTLL5, 612268), but no pathogenic variants were detected in those genes that segregated with disease in the family.
Molecular Genetics
In 4 affected individuals from a large consanguineous Pakistani family (PKRD272) with early-onset retinal degeneration mapping to chromosome 14, Biswas et al. (2017) analyzed exome sequencing data and identified homozygosity for a missense mutation in the IFT43 gene (E34K; 614068.0004), located within an 18-Mb shared region of homozygosity and segregating fully with disease in the family. The mutation was not found in 150 ethnicity-matched controls or in 800 other controls, and screening whole-exome or whole-genome data from 1,771 and 120 patients, respectively, from pedigrees with inherited retinal diseases did not identify any additional mutations in the IFT43 gene. The authors concluded that IFT43-associated retinal disease is uncommon.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Reduced night vision in early childhood \- Optic nerve pallor \- Retinal vessel attenuation \- Bone-spicule pigmentary changes \- Atrophy of retinal pigment epithelium in the macula \- Choroidal atrophy in the macula \- Undetectable responses on electroretinography MISCELLANEOUS \- Retinal degeneration worsens with age \- Based on report of 1 family (last curated February 2018) MOLECULAR BASIS \- Caused by mutation in the intraflagellar transport 43 gene (IFT43, 614068.0004 ) ▲ 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 inhibitors
*[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
| RETINITIS PIGMENTOSA 81 | c4693443 | 4,867 | omim | https://www.omim.org/entry/617871 | 2019-09-22T15:44:40 | {"omim": ["617871"]} |
A chronic monophasic, progressive or relapsing symmetric sensorimotor disorder characterized by progressive muscular weakness with impaired sensation, absent or diminished tendon reflexes and elevated cerebrospinal fluid (CSF) proteins.
## Epidemiology
Prevalence is about 1/200,000 children and 1-7/100,000 adults, but it is generally accepted that the frequency is underestimated.
## Clinical description
Onset may occur at any age but is more common in the 5th and 6th decades. Main clinical manifestations include progressive symmetrical weakness in both proximal and distal muscles of lower and/or upper limbs with partial or complete recovery between recurrences, associated with impaired sensation and absent/diminished tendon reflexes. Disease course is relapsing in 30% of cases, chronic and progressive in 60%, and monophasic with full generally permanent recovery in 10%. In 5-30% of cases, cranial nerve dysfunction may occur. Neuropathic pain, respiratory muscle and sub-clinical CNS involvement have been reported. Autonomic system dysfunction can occur. Children have a more rapid onset, greater disability at the peak and a more frequent relapsing course. CIDP may be associated with hepatitis C, inflammatory bowel disease, lymphoma, HIV, organ transplant, melanoma, or connective tissue disorders.
## Etiology
CIDP could be due to an immune reaction, resulting in segmental and multifocal demyelination that may induce axonal loss with time.
## Diagnostic methods
To be diagnosed with CIDP, patients have to present a 2 month history of progression of demyelinating neuropathy (DN), some have a history of infection. CIDP may also appear more than 8 weeks after Guillain-Barré syndrome (GBS, so-called ``acute CIDP''; see this term). Diagnosis is based primarily on clinical and electrophysiological findings. The need for CSF examination and nerve biopsy depends on the level of clinical diagnostic certainty. When manifestations are present for at least 2 months, electroneuromyogram (ENMG) confirms the diagnosis if 3 of the following criteria are present on several nerves: partial motor-nerve (M-N) conduction blocks, reduced M-N conduction velocity, prolonged distal M-N and F-wave latencies. MRI may demonstrate gadolinium enhancement and proximal nerve/root enlargement. Elevated CSF proteins, with no cells, and demyelination/remyelination, often with inflammation, in nerve-biopsy specimens can provide additional supportive data. Biopsy is currently only recommended in cases of clinical suspicion of CIDP in which ENMG is not conclusive. CIDP should be suspected in virtually any multifocal or generalized neuropathy of unknown cause.
## Differential diagnosis
Differential diagnoses include chronic acquired polyneuropathies (monoclonal gammopathies, diabetes, toxic neuropathies) or inherited neuropathies (Charcot-Marie-Tooth disease or transthyretin amyloid neuropathy; see these terms).
## Management and treatment
The decision to treat depends on initial disease severity, age, general health status and potential contraindications to the 3 validated treatments: steroids, intravenous immunoglobulins (IVIg) or plasma exchanges. Patients with pure motor CIDP should be treated with IVIg rather than steroids. In milder forms, clinical observation and possibly steroid therapy (depending on ENMG results) are advised. Plasmapheresis or a combination of steroids and IVIg can be started if none of these treatments are effective. Refractory cases can be treated with intensive immunosuppression. The effect of interferon beta-1a and alpha, etanercept or rituximab remains uncertain. Neuropathic pain can be treated with antiepileptic medications or tricyclic antidepressants.
## Prognosis
Quadriplegia, respiratory failure and death can occur but are rare. Patients may present residual symptoms that can lead to reduced quality of life. However long-term prognosis is usually good.
*[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 inhibitors
*[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
| Chronic inflammatory demyelinating polyneuropathy | c0393819 | 4,868 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2932 | 2021-01-23T17:51:39 | {"gard": ["6102"], "mesh": ["D020277"], "umls": ["C0393819"], "icd-10": ["G61.8"], "synonyms": ["CIDP", "Chronic inflammatory demyelinating polyradiculoneuropathy"]} |
## Summary
### Clinical characteristics.
Hartsfield syndrome comprises two core features: holoprosencephaly (HPE) spectrum disorders and ectrodactyly spectrum disorders.
* HPE spectrum disorders, resulting from failed or incomplete forebrain division early in gestation, include alobar, semilobar, or lobar HPE. Other brain malformations observed in persons with Hartsfield syndrome include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Varying degrees of developmental delay are observed. Microcephaly, spasticity, seizures, and feeding difficulties are common. Hypothalamic dysfunction (manifest as temperature dysregulation and erratic sleep patterns) can occur, as well as hypogonadotropic hypogonadism and central insipidus diabetes.
* Ectrodactyly spectrum disorders are unilateral or bilateral malformations of the hands and/or feet characterized by a median cleft of hand or foot due to absence of the longitudinal central rays (also called split hand/foot malformation). The number of digits on the right and left can vary. Polydactyly and syndactyly can also be seen.
### Diagnosis/testing.
The diagnosis is established in a proband with the two core features: an HPE spectrum disorder and an ectrodactyly spectrum disorder. It can be confirmed by identification of either an FGFR1 heterozygous pathogenic variant (in those with autosomal dominant inheritance) or FGFR1 biallelic pathogenic variants (in those with autosomal recessive inheritance).
### Management.
Treatment of manifestations: Medically refractory epilepsy typically requires multiple antiepileptic drugs. Spasticity can be treated with physical and occupational therapy and bracing, as well as muscle relaxants (when moderate or severe). Sometimes surgery may be required. Diabetes insipidus may need treatment with desmopressin; temperature dysregulation can be managed by modifying the environment; disturbance of sleep-wake cycles can be managed with good sleep hygiene and, if needed, with use of melatonin or other sleep aids such as clonidine. Some children may require a gastrostomy and/or a tracheostomy.
### Genetic counseling.
Hartsfield syndrome is inherited most commonly in an autosomal dominant (AD) and less commonly in an autosomal recessive (AR) manner.
* AD inheritance: Most probands have a de novo FGFR1 pathogenic variant. Germline mosaicism has been observed in two unrelated families.
* AR inheritance: At conception, 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.
Once the FGFR1 pathogenic variant(s) have been identified in an affected family member, prenatal testing or preimplantation genetic diagnosis for a pregnancy at increased risk is possible.
## Diagnosis
### Suggestive Findings
Hartsfield syndrome should be suspected in individuals with the following core features:
* Holoprosencephaly (HPE) spectrum disorders. The spectrum results from failed or incomplete forebrain division early in gestation and includes alobar, semilobar, or lobar HPE. Other brain malformations can include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Microcephaly is common.
* Ectrodactyly spectrum disorders. These unilateral or bilateral malformations of the hands and/or feet are characterized by a median cleft of hand or foot due to absence of longitudinal central rays (also called split hand/foot malformation). The number of digits on the right and left hand/foot can vary. Polydactyly and syndactyly can be part of the spectrum.
Additional features that may be present [Imaizumi et al 1998, Abdel-Meguid & Ashour 2001, Keaton et al 2010, Simonis et al 2013]:
* Facial dysmorphism (hypertelorism or hypotelorism)
* Cleft lip and/or palate (midline or bilateral)
* Malformed ears
* Cardiac defects
* Abnormal genitalia (micropenis, cryptorchidism)
* Vertebral anomalies
* Radial or ulnar defects
* Central diabetes insipidus
* Growth hormone deficiency, hypogonadotropic hypogonadism, central diabetes insipidus
* Varying degrees of developmental delay, seizures
### Establishing the Diagnosis
The diagnosis of Hartsfield syndrome is established clinically in a proband with the two core features of a holoprosencephaly (HPE) spectrum disorder and an ectrodactyly spectrum disorder and can be confirmed on molecular genetic testing by identification of either an FGFR1 heterozygous pathogenic variant (in those with autosomal dominant inheritance) or FGFR1 biallelic pathogenic variants (in those with autosomal recessive inheritance) (see Table 1) [Simonis et al 2013, Dhamija et al 2014].
Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
* Single-gene testing. Sequence analysis of FGFR1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found [Simonis et al 2013, Dhamija et al 2014].
* A multigene panel that includes FGFR1 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.
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, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes FGFR1) fails to confirm a diagnosis in an individual with features of Hartsfield syndrome. 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 1.
Molecular Genetic Testing Used in Hartsfield Syndrome
View in own window
Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
FGFR1Sequence analysis 36/7, 1/1, 3/3 4
Gene-targeted deletion/duplication analysis 5Unknown 6
Unknown 7NA
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\.
Simonis et al [2013]; Dhamija et al [2014]; C Vilain and G Smits, unpublished data
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.
7\.
Imaizumi et al [1998], Abdel-Meguid & Ashour [2001], Simonis et al [2013]
## Clinical Characteristics
### Clinical Description
Hartsfield syndrome, comprising malformations of the two major groups holoprosencephaly (HPE) spectrum malformations and ectrodactyly spectrum malformations, has been reported to date in fewer than 20 individuals [Keaton et al 2010, Simonis et al 2013]. Among the individuals reported, all but two were males.
Following discovery of the genetic basis of Hartsfield syndrome, the diagnosis has been molecularly confirmed in ten probands: 6/7 reported by Simonis et al [2013], 1/1 reported by Dhamija et al [2014], and 3/3 unreported cases [C Vilain and G Smits, unpublished data].
In addition to HPE spectrum malformations and ectrodactyly spectrum malformations, Hartsfield syndrome may include the following features:
Craniofacial dysmorphism
* Hypotelorism or hypertelorism; malformed, low-set and posteriorly rotated ears; eye anomalies; and cleft lip and or palate (median or bilateral) are common.
* Craniosynostosis (metopic and coronal) has been reported.
Central nervous system
* HPE is associated with varying degrees of developmental delay.
* Spasticity is common.
* Seizures are common, and may be difficult to control.
* Hypothalamic dysfunction, manifest as temperature dysregulation and erratic sleep patterns, can occur.
* Microphthalmia and coloboma have been reported as a part of the HPE spectrum of malformations.
* Tethered cord has been seen in a few patients.
Skeletal anomalies. Other skeletal anomalies include vertebral anomalies and radial and ulnar aplasia.
Gastrointestinal. Feeding difficulties due to axial hypotonia, gastrointestinal reflux, and oro-motor dysfunction may be a major problem and result in failure to thrive.
Respiratory. Aspiration pneumonia can result from poorly coordinated suck and swallow.
Endocrine. Due to midline brain defects that involve the pituitary, central endocrine disorders are common (including growth hormone deficiency, central diabetes insipidus, and hypogonadotropic hypogonadism).
Genitourinary. Some males have micropenis, cryptorchidism (due to hypogonadotropic hypogonadism), and hypospadias.
Cardiovascular. One individual had coarctation of the aorta.
#### Phenotype of Autosomal Recessive Hartsfield Syndrome
Compared with four individuals with a heterozygous FGFR1 pathogenic variant, the two with biallelic FGFR1 pathogenic variants had a more severe phenotype [Simonis et al 2013]:
* HPE spectrum:
* Alobar holoprosencephaly (1/2)
* Diminished cortical thickening (2/2)
* Absent corpus callosum (2/2)
* Median cleft (1/2)
* Hypotelorism (2/2)
* Severe developmental delay and growth retardation (2/2)
* Ectrodactyly spectrum: split hand/foot malformation of both hands and feet, and fewer than three digits bilaterally (2/2)
* Death before age five years (2/2)
### Nomenclature
In the older literature, Harstfield syndrome has been referred to as:
* Holoprosencephaly and split hand/foot syndrome
* Holoprosencephaly, hypertelorism, and ectrodactyly syndrome (HHES)
### Genotype-Phenotype Correlations
No genotype-phenotype correlations have been established among the small number of affected individuals with a molecularly confirmed diagnosis of Hartsfield syndrome reported to date.
FGFR1 pathogenic variants described to date in individuals with Hartsfield syndrome cluster in specific domains of the receptor [Simonis et al 2013; C Vilain and G Smits, unpublished data]:
* A heterozygous pathogenic variant affecting amino acid residues located in the ATP binding pocket of the intracellular tyrosine kinase domain (TKD) is found in most affected individuals with variable phenotypes.
* Biallelic pathogenic variants affecting amino acid residues located in the extracellular ligand binding domain D2 of FGFR1 have been found in two individuals with a severe phenotype.
* A heterozygous pathogenic variant in the intracellular C-terminal loop of the TKD was found in one individual with a mild phenotype.
### Prevalence
Hartsfield syndrome is very rare: of the fewer than 20 individuals reported in the medical literature only 13 (from 10 families) have been confirmed to have loss-of-function variants in FGFR1.
## Differential Diagnosis
Holoprosencephaly (HPE). See Holoprosencephaly Overview.
Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Ectrodactyly with or without syndactyly is present in approximately 70% of all affected individuals and ranges widely in severity and location of the digital abnormalities. Ectodermal defects typically manifest as silvery-blond, sparse fine hair; dry skin and unique pigmentary skin changes; nail changes; dental changes including oligodontia and enamel defects; and xerostomia and subjective decrease in sweating capacity. Cleft lip/palate is present in approximately 40% of affected individuals; the spectrum includes submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, and the combination of cleft lip and cleft palate. EEC3 is caused by mutation of TP63 and inherited in an autosomal dominant manner.
Overexpression of KAL1. One male with hyperosmia, ectrodactyly, genital anomalies, and mild intellectual disability had partial duplication of the X-linked gene KAL1. KAL1 protein at high levels may interfere with FGFR1 signaling activity, leading to an overlapping phenotype [Sowińska-Seidler et al 2015].
Microduplication of Xq24. One individual with duplication of Xq24 and Hartsfield syndrome phenotype has been reported [Takenouchi et al 2012].
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Hartsfield syndrome, the following evaluations are recommended:
* Determine the type of holoprosencephaly (alobar, semilobar, or lobar) by neuroimaging, preferably a brain MRI.
* Assess development including evidence of spasticity.
* Evaluate suspicious activity for evidence of seizures.
* Evaluate nutritional status and feeding for evidence of problems that may result from cleft lip/palate and/or oromotor dysfunction and other problems that may result from gastrointestinal involvement (e.g., slow gastric emptying, gastroesophageal reflux, constipation).
* Evaluate for evidence of diabetes insipidus, temperature dysregulation, and/or disturbance of sleep-wake cycles.
* Evaluate for evidence of endocrine deficiency (growth hormone deficiency, hypogonadotropic hypogonadism, central diabetes insipidus).
* Consult with a clinical geneticist and/or genetic counselor.
### Treatment of Manifestations
Neurologic. Medically refractory epilepsy typically requires multiple antiepileptic drugs (AEDs).
Spasticity can be treated with physical and occupational therapy and bracing. Muscle relaxants may be used to treat moderate or severe spasticity. Surgery may be required.
Hypothalamic involvement
* Central diabetes insipidus may require treatment with desmopressin.
* Temperature dysregulation can be managed by modifying the environment.
* Disturbance of sleep-wake cycles can be managed with good sleep hygiene and, if needed, with use of melatonin or other sleep aids such as clonidine.
Skeletal. Surgery of hand and foot defects can improve dexterity.
Other
* Tethered cord may require surgical intervention.
* Cleft lip and palate: reparative surgery is needed in most.
* Some children may require a gastrostomy and/or tracheostomy.
### 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 inhibitors
*[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
| Hartsfield Syndrome | c1845146 | 4,869 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK349073/ | 2021-01-18T21:22:08 | {"mesh": ["C564484"], "synonyms": []} |
Human disease
Cyanide poisoning
Other namesCyanide toxicity, hydrocyanic acid poisoning[1]
Cyanide ion
SpecialtyToxicology, critical care medicine
SymptomsEarly: headache, dizziness, fast heart rate, shortness of breath, vomiting[2]
Later: seizures, slow heart rate, low blood pressure, loss of consciousness, cardiac arrest[2]
Usual onsetFew minutes[2][3]
CausesCyanide compounds[4]
Risk factorsHouse fire, metal polishing, certain insecticides, eating seeds such as from apples[2][3][5]
Diagnostic methodBased on symptoms, high blood lactate[2]
TreatmentDecontamination, supportive care (100% oxygen), hydroxocobalamin[2][3][6]
Cyanide poisoning is poisoning that results from exposure to any of a number of forms of cyanide.[4] Early symptoms include headache, dizziness, fast heart rate, shortness of breath, and vomiting.[2] This phase may then be followed by seizures, slow heart rate, low blood pressure, loss of consciousness, and cardiac arrest.[2] Onset of symptoms usually occurs within a few minutes.[2][3] Some survivors may[vague] have long-term neurological problems.[2]
Toxic cyanide-containing compounds include hydrogen cyanide gas and a number of cyanide salts.[2] Poisoning is relatively common following breathing in smoke from a house fire.[2] Other potential routes of exposure include workplaces involved in metal polishing, certain insecticides, the medication nitroprusside, and certain seeds such as those of apples and apricots.[3][7][8] Liquid forms of cyanide can be absorbed through the skin.[9] Cyanide ions interfere with cellular respiration, resulting in the body's tissues being unable to use oxygen.[2]
Diagnosis is often difficult.[2] It may be suspected in a person following a house fire who has a decreased level of consciousness, low blood pressure, or high blood lactate.[2] Blood levels of cyanide can be measured but take time.[2] Levels of 0.5–1 mg/L are mild, 1–2 mg/L are moderate, 2–3 mg/L are severe, and greater than 3 mg/L generally result in death.[2]
If exposure is suspected, the person should be removed from the source of exposure and decontaminated.[3] Treatment involves supportive care and giving the person 100% oxygen.[2][3] Hydroxocobalamin (vitamin B12a) appears to be useful as an antidote and is generally first-line.[2][6] Sodium thiosulphate may also be given.[2] Historically cyanide has been used for mass suicide and by Nazi Germany for genocide.[3]
## Contents
* 1 Signs and symptoms
* 1.1 Acute exposure
* 1.2 Chronic exposure
* 2 Causes
* 3 Mechanism
* 4 Diagnosis
* 5 Treatment
* 5.1 Decontamination
* 5.2 Antidote
* 6 History
* 6.1 Fires
* 6.2 Gas chambers
* 6.3 Suicide
* 6.4 Mining and industrial
* 6.5 Murder
* 6.6 Terrorism
* 7 Research
* 8 See also
* 9 References
* 9.1 Explanatory notes
* 9.2 Citations
* 9.3 Sources
## Signs and symptoms[edit]
### Acute exposure[edit]
If cyanide is inhaled it can cause a coma with seizures, apnea, and cardiac arrest, with death following in a matter of seconds. At lower doses, loss of consciousness may be preceded by general weakness, dizziness, headaches, vertigo, confusion, and perceived difficulty in breathing. At the first stages of unconsciousness, breathing is often sufficient or even rapid, although the state of the person progresses towards a deep coma, sometimes accompanied by pulmonary edema, and finally cardiac arrest. A cherry red skin color that changes to dark may be present as the result of increased venous hemoglobin oxygen saturation. Despite the similar name, cyanide does not directly cause cyanosis. A fatal dose for humans can be as low as 1.5 mg/kg body weight.[10] Other sources say a lethal dose is 1–3 mg per kg body weight for vertebrates.[11]
### Chronic exposure[edit]
Exposure to lower levels of cyanide over a long period (e.g., after use of improperly processed cassava roots, which are a primary food source in tropical Africa) results in increased blood cyanide levels, which can result in weakness and a variety of symptoms, including permanent paralysis, nervous lesions,[12][13][14] hypothyroidism,[13] and miscarriages.[15][16] Other effects include mild liver and kidney damage.[17][18]
## Causes[edit]
Removal of cyanide poison from cassava in Nigeria
Acute hydrogen cyanide poisoning can result from inhalation of fumes from burning polymer products that use nitriles in their production, such as polyurethane,[19] or vinyl.[20] It can also be caused by breakdown of nitroprusside into nitric oxide and cyanide.[8] Nitroprusside may be used during treatment of hypertensive crisis.[8]
In addition to its uses as a pesticide and insecticide, cyanide is contained in tobacco smoke and smoke from building fires, and is present in
* many seeds or kernels such as those of almonds, apricots, apples, oranges, and in
* foods including cassava (also known as tapioca, yuca or manioc), and bamboo shoots.
Vitamin B12, in the form of hydroxocobalamin (also spelled hydroxycobalamin), may reduce the negative effects of chronic exposure, and a deficiency can lead to negative health effects following exposure.[vague][21]
Flaxseed also contains cyanogenic glycosides,[22] so regular consumption of it may warrant medical advice or treatment.
## Mechanism[edit]
Cyanide poisoning is a form of histotoxic hypoxia because the cells of an organism are unable to create ATP; this is primarily due to the inhibition of the mitochondrial enzyme cytochrome c oxidase. Cyanide is quickly metabolized to 2-amino-2-thiazoline-4-carboxylic acid and thiocyanate, with a half life of 10–30 minutes as a detoxifying mechanism.
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Within a few hours of single ingestion, no cyanide can be detected, since all of it is metabolized, if death does not occur first. This thiocyanate has a long half life (24hrs); is it typically eliminated through the kidneys, and its toxicity is about 0.01% (ten thousand times lower) than that of the cyanide parent molecule that it results from.
## Diagnosis[edit]
Lactate concentrations above 10 mmol per liter are an indicator of cyanide poisoning, as defined by the presence of a blood cyanide concentration above 40 µmol per liter. Lactate levels greater than 6 mmol/L after reported or strongly suspected pure cyanide poisoning, such as cyanide-containing smoke exposure, suggests significant cyanide exposure.[23]
Methods of detection include colorimetric assays such as the Prussian blue test, the pyridine-barbiturate assay, also known as the "Conway diffusion method"[24] and the taurine fluorescence-HPLC but like all colorimetric assays these are prone to false positives. Lipid peroxidation resulting in "TBARS," an artifact of heart attack produces dialdehydes that cross-react with the pyridine-barbiturate assay. Meanwhile, the taurine-fluorescence-HPLC assay used for cyanide detection is identical to the assay used to detect glutathione in spinal fluid.
Cyanide and thiocyanate assays have been run with mass spectrometry (LC/MS/MS), which are considered specific tests. Since cyanide has a short half-life, the main metabolite, thiocyanate is typically measured to determine exposure. Other methods of detection include the identification of plasma lactate.
## Treatment[edit]
### Decontamination[edit]
Decontamination of people exposed to hydrogen cyanide gas only requires removal of the outer clothing and the washing of their hair.[9] Those exposed to liquids or powders generally require full decontamination.[9]
### Antidote[edit]
The International Programme on Chemical Safety issued a survey (IPCS/CEC Evaluation of Antidotes Series) that lists the following antidotal agents and their effects: oxygen, sodium thiosulfate, amyl nitrite, sodium nitrite, 4-dimethylaminophenol, hydroxocobalamin, and dicobalt edetate ('Kelocyanor'), as well as several others.[25] Other commonly-recommended antidotes are 'solutions A and B' (a solution of ferrous sulfate in aqueous citric acid, and aqueous sodium carbonate, respectively) and amyl nitrite.
The United States standard cyanide antidote kit first uses a small inhaled dose of amyl nitrite, followed by intravenous sodium nitrite, followed by intravenous sodium thiosulfate.[26] Hydroxocobalamin is newly approved in the US and is available in Cyanokit antidote kits.[27] Sulfanegen TEA, which could be delivered to the body through an intra-muscular (IM) injection, detoxifies cyanide and converts the cyanide into thiocyanate, a less toxic substance.[28] Alternative methods of treating cyanide intoxication are used in other countries.
The UK Health and Safety Executive (HSE) has recommended against the use of solutions A and B because of their limited shelf life, potential to cause iron poisoning, and limited applicability (effective only in cases of cyanide ingestion, whereas the main modes of poisoning are inhalation and skin contact). The HSE has also questioned the usefulness of amyl nitrite due to storage/availability problems, risk of abuse, and lack of evidence of significant benefits. It also states that the availability of Kelocyanor at the workplace may mislead doctors into treating a patient for cyanide poisoning when this is an erroneous diagnosis. The HSE no longer recommends a particular cyanide antidote.[29]
Agent Description
Nitrites The nitrites oxidize some of the hemoglobin's iron from the ferrous state to the ferric state, converting the hemoglobin into methemoglobin.
Cyanide binds avidly to methemoglobin, forming cyanmethemoglobin, thus releasing cyanide from cytochrome oxidase.[30] Treatment with nitrites is not innocuous as methemoglobin cannot carry oxygen, and severe methemoglobinemia may need to be treated in turn with methylene blue.[note 1]
Thiosulfate The evidence for sodium thiosulfate's use is based on animal studies and case reports: the small quantities of cyanide present in dietary sources and in cigarette smoke are normally metabolized to relatively harmless thiocyanate by the mitochondrial enzyme rhodanese (thiosulfate cyanide sulfurtransferase), which uses thiosulfate as a substrate. However, this reaction occurs too slowly in the body for thiosulfate to be adequate by itself in acute cyanide poisoning. Thiosulfate must therefore be used in combination with nitrites.[30]
Hydroxocobalamin Hydroxocobalamin, a form (or vitamer) of vitamin B12 made by bacteria, and sometimes denoted vitamin B12a, is used to bind cyanide to form the harmless cyanocobalamin form of vitamin B12.
4-Dimethylaminophenol 4-Dimethylaminophenol (4-DMAP) has been proposed[by whom?] in Germany as a more rapid antidote than nitrites with (reportedly) lower toxicity. 4-DMAP is used currently by the German military and by the civilian population. In humans, intravenous injection of 3 mg/kg of 4-DMAP produces 35 percent methemoglobin levels within 1 minute. Reportedly, 4-DMAP is part of the US Cyanokit, while it is not part of the German Cyanokit due to side effects (e. g. hemolysis).
Dicobalt edetate Cobalt ions, being chemically similar to iron ions, can also bind cyanide. One current cobalt-based antidote available in Europe is dicobalt edetate or dicobalt-EDTA, sold as Kelocyanor. This agent chelates cyanide as the cobalticyanide. This drug provides an antidote effect more quickly than formation of methemoglobin, but a clear superiority to methemoglobin formation has not been demonstrated. Cobalt complexes are quite toxic, and there have been accidents reported in the UK where patients have been given dicobalt-EDTA by mistake based on a false diagnosis of cyanide poisoning. Because of its side effects, it should be reserved only for patients with the most severe degree of exposure to cyanide; otherwise, nitrite/thiosulfate is preferred.[33]
Glucose Evidence from animal experiments suggests that coadministration of glucose protects against cobalt toxicity associated with the antidote agent dicobalt edetate. For this reason, glucose is often administered alongside this agent (e.g. in the formulation 'Kelocyanor').
It has also been anecdotally suggested that glucose is itself an effective counteragent to cyanide, reacting with it to form less toxic compounds that can be eliminated by the body. One theory on the apparent immunity of Grigori Rasputin to cyanide was that his killers put the poison in sweet pastries and madeira wine, both of which are rich in sugar; thus, Rasputin would have been administered the poison together with massive quantities of antidote. One study found a reduction in cyanide toxicity in mice when the cyanide was first mixed with glucose.[34] However, as yet glucose on its own is not an officially acknowledged antidote to cyanide poisoning.
3-Mercaptopyruvate prodrugs The most widely studied cyanide-metabolizing pathway involves utilization of thiosulfate by the enzyme rhodanese, as stated above. In humans, however, rhodanese is concentrated in the kidneys (0.96 units/mg protein) and liver (0.15 u/mg), with concentrations in lung, brain, muscle and stomach not exceeding 0.03 U/ml.[35] In all these tissues, it is found in the mitochondrial matrix, a site of low accessibility for ionized, inorganic species, such as thiosulfate. This compartmentalization of rhodanese in mammalian tissues leaves major targets of cyanide lethality, namely, the heart and central nervous system, unprotected. (Rhodanese is also found in red blood cells, but its relative importance has not been clarified.[36][37])
A different cyanide-metabolizing pathway, 3-mercaptopyruvate sulfurtransferase (3-MPST, EC 2.8.1.2), which is more widely distributed in mammalian tissues than rhodanese, is being explored. 3-MPST converts cyanide to thiocyanate, using the cysteine catabolite, 3-mercaptopyruvate (3-MP). However, 3-MP is extremely unstable chemically. Therefore, a prodrug, sulfanegen sodium (2, 5-dihydroxy-1,4-dithiane-2,5-dicarboxylic acid disodium salt), which hydrolyzes into 2 molecules of 3-MP after being administered orally or parenterally, is being evaluated in animal models.[38][39]
Oxygen therapy Oxygen therapy is not a cure in its own right. However, the human liver is capable of metabolizing cyanide quickly in low doses (smokers breathe in hydrogen cyanide, but it is such a small amount and metabolized so fast that it does not accumulate).
1. ^ Methylene blue has historically been used as an antidote to cyanide poisoning,[31] but is not a preferred therapy due to its theoretical risk of worsening of cyanide symptoms by displacement of cyanide from methemoglobin, allowing the toxin to bind to tissue electron transport chains.[32]
## History[edit]
### Fires[edit]
The República Cromañón nightclub fire occurred in Buenos Aires, Argentina on 30 December 2004, killing 194 people and leaving at least 1,492 injured. Most of the victims died from inhaling poisonous gases, and carbon monoxide. After the fire, the technical institution INTI found that the level of toxicity due to the materials and volume of the building was 225 ppm of cyanide in the air. A lethal dose for rats is between 150 ppm and 220 ppm, meaning the air in the building was highly toxic.
On 5 December 2009, a fire in the night club Lame Horse (Khromaya Loshad) in the Russian city of Perm took the lives of 156 people. Fatalities consisted of 111 people at the site and 45 later in hospitals. One of the main causes of death was poisoning from cyanide and other toxic gases released by the burning of plastic and polyurethane foam used in the construction of club interiors. Taking into account the number of deaths, this was the largest fire in post-Soviet Russia.[citation needed]
On 27 January 2013, a fire at the Kiss nightclub in the city of Santa Maria, in the south of Brazil, caused the poisoning of hundreds of young people by cyanide released by the combustion of soundproofing foam made with polyurethane. By March 2013, 241 fatalities were confirmed.[40][41][when?]
### Gas chambers[edit]
Empty Zyklon B canisters, found by the Soviets in January 1945 at Auschwitz
In early 1942, Zyklon B, which contains hydrogen cyanide, emerged as the preferred killing tool of Nazi Germany for use in extermination camps during the Holocaust.[42] The chemical was used to kill roughly one million people in gas chambers installed in extermination camps at Auschwitz-Birkenau, Majdanek, and elsewhere.[43] Most of the people who were killed were Jews, and by far the majority killed using this method died at Auschwitz.[44][45][a] Zyklon B was supplied to concentration camps at Mauthausen, Dachau, and Buchenwald by the distributor Heli, and to Auschwitz and Majdanek by Testa. Camps also occasionally bought Zyklon B directly from the manufacturers.[47] Of the 729 tonnes of Zyklon B sold in Germany in 1942–44, 56 tonnes (about eight percent of domestic sales) were sold to concentration camps.[48] Auschwitz received 23.8 tonnes, of which six tonnes were used for fumigation. The remainder was used in the gas chambers or lost to spoilage (the product had a stated shelf life of only three months).[49] Testa conducted fumigations for the Wehrmacht and supplied them with Zyklon B. They also offered courses to the SS in the safe handling and use of the material for fumigation purposes.[50] In April 1941, the German agriculture and interior ministries designated the SS as an authorized applier of the chemical, and thus they were able to use it without any further training or governmental oversight.[51]
Hydrogen cyanide gas has been used for judicial execution in some states of the United States, where cyanide was generated by reaction between potassium cyanide (or sodium cyanide[52][53]) dropped into a compartment containing sulfuric acid, directly below the chair in the gas chamber.[54]
### Suicide[edit]
Cyanide salts are sometimes used as fast-acting suicide devices. Cyanide reacts at a higher level with high stomach acidity.
* On 26 January 1904, company promoter and swindler Whitaker Wright committed suicide by ingesting cyanide in a court anteroom immediately after being convicted of fraud.
* In February 1937, the Uruguayan short story writer Horacio Quiroga committed suicide by drinking cyanide in a hospital at Buenos Aires.
* In 1937, polymer chemist Wallace Carothers committed suicide by cyanide.
* In the 1943 Operation Gunnerside to destroy the Vemork Heavy Water Plant in World War II (an attempt to stop or slow German atomic bomb progress), the commandos were given cyanide tablets (cyanide enclosed in rubber) kept in the mouth and were instructed to bite into them in case of German capture. The tablets ensured death within three minutes.[55]
* Cyanide, in the form of pure liquid prussic acid (a historical name for hydrogen cyanide), was the favored suicide agent of the Third Reich. It was used to commit suicide by Erwin Rommel (1944), Adolf Hitler's wife, Eva Braun (1945), and by Nazi leaders Heinrich Himmler (1945), possibly Martin Bormann (1945), and Hermann Göring (1946).
* It is speculated that, in 1954, Alan Turing used an apple that had been injected with a solution of cyanide to commit suicide after being convicted of having a homosexual relationship—illegal at the time in the UK—and forced to undergo hormonal castration.
* Members of the Sri Lankan LTTE (Liberation Tigers of Tamil Eelam, whose insurgency lasted from 1983 to 2009), used to wear cyanide vials around their necks with the intention of committing suicide if captured by the government forces.
* On 18 November 1978, Jonestown. A total of 909 individuals died in Jonestown, many from apparent cyanide poisoning, in an event termed "revolutionary suicide" by Jones and some members on an audio tape of the event and in prior discussions. The poisonings in Jonestown followed the murder of five others by Temple members at Port Kaituma, including United States Congressman Leo Ryan, an act that Jones ordered. Four other Temple members committed murder-suicide in Georgetown at Jones' command.
* On 6 June 1985, serial killer Leonard Lake died in custody after having ingested cyanide pills he had sewn into his clothes.
* On 28 June 2012, Wall Street trader Michael Marin ingested a cyanide pill seconds after a guilty verdict was read in his arson trial in Phoenix, AZ; he died minutes after.[56]
* On 22 June 2015, John B. McLemore, a horologist and the central figure of the podcast S-Town, died after ingesting cyanide.[57]
* On 29 November 2017, Slobodan Praljak died from drinking potassium cyanide, after being convicted of war crimes by the International Criminal Tribunal for the former Yugoslavia.[58]
### Mining and industrial[edit]
* In 2000, a spill at Baia Mare, Romania, resulted in the worst environmental disaster in Europe since Chernobyl.[59]
* In 2000, Allen Elias, CEO of Evergreen Resources was convicted of knowing endangerment for his role in the cyanide poisoning of employee Scott Dominguez.[60][61] This was one of the first successful criminal prosecutions of a corporate executive by the Environmental Protection Agency.
### Murder[edit]
* John Tawell, a murderer who in 1845 became the first person to be arrested as the result of telecommunications technology.
* Grigori Rasputin (1916; attempted, later killed by gunshot)
* Goebbels children (1945)
* Stepan Bandera (1959)
* Jonestown, Guyana, was the site of a large mass murder–suicide,[62] in which over 900 members of the Peoples Temple drank potassium cyanide–laced Flavor Aid in 1978.
* Chicago Tylenol murders (1982)
* Ronald Clark O'Bryan (1944–1984)
* Bruce Nickell (5 June 1986) Murdered by his wife who poisoned a bottle of Excedrin.
* Richard Kuklinski (1935–2006)
* Janet Overton (1942–1988) Her husband, Richard Overton was convicted of poisoning her,[63] but Janet's symptoms did not match those of classic cyanide poisoning, the timeline was inconsistent with cyanide poisoning, and the amount found was just a trace. The diagnostic method used was prone to false positives. Richard Overton died in prison in 2009.
* Urooj Khan (1966–2012), won the lottery and was found dead a few days later.[64] A blood diagnostic reported a lethal level of cyanide in his blood, but the body did not display any classic symptoms of cyanide poisoning, and no link to cyanide could be found in Urooj's social circle. The diagnostic method used was the Conway diffusion method, prone to false positives with artifacts of heart attack and kidney failure.
* Autumn Marie Klein (20 April 2013), a prominent 41-year-old neuroscientist and physician, died from cyanide poisoning. Klein's husband, Robert J. Ferrante, also a prominent neuroscientist who used cyanide in his research, was convicted of murder and sentenced to life in prison for her death. However, Klein never exhibited symptoms of cyanide poisoning and the amount measured in relation to the timeline (2.2 mg/L at 15 hours after supposed ingestion but zero thiocyanate levels) suggest that the measurement was a false positive. Robert Ferrante is appealing his conviction.[65]
* Mirna Salihin died in hospital on 6 January 2016, after drinking a Vietnamese iced coffee at a cafe in a shopping mall in Jakarta. Police reports claim that cyanide poisoning was the most likely cause of her death.
* Jolly Thomas of Kozhikode, Kerala, India, was arrested in 2019 for the murder of 6 family members. Murders took place over 14-year period and each victim ate a meal prepared by the killer. The murders were allegedly motivated by wanting control of the family finances and property.[66]
* Mei Xiang Li of Brooklyn, NY, collapsed and died in April 2017, with cyanide later reported to be in her blood.[67] However, Mei never exhibited symptoms of cyanide poisoning and no link to cyanide could be found in her life.
### Terrorism[edit]
* In 1995, a device was discovered in a restroom in the Kayabacho Tokyo subway station, consisting of bags of sodium cyanide and sulfuric acid with a remote controlled motor to rupture them in what was believed to be an attempt by the Aum Shinrikyo cult to produce toxic amounts of hydrogen cyanide gas.[68]
* In 2003, Al Qaeda reportedly planned to release cyanide gas into the New York City Subway system. The attack was supposedly aborted because there would not be enough casualties.[69]
## Research[edit]
Cobinamide is the final compound in the biosynthesis of cobalamin. It has greater affinity for the cyanide than cobalamin itself, which suggests that it could be a better option for emergency treatment.[70]
## See also[edit]
* List of poisonings
* Konzo
## References[edit]
### Explanatory notes[edit]
1. ^ Soviet officials initially stated that over four million people were killed using Zyklon B at Auschwitz, but this figure was later proven to be greatly exaggerated.[46]
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26. ^ Toxicity, Cyanide~overview at eMedicine
27. ^ Toxicity, Cyanide~treatment at eMedicine
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31. ^ Hanzlik, PJ (4 February 1933). "Methylene blue as an antidote for cyanide poisoning". JAMA. 100 (5): 357. doi:10.1001/jama.1933.02740050053028.
32. ^ Dart, Richard, ed. (2004). Medical Toxicology (Third ed.). Lippincott Williams & Wilkins. p. 221. ISBN 9780781728454. Archived from the original on 8 September 2017.
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35. ^ Aminlari, Mahmoud; Malekhusseini, Ali; Akrami, Fatemeh; Ebrahimnejad, Hadi (2006). "Cyanide-metabolizing enzyme rhodanese in human tissues: Comparison with domestic animals". Comparative Clinical Pathology. 16: 47–51. doi:10.1007/s00580-006-0647-x. S2CID 12978560.
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42. ^ Longerich 2010, pp. 281–282.
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46. ^ Steinbacher 2005, pp. 132–133. sfn error: no target: CITEREFSteinbacher2005 (help)
47. ^ Hayes 2004, pp. 288–289.
48. ^ Hayes 2004, p. 296.
49. ^ Hayes 2004, pp. 294–297, chpt. "Degesch and Zyklon B.". "The SS learned in 1944 that the expiration dates on the Zyklon tins were not hard and fast. All in all, it seems reasonable to assume that the SS over- rather than underdosed ..." —Peter Hayes
50. ^ Hayes 2004, p. 283.
51. ^ Hayes 2004, p. 284.
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### Sources[edit]
* Longerich, Peter (2010). Holocaust: The Nazi Persecution and Murder of the Jews. Oxford; New York: Oxford University Press. ISBN 978-0-19-280436-5.
* Hayes, Peter (2004). From Cooperation to Complicity: Degussa in the Third Reich. Cambridge; New York; Melbourne: Cambridge University Press. ISBN 978-0-521-78227-2.
* Piper, Franciszek (1994). "Gas Chambers and Crematoria". In Gutman, Yisrael; Berenbaum, Michael (eds.). Anatomy of the Auschwitz Death Camp. Bloomington, Indiana: Indiana University Press. pp. 157–182. ISBN 978-0-253-32684-3.
Classification
D
* ICD-10: T65.0
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* DiseasesDB: 3280
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*[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 inhibitors
*[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
| Cyanide poisoning | c0238080 | 4,870 | wikipedia | https://en.wikipedia.org/wiki/Cyanide_poisoning | 2021-01-18T18:46:36 | {"icd-9": ["989.0"], "icd-10": ["T65.0"], "orphanet": ["466670"], "synonyms": [], "wikidata": ["Q883082"]} |
X-linked leukodystrophy
Pelizaeus–Merzbacher disease
Pelizaeus–Merzbacher disease is inherited in an x-linked recessive manner[1]
SpecialtyNeurology
Pelizaeus–Merzbacher disease is an X-linked neurological disorder that damages oligodendrocytes in the central nervous system. It is caused by mutations in proteolipid protein 1 (PLP1), a major myelin protein. It is characterized by hypomyelination and belongs to a group of genetic diseases referred to as leukodystrophies.[2]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Diagnosis
* 3.1 Classification
* 4 Treatment
* 5 Research
* 6 See also
* 7 References
* 8 Further reading
* 9 External links
## Signs and symptoms[edit]
Hallmark signs and symptoms of Pelizaeus–Merzbacher disease include little or no movement in the arms or legs, respiratory difficulties, and characteristic horizontal movements of the eyes left to right.[citation needed]
The onset of Pelizaeus–Merzbacher disease is usually in early infancy. The most characteristic early signs are nystagmus (rapid, involuntary, rhythmic motion of the eyes) and low muscle tone. Motor abilities are delayed or never acquired, mostly depending upon the severity of the mutation. Most children with Pelizaeus–Merzbacher disease learn to understand language, and usually have some speech. Other signs may include tremor, lack of coordination, involuntary movements, weakness, unsteady gait, and over time, spasticity in legs and arms. Muscle contractures often occur over time. Mental functions may deteriorate. Some patients may have convulsions and skeletal deformation, such as scoliosis, resulting from abnormal muscular stress on bones.[citation needed]
## Cause[edit]
Pelizaeus–Merzbacher disease is caused by X-linked recessive mutations in the major myelin protein proteolipid protein 1 (PLP1). This causes hypomyelination in the central nervous system and severe neurological disease.The majority of mutations result in duplications of the entire PLP1 gene. Deletions of PLP1 locus (which are rare) cause a milder form of Pelizaeus–Merzbacher disease than is observed with the typical duplication mutations, which demonstrates the critical importance of gene dosage at this locus for normal CNS function.[citation needed]
## Diagnosis[edit]
The diagnosis of Pelizaeus–Merzbacher disease is often first suggested after identification by magnetic resonance imaging of abnormal white matter (high T2 signal intensity, i.e. T2 lengthening) throughout the brain, which is typically evident by about 1 year of age, but more subtle abnormalities should be evident during infancy. Unless a family history consistent with sex-linked inheritance exists, the condition is often misdiagnosed as cerebral palsy. Once a PLP1 mutation is identified, prenatal diagnosis or preimplantation genetic diagnostic testing is possible.[citation needed]
### Classification[edit]
The disease is one in a group of genetic disorders collectively known as leukodystrophies that affect growth of the myelin sheath, the fatty covering—which acts as an insulator—on nerve fibers in the central nervous system. The several forms of Pelizaeus–Merzbacher disease include classic, connatal, transitional, and adult variants.[citation needed]
Milder mutations of the PLP1 gene that mainly cause leg weakness and spasticity, with little or no cerebral involvement, are classified as spastic paraplegia 2 (SPG2).[citation needed]
## Treatment[edit]
No cure or standard treatment for Pelizaeus–Merzbacher disease has been developed.[3] Outcomes are variable: people with the most severe form of the disease do not usually survive to adolescence, although with milder forms, survival into adulthood is possible.[3]
## Research[edit]
In December 2008, StemCells, Inc received clearance in the United States to conduct a phase I clinical trials of human neural stem cell transplantation.[4] The trial did not show meaningful efficacy and the company has since gone bankrupt.[5]
In 2019 Paul Tesar used CRISPR and antisense therapy in a mouse model of Pelizaeus–Merzbacher with success.[6][7][8] Iron chelation as a potential treatment is also being studied.[9]
## See also[edit]
* The Myelin Project
* The Stennis Foundation
## References[edit]
1. ^ "OMIM Entry - # 312080 - Pelizaeus-Merzbacher Disease; PMD". omim.org. Retrieved 5 August 2017.
2. ^ Hobson, Grace; Garbern, James (2012). "Pelizaeus-Merzbacher Disease, Pelizaeus-Merzbacher-Like Disease 1, and Related Hypomyelinating Disorders". Seminars in Neurology. 32 (1): 062–067. doi:10.1055/s-0032-1306388. ISSN 0271-8235. PMID 22422208.
3. ^ a b "Pelizaeus-Merzbacher Disease Information Page". National Institute of Neurological Disorders and Stroke.
4. ^ "Stem Cells, Inc".
5. ^ "End of line for StemCells Inc., pioneering & controversial stem cell biotech". 2016-05-31.
6. ^ Elitt, Matthew S.; Barbar, Lilianne; Shick, H. Elizabeth; Powers, Berit E.; Maeno-Hikichi, Yuka; Madhavan, Mayur; Allan, Kevin C.; Nawash, Baraa S.; Nevin, Zachary S.; Olsen, Hannah E.; Hitomi, Midori; LePage, David F.; Jiang, Weihong; Conlon, Ronald A.; Rigo, Frank; Tesar, Paul J. (31 December 2018). "Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice". bioRxiv: 508192. doi:10.1101/508192.
7. ^ "Suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease". 2020-07-01.
8. ^ "Research finds new approach to treating certain neurological diseases". MedicalXpress. 1 July 2020. Retrieved 1 July 2020. "Their research was published online July 1 in the journal Nature. "The pre-clinical results were profound. PMD mouse models that typically die within a few weeks of birth were able to live a full lifespan after treatment," said Paul Tesar"
9. ^ Nobuta, Hiroko; Yang, Nan; Ng, Yi Han; Marro, Samuele G.; Sabeur, Khalida; Chavali, Manideep; Stockley, John H.; Killilea, David W.; Walter, Patrick B.; Zhao, Chao; Huie, Philip; Goldman, Steven A.; Kriegstein, Arnold R.; Franklin, Robin J.M.; Rowitch, David H.; Wernig, Marius (October 2019). "Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation". Cell Stem Cell. 25 (4): 531–541.e6. doi:10.1016/j.stem.2019.09.003. PMID 31585094.
## Further reading[edit]
* Uhlenberg, Birgit; Schuelke, Markus; Rüschendorf, Franz; Ruf, Nico; Kaindl, Angela M.; Henneke, Marco; Thiele, Holger; Stoltenburg-Didinger, Gisela; Aksu, Fuat; Topaloğlu, Haluk; Nürnberg, Peter; Hübner, Christoph; Weschke, Bernhard; Gärtner, Jutta (August 2004). "Mutations in the Gene Encoding Gap Junction Protein α12 (Connexin 46.6) Cause Pelizaeus-Merzbacher–Like Disease". The American Journal of Human Genetics. 75 (2): 251–260. doi:10.1086/422763. PMC 1216059. PMID 15192806.
## External links[edit]
* Pelizaeus-Merzbacher Disease. NINDS/National Health Institutes.
* pmd at NIH/UW GeneTests
Classification
D
* ICD-10: E75.2
* ICD-9-CM: 330.0
* OMIM: 312080
* MeSH: D020371
* DiseasesDB: 29467
External resources
* eMedicine: neuro/520
* Patient UK: Pelizaeus–Merzbacher disease
* Orphanet: 702
* v
* t
* e
Lysosomal storage diseases: Inborn errors of lipid metabolism (Lipid storage disorders)
Sphingolipidoses
(to ceramide)
From ganglioside
(gangliosidoses)
* Ganglioside: GM1 gangliosidoses
* GM2 gangliosidoses (Sandhoff disease
* Tay–Sachs disease
* AB variant)
From globoside
* Globotriaosylceramide: Fabry's disease
From sphingomyelin
* Sphingomyelin: phospholipid: Niemann–Pick disease (SMPD1-associated
* type C)
* Glucocerebroside: Gaucher's disease
From sulfatide
(sulfatidoses
* leukodystrophy)
* Sulfatide: Metachromatic leukodystrophy
* Multiple sulfatase deficiency
* Galactocerebroside: Krabbe disease
To sphingosine
* Ceramide: Farber disease
NCL
* Infantile
* Jansky–Bielschowsky disease
* Batten disease
Other
* Cerebrotendineous xanthomatosis
* Cholesteryl ester storage disease (Lysosomal acid lipase deficiency/Wolman disease)
* Sea-blue histiocytosis
* v
* t
* e
Multiple sclerosis and other demyelinating diseases of the central nervous system
Signs and symptoms
* Ataxia
* Depression
* Diplopia
* Dysarthria
* Dysphagia
* Fatigue
* Incontinence
* Nystagmus
* Optic neuritis
* Pain
* Uhthoff's phenomenon
Investigations and diagnosis
* Multiple sclerosis diagnosis
* McDonald criteria
* Poser criteria
* Clinical
* Clinically isolated syndrome
* Expanded Disability Status Scale
* Serological and CSF
* Oligoclonal bands
* Radiological
* Radiologically isolated syndrome
* Lesional demyelinations of the central nervous system
* Dawson's fingers
Approved[by whom?] treatment
* Management of multiple sclerosis
* Alemtuzumab
* Cladribine
* Dimethyl fumarate
* Fingolimod
* Glatiramer acetate
* Interferon beta-1a
* Interferon beta-1b
* Mitoxantrone
* Natalizumab
* Ocrelizumab
* Ozanimod
* Siponimod
* Teriflunomide
Other treatments
* Former
* Daclizumab
* Multiple sclerosis research
Demyleinating diseases
Autoimmune
* Multiple sclerosis
* Neuromyelitis optica
* Diffuse myelinoclastic sclerosis
Inflammatory
* Acute disseminated encephalomyelitis
* MOG antibody disease
* Balo concentric sclerosis
* Marburg acute multiple sclerosis
* Neuromyelitis optica
* Diffuse myelinoclastic sclerosis
* Tumefactive multiple sclerosis
* Experimental autoimmune encephalomyelitis
Hereditary
* Adrenoleukodystrophy
* Alexander disease
* Canavan disease
* Krabbe disease
* Metachromatic leukodystrophy
* Pelizaeus–Merzbacher disease
* Leukoencephalopathy with vanishing white matter
* Megalencephalic leukoencephalopathy with subcortical cysts
* CAMFAK syndrome
Other
* Central pontine myelinolysis
* Marchiafava–Bignami disease
* Mitochondrial DNA depletion syndrome
Other
* List of multiple sclerosis organizations
* List of people with multiple sclerosis
* Multiple sclerosis drug pipeline
* Pathophysiology
* v
* t
* e
X-linked disorders
X-linked recessive
Immune
* Chronic granulomatous disease (CYBB)
* Wiskott–Aldrich syndrome
* X-linked severe combined immunodeficiency
* X-linked agammaglobulinemia
* Hyper-IgM syndrome type 1
* IPEX
* X-linked lymphoproliferative disease
* Properdin deficiency
Hematologic
* Haemophilia A
* Haemophilia B
* X-linked sideroblastic anemia
Endocrine
* Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy
* KAL1 Kallmann syndrome
* X-linked adrenal hypoplasia congenita
Metabolic
* Amino acid: Ornithine transcarbamylase deficiency
* Oculocerebrorenal syndrome
* Dyslipidemia: Adrenoleukodystrophy
* Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency
* Pyruvate dehydrogenase deficiency
* Danon disease/glycogen storage disease Type IIb
* Lipid storage disorder: Fabry's disease
* Mucopolysaccharidosis: Hunter syndrome
* Purine–pyrimidine metabolism: Lesch–Nyhan syndrome
* Mineral: Menkes disease/Occipital horn syndrome
Nervous system
* X-linked intellectual disability: Coffin–Lowry syndrome
* MASA syndrome
* Alpha-thalassemia mental retardation syndrome
* Siderius X-linked mental retardation syndrome
* Eye disorders: Color blindness (red and green, but not blue)
* Ocular albinism (1)
* Norrie disease
* Choroideremia
* Other: Charcot–Marie–Tooth disease (CMTX2-3)
* Pelizaeus–Merzbacher disease
* SMAX2
Skin and related tissue
* Dyskeratosis congenita
* Hypohidrotic ectodermal dysplasia (EDA)
* X-linked ichthyosis
* X-linked endothelial corneal dystrophy
Neuromuscular
* Becker's muscular dystrophy/Duchenne
* Centronuclear myopathy (MTM1)
* Conradi–Hünermann syndrome
* Emery–Dreifuss muscular dystrophy 1
Urologic
* Alport syndrome
* Dent's disease
* X-linked nephrogenic diabetes insipidus
Bone/tooth
* AMELX Amelogenesis imperfecta
No primary system
* Barth syndrome
* McLeod syndrome
* Smith–Fineman–Myers syndrome
* Simpson–Golabi–Behmel syndrome
* Mohr–Tranebjærg syndrome
* Nasodigitoacoustic syndrome
X-linked dominant
* X-linked hypophosphatemia
* Focal dermal hypoplasia
* Fragile X syndrome
* Aicardi syndrome
* Incontinentia pigmenti
* Rett syndrome
* CHILD syndrome
* Lujan–Fryns syndrome
* Orofaciodigital syndrome 1
* Craniofrontonasal dysplasia
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[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
| Pelizaeus–Merzbacher disease | c0205711 | 4,871 | wikipedia | https://en.wikipedia.org/wiki/Pelizaeus%E2%80%93Merzbacher_disease | 2021-01-18T18:55:21 | {"gard": ["4265"], "mesh": ["D020371"], "umls": ["C0205711"], "icd-9": ["330.0"], "orphanet": ["702"], "wikidata": ["Q1876206"]} |
Benign partial epilepsy of infancy with complex partial seizures is a rare infantile epilepsy syndrome characterized by complex partial seizures presenting with motion arrest, decreased responsiveness, staring, automatisms and mild clonic movements, with or without apneas, normal interictal EEG and focal, mostly temporal discharges in ictal EEG. Most often, seizures occur in clusters and have a good response to treatment. Psychomotor development is normal.
*[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 inhibitors
*[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
| Benign partial epilepsy of infancy with complex partial seizures | None | 4,872 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=166299 | 2021-01-23T19:01:51 | {"icd-10": ["G40.2"]} |
Ramsay Hunt syndrome
Other namesFacial nerve palsy due to herpes zoster infection
SpecialtyNeurology
Three different neurological syndromes carry the name of Ramsay Hunt syndrome. Their only connection is that they were all first described by the famous neurologist James Ramsay Hunt (1872–1937).
* Ramsay Hunt syndrome type 1, also called Ramsay Hunt cerebellar syndrome, is a rare form of cerebellar degeneration which involves myoclonic epilepsy, progressive ataxia, tremor, and a dementing process.[1]
* Ramsay Hunt syndrome type 2 is the reactivation of herpes zoster in the geniculate ganglion. It is sometimes called herpes zoster oticus, and has variable presentation which may include a lower motor neuron lesion of the facial nerve, deafness, vertigo, and pain.[2][3] A triad of ipsilateral facial paralysis, ear pain, and vesicles on the face, on the ear, or in the ear is the typical presentation.
* Ramsay Hunt syndrome type 3 is a less commonly referenced condition, an occupationally induced neuropathy of the deep palmar branch of the ulnar nerve. It is also called Hunt's disease or artisan's palsy.[4]
## Notes[edit]
1. ^ "NINDS Dyssynergia Cerebellaris Myoclonica Information Page". National Institute of Neurological Disorders and Stroke. 14 February 2011. Archived from the original on 16 February 2015. Retrieved 6 January 2015.
2. ^ Ramsay Hunt, J. (1907). "On herpetic inflammations of the geniculate ganglion: a new syndrome and its complications". Journal of Nervous and Mental Disease. 34 (2): 73–96. doi:10.1097/00005053-190702000-00001.
3. ^ Sweeney, C.J.; Gilden, D.H. (August 2001). "Ramsay Hunt Syndrome". Journal of Neurology, Neurosurgery, and Psychiatry. 71 (2): 149–54. doi:10.1136/jnnp.71.2.149. PMC 1737523. PMID 11459884.
4. ^ Pearce, J.M.S. (2007). "Some Syndromes of James Ramsay Hunt". Practical Neurology. 7 (3): 182–185. PMID 17515597. Retrieved 8 July 2016.
## External links[edit]
Classification
D
* ICD-10: B02.2+ G53.0*
External resources
* eMedicine: article/1166804
* Orphanet: 3020
*[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 inhibitors
*[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
| Ramsay Hunt syndrome | c0017409 | 4,873 | wikipedia | https://en.wikipedia.org/wiki/Ramsay_Hunt_syndrome | 2021-01-18T19:08:00 | {"mesh": ["D016697"], "wikidata": ["Q2697371"]} |
Infant respiratory distress syndrome
Other namesNeonatal respiratory distress syndrome [1]
Chest X-ray of a case of IRDS, with fine granular opacities, air bronchograms and bell-shaped thorax
SpecialtyPediatrics, obstetrics
Infantile respiratory distress syndrome (IRDS), also called respiratory distress syndrome of newborn, or increasingly surfactant deficiency disorder (SDD),[2] and previously called hyaline membrane disease (HMD), is a syndrome in premature infants caused by developmental insufficiency of pulmonary surfactant production and structural immaturity in the lungs. It can also be a consequence of neonatal infection and can result from a genetic problem with the production of surfactant-associated proteins.[3][4] IRDS affects about 1% of newborns and is the leading cause of death in preterm infants.[5] Notably, data has shown the choice of elective caesarean sections to strikingly increase the incidence of respiratory distress in term infants; dating back to 1995, the UK first documented 2,000 annual caesarean section births requiring neonatal admission for respiratory distress.[6]The incidence decreases with advancing gestational age, from about 50% in babies born at 26–28 weeks to about 25% at 30–31 weeks. The syndrome is more frequent in males, Caucasians, infants of diabetic mothers and the second-born of premature twins.[7][8]
IRDS is distinct from pulmonary hypoplasia, another leading cause of neonatal death that involves respiratory distress.
## Contents
* 1 Signs and symptoms
* 1.1 Related disorders
* 2 Histopathology
* 3 Pathophysiology
* 4 Diagnosis
* 5 Prevention
* 6 Treatment
* 7 Culture
* 8 See also
* 9 References
* 10 External links
## Signs and symptoms[edit]
IRDS begins shortly after birth and is manifested by fast breathing (more than 60 breaths per minute), a fast heart rate, chest wall retractions (recession), expiratory grunting, nasal flaring and blue discoloration of the skin during breathing efforts.[citation needed]
As the disease progresses, the baby may develop ventilatory failure (rising carbon dioxide concentrations in the blood) and prolonged cessations of breathing ("apnea"). Whether treated or not, the clinical course for the acute disease lasts about two to three days. During the first day, the child worsens and requires more support. During the second day, the baby may be remarkably stable on adequate support and resolution is noted during the third day, heralded by a prompt diuresis. Despite huge advances in care, IRDS remains the most common single cause of death in the first month of life in the developed world. Complications include metabolic disorders (acidosis, low blood sugar), patent ductus arteriosus, low blood pressure, chronic lung changes and bleeding in the brain. The syndrome is frequently complicated by prematurity and its additional effect on other organ functions.[citation needed]
### Related disorders[edit]
Acute respiratory distress syndrome (ARDS) has some similarities to IRDS. Transient tachypnea of the newborn presents with respiratory distress syndrome in the preterm child.[citation needed]
## Histopathology[edit]
The characteristic histopathology seen in babies who die from RDS was the source of the name "hyaline membrane disease". Waxlike layers of hyaline membrane line the collapsed alveoli of the lung. In addition, the lungs show bleeding, overdistention of airways and damage to the lining cells.[citation needed]
## Pathophysiology[edit]
The lungs of infants with respiratory distress syndrome are developmentally deficient in a material called surfactant, which helps prevent collapse of the terminal air spaces (the future site of alveolar development) throughout the normal cycle of inhalation and exhalation. This deficiency of surfactant is related to an inhibition from the insulin that is produced in the newborn, especially those of diabetic mothers.[9]
Pulmonary surfactant is a complex system of lipids, proteins and glycoproteins that is produced in specialized lung cells called Type II cells or Type II pneumocytes. The surfactant is packaged by the cell in structures called lamellar bodies, and extruded into the air spaces. The lamellar bodies then unfold into a complex lining of the air space. This layer reduces the surface tension of the fluid that lines the alveolar air space. Surface tension is responsible for approximately 2/3 of the inward elastic recoil forces. In the same way that a bubble will contract to give the smallest surface area for a given volume, so the air/water interface means that the liquid surface will tend toward being as small as possible, thereby causing the air space to contract. By reducing surface tension, surfactant prevents the air spaces from completely collapsing on exhalation. In addition, the decreased surface tension allows reopening of the air space with a lower amount of force. Therefore, without adequate amounts of surfactant, the air spaces collapse and are very difficult to expand.[citation needed]
Microscopically, a pulmonary surfactant-deficient lung is characterized by collapsed air spaces alternating with hyperexpanded areas, vascular congestion and, in time, hyaline membranes. Hyaline membranes are composed of fibrin, cellular debris, red blood cells, rare neutrophils and macrophages. They appear as an eosinophilic, amorphous material, lining or filling the air spaces and blocking gas exchange. As a result, blood passing through the lungs is unable to pick up oxygen and unload carbon dioxide. Blood oxygen levels fall and carbon dioxide rises, resulting in rising blood acid levels and hypoxia. Structural immaturity, as manifested by a decreased number of gas-exchange units and thicker walls, also contributes to the disease process. Therapeutic oxygen and positive-pressure ventilation, while potentially life-saving, can damage the lung.[citation needed]
## Diagnosis[edit]
The diagnosis is made by the clinical picture and the chest X-ray, which demonstrates decreased lung volumes (bell-shaped chest), absence of the thymus (after about six hours), a small (0.5–1 mm), discrete, uniform infiltrate (sometimes described as a "ground glass" appearance or "diffuse airspace and interstitial opacities") that involves all lobes of the lung and air-bronchograms (i.e. the infiltrate will outline the larger airways passages, which remain air-filled). In severe cases, this becomes exaggerated until the cardiac borders become indiscernable (a 'white-out' appearance).[citation needed]
## Prevention[edit]
Giving the baby's mother glucocorticoids speeds the production of surfactant. For very premature deliveries, a glucocorticoid is given without testing the fetal lung maturity. The American College of Obstetricians and Gynecologists (ACOG), Royal College of Medicine and other major organizations have recommended antenatal glucocorticoid treatment for women at risk for preterm delivery prior to 34 weeks of gestation.[10] Multiple courses of glucocorticoid administration, compared with a single course, do not seem to increase or decrease the risk of death or neurodevelopmental disorders of the child.[11]
In pregnancies of longer than 30 weeks, the fetal lung maturity may be tested by sampling the amount of surfactant in the amniotic fluid by amniocentesis, wherein a needle is inserted through the mother's abdomen and uterus. Several tests are available that correlate with the production of surfactant. These include the lecithin-sphingomyelin ratio ("L/S ratio"), the presence of phosphatidylglycerol (PG), and, more recently, the surfactant/albumin (S/A) ratio. For the L/S ratio, if the result is less than 2:1, the fetal lungs may be deficient in surfactant. The presence of PG usually indicates fetal lung maturity. For the S/A ratio, the result is given as milligrams of surfactant per gram of protein. An S/A ratio less than 35 indicates immature lungs, between 35-55 is indeterminate and greater than 55 indicates mature surfactant production (correlating with an L/S ratio of 2.2 or greater).[citation needed]
## Treatment[edit]
Oxygen is given with a small amount of continuous positive airway pressure (CPAP), and intravenous fluids are administered to stabilize the blood sugar, blood salts and blood pressure. If the baby's condition worsens, an endotracheal tube (breathing tube) is inserted into the trachea and intermittent breaths are given by a mechanical device. An exogenous preparation of pulmonary surfactant, either synthetic or extracted from animal lungs, is given through the breathing tube into the lungs. Surfactant medications can decrease the risk of death for very low-birth-weight infants who are hospitalized by 30%.[12] Such small premature infants may remain ventilated for months. A study shows that an aerosol of a perfluorocarbon such as perfluoromethyldecalin can reduce inflammation in swine model of IRDS.[13] Chronic lung disease, including bronchopulmonary dysplasia, is common in severe RDS. The etiology of BPD is problematic and may be the result of oxygen, overventilation or underventilation. The mortality rate for babies greater than 27 weeks of gestation is less than 20%.[citation needed]
Extracorporeal membrane oxygenation (ECMO) is a potential treatment, providing oxygenation through an apparatus that imitates the gas exchange process of the lungs. However, newborns cannot be placed on ECMO if they are under 4.5 pounds (2 kg), because they have extremely small vessels for cannulation, thus hindering adequate flow because of limitations from cannula size and subsequent higher resistance to blood flow (compare with vascular resistance). Furthermore, in infants aged less than 34 weeks of gestation, several physiologic systems are not well-developed, especially the cerebral vasculature and germinal matrix, resulting in high sensitivity to slight changes in pH, PaO2 and intracranial pressure. Subsequently, preterm infants are at unacceptably high risk for intraventricular hemorrhage (IVH) if administered ECMO at a gestational age of less than 32 weeks.[14]
Henrik Verder is the inventor and pioneer of the INSURE method, a very effective approach to managing preterm neonates with respiratory distress. The method itself has been shown, through meta-analysis, to successfully decrease the use of mechanical ventilation and lower the incidence of bronchopulmonary dysplasia (BPD).[15] Since its conception in 1989, the INSURE method has been academically cited in more than 500 papers.[16] The first randomised study involving the INSURE method was published in 1994[17] and a second randomised study in infants less than 30 weeks gestation was published by the group in 1999.[18] In the last 15 years, Verder has worked with lung-maturity diagnostics on gastric aspirates obtained at birth. By combining this diagnostic method with INSURE, Verder has worked to further improve the clinical outcome of RDS. The lung-maturity tests used have included the microbubble test,[19] lamellar body counts (LBC)[20] and measurements of lecithin-sphingomyelin ratio (L/S)[21] with chemometrics, which involved a collaboration with Agnar Höskuldsson.[22]
## Culture[edit]
* In 1963, Patrick Bouvier Kennedy, son of President John F. Kennedy and First Lady Jacqueline Kennedy, died of RDS two days after his premature birth at 34 weeks gestation.[23]
* Two daughters of Dominick Dunne and his wife Ellen Griffin Dunne died of RDS, one in 1958 and one in 1963.[24]
## See also[edit]
* Bubble CPAP
* Bronchopulmonary dysplasia
* Pulmonary hypoplasia
* Surfactant metabolism dysfunction
* Surfactant therapy
* Wilson–Mikity syndrome
## References[edit]
1. ^ "neonatal respiratory distress syndrome" at Dorland's Medical Dictionary
2. ^ Northway Jr, WH; Rosan, RC; Porter, DY (Feb 16, 1967). "Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia". The New England Journal of Medicine. 276 (7): 357–68. doi:10.1056/NEJM196702162760701. PMID 5334613.
3. ^ Santosham, Mathuram; Chan, Grace J.; Lee, Anne CC; Baqui, Abdullah H.; Tan, Jingwen; Black, Robert E. (2013). "Risk of Early-Onset Neonatal Infection with Maternal Infection or Colonization: A Global Systematic Review and Meta-Analysis". PLOS Medicine. 10 (8): e1001502. doi:10.1371/journal.pmed.1001502. ISSN 1549-1676. PMC 3747995. PMID 23976885.
4. ^ Sinha, Sunil (2012). Essential neonatal medicine. Chichester, West Sussex: John Wiley & Sons. ISBN 9780470670408; Access provided by the University of Pittsburgh
5. ^ Rodriguez RJ, Martin RJ, Fanaroff AA (2002). "Respiratory distress syndrome and its management". In Fanaroff, Avroy A, Martin, Richard J (eds.). Neonatal-perinatal medicine: diseases of the fetus and infant. St. Louis: Mosby. pp. 1001–1011. ISBN 978-0-323-00929-4.
6. ^ Edwards, Martin O.; Kotecha, Sarah J.; Kotecha, Sailesh (1 March 2013). "Respiratory Distress of the Term Newborn Infant". Paediatric Respiratory Reviews. 14 (1): 29–37. doi:10.1016/j.prrv.2012.02.002. PMID 23347658.
7. ^ "Lung Problems in the Premature Baby". 2012-03-15.
8. ^ "Infant Respiratory Distress Syndrome. IRDS information".
9. ^ Snyder JM, Mendelson CR (1987). "Insulin inhibits the accumulation of the major lung surfactant apoprotein in human fetal lung explants maintained in vitro". Endocrinology. 120 (4): 1250–7. doi:10.1210/endo-120-4-1250. PMID 3549256.
10. ^ Men-Jean Lee; Debra Guinn; Charles J Lockwood; Vanessa A Barss. "Antenatal use of glucocorticoids in women at risk for preterm delivery". Retrieved December 16, 2013.
11. ^ Asztalos, EV; Murphy, KE; Willan, AR; Matthews, SG; Ohlsson, A; Saigal, S; Armson, BA; Kelly, EN; Delisle, MF; Gafni, A; Lee, SK; Sananes, R; Rovet, J; Guselle, P; Amankwah, K; Saleem, M; Sanchez, J; MACS-5 Collaborative, Group (Dec 1, 2013). "Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study: Outcomes in Children at 5 Years of Age (MACS-5)". JAMA Pediatrics. 167 (12): 1102–10. doi:10.1001/jamapediatrics.2013.2764. PMID 24126948.
12. ^ Schwartz, RM; Luby, AM; Scanlon, JW; Kellogg, RJ (May 26, 1994). "Effect of surfactant on morbidity, mortality, and resource use in newborn infants weighing 500 to 1500 g". The New England Journal of Medicine. 330 (21): 1476–80. doi:10.1056/NEJM199405263302102. PMID 8164699.
13. ^ von der Hardt, K; Schoof, E; Kandler, MA; Dötsch, J; Rascher, W (February 2002). "Aerosolized perfluorocarbon suppresses early pulmonary inflammatory response in a surfactant-depleted piglet model". Pediatric Research. 51 (2): 177–82. doi:10.1203/00006450-200202000-00009. PMID 11809911.
14. ^ Jobe, Alan H. (August 2004). "Post-conceptional age and IVH in ECMO patients". The Journal of Pediatrics. 145 (2): A2. doi:10.1016/j.jpeds.2004.07.010.
15. ^ Stevens, TP; Blennow, M; Soll, RF (2004). Stevens, Timothy (ed.). "Early surfactant administration with brief ventilation vs selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome". The Cochrane Database of Systematic Reviews (3): CD003063. doi:10.1002/14651858.CD003063.pub2. PMID 15266470.
16. ^ "Henrik Verder research profile". www.Researchgate.net. Retrieved 15 July 2014.
17. ^ Verder, H; Robertson, B; Greisen, G; Ebbesen, F; Albertsen, P; Lundstrøm, K; Jacobsen, T (Oct 20, 1994). "Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. Danish-Swedish Multicenter Study Group". The New England Journal of Medicine. 331 (16): 1051–5. doi:10.1056/nejm199410203311603. PMID 8090164.
18. ^ Verder, H; Albertsen, P; Ebbesen, F; Greisen, G; Robertson, B; Bertelsen, A; Agertoft, L; Djernes, B; Nathan, E; Reinholdt, J (Feb 1999). "Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of less than 30 weeks' gestation". Pediatrics. 103 (2): E24. doi:10.1542/peds.103.2.e24. PMID 9925870.
19. ^ Verder, H; Ebbesen, F; Linderholm, B; Robertson, B; Eschen, C; Arrøe, M; Lange, A; Grytter, C; Bohlin, K; Bertelsen, A; Danish-Swedish Multicentre Study, Group (Jun 2003). "Prediction of respiratory distress syndrome by the microbubble stability test on gastric aspirates in newborns of less than 32 weeks' gestation". Acta Paediatrica. 92 (6): 728–33. doi:10.1080/08035250310002597. PMID 12856986.
20. ^ Verder, H; Ebbesen, F; Fenger-Grøn, J; Henriksen, TB; Andreasson, B; Bender, L; Bertelsen, A; Björklund, LJ; Dahl, M; Esberg, G; Eschen, C; Høvring, M; Kreft, A; Kroner, J; Lundberg, F; Pedersen, P; Reinholdt, J; Stanchev, H (2013). "Early surfactant guided by lamellar body counts on gastric aspirate in very preterm infants". Neonatology. 104 (2): 116–22. doi:10.1159/000351638. PMID 23942627. S2CID 2699650.
21. ^ Gluck, L; Kulovich, MV; Borer RC Jr; Brenner, PH; Anderson, GG; Spellacy, WN (Feb 1, 1971). "Diagnosis of the respiratory distress syndrome by amniocentesis". American Journal of Obstetrics and Gynecology. 109 (3): 440–5. doi:10.1016/0002-9378(71)90342-5. PMID 5107880.
22. ^ Jessen, Torben E.; Höskuldsson, Agnar T.; Bjerrum, Poul J.; Verder, Henrik; Sørensen, Lars; Bratholm, Palle S.; Christensen, Bo; Jensen, Lene S.; Jensen, Maria A.B. (2014). "Simultaneous determination of glucose, triglycerides, urea, cholesterol, albumin and total protein in human plasma by Fourier transform infrared spectroscopy: Direct clinical biochemistry without reagents". Clinical Biochemistry. 47 (13–14): 1306–12. doi:10.1016/j.clinbiochem.2014.05.064. PMID 24943400.
23. ^ Altman, Lawrence (2013-07-29). "A Kennedy Baby's Life and Death". The New York Times. Retrieved 6 June 2015.
24. ^ Dunne, Dominick (2008-04-08). "Justice". Vanity Fair. Retrieved 31 October 2019.
## External links[edit]
Classification
D
* ICD-10: P22
* ICD-9-CM: 769
* OMIM: 267450
* MeSH: D012127
* DiseasesDB: 6087
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| Infant respiratory distress syndrome | c0020192 | 4,874 | wikipedia | https://en.wikipedia.org/wiki/Infant_respiratory_distress_syndrome | 2021-01-18T18:48:43 | {"gard": ["112"], "mesh": ["D006819"], "umls": ["C0020192"], "icd-9": ["769"], "orphanet": ["70587"], "wikidata": ["Q754348"]} |
A number sign (#) is used with this entry because of evidence that atrial septal defect of the secundum type, with or without atrioventricular conduction defects, is caused by heterozygous mutation in the NKX2-5 gene (600584) on chromosome 5q35.
For a discussion of genetic heterogeneity of atrial septal defect, see ASD1 (108800).
Clinical Features
Amarasingham and Fleming (1967) and Kahler et al. (1966) reported a total of 3 families with this combination. Because of the rarity of conduction defects with atrial septal defects of the secundum type, this may be a specific mendelizing form of atrial septal defect. Bizarro et al. (1970) referred to the form of atrial septal defect as fossa ovalis type (a synonym for secundum type). They demonstrated male-to-male transmission. The family of Weil and Allenstein (1961) probably represented an example of this syndrome. The occurrence of other forms of congenital heart disease in this syndrome was suggested by the family reported by Pease et al. (1976). Bosi et al. (1992) suggested that a prolonged PR interval can be the only manifestation of the gene in this condition. The finding of a prolonged PR interval in healthy first-degree relatives of patients with ASD secundum can be useful in genetic counseling.
Schott et al. (1998) studied 4 multigenerational families segregating autosomal dominant ASD with atrioventricular conduction defect, one of which (family MXP) was originally reported by Pease et al. (1976) and later restudied by Basson et al. (1995). Of 33 affected individuals, 27 had secundum ASDs; all underwent surgical repair except for 1 individual whose defect spontaneously closed. Other structural heart defects were identified in 8 affected individuals; these included ventricular septal defect (see VSD3; 614432), tetralogy of Fallot (TOF; see 187500), subvalvular aortic stenosis, left ventricular hypertrophy, pulmonary atresia, and redundant mitral valve leaflets with fenestrations. Electrocardiograms demonstrated atrioventricular conduction defects in all individuals with congenital heart defects and in 1 individual with normal cardiac structures. Invasive electrophysiologic studies performed in 3 individuals localized the prolonged conduction to the atrioventricular node; electrophysiologic properties of other conduction system components were normal. Pacemakers had been implanted in 14 affected individuals.
Mapping
In a large 5-generation family segregating autosomal dominant ASD with atrioventricular conduction defects (family MXP), originally reported by Pease et al. (1976), Schott et al. (1998) performed genomewide linkage analysis and obtained a lod score of 3.91 (theta = 0) at locus D5S1456. A common disease haplotype was identified in family MXP and another 5-generation family with ASD and AV conduction defects (family MBF), suggesting that there was a founding mutation in a distant unknown ancestor of both kindreds. Analyses of flanking loci on chromosome 5q35 indicated that no recombination events had occurred in either family MBX or MBF at loci within 12 cM of D5S1456 or D5S211.
Molecular Genetics
In 4 multigenerational families with autosomal dominant atrial septal defect and atrioventricular conduction defects, one of which was originally reported by Pease et al. (1976), Schott et al. (1998) analyzed the candidate gene NKX2-5 and identified 3 different heterozygous mutations that segregated with disease in the 4 families (600584.0001-600584.0003, respectively).
McElhinney et al. (2003) analyzed the NKX2-5 gene in 474 patients with congenital heart defects and identified heterozygous mutations in 3 (4%) of 71 patients with secundum ASD, 2 of whom had no atrioventricular conduction defects (600584.0018 and 600584.0019, respectively).
In a male patient with ASD secundum and AV block that progressed to Wenckebach-type second-degree heart block, Hirayama-Yamada et al. (2005) identified a T178M mutation in the NKX2E gene (600584.0001). The patient later developed sick sinus syndrome and required permanent pacemaker implantation. His mother had the same mutation and ASD with atrial fibrillation; her elder sister had ASD secundum with AV block and sick sinus syndrome requiring permanent pacemaker implantation, and a nephew had ASD with AV block. The patient's 2 sibs had arrhythmias but no cardiac malformations.
In 2 multiplex families with ASD and atrioventricular conduction defects, Watanabe et al. (2002) identified frameshift mutations in the NKX2E gene. In 1 family (see 600584.0009), surgical closure of the atrial septal defect had been performed in 4 of the genotype-positive members, in 3 of whom sinus venosus ASD had been identified. In addition, 1 of these 4 had a double orifice mitral valve and underwent mitral valve replacement at the time of ASD surgery. ECG evidence of AV block was confirmed in 4 patients; in 2 patients, this manifested as Mobitz type I second-degree block and was associated with atrial fibrillation. In 1 patient, atrial fibrillation was first noted 28 years after ASD surgery, and in another patient atrial fibrillation, first noted at age 46 years, was the sole manifestation of cardiac disease. Additionally, 1 member of the family heterozygous for the mutation was found to have polysplenia and a midline, symmetric liver by CT scan; malrotation was diagnosed by a barium x-ray study that showed the ascending colon and cecum were shifted to the midline and forward with the small intestine on the left. In 3 members of the other family (see 600584.0010), surgical closure of a secundum ASD had been performed; all 3 had ECG evidence of first- or second-degree AV block. In 1 member of the family, first-degree AV block was the only manifestation of heart disease.
Hirayama-Yamada et al. (2005) reported that 4 sibs from a family with ASD and AV conduction defects had the same deletion mutation (600584.0012) in the NKX2E gene. The proband was diagnosed with ASD secundum and first-degree AV block that progressed to second-degree block; in 2 of her sibs, AV block also progressed to second degree, although 1 of those sibs had no cardiac malformation. Their father had heart disease of unknown type. In a female patient with a combination secundum- and cribriform-type ASD at age 7 who later developed AV block that ultimately required pacemaker implantation, Hirayama-Yamada et al. (2005) identified a missense mutation in the NKX2E gene (600584.0013). The patient's deceased paternal grandmother died of an unknown type of heart disease and a cousin had an ASD; her father died of subarachnoid hemorrhage at age 63.
Gutierrez-Roelens et al. (2006) screened the NKX2E gene in 4 sporadic patients and 3 index cases of families with ASD and/or conduction defects and identified a nonsense mutation (600584.0014) in affected members of a 3-generation family; no mutations were found in the other 2 probands or 4 sporadic patients. One apparent asymptomatic carrier was found to have first-degree AV block on Holter monitoring. The conduction defect in this family was at the AV node, manifesting as first-degree block and evolving toward second-degree block; 3 patients also had atrial fibrillation, and 1 had unexplained ventricular tachycardia seen on Holter monitoring. Gutierrez-Roelens et al. (2006) suggested that atrial fibrillation and syncope may be part of the phenotype.
INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Atrial septal defect, secundum type \- Atrial septal defect, cribriform type (rare) \- Atrioventricular conduction defects (in most patients) \- Atrial fibrillation \- Ventricular septal defect (in some patients) \- Tetralogy of Fallot (rare) \- Left ventricular hypertrophy (in some patients) \- Electrocardiographic prolonged PR interval Vascular \- Subvalvular aortic stenosis (rare) \- Pulmonary artery atresia (rare) \- Mitral valve, double orifice (rare) MOLECULAR BASIS \- Caused by mutation in the NK2 homeobox-5 gene (NKX2-5, 600584.0001 ) ▲ 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 inhibitors
*[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
| ATRIAL SEPTAL DEFECT 7 WITH OR WITHOUT ATRIOVENTRICULAR CONDUCTION DEFECTS | c3502353 | 4,875 | omim | https://www.omim.org/entry/108900 | 2019-09-22T16:44:38 | {"doid": ["0110112"], "mesh": ["C566238"], "omim": ["108900"], "orphanet": ["1479"], "synonyms": ["Alternative titles", "ASD WITH OR WITHOUT ATRIOVENTRICULAR CONDUCTION DEFECTS"]} |
A number sign (#) is used with this entry because of evidence that Diamond-Blackfan anemia-17 (DBA17) is caused by heterozygous mutation in the RPS27 gene (603702) on chromosome 1q21. One such patient has been reported.
For a general phenotypic description and discussion of genetic heterogeneity of Diamond-Blackfan anemia, see DBA1 (105650).
Clinical Features
Wang et al. (2015) studied a 4-year-old Japanese girl (patient 42) who was diagnosed with Diamond-Blackfan anemia at 2 months of age. She had no other abnormalities except for skin pigmentation, and she responded to steroid treatment. There was no family history of anemia.
Molecular Genetics
In 48 Japanese patients with DBA in whom screening for mutations or large deletions in 8 of the known DBA-associated genes was negative, Wang et al. (2015) performed whole-exome sequencing and identified heterozygosity for a 1-bp deletion in the RPS27 gene (603702.0001) in an affected 4-year-old girl (patient 42).
INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Skin \- Abnormal pigmentation HEMATOLOGY \- Anemia MISCELLANEOUS \- Based on report of 1 patient (last curated March 2017) \- Diagnosed at 2 months of age MOLECULAR BASIS \- Caused by mutation in the ribosomal protein S27 gene (RPS27, 603702.0001 ) ▲ 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 inhibitors
*[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
| DIAMOND-BLACKFAN ANEMIA 17 | c1260899 | 4,876 | omim | https://www.omim.org/entry/617409 | 2019-09-22T15:45:51 | {"mesh": ["D029503"], "omim": ["617409"], "orphanet": ["124"]} |
## Summary
### Clinical characteristics.
POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood.
* Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure.
* Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss.
* Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE).
* The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare.
* Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades.
* Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").
### Diagnosis/testing.
Establishing the diagnosis of a POLG-related disorder relies on clinical findings and identification of biallelic POLG pathogenic variants for all phenotypes except adPEO, for which identification of a heterozygous POLG pathogenic variant is diagnostic.
### Management.
Treatment of manifestations: Clinical management is largely supportive and involves conventional approaches for associated complications including occupational, physical, and speech therapy; nutritional interventions; and standard respiratory support, treatment for liver failure and disorders of arousal and sleep, and management of seizures and movement disorders.
Prevention of secondary complications: Dose reductions of medications metabolized by hepatic enzymes to avoid toxicity.
Surveillance: Evaluations by a multidisciplinary team of health care providers based on clinical findings; monitoring of liver enzymes every two to four weeks after introduction of any new anticonvulsant.
Agents/circumstances to avoid: Valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) because of the risk of precipitating and/or accelerating liver disease.
### Genetic counseling.
The POLG-related disorders in the spectrum of AHS, MCHS, MEMSA, ANS, and arPEO are inherited in an autosomal recessive manner. Autosomal dominant PEO (adPEO) is inherited in an autosomal dominant manner. For autosomal recessive phenotypes: heterozygotes (carriers) are generally believed to be asymptomatic; the offspring of carrier parents have a 25% chance of being affected, a 50% chance of being carriers, and a 25% chance of being unaffected and not carriers; carrier testing for at-risk family members is possible if the pathogenic variants in the family are known. For the autosomal dominant phenotype: most affected individuals have an affected parent; each child of an affected individual has a 50% chance of inheriting the pathogenic variant. For pregnancies at increased risk for all phenotypes, prenatal diagnosis is possible if the pathogenic variant(s) in the family are known.
## Diagnosis
### Suggestive Findings
POLG-related disorders comprise a continuum of overlapping phenotypes. A POLG-related disorder should be suspected in individuals with combinations of the following clinical features and laboratory findings.
Clinical features
* Hypotonia
* Developmental delay
* Seizures
* Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism)
* Myopathy (e.g., ptosis, ophthalmoplegia, proximal > distal limb weakness with fatigue and exercise intolerance)
* Ataxia
* Peripheral neuropathy
* Episodic psychomotor regression
* Psychiatric illness (e.g., depression, mood disorder)
* Endocrinopathy (e.g., diabetes mellitus, premature ovarian failure)
Laboratory findings
* Liver dysfunction or failure, which may follow exposure to certain antiepileptic drugs. This could result in elevations in the liver enzymes ALT, AST, and GTT as well as synthetic liver dysfunction causing hypoglycemia, hyperammonemia, elevated glutamine, hyperbilirubinemia, prolonged bleeding times (INR, PT, PTT), hypoalbuminemia, and low cholesterol.
* Respiratory chain defect and/or a defect of mitochondrial (mt) DNA (depletion or multiple deletions). This could result in respiratory chain dysfunction, identified by either enzymatic assays or polarographic assays. Depletion of mtDNA can be measured by comparing the value of mtDNA content in an affected tissue (e.g., liver) with the nuclear DNA content. The use of Southern blot or long-range PCR of the mtDNA can detect deletions or multiple deletions in some individuals. Note: Biochemical findings on muscle biopsy can be normal, and normal respiratory chain function or absence of mtDNA depletion should not rule out consideration of a POLG-related disorder.
* Cerebrospinal fluid (CSF) protein is generally elevated in individuals with Alpers-Huttenlocher syndrome (AHS).
Radiographic features
* Brain computerized tomography (CT) or magnetic resonance imaging (MRI) may be normal early in the course of AHS.
* As the illness evolves neuroimaging shows gliosis (initially more pronounced in the occipital lobe regions) and generalized brain atrophy.
### Establishing the Diagnosis
Clinical diagnostic criteria do not exist. The diagnosis of most POLG-related disorders is established in a proband by identification of biallelic pathogenic variants in POLG by molecular genetic testing (see Table 1). The diagnosis of adPEO is established in a proband by identification of a heterozygous pathogenic variant in POLG by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
* Serial single-gene testing. Sequence analysis of POLG is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
Sequence analysis of TWNK (formerly C10orf2 or PEO1) may be considered in persons with a suspected autosomal recessive POLG-related disorder but in whom only one POLG pathogenic variant was identified by single-gene testing, to investigate the possibility of digenic inheritance (see Differential Diagnosis). Digenic inheritance has been reported in autosomal recessive progressive external ophthalmoplegia (arPEO) in a simplex case with pathogenic variants in POLG and TWNK [Van Goethem et al 2003a].
Note: In the 5% of simplex cases of PEO in which only a single pathogenic variant is identified, it can be difficult to distinguish between autosomal recessive inheritance and autosomal dominant inheritance caused by a de novo POLG pathogenic variant.
* A multigene panel that includes POLG, TWNK (formerly C10orf2 or PEO1), and other genes of interest (see Differential Diagnosis) may 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, mtDNA sequencing, and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes 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 1.
Molecular Genetic Testing Used in POLG-Related Disorders
View in own window
Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
POLGSequence analysis 3>95% 4
Gene-targeted deletion/duplication analysis 5Three alleles 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\.
Ashley et al [2008], Hunter et al [2011]
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\.
Compton et al [2011], Naess et al [2012], Rouzier et al [2014]
## Clinical Characteristics
### Clinical Description
POLG-related disorders comprise a continuum of broad and overlapping phenotypes that can be distinct clinical entities or consist of a spectrum of overlapping phenotypes. Presentations within a given family are usually similar. Although almost any organ system can be involved, evidence to date suggests that diabetes and cardiomyopathy are not common in POLG-related disorders, distinguishing them from other multisystem mitochondrial diseases.
Table 2 summarizes the clinical findings in POLG-related disorders. Because the description of new POLG pathogenic variants is ongoing, knowledge of their associated phenotypes continues to evolve.
### Table 2.
Clinical Findings in POLG-Related Disorders
View in own window
FindingManifestationNotes/References
CorticalHypotoniaNguyen et al [2006], Wong et al [2008]
Developmental delay
Seizure disorderMyoclonusCommon in children [Horvath et al 2006] & adults w/ataxia [Van Goethem et al 2004, Hakonen et al 2005, Tzoulis et al 2006]
Focal motor seizuresTzoulis et al [2006]
Generalized seizuresHakonen et al [2005], Winterthun et al [2005], Horvath et al [2006]
Status epilepticusTzoulis et al [2006]
"Cerebrovascular" involvementMigraineMay precede other features by many years [Hakonen et al 2005, Tzoulis et al 2006]
Stroke-like episodesUsually asymptomatic in children, diagnosed on imaging [Horvath et al 2006]
Extrapyramidal movement disorderParkinsonismResponds to levodopa [Luoma et al 2004, Mancuso et al 2004]
ChoreaHakonen et al [2005]
Peripheral neuropathySensory neuronopathy / ganglionopathyCorresponds to the acronym SANDO [Van Goethem et al 2003b]; profound sensory ataxia
Axonal sensorimotor neuropathyDavidzon et al [2006], Horvath et al [2006]
Cerebellar involvementAtaxiaVan Goethem et al [2004], Hakonen et al [2005], Winterthun et al [2005], Horvath et al [2006]
Psychiatric illnessDepressionLuoma et al [2004]
PsychosisHakonen et al [2005], Horvath et al [2006]
DementiaVan Goethem et al [2004], Horvath et al [2006]
Special sensorySensorineural deafnessDi Fonzo et al [2003], Filosto et al [2003], Hakonen et al [2005], Horvath et al [2006]
RetinopathyDi Fonzo et al [2003], Luoma et al [2004], Hakonen et al [2005]
OcularCataractBekheirnia et al [2012]
Gastrointestinal systemLiver failureSpontaneous or precipitated by sodium valproate in children [Naviaux & Nguyen 2004, Nguyen et al 2005, Horvath et al 2006]; also in adults w/ataxia [Van Goethem et al 2004, Tzoulis et al 2006]
Gastrointestinal dysmotilityFilosto et al [2003]
MyopathyPtosis & external ophthalmoplegiaMay be isolated ptosis [Luoma et al 2005]
Proximal myopathyDistal myopathy reported [Horvath et al 2006]
Exercise intoleranceDi Fonzo et al [2003], Luoma et al [2004], Hakonen et al [2005]
Endocrine/gonadal systemDiabetes mellitusHorvath et al [2006]
Primary ovarian failureLuoma et al [2004], Hakonen et al [2005]
Ovarian dysgenesisBekheirnia et al [2012]
Primary testicular failureFilosto et al [2003]
HeartCardiomyopathyVan Goethem et al [2004], Horvath et al [2006]
Reproduced and modified from Hudson & Chinnery [2006]
Although some affected individuals present with a classic syndrome, many have some, but not all, of the features of one or more of the recognized phenotypes. POLG-related disorders can therefore be considered as an overlapping spectrum of disease presenting from early childhood to late adulthood. The age of onset broadly correlates with the clinical phenotype.
#### Alpers-Huttenlocher Syndrome (AHS)
AHS, one of the most severe phenotypic manifestations in the spectrum of POLG-related disorders, is characterized by a progressive and ultimately severe encephalopathy with intractable epilepsy, neuropathy, and hepatic failure. While AHS is usually fatal, the age of onset, rate of neurologic degeneration, presence of hepatic failure, and age of death vary [Davidzon et al 2006, Nguyen et al 2006, Wong et al 2008, Cohen & Naviaux 2010, Saneto et al 2013].
Children with AHS appear healthy at birth and may develop normally over the first few weeks to years of life. Some have variable degrees of developmental delay prior to the initial recognition of neurodegeneration. Onset is usually between ages two and four years, but ranges from one month to 36 years.
Seizures are the first sign of AHS in about 50% of affected children. Seizures may be simple focal, primary generalized, or myoclonic. The most common early seizure types are partial seizures and secondary generalized tonic-clonic seizures. In some children the first seizure presents with status epilepticus. EEG findings include high-amplitude slow activity with smaller polyspikes or intermittent continuous spike-wave activity [Wörle et al 1998].
In some instances the first seizure type is epilepsia partialis continua (EPC), a classic seizure type in which the motor seizure involves only one portion of the body (e.g., a limb) with a constant and repetitive myoclonic jerking, continuing for hours or days with or without dramatic effects on consciousness. EPC is not always apparent as an abnormality on EEG and can be mistaken for a conversion reaction. EEG may be normal or show only focal slowing of the background rhythm.
Over time the seizures can evolve into a complex epileptic disorder such as focal status epilepticus, epilepsia partialis continua, or multifocal myoclonic epilepsy [Horvath et al 2006, Tzoulis et al 2006].
In some children the seizures are initially controllable with usual dosages of anticonvulsants; in others the seizures, such as EPC, are refractory from the onset. Over time the seizures become increasingly resistant to anticonvulsant therapy. See Treatment of Manifestations for further information about management of seizures. Of note, valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) can precipitate the liver dysfunction in AHS and should be avoided [Saneto et al 2010].
Headaches, another common first presenting symptom, are typically associated with visual sensations or visual auras that reflect early occipital lobe dysfunction [Hakonen et al 2005, Tzoulis et al 2006]. Stroke and stroke-like episodes may occur in this disorder as well [Horvath et al 2006].
Movement disorders, primarily myoclonus and choreoathetosis, are common [Horvath et al 2006]. Myoclonus can be difficult to distinguish from myoclonic seizures and EPC. Palatal myoclonus resulting from involvement of the inferior olivary nuclei can be seen as well. Some develop parkinsonism, which may temporarily respond to levodopa [Luoma et al 2004, Mancuso et al 2004].
Neuropathy and ataxia develop in all persons with AHS unless the disease process is so rapid that it results in early death. All neurologic signs and symptoms, including ataxia and nystagmus, may worsen during infections or with other physiologic stressors.
Areflexia (resulting from neuropathy) and hypotonia (possibly the result of generalized weakness as part of systemic illness or pyramidal or extrapyramidal dysfunction) are often both present early in the disease course.
Episodic psychomotor regression is variably present at the time of initial consideration of the diagnosis. The major motor manifestation is a progressive spastic paraparesis resulting from progressive loss of cortical neuronal function. Progressive spasticity occurs universally; has variable onset, and evolves over months to years.
Loss of cognitive function occurs throughout the course of the disease, but the time of onset and rate of progression are variable. Significant sudden or rapid regression is often seen during infectious illnesses. The clinical manifestations may include somnolence, loss of concentration, loss of language skills (both receptive and expressive), irritability with loss of normal emotional responses, and memory deficits. In addition to the dementia caused by loss of brain tissue and the refractory seizures, the high dosages of medication used to treat those seizures can lead to significant cognitive impairment. The degree of dementia is often difficult to assess because of the frequent seizures and high therapeutic doses of anticonvulsants, which can cloud the sensorium.
Cortical visual loss leading to blindness may appear months to years after the onset of other neurologic manifestations. Retinopathy (retinitis pigmentosa) may also play a less important role in vision loss [Hakonen et al 2005]. Hearing loss is variable [Hakonen et al 2005, Horvath et al 2006].
Liver involvement can progress rapidly to end-stage liver failure within a few months, although this is highly variable. End-stage liver disease is often heralded by hypoalbuminemia and prolonged coagulation time, followed shortly thereafter by fasting hypoglycemia and hyperammonemia. Rapid onset of liver failure is described when valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) have been used to treat seizures, although the introduction of other anticonvulsants, including phenytoin, may also play a role in onset of hepatic failure. Longer survival in AHS through improved care for those with profound dementia and motor dysfunction results in the occurrence of late-onset hepatic involvement in a higher percentage of children with AHS now than previously noted.
Disease progression is variable in timing and rapidity. Loss of neurologic function culminates in dementia, spastic quadriparesis from corticospinal tract involvement, visual loss, and death. The rate of neurodegeneration varies and is marked by periods of stability. The typical life expectancy from onset of first symptoms ranges from three months to 12 years.
Neuroimaging. CT or MRI of the brain may be normal early in the course of AHS. As the illness evolves neuroimaging shows gliosis (initially more pronounced in the occipital lobe regions) and generalized brain atrophy.
FLAIR and T2-weighted sequence images demonstrate high signal intensity in deep gray matter nuclei, especially in the thalamus and cerebellum [Smith et al 1996]. Lesions described in the inferior olivary nuclei may also be a part of AHS and are associated with palatal myoclonus.
Pathophysiology. Depletion of mtDNA develops in clinically affected tissues causing a mitochondrial oxidative-phosphorylation defect resulting in the clinical findings of AHS.
Brain. The gross appearance of the brain varies from normal to severe atrophy, depending on the state of disease progression. The central nervous system regions affected in AHS are the same as those affected by Leigh syndrome but typically evolve in the reverse order. For example, in AHS the gliosis is most severe and occurs earliest in the cerebral cortex, followed by the cerebellum, basal ganglia, and brain stem. Involved regions demonstrate neuronal degeneration, characteristic spongiform or microcystic degeneration, and – as seen in Leigh syndrome – gliosis, necrosis, and capillary proliferation. The cortical ribbon shows patchy lesions, but the calcarine cortex, which is characteristically involved early in the course of the disease, is usually narrowed, granular, and discolored.
Microscopic abnormalities, present throughout the cerebral cortex, evolve as the disease progresses. Early in the course of the disease spongiosis, astrocytosis, and neuronal loss are prevalent in the superficial cortex. Later the deeper laminae are affected. In the most advanced stage the entire cortex becomes a thin dense gliotic scar. Usually the striate cortex is the most affected part of the brain followed by the thalamus, hippocampus, and cerebellum. These pathologic features differ from those resulting from hypoxic injury, recurrent seizures, or other causes of hepatic failure.
Liver. Liver histology may demonstrate macro- and microvesicular steatosis, centrilobular necrosis, disorganization of the normal lobular architecture, hepatocyte loss with or without bridging fibrosis or cirrhosis, regenerative nodules, bile duct proliferation, or mitochondrial proliferation with a vivid eosinophilic cytoplasm (oncocytic change). Florid cirrhosis occurs late in the disease. This pathology differs from that seen in chemically induced or toxic hepatopathies.
#### Childhood Myocerebrohepatopathy Spectrum (MCHS)
MCHS presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other features of a mitochondrial disorder that may be present include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Seizures are not present, at least early in the disease course [Wong et al 2008].
#### Myoclonic Epilepsy Myopathy Sensory Ataxia (MEMSA)
Previously referred to as spinocerebellar ataxia with epilepsy (SCAE), MEMSA now describes the spectrum of disorders with myopathy, epilepsy, and ataxia without ophthalmoplegia. Cerebellar ataxia, generally the first sign, begins in young adulthood as a subclinical sensory polyneuropathy. Epilepsy develops in later years, often beginning focally in the right arm and then spreading to become generalized. The seizures may be refractory to conventional therapy, including anesthesia. Recurrent bouts of seizure activity are accompanied by progressive interictal encephalopathy. The myopathy in MEMSA may be distal or proximal, and, as in the other POLG-related disorders, it also may present as exercise intolerance.
#### Ataxia Neuropathy Spectrum (ANS)
ANS includes mitochondrial recessive ataxia syndrome (MIRAS) and a separate entity known as sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) [Fadic et al 1997]. ANS is characterized by ataxia, neuropathy, and (in most but not all affected individuals) an encephalopathy with seizures. The encephalopathy is similar to that seen in AHS but tends to be more slowly progressive and can even be mild. The neuropathy may be sensory, motor, or mixed and can be severe enough to contribute to ataxia – so-called sensory ataxia. About 25% of affected individuals have cramps, but clinical myopathy is rare.
Other features may include myoclonus, blindness, and liver dysfunction [Wong et al 2008]. Liver findings range from no dysfunction to elevated enzymes and mild synthetic dysfunction, to (in some cases) florid liver failure [Tzoulis et al 2006, Wong et al 2008]. Psychiatric illness including depression is common. Headache, generally migrainous, is also common and may precede other symptoms by many years.
Although muscle pathology may show COX-negative fibers, there may be no pathologic findings.
#### Autosomal Recessive Progressive External Ophthalmoplegia (arPEO)
Progressive PEO without systemic involvement is the hallmark of arPEO. Caution needs to be exercised, however, when making the diagnosis of arPEO, as some POLG pathogenic variants associated with arPEO are also associated with ANS and other POLG-related disorders with systemic involvement. Thus, many individuals who have no other clinical findings at the time of diagnosis with isolated arPEO develop other manifestations of POLG-related disorders over subsequent years or decades [Van Goethem et al 2001, Lamantea et al 2002, Van Goethem et al 2003b]. In the past these findings were designated "PEO+" or "PEO+ disease."
#### Autosomal Dominant Progressive External Ophthalmoplegia (adPEO)
The universal manifestation of this adult-onset disorder is progressive weakness of the extraocular eye muscles resulting in ptosis and strabismus [Van Goethem et al 2001]. A generalized myopathy is present in most affected individuals, leading to early fatigue and exercise intolerance. Some affected individuals (in what has been called "chronic progressive external ophthalmoplegia plus," or CPEO+) have variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts [Luoma et al 2004, Pagnamenta et al 2006]. Cardiomyopathy and gastrointestinal dysmotility are less common.
### Genotype-Phenotype Correlations
Genotype-phenotype correlations are not possible because all combinations of pathogenic variant type and location have been associated with the entire phenotypic spectrum and with both autosomal recessive and autosomal dominant inheritance.
### Nomenclature
Alpers-Huttenlocher syndrome (AHS) is named after Bernard Alpers, who first described the disease in 1931, and Peter Huttenlocher, who with his colleagues described the associated liver disease and autosomal recessive mode of inheritance [Huttenlocher et al 1976].
In the older literature, autosomal dominant progressive external ophthalmoplegia (adPEO) associated with additional findings was labeled "chronic progressive external ophthalmoplegia plus" (CPEO+).
### Prevalence
AHS is reported to affect approximately one in 51,000 people [Darin et al 2001]; however, because some pathogenic variants are found at high frequencies in certain populations and founder variants occur in some populations, the frequency may vary greatly by ethnicity.
The sum frequency of the most common autosomal recessive pathogenic variants can be used to estimate disease frequency at 1:10,000:
* p.Ala467Thr. ~0.2%-0.6% (up to 1% in Norway)
* p.[Trp748Ser;Glu1143Gly]. ~0.1%-0.8%
* p.Gly848Ser. ~0.05%-0.1%
* p.Pro587Leu. ~0.05%
Pathogenic variants in POLG, identified in nearly 50% of individuals with autosomal dominant PEO (adPEO) in one study [Lamantea et al 2002], may be the most frequent cause of adPEO.
## Differential Diagnosis
Epilepsia partialis continua (EPC), seen in Alpers-Huttenlocher syndrome, can result from structural brain lesions (e.g., stroke, neoplasia, cortical dysplasia, traumatic lesion). EPC has also been described in individuals with COQ8A-related primary coenzyme Q10 deficiency [Hikmat et al 2016], NADH coenzyme Q reductase deficiency [Antozzi et al 1995], MERRF, Leigh syndrome [Mameniškienė & Wolf 2017], and nonketotic hyperglycemia [Mameniškienė & Wolf 2017]. Recently, biallelic TBC1D24 pathogenic variants were identified in an individual with EPC [Zhou et al 2018].
### Mitochondrial DNA Depletion (MDD) Disorders
MDD disorders may affect either a specific tissue (most commonly muscle or liver) or multiple organs, including the heart, brain, and kidney. MDD disorders need to be distinguished from the disorders of mtDNA mutation, duplication, or deletion (see Mitochondrial Disorders Overview).
Mitocondrial DNA depletion syndromes, a genetically and clinically heterogeneous group of autosomal recessive disorders, are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs.
Mitochondrial DNA depletion syndromes occur as a result of defects in mtDNA maintenance caused by pathogenic variants in nuclear genes that function in either mitochondrial nucleotide synthesis (e.g., TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (e.g., POLG and TWNK).
Mitochondrial DNA depletion syndromes are phenotypically classified into myopathic, encephalomyopathic, hepatocerebral, and neurogastrointestinal forms (see Table 3) [El-Hattab & Scaglia 2013].
* Myopathic forms present in infancy or early childhood with hypotonia, proximal muscle weakness, and feeding difficulty. Cognition is usually spared. Typically, there is rapid progression of muscle weakness with respiratory failure and death within a few years of onset.
* Encephalomyopathic mtDNA depletion syndromes present in infancy with hypotonia and global developmental delay. Depending on the underlying defect, other features including deafness, movement disorders, Leigh like syndrome, and renal disease can be observed.
* Hepatocerebral forms present with early-onset liver dysfunction and neurologic involvement, including developmental delay, abnormal eye movements, and peripheral neuropathy.
* Neurogastrointestinal forms, the prototype of which is mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease, present in adolescence to early adulthood with progressive gastrointestinal dysmotility, cachexia, and peripheral neuropathy.
Table 3 classifies the mtDNA depletion syndromes by phenotypic category and associated genes.
Note: For some of the genes (POLG and TWNK), other phenotypes not associated with mtDNA depletion with autosomal dominant or recessive inheritance have been reported.
### Table 3.
Mitochondrial DNA Depletion Syndromes
View in own window
Phenotype 1GeneMitochondrial DNA Depletion Syndrome #, Type 2Function of Gene Product
HepatocerebralDGUOK3, hepatocerebral typedNTP pools
POLG4A, Alpers type
(POLG-related disorders)mtDNA replication
MPV176, hepatocerebral type
(MPV17-related hepatocerebral mtDNA depletion syndrome)dNTP pools
TWNK (C10orf2, PEO1)7, hepatocerebral type
(OMIM 271245)mtDNA replication
TFAM15, hepatocerebral type
(OMIM 617156)transcription factor
EncephalomyopathicSUCLA25, encephalomyopathic type w/ methylmalonic aciduria
(SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria)dNTP pools
FBXL413, encephalomyopathic type
(FBXL4-related encephalomyopathic mtDNA depletion syndrome)F-box and leucine-rich repeat protein 4
SUCLG19, encephalomyopathic type w/ methylmalonic aciduria
(SUCLG1-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria)dNTP pools
RRM2B8A, encephalomyopathic type w/ renal tubulopathy
(RRM2B-related mitochondrial disease)dNTP pools
OPA114, encephalocardiomyopathic type
(OMIM 616896)Mitochondrial dynamics
ABATEncephalomyopathic type
(OMIM 613163)4-aminobutyrate aminotransferase
NeurogastrointestinalTYMP1, MNGIE type
(mitochondrial neurogastrointestinal encephalopathy disease)Thymidine phosphorylase, dNTP pools
POLG4B, MNGIE type
(POLG-related disorders)mtDNA replication
RRM2B8B, MNGIE type
(RRM2B-related mitochondrial disease)dNTP pools
MyopathicTK22, myopathic type
(TK2-related mtDNA depletion syndrome, myopathic form)dNTP pools
AGK10, cardiomyopathic type (Sengers syndrome)
(OMIM 212350)Acylglycerol kinase
MGME111, myopathic type
(OMIM 615084)Exonuclease in mtDNA replication
SLC25A412B, cardiomyopathic type
(OMIM 615418)Adenine nucleotide, translocator, dNTP pools
dNTP = deoxyribonucleoside triphosphate
1\.
Within each phenotypic category, mtDNA depletion syndromes are ordered by relative prevalence.
2\.
See hyperlinked GeneReview or OMIM phenotype entry for more information. Additional information on selected disorders appears following the table.
Deoxyguanosine kinase deficiency (DGUOK deficiency). The two forms of DGUOK deficiency are a hepatocerebral mtDNA depletion syndrome (multisystem disease in neonates) and isolated hepatic disease later in infancy or childhood. The majority of affected individuals have the multisystem illness with hepatic disease (jaundice, cholestasis, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and psychomotor retardation) evident within weeks of birth. In contrast to AHS caused by POLG pathogenic variants, DGUOK deficiency is not characterized by seizures or brain imaging abnormalities [Dimmock et al 2008]. Those with isolated liver disease may also have renal involvement and some later develop mild hypotonia. Progressive hepatic disease is the most common cause of death in both forms. Reduced mtDNA copy number in liver or muscle can be used to confirm mtDNA depletion. Molecular genetic testing of DGUOK is necessary to establish the specific diagnosis of DGUOK deficiency [Mandel et al 2001].
MPV17-related hepatocerebral mtDNA depletion syndrome (Navajo neurohepatopathy) is characterized by liver failure, severe sensory neuropathy, corneal anesthesia and scarring, cerebral leukoencephalopathy, failure to thrive, and metabolic acidosis. Homozygosity for the MPV17 pathogenic variant NP_002428.1:p.Arg50Gln (NM_002437.4:c.149G>A) is associated with Navajo neurohepatopathy, a mtDNA depletion syndrome displaying hepatic failure early in life, prevalent in the Navajo tribes in the southwestern United States.
SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized by severe hypotonia in early infancy (birth to 5 months), severe muscular atrophy with failure to achieve independent ambulation, progressive scoliosis or kyphosis, dystonia and/or hyperkinesias (i.e., athetoid or choreiform movements), epilepsy (infantile spasms or generalized convulsions with onset from birth to 3 years) in a few children, postnatal growth retardation, and severe sensorineural hearing impairment. The outcome is poor with early lethality. Metabolic findings usually include urinary excretion of methylmalonic acid (MMA), elevated plasma methylmalonic acid concentration, and elevated plasma lactate concentration. Plasma carnitine ester profiling shows increased C3-carnitine and C4-dicarboxylic-carnitine. Urinary excretion of C4-dicarboxylic carnitine is usually approximately 20 times normal. CT/MRI may show central and cortical atrophy, bilateral basal ganglia involvement (mainly the putamen and caudate nuclei), and delayed myelination.
FBXL4-related encephalomyopathic mtDNA depletion syndrome is a multisystem disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and global developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant global developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days - 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.
SUCLG1-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized in the majority of affected newborns by hypotonia, muscle atrophy, feeding difficulties, and lactic acidosis. Affected infants commonly manifest developmental delay / cognitive impairment, growth retardation / failure to thrive, hepatopathy, sensorineural hearing impairment, dystonia, and hypertonia. Notable findings in some affected individuals include hypertrophic cardiomyopathy, epilepsy, myoclonus, microcephaly, sleep disturbance, rhabdomyolysis, contractures, hypothermia, and/or hypoglycemia. Life span is shortened, with median survival of 20 months. The phenotype may be indistinguishable from SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form, with mild methylmalonic aciduria. Affected individuals have urinary excretion of MMA, combined respiratory chain enzyme deficiency, and mtDNA depletion.
RRM2B-related mitochondrial disease. Mutation of RRM2B has been associated with severe muscle mtDNA depletion in several families. This disorder manifests as severe encephalopathy, myopathy with persistent lactic acidosis, hypotonia, renal tubular defects, seizures, and diarrhea. Death has been reported to occur by age four months, but affected individuals have demonstrated longer survival [B Cohen, personal communication].
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is characterized by progressive gastrointestinal dysmotility (manifesting as early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and/or distention, and diarrhea); cachexia; ptosis/ophthalmoplegia or ophthalmoparesis; leukoencephalopathy; and demyelinating peripheral neuropathy (manifesting as paresthesias [tingling, numbness, and pain] and symmetric and distal weakness more prominently affecting the lower extremities). The order in which manifestations appear is unpredictable. Onset is usually between the first and fifth decades; in about 60% of individuals, symptoms begin before age 20 years. The diagnosis of MNGIE disease can be established in a proband by detection of one of the following: (1) biallelic pathogenic variants in TYMP; (2) markedly reduced levels of thymidine phosphorylase enzyme activity; or (3) elevated plasma concentrations of thymidine and deoxyuridine.
TK2-related mtDNA depletion syndrome. Mitochondrial myopathy with mtDNA depletion is caused by pathogenic variants in TK2.
MGME1-related mtDNA depletion syndrome 11 (OMIM 615084) is caused by biallelic pathogenic variants in MGME1. Individuals present between ages ten and 36 years with ptosis, followed by mild PEO, diffuse skeletal muscle wasting and myopathy, profound emaciation, and respiratory failure. Intellectual disability was found in only one family of three affected individuals.
SLC25A4-related mtDNA depletion syndrome 12B, cardiomyopathic type (OMIM 615418) is caused by biallelic pathogenic variants in SLC25A4. Affected individuals may present with the SANDO (ANS) phenotype.
### Other Disorders to Consider
Leigh syndrome is a progressive neurodegenerative disorder characterized by hypotonia, spasticity, dystonia, muscle weakness, hypo- or hyperreflexia, seizures, movement disorders, cerebellar ataxia, and peripheral neuropathy. In individuals with Leigh syndrome MRI changes most often occur initially in the brain stem and the gliosis "migrates" over time to involve the deep gray masses and cortex, whereas in AHS the initial lesions form in the cerebral cortex (usually the occipital lobes), followed by the cerebellum, basal ganglia, thalamus, and brain stem. (See Nuclear Gene-Encoded Leigh Syndrome Overview, Mitochondrial DNA-Associated Leigh Syndrome and NARP, and Mitochondrial DNA Deletion Syndromes.)
Autosomal dominant progressive external ophthalmoplegia (OMIM PS157640) is caused by pathogenic variants in DGUOK, DNA2, OPA1, POLG2, RNASEH1, RRM2B, SLC25A4, TK2, or TWNK.
Oculopharyngeal muscular dystrophy (OPMD) with onset usually after age 45 years may result in progressive ptosis and bulbar dysfunction manifest as swallowing difficulty. This disorder may mimic the clinical manifestations of the POLG-related disorders in which PEO is the predominant feature. OPMD is caused by pathogenic variants in PABPN1 and inherited in either an autosomal dominant or an autosomal recessive manner.
Amish lethal microcephaly is characterized by microcephaly and early death. The occipitofrontal circumference is typically six to 12 SD below the mean; anterior and posterior fontanels are closed at birth and facial features are distorted. The average life span is between five and six months. Diagnosis is based on a tenfold increase in the levels of the urinary organic acid 2-ketoglutarate. SLC25A19 is the only gene known to be associated with Amish lethal microcephaly. All affected individuals within the Old Order Amish population are homozygous for the same single-base pair substitution.
Chronic progressive external ophthalmoplegia (CPEO) in a simplex case or when there is a maternal family history can be the result of a large-scale single deletion of mtDNA that may only be detected in limited tissues (e.g., skeletal muscle). CPEO is sometimes complicated by mild proximal muscle weakness and dysphagia, and can be considered to lie on a spectrum of disease from pure CPEO to the Kearns-Sayre syndrome. Some individuals with CPEO (<20%) have a pathogenic single-nucleotide variant of mtDNA (e.g., m.3243A>G).
Kearns-Sayre syndrome (KSS), a mtDNA deletion syndrome, is a multisystem disorder defined by the triad of onset before age 20 years, pigmentary retinopathy, and progressive external ophthalmoplegia (PEO). In addition, affected individuals have at least one of the following: cardiac conduction block, cerebrospinal fluid protein concentration greater than 100 mg/dL, or cerebellar ataxia. Onset is usually in childhood. PEO, characterized by ptosis, paralysis of the extraocular muscles (ophthalmoplegia), and variably severe proximal limb weakness, is relatively benign. Mitochondrial DNA deletion syndromes are caused by deletion of mtDNA and, when inherited, are transmitted by maternal inheritance. Most individuals with KSS have a common deletion of 4,977 nucleotides involving 12 mitochondrial genes.
BCS1L-related disorders. Pathogenic variants in BCS1L are associated with GRACILE (growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death) syndrome (OMIM 603358), Bjørnstad syndrome (congenital profound hearing loss and pili torti) (OMIM 262000), and an overlapping GRACILE syndrome-Bjørnstad syndrome phenotype. Children with the pure form of Bjørnstad syndrome have normal intellect. The BCS1L protein is an assembly factor for complex III responsible for insertion of the Fe-S core into the complex. Affected children have a biochemical defect in complex III. The clinical scenario of a hepatoencephalopathy may appear similar to AHS at a single point in time, but mtDNA depletion is not part of the pathology described in those with BCS1L pathogenic variants.
SCO1-related disorders (OMIM 603644). Hepatic failure and severe encephalopathy have also been associated with biallelic pathogenic variants in SCO1.
Infantile or late-infantile progressive encephalopathies with primary involvement of cortical gray matter and refractory epilepsy
* Neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive mental and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Phenotypes included in the NCLs that overlap with AHS are CLN1 disease, classic infantile (previously classic infantile NCL, INCL, Santavuori-Haltia), and CLN2 disease, classic late infantile (previously late-infantile NCL, LINCL, Jansky-Bielschowsky disease). Inheritance of CLN1 disease and CLN2 disease is autosomal recessive.
* CLN1 disease. Children with CLN1 disease are normal at birth; symptoms usually present acutely between ages six and 24 months. Initial signs include delayed development, myoclonic jerks and/or seizures, deceleration of head growth, and specific EEG changes. Affected infants develop retinal blindness and seizures by age two years, followed by progressive mental deterioration. Pathogenic variants in PPT1 can be causative.
* CLN2 disease. The first symptoms of CLN2 disease typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, dementia, ataxia, and extrapyramidal and pyramidal signs. Visual impairment typically appears between ages four and six years and rapidly progresses to blindness. Life expectancy ranges from age six years to greater than age 40 years. Pathogenic variants in PPT1, TPP1, CLN5, CLN6, and CLN8 can be causative.
* MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, and dementia. Onset is usually in childhood, following normal early development. Common findings are hearing loss, short stature, optic atrophy, and cardiomyopathy with Wolff-Parkinson-White syndrome. Occasionally pigmentary retinopathy and lipomatosis are observed. MERRF is transmitted by maternal inheritance.
* MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) is a multisystem disorder with onset typically occurring in childhood. Early psychomotor development is usually normal. Onset of symptoms is often between ages two and ten years. The most common initial symptoms are generalized tonic-clonic seizures, recurrent headaches, anorexia, and recurrent vomiting. Seizures are often associated with stroke-like episodes of transient hemiparesis or cortical blindness. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and mentation, often by adolescence or young adulthood. Sensorineural hearing loss is common. MELAS is transmitted by maternal inheritance.
* Storage diseases during infancy and early childhood, such as atypical hexosaminidase A deficiency, Sandhoff disease (OMIM 268800), infantile sialidosis (OMIM 256550), and galactosialidosis (OMIM 256540), can be diagnosed by testing for lysosomal enzyme activity in the appropriate tissue.
* Other rare neonatal-onset causes of a progressive encephalopathy with refractory seizures include pyridoxine-dependent epilepsy, cerebral folate deficiency (OMIM 613068), glycine encephalopathy (also known as nonketotic hyperglycinemia), biotinidase deficiency, and disorders of biogenic amine metabolism, such as folate-responsive seizures (see Hereditary Folate Malabsorption). Pyridoxine-dependent seizures and biotinidase deficiency are treatable and on occasion reversible [Wolf 2005, Gallagher et al 2009].
* Sulfite oxidase deficiency (OMIM 272300) and Menkes disease (see ATP7A-Related Copper Transport Disorders) usually present earlier in infancy. Sulfite oxidase deficiency can be screened for by use of a commercially available sulfite oxidase urine dipstick test and Menkes disease by detection of low serum concentrations of copper and ceruloplasmin. Menkes disease is caused by pathogenic variants in ATP7A and in inherited in an X-linked manner.
Slow virus diseases (subacute sclerosing panencephalitis) are extremely rare at this age.
Within the differential diagnosis are also epileptic syndromes that appear to be progressive at the onset but that usually plateau into developmental arrest/delay.
The channelopathies are with a group of severe infantile epileptic disorders caused by pathogenic variants in CACNA1A, CACNB4, SCN1A, SCN2A, or SCN9A which encode for sodium and calcium channels. See SCN1A-Related Seizure Disorders.
Both myoclonic epilepsy (OMIM PS254800) and the Lennox-Gastaut syndrome can cause dementia or pseudodementia as a result of unrelenting seizures and anticonvulsant side effects.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a POLG-related disorder, evaluation should always include measures of functional neurologic status.
In order to determine the baseline function for a given affected individual, it is reasonable to conduct the following evaluations as appropriate for the phenotypic presentation if they have not already been completed:
* Electroencephalogram (EEG) and video EEG monitoring
* Formal developmental assessment to provide a baseline of function as well as offer insights into the need for occupational, physical, and/or speech therapy
* Brain MRI. On occasion the first neuroimaging study may be normal, but with certain phenotypes, such as AHS, changes may be seen in a relatively short amount of time.
* Echocardiogram and electrocardiogram
* Ophthalmology evaluation with vision assessment
* Audiology evaluation
* Swallowing study if bulbar signs are present
* Nutritional assessment
* Baseline pulmonary function testing
* Sleep polysomnogram specifically for the purpose of evaluating for central or obstructive apnea or hypopnea that result in either pCO2 elevation or O2 desaturation
* Liver function tests including fasting serum glucose concentration, ALT, and AST; serum concentrations of ammonia, glutamine and tyrosine (found in an amino acid panel), bilirubin, albumin, and cholesterol; and the coagulation factors (prothrombin time or INR)
Note: AST elevation, and to a lesser extent ALT elevation, may be due to muscle disease; simultaneously obtaining a serum CK level differentiates between liver and muscle involvement, although both liver and muscle disease can be seen in individuals with POLG-related disorders.
* Consideration of liver ultrasound examination to evaluate for presence of fibrosis
* Consultation with a biochemical geneticist and/or genetic counselor
### Treatment of Manifestations
Treatment is limited to symptom management and supportive care.
#### Alpers-Huttenlocher Syndrome
Family education is critical. It is important to address the quality of life / intensity of treatment issues frequently and when major changes occur in disease status. Once the family has started the process of accepting the diagnosis, it is important to involve the family with options for supportive care that can be offered as the illness progresses. These will include (but are not limited to) the use of a gastrostomy feeding tube and the different levels of artificial ventilation that could include less invasive treatments such as CPAP or BiPAP, assisted nasal ventilation, and/or intubation, and the use of a tracheostomy and ventilator. Involvement of palliative care services can assist the care team in these discussions, as well as in practical aspects of implementation. Although rehabilitative services are a necessary part of the treatment and care plan for these children, and rehabilitation units are often where parents of children with new gastrostomy tubes and ventilator support learn to care for their children, the global perspective of care should be palliative even if death is not imminent.
Supportive therapies. Occupational, physical, and/or speech therapy is indicated to maintain neurologic function for as long as possible and to insure comfort when deterioration begins.
Gastrointestinal. A consult with a gastroenterologist regarding feeding or nutritional issues or evidence of liver involvement may be appropriate. Surgical placement of a gastric feeding tube when appropriate can maintain nutritional status and/or prevent aspiration of oral feeding.
Hepatic. Standard treatment for liver failure may include small frequent meals or continuous feeding to compensate for defective gluconeogenesis, reduction in dietary protein to a minimum, use of non-absorbable sugars to create an osmotic diarrhea, and use of conjugating agents to treat hyperammonemia.
Because levocarnitine may have some benefit in the setting of liver failure and because of its low toxicity, some recommend its use from the time of diagnosis.
Respiratory. Tracheostomy placement and artificial ventilation may be performed as appropriate.
Assessment of nocturnal ventilatory function can be performed for evidence of central and/or obstructive apnea using polysomnography with measurement of pCO2 and monitoring by pulse oximetry. Treatment with CPAP or BiPAP as indicated is appropriate.
Seizures. Seizure control is a goal of treatment; however, refractory epilepsy, especially epilepsia partialis continua (EPC), may be impossible to control with any treatment. In individuals with EPC, the use of high-dose anticonvulsants may control the clinical seizures, but the associated obtundation with subsequent risk of aspiration and ventilatory failure may outweigh the benefit.
Although anticonvulsant monotherapy is preferred, treatment with more than one medication often becomes necessary as the child's seizures worsen and as multiple types of seizures occur. If high-dose anticonvulsant therapy is not effective in improving the quality of life by reducing the seizure burden, reducing the number and/or dose of medications may improve quality of life by reducing medication side effects.
There is no evidence that newer anticonvulsants such as felbamate, lamotrigine, topiramate, oxcarbazepine, or levetiracetam offer a better therapeutic benefit than older medications (phenobarbital, phenytoin, carbamazepine, primidone); however, the newer medications tend to be less sedating, may require less processing by the liver, and have fewer drug-drug interactions. Intravenous magnesium, used most often to treat seizures in eclampsia, has shown efficacy in one report where affected individuals with status epilepicus were refractory to other typical anticonvulsants [Visser et al 2011].
One unpublished pathway for management of seizures is to begin with lamotrigine monotherapy, and when this is no longer effective for adequate control of seizures, to add lacosamide. Adding clobazam may also help when these medications are no longer effective [RP Saneto, personal communication]. With the exception of valproate (see Note), other standard anticonvulsants are reasonable to use, although medications that are heavily metabolized by the liver, such as phenytoins or the barbiturates, should be reserved until other medications fail.
Note: Valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) should be avoided (see Agents/Circumstances to Avoid). Because other anticonvulsants have also been implicated in accelerating liver deterioration, it is reasonable to monitor liver enzymes every two to four weeks after introducing any new anticonvulsant [Bicknese et al 1992].
Movement disorder. In addition to electroencephalographic seizures, myoclonus and other non-epileptic movement disorders occur as part of AHS and can be as disabling as seizures. These movements should not be confused with seizures, and video EEG is often the only way to differentiate a seizure from a non-epileptic movement disorder. The use of benzodiazepines often reduces the severity of these abnormal movements and also assists in seizure management and reduction of spasticity.
Chorea and athetosis [Hakonen et al 2005] may cause pain, and treatment with muscle relaxants and pain medications, including narcotics, would be advised. Some movement disorders can be treated with dopaminergic medication such as levodopa-carbidopa or tetrabenazine; a trial of either of these medications can be considered.
In most individuals, some seizures and/or non-epileptic movements cannot be suppressed with medication, and a balance between the adverse effects of the medication(s) and the disability created by the seizures or movements must be accepted by both the family and physician. Often a modest reduction in seizure control is offset by an improved level of alertness, although the benefit may not be lasting.
#### Other Phenotypes
Management is supportive and involves conventional approaches such as physiotherapy, speech therapy, and seizure management.
Gastrostomy may be required to provide adequate nutrition.
Surgery for ptosis may provide symptomatic relief for some.
### Prevention of Secondary Complications
For individuals with any of the POLG-related phenotypes, dose reduction in medications metabolized by hepatic enzymes may be necessary to avoid toxicity.
Reports suggest that CSF folate may be deficient in disorders that lead to mtDNA depletion [Hasselmann et al 2010]. Therefore, testing for CSF folate deficiency and offering treatment to those with deficiency is one option; the other option is empiric therapy with folinic acid (calcium leucovorin).
### Surveillance
Individuals with POLG-related disorders require frequent examination and interval evaluation by a team comprising the following:
* Primary care provider
* Neurologist
* Biochemical geneticist
* Hepatologist or gastroenterologist
* Physiatrist
* Psychiatrist
* Neuropsychologist and/or psychologist
* Ophthalmologist
* Pulmonologist
#### Laboratory Tests
No standard-of-care guidelines regarding the recommended frequency of the following tests are available. Testing should be guided by clinical features and the proposed schedule should be modified if the clinical course is stable. For those with the most severe phenotypes, the following could be considered.
Every three months:
* Complete blood count
* Electrolytes
* Liver enzymes (AST, ALT, GGT)
* CK
* Liver function tests including:
* Preprandial serum glucose concentration
* Serum concentration of ammonia, albumin, bilirubin (free and conjugated), and cholesterol
* PT or INR as a measure of coagulation factors
Annually:
* Urine analysis
* Serum concentration of lactic acid
Biannually:
* Plasma amino acids
* Urine organic acids
* Plasma concentration of free and total carnitine (unless treated with levocarnitine, in which case measure annually)
Note: After introducing any new anticonvulsant it is reasonable to monitor liver enzymes every two to four weeks.
#### Imaging and Diagnostic Procedures
The following are appropriate:
* Liver ultrasound examination annually
* EEG and video EEG monitoring (e.g., for suspicion of subclinical status epilepticus, presence of epilepsia partialis continua, need to determine if events are seizures or non-epileptic movements)
* Audiogram and brain stem auditory evoked responses as clinically indicated
* Barium swallow study as clinically indicated
* Polysomnogram with CPAP titration as part of an evaluation of subacute mental status changes or every two to three years
### Agents/Circumstances to Avoid
Valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) should be avoided because of the risk of precipitating and/or accelerating liver disease [Saneto et al 2010].
As with some other mitochondrial diseases, physical stressors such as infection, fever, dehydration, and anorexia can result in a sudden deterioration and should be avoided if possible.
### 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 information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
### Other
Liver transplantation is not advised in children with AHS because transplanting the liver does not alter the rapid progression of the brain disease [Kelly 2000].
However, liver transplantation in adults who have an acceptable quality of life may be of benefit:
* In one report, one of two individuals undergoing liver transplantation survived [Tzoulis et al 2006].
* In another report, a woman underwent liver transplantation at age 19 years, eight years after experiencing fulminant hepatic failure following onset of valproate therapy. Molecular genetic testing seven years after her liver transplantation confirmed the diagnosis of a POLG-related disorder; her phenotype fit best with SANDO [Wong et al 2008]. As of late 2017 (20 years after liver transplantation), she was alive and living semi-independently, albeit with severe PEO, myopathy, and progressive CNS dysfunction, specifically failing memory with increasing ataxia, dysarthria, chorea, and hemiballismus. Although seizures were a presenting symptom, they are currently controlled.
The use of other treatments for refractory epilepsy, such as corticotropin or prednisone, ketogenic diet, and intravenous IgG, are unproven in the treatment of AHS. The following, however, may be considered:
* Vitamin and cofactor therapy with the intent to fortify mitochondrial function may be offered. There have not been formal studies of the use of these vitamins and cofactors in AHS or other POLG-related disorders [Parikh et al 2009, Camp et al 2016].
* The use of folinic acid should be strongly considered (see Prevention of Secondary Complications).
* The use of levo-arginine has been reported helpful in reducing the frequency and severity of the strokes associated with MELAS, and can be considered for use in persons with POLG-related disorders, especially if deficiency in the plasma or CSF arginine concentration is confirmed [El-Hattab et al 2017].
* Levocarnitine, creatine monohydrate, coenzyme Q10, B vitamins, and antioxidants such as alpha lipoic acid, vitamin E, and vitamin C have been used as mitochondrial supplements. Use of all in POLG-related disorders is reasonable based on limited published evidence and their general lack of toxicity [Gold & Cohen 2001, Rodriguez et al 2007, Horvath et al 2008, Parikh et al 2013].
*[v]: View this template
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*[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 inhibitors
*[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
| POLG-Related Disorders | None | 4,877 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK26471/ | 2021-01-18T21:05:20 | {"synonyms": []} |
Peeling skin syndrome (PSS) type A is a non inflammatory form of generalized PSS (see this term), a type of ichthyosis (see this term), characterized by generalized white scaling and superficial painless peeling of the skin.
## Epidemiology
The prevalence is unknown. The disease is rare with approximately 40 families reported in the literature to date
## Clinical description
The disease manifests at birth or during infancy with generalized white scaling, most prominent over the upper and lower extremities, that is associated with painless and spontaneous peeling of the skin. Areas of hyperpigmentation can be observed. Direct contact with water, dust and sand may cause skin irritation. There is no history of erythema or atopy and patients are in good general health. Pruritus is rarely observed. Hair is normal.
## Etiology
A mutation in the CHST8 gene (19q13.1) encoding GalNAc4-ST1, a transmembrane sulfotransferase has been identified in one family. This mutation increases the degradation of GalNAc4-ST1 which seems to play an important role in epidermal homeostasis, thus leading to increased and continuous desquamation of the stratum corneum. It is not known if other genes can cause PSS type A and if the disease is genetically heterogeneous.
## Diagnostic methods
Diagnosis is based on clinical features. Histological examination of skin lesion biopsies reveals a slight hyperkeratosis, thinning of the granular layer and a separation of the stratum corneum from the underlying stratum granulosum or an intracorneal split. Molecular analysis, if performed, may reveal CHST8 mutations.
## Differential diagnosis
Differential diagnosis includes other forms of PSS and staphylococcal scalded skin syndrome (see these terms).
## Antenatal diagnosis
The disease is not severe enough to justify prenatal screening.
## Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to affected families informing them of the risk of 25% for a healthy carrier parent to have an affected child.
## Management and treatment
No effective treatment has been reported. Emollients are often used to reduce skin peeling.
## Prognosis
Life expectancy is normal. No significant impairment in quality of life is reported.
*[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 inhibitors
*[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
| Peeling skin syndrome type A | c4015729 | 4,878 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=263548 | 2021-01-23T18:54:39 | {"omim": ["616265", "618084"], "icd-10": ["Q80.8"], "synonyms": ["Generalized deciduous skin type A", "Generalized peeling skin syndrome type A", "Non-inflammatory generalized peeling skin syndrome type A.", "Non-inflammatory peeling skin syndrome type A", "PSS type A"]} |
X-linked central congenital hypothyroidism with late-onset testicular enlargement is a rare, genetic, endocrine disease characterized by central hypothyroidism, testis enlargement in adolescence resulting in adult macroorchidism, delayed pubertal testosterone rise with a subsequent delayed pubertal growth spurt, small thyroid gland, and variable prolactin and growth hormone 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 inhibitors
*[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
| X-linked central congenital hypothyroidism with late-onset testicular enlargement | c3550963 | 4,879 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=329235 | 2021-01-23T18:09:22 | {"omim": ["300888"], "icd-10": ["E03.1"], "synonyms": ["IGSF1 deficiency syndrome", "X-linked central congenital hypothyroidism with late-onset macroorchidism"]} |
A number sign (#) is used with this entry because LW blood group antigens reside on a protein encoded by the ICAM4 gene (614088) on chromosome 19p13.
Description
The LW blood group antigens reside on a 42-kD red cell intercellular adhesion molecule designated ICAM4 (Bailly et al., 1994; Bailly et al., 1995).
Mapping
Sistonen (1984) showed that the LW locus is closely linked to C3 (120700) and Lutheran (111200) on chromosome 19. The maximum lod score was 3.61 at theta = 0.00 for LW:C3 and 3.67 at theta = 0.05 for LW:Lu. The data suggested that the Lewis blood group locus is situated outside the C3-LW region.
Using a C3 DNA probe, Lewis et al. (1987) found no recombinants between LW and C3 (maximum lod score = 4.216 at theta = 0.00). No recombinants were found in 16 female meioses. Combined with the data of Sistonen (1984), the recombination fraction between LW and C3 was estimated to be 0.09 in females (maximum lod score = 3.773).
Lewis et al. (1988) established close linkage between LW and LDLR (606945); maximum lod = 8.43 at theta = 0.00. They concluded that LDLR, C3, and LW constitute a tightly linked gene cluster. Their findings supported a 19p13.2-cen position for LW.
The LW locus was assigned to 19p13.3 by isotopic in situ hybridization (Hermand et al., 1995).
Molecular Genetics
### LW(a)/LW(b) Polymorphism
Hermand et al. (1995) demonstrated that the molecular basis for the LW(a)/LW(b) polymorphism is a single-basepair change (308A-G) in the ICAM4 gene that correlates with a PvuII restriction site and results in a gln70-to-arg (Q70R) amino acid substitution (614088.0001). COS-7 cells transfected with LW(a) or LW(b) cDNAs reacted with human anti-LW(a) and anti-LW(b) sera, respectively, as well as with a murine monoclonal anti-LW(ab) antibody, as shown by flow cytometry analysis. Study by Southern blot analysis indicated that the LW locus is composed of a single gene that is not grossly rearranged in the rare LW(a-b-) individuals or in Rh-null individuals deficient for LW antigens. RFLP analysis using PvuII indicated that these variants were homozygous for a phenotypically silent LW(a) allele in all cases.
### LW(a-b-) Phenotype
Individuals with the rare LW(a-b-) phenotype lack LW antigens and LW protein expression on red blood cells. Some of these individuals express normal Rh antigens, but others also lack Rh and Rh-associated antigens and proteins. Using Southern blot analysis, Hermand et al. (1995) showed that the ICAM4 gene was not grossly rearranged in an individual with the LW(a-b-) phenotype or in individuals with the Rh-null phenotype, who also lack LW antigens. RFLP analysis using PvuII indicated that the LW(a-b-) individual and 3 Rh-null individuals were homozygous for a phenotypically silent LW(a) allele.
In an individual with the LW(a-b-) phenotype who carried a normal Rh phenotype, Hermand et al. (1996) identified a 10-bp deletion in exon 1 of the ICAM4 gene (614088.0002) that generated a premature stop codon, resulting in a truncated protein without the transmembrane and cytoplasmic domains. Heterogeneity was indicated by the fact that no detectable abnormality of the LW gene or transcript could be detected in another LW(a-b-) individual.
History
LW stands for Landsteiner and Wiener, the researchers who first discovered the LW blood group with antibody raised in guinea pigs injected with the cells of rhesus monkeys. It was originally thought to be identical to the anti-D first described in a woman with an erythroblastotic infant studied by Levine and Stetson (1939). Hence, the name of the Rh system. It was later found to be distinct; LW is the true Rhesus blood group, but this designation had been preempted. Levine suggested the designation LW.
*[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 inhibitors
*[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
| BLOOD GROUP SYSTEM, LANDSTEINER-WIENER | None | 4,880 | omim | https://www.omim.org/entry/111250 | 2019-09-22T16:44:25 | {"omim": ["111250"], "synonyms": ["Alternative titles", "LANDSTEINER-WIENER BLOOD GROUP SYSTEM"]} |
Pogosta disease
Other namesKarelian fever, Ockelbo disease
SpecialtyInfectious disease
Pogosta disease is a viral disease.[1][2] The symptoms of the disease include usually rash, as well as mild fever and other flu-like symptoms; in most cases the symptoms last less than 5 days. However, in some cases, the patients develop a painful arthritis. There are no known chemical agents available to treat the disease.[3]
## Contents
* 1 Cause
* 2 Epidemiology
* 3 Etymology
* 4 References
* 5 External links
## Cause[edit]
It has long been suspected that the disease is caused by a Sindbis-like virus, a positive-stranded RNA virus belonging to the Alphavirus genus and family Togaviridae.[1] In 2002 a strain of Sindbis was isolated from patients during an outbreak of the Pogosta disease in Finland, confirming the hypothesis.[3]
## Epidemiology[edit]
This disease is mainly found in the Eastern parts of Finland; a typical Pogosta disease patient is a middle-aged person who has been infected through a mosquito bite while picking berries in the autumn. The prevalence of the disease is about 100 diagnosed cases every year, with larger outbreaks occurring in 7-year intervals.[3]
## Etymology[edit]
It is also known as Karelian fever and Ockelbo disease. The names are derived from the words Pogosta, Karelia and Ockelbo.
## References[edit]
1. ^ a b Lvov, D. K.; Vladimirtseva, E. A.; Butenko, A. M.; Karabatsos, N.; Trent, D. W.; Calisher, C. H. (1988). "Identity of Karelian fever and Ockelbo viruses determined by serum dilution-plaque reduction neutralization tests and oligonucleotide mapping". The American Journal of Tropical Medicine and Hygiene. 39 (6): 607–610. doi:10.4269/ajtmh.1988.39.607. PMID 2849885.
2. ^ Laine, Maria (2002). Pogosta Disease. University of Turku. ISBN 951-29-2129-4.
3. ^ a b c Kurkela S, Manni T, Vaheri A, Vapalahti O (May 2004). "Causative agent of Pogosta disease isolated from blood and skin lesions". Emerg Infect Dis. 10 (5): 889–894. doi:10.3201/eid1005.030689. PMC 3323234. PMID 15200824.
## External links[edit]
Classification
D
* ICD-10: A92.8
*[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 inhibitors
*[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
| Pogosta disease | c0343597 | 4,881 | wikipedia | https://en.wikipedia.org/wiki/Pogosta_disease | 2021-01-18T18:29:29 | {"icd-10": ["A92.8"], "wikidata": ["Q4346007"]} |
Infantile neuroaxonal dystrophy is a type of lipid storage disorder that mostly affects the nervous system. It has two forms, a classic form and an atypical form. The classic form is usually diagnosed in infancy or early childhood and leads to a progressive loss of vision and developmental milestones. The atypical form usually begins in early childhood, but can start as late as the teens. Infantile neuroaxonal dystrophy is caused by changes (pathogenic variants) in the PLA2G6 gene and is inherited in an autosomal recessive pattern.
*[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 inhibitors
*[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
| Infantile neuroaxonal dystrophy | c0270724 | 4,882 | gard | https://rarediseases.info.nih.gov/diseases/3957/infantile-neuroaxonal-dystrophy | 2021-01-18T17:59:47 | {"mesh": ["D019150"], "omim": ["256600", "610217"], "umls": ["C0270724"], "orphanet": ["35069"], "synonyms": ["Seitelberger disease", "INAD", "Infantile neuroaxonal dystrophy/atypical neuroaxonal dystrophy", "Neurodegeneration with brain iron accumulation 2B ", "NEUROAXONAL DYSTROPHY, ATYPICAL", "KARAK SYNDROME, INCLUDED", "NEURODEGENERATION WITH BRAIN IRON ACCUMULATION, PLA2G6-RELATED", "NBIA2B ", "INAD1", "Phospholipase A2-associated neurodegeneration", "PLAN", "Neuroaxonal dystrophy, infantile"]} |
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Sertoli–Leydig cell tumour
Micrograph of a Sertoli–Leydig cell tumour. The Leydig cells have abundant eosinophilic or light pink cytoplasm. The Sertoli cells have a pale/clear cytoplasm. H&E stain.
SpecialtyEndocrinology, oncology
Sertoli–Leydig cell tumour is a group of tumors composed of variable proportions of Sertoli cells, Leydig cells, and in the case of intermediate and poorly differentiated neoplasms, primitive gonadal stroma and sometimes heterologous elements.[1]
Sertoli–Leydig cell tumour (a sex-cord stromal tumor), is a testosterone-secreting ovarian tumor and is a member of the sex cord-stromal tumour group[2] of ovarian and testicular cancers. The tumour occurs in early adulthood (not seen in newborn), is rare, comprising less than 1% of testicular tumours.[1] While the tumour can occur at any age, it occurs most often in young adults. Recent studies have shown that many cases of Sertoli–Leydig cell tumor of the ovary are caused by germline mutations in the DICER1 gene.[3][4] These hereditary cases tend to be younger, often have a multinodular thyroid goiter and there may be a personal or family history of other rare tumors such as pleuropulmonary blastoma, Wilms tumor and cervical rhabdomyosarcoma.
Closely related terms include arrhenoblastoma[5] and androblastoma.[6] Both terms are classified under Sertoli–Leydig cell tumour in MeSH.
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Diagnosis
* 3.1 Classification
* 4 Treatment
* 5 See also
* 6 References
* 7 External links
## Signs and symptoms[edit]
Due to excess testosterone secreted by the tumour, one-third of adult females present with a recent history of progressive masculinization. Masculinization is preceded by anovulation, oligomenorrhoea, amenorrhoea and defeminization. Additional signs include acne and hirsutism, voice deepening, clitoromegaly, temporal hair recession, and an increase in musculature. Serum testosterone level is high.
## Cause[edit]
The exact cause of Sertoli–Leydig cell tumour is not known. Research studies seem to indicate that certain genetic mutations (in the DICER1 gene) may play a role in many cases.
## Diagnosis[edit]
Presence of an ovarian tumour plus hormonal disturbances suggests a Sertoli–Leydig cell tumour. However, hormonal disturbance is present in only two-thirds of cases. A conclusive diagnosis is made via histology, as part of a pathology report made during or after surgery. See also sex cord–gonadal stromal tumour.
* High magnification micrograph of a Leydig cell tumour. H&E stain.
* High magnification micrograph of a Sertoli cell tumour. H&E stain.
### Classification[edit]
The tumour is subdivided into many different subtypes. The most typical is composed of tubules lined by Sertoli cells and interstitial clusters of Leydig cells.
## Treatment[edit]
The usual treatment is surgery. The surgery usually is a fertility-sparing unilateral salpingo-oophorectomy. For malignant tumours, the surgery may be radical and usually is followed by adjuvant chemotherapy, sometimes by radiation therapy. In all cases, initial treatment is followed by surveillance. Because in many cases Sertoli–Leydig cell tumour does not produce elevated tumour markers,[7] the focus of surveillance is on repeated physical examination and imaging. Given that many cases of Sertoli–Leydig cell tumor of the ovary are hereditary, referral to a clinical genetics service should be considered.
The prognosis is generally good as the tumour tends to grow slowly and usually is benign: 25% are malignant.[citation needed] For malignant tumours with undifferentiated histology, prognosis is poor.[7]
## See also[edit]
* Androgen-dependent syndromes
* Leydig cell tumour
* Sertoli cell tumour
## References[edit]
1. ^ a b WHO, 2003[verification needed]
2. ^ Sachdeva, Poonam; Arora, Raksha; Dubey, Chandan; Sukhija, Astha; Daga, Mridula; Kumar Singh, Deepak (2008). "Sertoli–Leydig cell tumor: A rare ovarian neoplasm. Case report and review of literature". Gynecological Endocrinology. 24 (4): 230–4. doi:10.1080/09513590801953465. PMID 18382911.
3. ^ Frio, Thomas Rio; Bahubeshi, Amin; Kanellopoulou, Chryssa; Hamel, Nancy; Niedziela, Marek; Sabbaghian, Nelly; Pouchet, Carly; Gilbert, Lucy; O'Brien, Paul K. (2011). "DICER1 Mutations in Familial Multinodular Goiter With and Without Ovarian Sertoli-Leydig Cell Tumors". JAMA. 305 (1): 68–77. doi:10.1001/jama.2010.1910. PMC 3406486. PMID 21205968.
4. ^ Slade, Ingrid; Bacchelli, Chiara; Davies, Helen; Murray, Anne; Abbaszadeh, Fatemeh; Hanks, Sandra; Barfoot, Rita; Burke, Amos; Chisholm, Julia (2011). "DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome". Journal of Medical Genetics. 48 (4): 273–8. doi:10.1136/jmg.2010.083790. PMID 21266384.
5. ^ "arrhenoblastoma" at Dorland's Medical Dictionary
6. ^ "androblastoma" at Dorland's Medical Dictionary
7. ^ a b Lenhard, Miriam; Kuemper, Caroline; Ditsch, Nina; Diebold, Joachim; Stieber, Petra; Friese, Klaus; Burges, Alexander (2007). "Use of novel serum markers in clinical follow-up of Sertoli–Leydig cell tumours". Clinical Chemistry and Laboratory Medicine. 45 (5): 657–61. doi:10.1515/CCLM.2007.120. PMID 17484630.
## External links[edit]
* Media related to Sertoli–Leydig cell tumors at Wikimedia Commons
Classification
D
* ICD-9-CM: 183.0, 256.1
* ICD-O: 8630-8631/0
* MeSH: D018310
External resources
* MedlinePlus: 001172
* v
* t
* e
Tumors of the female urogenital system
Adnexa
Ovaries
Glandular and epithelial/
surface epithelial-
stromal tumor
CMS:
* Ovarian serous cystadenoma
* Mucinous cystadenoma
* Cystadenocarcinoma
* Papillary serous cystadenocarcinoma
* Krukenberg tumor
* Endometrioid tumor
* Clear-cell ovarian carcinoma
* Brenner tumour
Sex cord–gonadal stromal
* Leydig cell tumour
* Sertoli cell tumour
* Sertoli–Leydig cell tumour
* Thecoma
* Granulosa cell tumour
* Luteoma
* Sex cord tumour with annular tubules
Germ cell
* Dysgerminoma
* Nongerminomatous
* Embryonal carcinoma
* Endodermal sinus tumor
* Gonadoblastoma
* Teratoma/Struma ovarii
* Choriocarcinoma
Fibroma
* Meigs' syndrome
Fallopian tube
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Uterus
Myometrium
* Uterine fibroids/leiomyoma
* Leiomyosarcoma
* Adenomyoma
Endometrium
* Endometrioid tumor
* Uterine papillary serous carcinoma
* Endometrial intraepithelial neoplasia
* Uterine clear-cell carcinoma
Cervix
* Cervical intraepithelial neoplasia
* Clear-cell carcinoma
* SCC
* Glassy cell carcinoma
* Villoglandular adenocarcinoma
Placenta
* Choriocarcinoma
* Gestational trophoblastic disease
General
* Uterine sarcoma
* Mixed Müllerian tumor
Vagina
* Squamous-cell carcinoma of the vagina
* Botryoid rhabdomyosarcoma
* Clear-cell adenocarcinoma of the vagina
* Vaginal intraepithelial neoplasia
* Vaginal cysts
Vulva
* SCC
* Melanoma
* Papillary hidradenoma
* Extramammary Paget's disease
* Vulvar intraepithelial neoplasia
* Bartholin gland carcinoma
* v
* t
* e
* Tumors of the male urogenital system
Testicles
Sex cord–
gonadal stromal
* Sertoli–Leydig cell tumour
* Sertoli cell tumour
* Leydig cell tumour
Germ cell
G
* Seminoma
* Spermatocytic tumor
* Germ cell neoplasia in situ
NG
* Embryonal carcinoma
* Endodermal sinus tumor
* Gonadoblastoma
* Teratoma
* Choriocarcinoma
* Embryoma
Prostate
* Adenocarcinoma
* High-grade prostatic intraepithelial neoplasia
* HGPIN
* Small-cell carcinoma
* Transitional cell carcinoma
Penis
* Carcinoma
* Extramammary Paget's disease
* Bowen's disease
* Bowenoid papulosis
* Erythroplasia of Queyrat
* Hirsuties coronae glandis
*[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 inhibitors
*[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
| Sertoli–Leydig cell tumour | None | 4,883 | wikipedia | https://en.wikipedia.org/wiki/Sertoli%E2%80%93Leydig_cell_tumour | 2021-01-18T19:02:16 | {"icd-9": ["256.1", "183.0"], "wikidata": ["Q586009"]} |
Hematopoietic ulcers are those occurring with sickle cell anemia, congenital hemolytic anemia, polycythemia vera, thrombocytopenic purpura, macroglobulinemia, and cryoglobulinemia.[1]:847
## See also[edit]
* Skin lesion
## References[edit]
1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6.
This cutaneous condition 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 inhibitors
*[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
| Hematopoietic ulcer | None | 4,884 | wikipedia | https://en.wikipedia.org/wiki/Hematopoietic_ulcer | 2021-01-18T19:00:09 | {"wikidata": ["Q5711181"]} |
Aberrant subclavian artery
Aberrant subclavian artery on MR angiography.
Scrollable version is available.
SpecialtyMedical genetics
Aberrant subclavian artery, or aberrant subclavian artery syndrome, is a rare anatomical variant of the origin of the right or left subclavian artery. This abnormality is the most common congenital vascular anomaly of the aortic arch,[1] occurring in approximately 1% of individuals.[1][2][3]
## Contents
* 1 Presentation
* 2 Pathophysiology
* 3 Diagnosis
* 4 Treatment
* 5 Images
* 6 See also
* 7 References
* 8 External links
## Presentation[edit]
This condition is usually asymptomatic.[1] The aberrant artery usually arises just distal to the left subclavian artery and crosses in the posterior part of the mediastinum on its way to the right upper extremity.[2] In 80% of individuals it crosses behind the esophagus.[2] Such course of this aberrant vessel may cause a vascular ring around the trachea and esophagus. Dysphagia due to an aberrant right subclavian artery is termed dysphagia lusoria, although this is a rare complication.[2][3] In addition to dysphagia, aberrant right subclavian artery may cause stridor, dyspnoea, chest pain, or fever.[1] An aberrant right subclavian artery may compress the recurrent laryngeal nerve causing a palsy of that nerve, which is termed Ortner's syndrome.[4]
The aberrant right subclavian artery frequently arises from a dilated segment of the proximal descending aorta, the so-called Diverticulum of Kommerell (which was named for the German Radiologist, Burkhard Friedrich Kommerell (1901–1990), who discovered it in 1936).[5][6] It is alternatively known as a lusorian artery.[1][3]
## Pathophysiology[edit]
The embryological basis of the retroesophageal aberrant right subclavian artery
In the normal embryological development of the aortic arches, the right dorsal aorta regresses caudal to the origin of the 7th intersegmental artery which gives rise to the right subclavian artery. In formation of an aberrant right subclavian artery, the regression occurs instead between the 7th intersegmental artery and the right common carotid so that the right subclavian artery is then connected to the left dorsal aorta via the part of the right dorsal aorta which normally regresses. During growth, the origin of the right subclavian artery migrates until it is just distal to that of the left subclavian.[3]
## Diagnosis[edit]
This section is empty. You can help by adding to it. (October 2017)
## Treatment[edit]
Surgery is occasionally used to treat the condition.[7]
## Images[edit]
* Aberrant subclavian artery at axial CT-scan. (1) trachea, (2) esophagus, (3) Aberrant subclavian artery.
* Aberrant right subclavian artery at angiography.
* Tape-like impression of the esophagus caused by aberrant subclavian artery. Below (arrows) narrowing of the esophagus by a tumor that is causing the swallowing problems.
* Aberrant subclavian artery seen at swallowing study: Impression of the esophagus from behind.
## See also[edit]
* Dysphagia lusoria
## References[edit]
1. ^ a b c d e Mahmodlou, Rahim; Sepehrvand, Nariman; Hatami, Sanaz (2014). "Aberrant Right Subclavian Artery: A Life-threatening Anomaly that should be considered during Esophagectomy". Journal of Surgical Technique and Case Report. 6 (2): 61–63. doi:10.4103/2006-8808.147262. PMC 4290042. PMID 25598945.
2. ^ a b c d Kau, Thomas; Sinzig, Marietta; Gasser, Johann; Lesnik, Gerald; Rabitsch, Egon; Celedin, Stefan; Eicher, Wolfgang; Illiasch, Herbert; Hausegger, Klaus Armin (2007). "Aortic Development and Anomalies". Seminars in Interventional Radiology. 24 (2): 141–152. doi:10.1055/s-2007-980040. PMC 3036416. PMID 21326792.
3. ^ a b c d Chaoui, R; Rake, A; Heling, KS (2008). "Aortic arch with four vessels: aberrant right subclavian artery". Ultrasound in Obstetrics and Gynecology. 31 (1): 115–117. doi:10.1002/uog.5240. PMID 18098341.
4. ^ Bickle, IC; Kelly, BE; Brooker, DS (2002). "Ortner's syndrome: a radiological diagnosis". The Ulster Medical Journal. 71 (1): 55–56. PMC 2475354. PMID 12137166.
5. ^ St-Amant, Maxime. "Kommerell diverticulum (right aberrant subclavian artery)". Radiopaedia. Retrieved 17 November 2017.
6. ^ Jha, Praveen. "Kommerell diverticulum". Radiopaedia. Retrieved 17 November 2017.
7. ^ Kouchoukos NT, Masetti P (April 2007). "Aberrant subclavian artery and Kommerell aneurysm: surgical treatment with a standard approach". The Journal of Thoracic and Cardiovascular Surgery. 133 (4): 888–92. doi:10.1016/j.jtcvs.2006.12.005. PMID 17382621.
## External links[edit]
Classification
D
* ICD-10: Q27.8
* ICD-9-CM: 747.21
* MeSH: C535555
* v
* t
* e
Congenital vascular defects / Vascular malformation
Great arteries/
other arteries
Aorta
* Patent ductus arteriosus
* Coarctation of the aorta
* Interrupted aortic arch
* Double aortic arch
* Right-sided aortic arch
* Overriding aorta
* Aneurysm of sinus of Valsalva
* Vascular ring
Pulmonary artery
* Pulmonary atresia
* Stenosis of pulmonary artery
Subclavian artery
* Aberrant subclavian artery
Umbilical artery
* Single umbilical artery
Great veins
Superior/inferior vena cava
* Congenital stenosis of vena cava
* Persistent left superior vena cava
Pulmonary vein
* Anomalous pulmonary venous connection (Total, Partial)
* Scimitar syndrome
Arteriovenous malformation
* Cerebral arteriovenous malformation
*[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 inhibitors
*[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
| Aberrant subclavian artery | c0431498 | 4,885 | wikipedia | https://en.wikipedia.org/wiki/Aberrant_subclavian_artery | 2021-01-18T18:59:55 | {"gard": ["5706"], "mesh": ["C535555"], "icd-9": ["747.21"], "icd-10": ["Q27.8"], "wikidata": ["Q446822"]} |
Achondrogenesis is a group of severe disorders that are present from birth and affect the development of cartilage and bone. Infants with achondrogenesis usually have a small body, extremely short arms and legs, other skeletal abnormalities, and underdeveloped lungs. There are at least three forms of achondrogenesis, type 1A, type 1B and type 2. Achondrogenesis is usually diagnosed during pregnancy by ultrasound and genetic testing is used to distinguish between the three types. Type 1A and 1B achondrogenesis are both inherited in an autosomal recessive pattern. Type 1A is caused by mutations in the TRIP11 gene. Type 1B is caused by mutations in the SLC26A2 gene. Type 2 achondrogenesis is caused by new (de novo) mutations in the COL2A1 gene. Because of the severity of this condition, most infants with achondrogenesis die before or shortly after birth.
*[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 inhibitors
*[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
| Achondrogenesis | c0001079 | 4,886 | gard | https://rarediseases.info.nih.gov/diseases/2882/achondrogenesis | 2021-01-18T18:02:22 | {"mesh": ["C579878"], "omim": ["200600", "600972", "200610"], "umls": ["C0001079"], "orphanet": ["932"], "synonyms": []} |
A number sign (#) is used with this entry because neuronal ceroid lipofuscinosis-8 (CLN8) is caused by homozygous or compound heterozygous mutation in the CLN8 gene (607837) on chromosome 8p23.
See also the Northern epilepsy variant of CLN8 (610003), an allelic disorder with a different phenotype.
Description
The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN8 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles (Mole et al., 2005).
For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730).
Clinical Features
Wheeler et al. (1999) reported 6 Turkish families with a phenotype similar to that of other forms of late-onset infantile CLN (see, e.g., CLN2, 204500; CLN5, 256731; CLN6, 601780), but who did not map to any known CLN loci. Four of the 6 families reported by Wheeler et al. (1999) were later found by Mitchell et al. (2001) to show linkage to the CLN8 gene on chromosome 8p23, and Ranta et al. (2004) identified mutations in the CLN8 gene in affected members from all 4 of these families (see, e.g., 607837.0003; 607837.0004), thus confirming that they in fact had CLN8.
Topcu et al. (2004) reported the so-called Turkish variant of late-infantile CLN in 17 of 28 Turkish patients. Most of the families were consanguineous. The mean age at disease onset was 5.1 years (range, 2 to 7 years), with seizures or motor impairment as the most common presenting symptom. As the disease progressed, mental regression, myoclonus, speech impairment, loss of vision, and personality disorders developed, and most of the patients became nonambulatory within 2 years after onset. The features distinguishing the Turkish variant from CLN2 and CLN3 included a more severe course regarding seizures, the presence of condensed fingerprint profiles on electron microscopic examination of lymphocytes, and lack of vacuolated lymphocytes.
Cannelli et al. (2006) reported 3 unrelated Italian patients with CLN8. Clinical features included delayed psychomotor development, seizures, myoclonus, and progressive loss of vision. Ultrastructural studies showed osmiophilic inclusions in curvilinear and fingerprint profiles in various tissues. Brain MRI showed cerebral and cerebellar atrophy. One of the patients was born of consanguineous parents.
Allen et al. (2012) reported a 5.5-year-old Irish boy, born of unrelated parents, with CLN8. He had early global developmental delay with suspected autism. At age 4 years, he developed clumsiness, deterioration of speech, and progressive social withdrawal. He later developed seizures and became immobile. Physical examination showed cognitive delay, visual impairment, jerky ocular pursuit, brisk deep tendon reflexes, and broad-based gait. There were no dysmorphic features. Visual evoked responses were delayed, and electroretinogram was absent. Brain MRI revealed hyperintensity in the white matter and cerebellar atrophy. Electron microscopic examination of lymphocytes showed membrane-bound fingerprint profiles without vacuolization and a mixture of curvilinear and rectilinear profiles, with small fingerprint stacks in sweat gland epithelia, blood vessel endothelia, and smooth muscle cells on skin biopsy. Molecular testing identified compound heterozygosity for a truncating mutation in the CLN8 gene inherited from the unaffected father and a de novo terminal deletion of 8p23.3 including the CLN8 gene on the maternal allele.
Mapping
Mitchell et al. (2001) detected linkage and homozygosity in the vicinity of the CLN8 locus in 4 Turkish families with the so-called Turkish variant of late-infantile CLN. Ranta et al. (2004) extended the Turkish vLINCL family panel to 18 families and found linkage to the CLN8 locus in 9 families. The other 9 families were excluded from CLN8 by lack of homozygosity in the 8p23 region.
Molecular Genetics
Ranta et al. (2004) identified 4 homozygous mutations in the CLN8 gene (see, e.g., 607837.0002-607837.0004) in affected members of 9 families with the so-called Turkish variant of late-infantile CLN, 4 of whom were reported by Wheeler et al. (1999) and Mitchell et al. (2001), and 5 of whom were reported by Topcu et al. (2004). The findings indicated that the disorder is allelic to Finnish Northern epilepsy variant of CLN8. There was no apparent genotype/phenotype correlation among the Turkish patients with CLN8 mutations, although the authors noted that the phenotype was distinct from that of Finnish Northern epilepsy patients.
In 3 unrelated Italian patients with CLN8, Cannelli et al. (2006) identified homozygous or compound heterozygous mutations in the CLN8 gene (see, e.g., 607837.0005 and 607837.0006, respectively).
Animal Model
In a naturally occurring mouse model of NCL, termed 'motor neuron degeneration' (mnd) mouse (Bronson et al., 1993), Ranta et al. (1999) identified a homozygous 1-bp insertion (267-268insC at codon 90) in the Cln8 gene, predicting a frameshift and a truncated protein. This was the first description of the molecular basis of a naturally occurring animal model for NCL.
Katz et al. (2005) identified a leu164-to-pro (L164P) mutation in the Cln8 gene in English setter dogs with autosomal recessive NCL.
In a mixed breed dog with Australian Shepherd and Blue Heeler ancestry, Guo et al. (2014) reported a G-to-A transition at nucleotide c.585 in the Cln8 gene, resulting in a nonsense mutation at codon 195 instead of the expected tryptophan. The dog had neurologic signs characteristic of CLN8 starting at 8 months of age. The authors found the mutation in heterozygosity or homozygosity in 7 of 1,488 archived Australian Shepherd DNA samples. All 3 dogs homozygous for the A allele exhibited clinical signs of NCL, and in 2 of them NCL was confirmed by postmortem evaluation of brain tissue.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Vision loss, progressive NEUROLOGIC Central Nervous System \- Developmental regression \- Seizures \- Ataxia \- Speech and language difficulties \- Myoclonus \- EEG abnormalities \- Cerebral atrophy \- Cerebellar atrophy \- Autofluorescent lipopigment in neurons LABORATORY ABNORMALITIES \- Intracellular fingerprint profiles on ultrastructural analysis \- Intracellular curvilinear profiles on ultrastructural analysis MISCELLANEOUS \- Onset age 2 to 7 years \- Most patients lose ambulation 2 years after onset \- Allelic disorder to Northern epilepsy ( 610003 ) MOLECULAR BASIS \- Caused by mutations in the CLN8 gene (CLN8, 607837.0002 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[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
| CEROID LIPOFUSCINOSIS, NEURONAL, 8 | c0022340 | 4,887 | omim | https://www.omim.org/entry/600143 | 2019-09-22T16:16:33 | {"doid": ["0110723"], "mesh": ["D009472"], "omim": ["600143"], "orphanet": ["168491", "228354", "79264"]} |
This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed.
Find sources: "Pelvic tumor" – news · newspapers · books · scholar · JSTOR (September 2017)
A pelvic tumor is any one of numerous tumors that occur in the pelvis. Within the pelvis, these tumors may involve specific organs, or occupy intra-organ spaces. Tumors of the presacral space and sacral space are most prevalent in children. Tumors occupying specific organs have a more complex natural history.
## Contents
* 1 Tumors occupying specific organs
* 2 Tumors occupying intra-organ spaces
* 3 Complications
* 4 References
## Tumors occupying specific organs[edit]
* Bladder cancer
* Prostate cancer
* Rectal cancer
* Anal cancer
* Ovarian cancer
* Uterine cancer
* Sacrococcygeal teratoma
## Tumors occupying intra-organ spaces[edit]
Presacral space:
* Teratoma
Sacral space (in approximate order of prevalence):
* Teratoma
* Lipoma
* Ganglioneuroma
* Myxopapillary ependymoma
* Primitive neuroectodermal tumor
* Aneurysmal bone cyst
* Ewing's sarcoma
* Metastases from brain stem tumors (medulloblastoma, ependymoma, high-grade astrocytoma)
## Complications[edit]
* Urinary incontinence
* Fecal incontinence
## References[edit]
* 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
This article about a neoplasm 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 inhibitors
*[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
| Pelvic tumor | c0030793 | 4,888 | wikipedia | https://en.wikipedia.org/wiki/Pelvic_tumor | 2021-01-18T18:31:15 | {"mesh": ["D010386"], "wikidata": ["Q7161811"]} |
GM1 gangliosidosis type 3 is a mild, chronic, adult form of GM1 gangliosidosis (see this term) characterized by onset generally during childhood or adolescence and by cerebellar dysfunction.
## Epidemiology
Type 3 is a less frequent form of GM1 gangliosidosis compared to infantile type 1 disease but the exact prevalence, although unknown, is likely to be underestimated. About 70 cases have been reported to date. Overall prevalence at birth of GM1 gangliosidosis is estimated to be approximately 1:100,000 to 200,000 live births. Most reported cases are in patients of Japanese origin.
## Clinical description
Marked variability of clinical signs and age of onset has been reported. Patients generally show slowly progressive dementia, dysarthria, dystonia, short stature, mild vertebral anomalies and ataxia. Eye movements are normal.
## Etiology
GM1 gangliosidosis is caused by mutations in the GLB1gene (3p22.3) coding for beta-galactosidase.
## Diagnostic methods
Diagnosis is clinically suggested by dystonia and slurred speech, usually detected at school age. Biochemical and/or molecular genetic tests confirm the diagnosis.
## Differential diagnosis
Differential diagnosis includes mucopolysaccharidoses, sphingolipidoses and oligosaccharidoses (see these terms).
## Antenatal diagnosis
Prenatal diagnosis can be performed by analysis of beta-galactosidase activity and/or by GLB1 molecular analysis in either chorionic villus (CV) cells or amniotic fluid cells if mutations are identified in an index case.
## Genetic counseling
GM1 gangliosidosis is an autosomal recessive disease. Genetic counseling should be provided to affected families.
## Management and treatment
Treatment for patients with GM1 gangliosidosis is symptomatic and supportive.
## Prognosis
Prognosis is variable.
*[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 inhibitors
*[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
| GM1 gangliosidosis type 3 | c0268273 | 4,889 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79257 | 2021-01-23T18:11:49 | {"gard": ["2431"], "mesh": ["D016537"], "omim": ["230650"], "umls": ["C0268273"], "icd-10": ["E75.1"], "synonyms": ["Adult-onset GM1 gangliosidosis"]} |
A number sign (#) is used with this entry because familial isolated hypoparathyroidism can be caused by mutation in the parathyroid hormone gene (PTH; 168450), or in the GCM2 gene (603716), a homolog of the Drosophila glial cells missing gene.
There is also an X-linked form of hypoparathyroidism (307700).
Description
Garfield and Karaplis (2001) reviewed the various causes and clinical forms of hypoparathyroidism. They noted that hypoparathyroidism is a clinical disorder characterized by hypocalcemia and hyperphosphatemia. It manifests when parathyroid hormone (PTH; 168450) secreted from the parathyroid glands is insufficient to maintain normal extracellular fluid calcium concentrations or, less commonly, when PTH is unable to function optimally in target tissues, despite adequate circulating levels.
Congenital absence of the parathyroid and thymus glands (III and IV pharyngeal pouch syndrome, or DiGeorge syndrome, 188400) is usually a sporadic condition (Taitz et al., 1966).
Clinical Features
Garfield and Karaplis (2001) stated that the predominant clinical manifestations of hypoparathyroidism are those related to hypocalcemia. In the acute setting, neuromuscular irritability, including perioral paresthesias, tingling of the fingers and toes, and spontaneous or latent tetany with grand mal seizures and laryngeal spasm can be evident. Chronically, hypocalcemia can be asymptomatic and only become apparent after routine blood screening. Alternatively, it can manifest with mild neuromuscular irritability, calcification of the basal ganglia, extrapyramidal disorders, cataracts, alopecia, abnormal dentition, coarse brittle hair, mental retardation, or personality disorders. Biochemically, hypoparathyroidism is characterized by low serum calcium and raised serum phosphorus in the presence of normal renal function. Serum concentrations of immunoreactive PTH are low or undetectable, except in the setting of PTH resistance, where levels can be high-normal or elevated. Circulating levels of 1,25-dihydroxyvitamin D are usually low or low-normal. The 24-hour urinary excretion of calcium is decreased. Nephrogenous cAMP excretion is low, whereas renal tubular reabsorption of phosphorus is elevated.
Some reports of idiopathic hypoparathyroidism, in which affected sibs were born of consanguineous parents (Sutphin et al., 1943; Chaptal et al., 1960), suggest autosomal recessive inheritance. The familial cases of Sutphin et al. (1943) showed moniliasis also (see hypoadrenocorticism with hypoparathyroidism and superficial moniliasis, 240300). Bronsky et al. (1968) described 2 brothers who developed idiopathic hypoparathyroidism when 11 and 21 years old. A sister, who died when 19 years old, may also have been affected. Bronsky et al. (1968) cited 6 other reported families in which more than 1 member was affected.
Recessive inheritance was simulated in the family of Buchs (1961) in which 3 brothers had congenital hypoparathyroidism, apparently as a response to maternal hyperparathyroidism. Aceto et al. (1966) reported fetal and infantile hyperparathyroidism due to maternal hypoparathyroidism. The second and third offspring of the affected mother, a girl and a boy, had hypoparathyroidism. The fathers of at least 2 of the offspring were different. The report of Niklasson (1970) may concern autosomal recessive isolated hypoparathyroidism.
Benson and Parsons (1964) described hypoparathyroidism in a mother and 2 of her children. They found no circulating antibodies to parathyroid hormone. Barr et al. (1971) reported hypoparathyroidism in 2 generations of 2 unrelated kindreds. In 1 kindred there was father-to-son transmission.
Yumita et al. (1986) described 2 families with idiopathic hypoparathyroidism. In the first family, a brother and sister were affected; in the second family, 2 brothers and a sister were affected, although only 1 of the 3 was studied extensively. Yumita et al. (1986) suggested that progressive sensorineural deafness, which was present in both families, was an integral part of the hypoparathyroidism syndrome. However, in the second family, it appears to have been segregating, probably as an autosomal dominant, independently of the hypoparathyroidism.
Ahn et al. (1986) studied 8 families with a total of 23 affected persons fulfilling strict criteria for familial isolated hypoparathyroidism: no demonstrable anatomic cause, no evidence of candidiasis or autoimmune polyglandular failure, no antithyroid or antiadrenal autoantibodies, no developmental defects that might indicate an embryologic disorder such as familial branchial pouch dysgenesis, and, of course, undetectable or subnormal plasma levels of immunoreactive PTH. Inheritance was consistent with autosomal dominance in 5 and autosomal recessivity in 3; 1 of the 'dominant pedigrees' and 2 of the 'recessive pedigrees' were also consistent with X-linked inheritance (see 307700). In none of 23 affected persons was there absence of the PTH gene or abnormal restriction patterns to suggest recognizable deletions, insertions or rearrangements. Furthermore, in 4 families affected sibs inherited different PTH alleles, as marked by RFLPs, implying that hypoparathyroidism was not due to an abnormality in the PTH gene. In 2 families concordance was found between the inheritance of hypoparathyroidism and specific PTH alleles, a finding consistent with but of course not proving the possibility that the FIH in these families was caused by mutation in or near the PTH structural gene.
Nusynowitz and Klein (1973) described a 20-year-old male college student with hypocalcemia, hyperphosphatemia, chronic tetany, and cataracts. Normal to high levels of immunoreactive parathyroid hormone were found. Renal responsiveness to exogenous PTH was demonstrated. The authors suggested that this patient suffered from a defect in conversion of proparathyroid hormone to its active form. The parents were not related and no other affected persons were found in the family (Nusynowitz, 1973). Ahn et al. (1986) restudied this family and found that the proband had markedly reduced or absent plasma PTH by radioimmunoassays that are midmolecule specific or carboxy-terminal specific despite symptomatic hypocalcemia. In addition an affected son had low plasma PTH. Thus, this is an instance of autosomal dominant hypoparathyroidism. Linkage analysis with the RFLPs used was uninformative because both parents were homozygous for the same haplotype.
Schmidtke et al. (1986) described a family in which 2 brothers and their mother had hypoparathyroidism. No gross abnormality of the PTH gene was found on Southern blotting. Linkage of the PTH gene to the hypoparathyroidism was excluded by the finding that the mother had passed a different PTH allele (as marked by a RFLP) to each of her sons. De Campo et al. (1988) described a 3-generation family in which 6 of 13 members were affected by primary hypoparathyroidism. In this family, male-to-male, female-to-female, and female-to-male transmission was demonstrated, confirming the autosomal dominant hypothesis.
McLeod et al. (1989) described a mother and 2 sons with clinical hypoparathyroidism and no detectable serum parathyroid hormone on radioimmunoassay. The propositus presented with seizures and on CT scan had bilateral basal ganglion calcification and calcification in the frontal lobes. His similarly affected mother had even more extensive intracerebral calcification.
Mapping
Using a polymorphic tetranucleotide, AAAT(n), within the first intron of the PTH gene, Parkinson et al. (1993) excluded linkage with autosomal dominant isolated hypoparathyroidism in 1 family with dominant inheritance and a second family with autosomal recessive inheritance. In another family with autosomal recessive inheritance, they demonstrated linkage to the PTH gene, which was not unexpected because the same family was found by Parkinson and Thakker (1992) to have a donor splice site mutation in the PTH gene (168450.0002). Thus, both autosomal dominant and autosomal recessive forms of familial isolated hypoparathyroidism have been related to mutations in the PTH gene.
Cytogenetics
Scire et al. (1994) reported clinical features of 2 adolescent males illustrating that the main manifestation of 22q11 deletion can be chronic symptomatic hypocalcemia secondary to hypoparathyroidism, together with seizures and cerebral calcifications. The patients had no cardiac abnormality or T-cell deficiency and had no cleft palate, features that occur in the DiGeorge syndrome (188400) and the velocardiofacial syndrome (VCFS; 192430). The patients did have facial features of VCFS, and one in particular had a hypernasal voice.
Makita et al. (1995) reported 2 further cases of isolated hypoparathyroidism in whom they demonstrated a 22q11 deletion by fluorescence in situ hybridization.
Molecular Genetics
In 1 of the families studied by Ahn et al. (1986), family D, Arnold et al. (1990) identified a point mutation in the signal peptide-encoding region of the PTH gene (C18R; 168450.0001).
In 2 sisters and a brother with isolated hypoparathyroidism, the offspring of a first-cousin marriage, Parkinson and Thakker (1992) identified homozygosity for a mutation in the PTH gene (168450.0002).
Sunthornthepvarakul et al. (1999) identified a mutation in the PTH gene (168450.0003) in a patient with neonatal hypocalcemic seizures who was born to consanguineous parents. Serum calcium was 1.5 mmol/L (normal, 2.0-2.5); phosphate was 3.6 mmol/L (normal, 0.9-1.5). A few years later, 2 younger sisters and her niece presented with neonatal hypocalcemic seizures. Their intact PTH levels were undetectable during severe hypocalcemia. Only affected family members were homozygous for the mutant allele, whereas the parents were heterozygous, supporting autosomal recessive inheritance.
In the proband of an extensive kindred with familial isolated hypoparathyroidism, Ding et al. (2001) identified homozygosity for a large intragenic deletion in the GCM2 gene (603716.0001). The nonconsanguineous, asymptomatic parents were heterozygous for the deletion. Haplotype analysis revealed shared genotypes that flanked the GCM2 gene over 5 cM, suggesting a founder effect with homozygosity by descent of the chromosomal segment containing the GCM2 deletion. Ding et al. (2001) concluded that homozygous loss of function of the GCM2 gene impairs normal parathyroid gland embryology and is responsible for isolated hypoparathyroidism in a subset of patients.
In affected members of a consanguineous Pakistani family with familial isolated hypoparathyroidism, Baumber et al. (2005) identified homozygosity for a missense mutation in the GCM2 gene (603716.0002).
Pathogenesis
In HEK293 cells transfected with C18R-mutant preproPTH cDNA, Datta et al. (2007) demonstrated that the expressed mutant hormone was trapped intracellularly, predominantly in the endoplasmic reticulum (ER), resulting in apoptosis. The C18R-expressing cells also showed marked upregulation of the ER stress-responsive hormones BIP (HSPA5; 138120) and PERK (EIF2AK3; 604032) and the proapoptotic transcription factor CHOP (DDIT3; 126337). When C18R-mutant PTH was expressed in the presence of the pharmacologic chaperone 4-phenylbutyric acid, intracellular accumulation was reduced and normal secretion was restored. Datta et al. (2007) suggested that ER stress-induced cell death is the underlying mechanism for autosomal dominant hypoparathyroidism.
The studies of Winer et al. (2003) suggested that treatment with synthetic human PTH can be a safe and effective alternative to calcitriol therapy and can maintain normal serum calcium levels without hypercalciuria for at least 3 years in patients with hypoparathyroidism.
Animal Model
Glial cells missing-2 (Gcm2), a mouse homolog of Drosophila Gcm, is the only transcription factor with expression restricted to the parathyroid glands (see 603716). Gunther et al. (2000) generated mice deficient in Gcm2 by targeted disruption. The Gcm2-deficient mice lacked parathyroid glands but, unlike PTH-receptor-deficient mice, were viable and fertile and had only a mildly abnormal bone phenotype. The conditionally deleted mice exhibited hypocalcemia associated with hyperphosphatemia and increased calcium elimination in the urine without evidence of renal failure, features characteristic of hypoparathyroidism. Despite their lack of parathyroid glands, the Gcm2-deficient mice had PTH serum levels identical to those of wildtype mice, as did parathyroidectomized wildtype mice. Expression and ablation studies identified the thymus, where Gcm1 (603715), another Gcm homolog, is expressed, as an additional, downregulatable source of PTH. Thus, Gcm2 deletion uncovered an auxiliary mechanism for the regulation of calcium homeostasis in the absence of parathyroid glands. Gunther et al. (2000) suggested that this backup mechanism may be a general feature of endocrine regulation.
INHERITANCE \- Autosomal dominant \- Autosomal recessive HEAD & NECK Eyes \- Cataracts ENDOCRINE FEATURES \- Hypoparathyroidism LABORATORY ABNORMALITIES \- No circulating antibodies to parathyroid hormone \- Undetectable or subnormal plasma immunoreactive PTH \- Hypocalcemia \- Hyperphosphatemia MOLECULAR BASIS \- Caused by mutation in the parathyroid hormone gene (PTH, 168450.0001 ) \- Caused by mutation in the glial cells missing transcription factor 2 gene (GCM2, 603716.0001 ) ▲ 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 inhibitors
*[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
| HYPOPARATHYROIDISM, FAMILIAL ISOLATED | c1832648 | 4,890 | omim | https://www.omim.org/entry/146200 | 2019-09-22T16:39:50 | {"doid": ["11199"], "mesh": ["C537156"], "omim": ["146200"], "orphanet": ["189466", "2238", "2239"], "synonyms": ["Alternative titles", "HYPOPARATHYROIDISM, AUTOSOMAL DOMINANT"]} |
This article needs to be updated. Please update this article to reflect recent events or newly available information. (March 2020)
Inherited neurodegenerative disorder
Huntington's disease
Other namesHuntington's chorea
An edited microscopic image of a medium spiny neuron (yellow) with an inclusion body (orange), which occurs as part of the disease process (image width 360 µm)
SpecialtyNeurology
SymptomsProblems with motor skills, including coordination and gait, mood, and mental abilities[1][2]
ComplicationsPneumonia, heart disease, physical injury from falls, suicide[3]
Usual onset30–50 years old[4]
DurationLong term[4]
CausesGenetic (inherited or new mutation)[4]
Diagnostic methodGenetic testing[5]
Differential diagnosisSydenham's chorea, benign hereditary chorea, lupus, paraneoplastic syndrome, Wilson's disease[6]
TreatmentSupportive care[2]
MedicationTetrabenazine[3]
Prognosis15–20 years from onset of symptoms[4]
Frequency4–15 in 100,000 (European descent)[1]
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited.[7] The earliest symptoms are often subtle problems with mood or mental abilities.[1] A general lack of coordination and an unsteady gait often follow.[2] As the disease advances, uncoordinated, involuntary body movements known as chorea become more apparent.[1] Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk.[1][2] Mental abilities generally decline into dementia.[3] The specific symptoms vary somewhat between people.[1] Symptoms usually begin between 30 and 50 years of age but can start at any age.[4][3] The disease may develop earlier in each successive generation.[1] About eight percent of cases start before the age of 20 years, and are known as juvenile HD, which typically present with the slow movement symptoms of Parkinson's disease rather than those of chorea.[3]
HD is typically inherited from an affected parent, who carries a mutation in the huntingtin gene (HTT).[4] However, up to 10% of cases are due to a new mutation.[1] The huntingtin gene provides the genetic information for huntingtin protein (htt).[1] Expansion of CAG repeats of cytosine-adenine-guanine (known as a trinucleotide repeat expansion) in the gene coding for the huntingtin protein results in an abnormal mutant protein (mhtt), which gradually damages brain cells through a number of possible mechanisms.[7][8] Diagnosis is by genetic testing, which can be carried out at any time, regardless of whether or not symptoms are present.[5] This fact raises several ethical debates: the age at which an individual is considered mature enough to choose testing; whether parents have the right to have their children tested; and managing confidentiality and disclosure of test results.[2]
There is no cure for HD, and full-time care is required in the later stages.[2] Treatments can relieve some symptoms and, in some, improve quality of life.[3] The best evidence for treatment of the movement problems is with tetrabenazine.[3] HD affects about 4 to 15 in 100,000 people of European descent.[1][3] It is rare among Japanese, while the occurrence rate in Africa is unknown.[3] The disease affects men and women equally.[3] Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy.[3] Suicide is the cause of death in about 9% of cases.[3] Death typically occurs 15–20 years from when the disease was first detected.[4]
The earliest known description of the disease was in 1841 by American physician Charles Oscar Waters.[9] The condition was described in further detail in 1872 by American physician George Huntington.[9] The genetic basis was discovered in 1993 by an international collaborative effort led by the Hereditary Disease Foundation.[10][11] Research and support organizations began forming in the late 1960s to increase public awareness, provide support for individuals and their families and promote research.[12][11] Research directions include determining the exact mechanism of the disease, improving animal models to aid with research, testing of medications to treat symptoms or slow the progression of the disease, and studying procedures such as stem-cell therapy with the goal of replacing damaged or lost neurons.[10]
## Contents
* 1 Signs and symptoms
* 2 Genetics
* 2.1 Genetic mutation
* 2.2 Inheritance
* 3 Mechanisms
* 3.1 Huntingtin function
* 3.2 Cellular changes
* 3.3 Macroscopic changes
* 3.4 Transcriptional dysregulation
* 4 Diagnosis
* 4.1 Clinical
* 4.2 Predictive genetic testing
* 4.3 Preimplantation genetic diagnosis
* 4.4 Prenatal testing
* 4.5 Differential diagnosis
* 5 Management
* 5.1 Therapy
* 5.2 Medications
* 5.3 Education
* 6 Prognosis
* 7 Epidemiology
* 8 History
* 9 Society and culture
* 9.1 Ethics
* 9.2 Support organizations
* 10 Research directions
* 10.1 Reducing huntingtin production
* 10.2 Increasing huntingtin clearance
* 10.3 Improving cell survival
* 10.4 Neuronal replacement
* 10.5 Clinical trials
* 11 See also
* 12 References
* 13 External links
## Signs and symptoms[edit]
Signs and symptoms of Huntington's disease most commonly become noticeable between the ages of 30 and 50 years, but they can begin at any age,[4] and present as a triad of motor, cognitive, and psychiatric symptoms.[13] In fifty per cent of cases the psychiatric symptoms appear first.[13] Their progression is often described in early stages, middle stages, and late stages with an earlier prodromal phase.[2] In the early stages, there are subtle personality changes, problems in cognition, and physical skills, irritability, and mood swings, that may all go unnoticed,[14][15] and these usually precede the motor symptoms.[16] Almost everyone with HD eventually exhibits similar physical symptoms, but the onset, progression and extent of cognitive and behavioral symptoms vary significantly between individuals.[17][18]
The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea.[19] Many people are not aware of their involuntary movements, or impeded by them.[1] Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements.[20] These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years.[17] The clear appearance of symptoms such as rigidity, writhing motions or abnormal posturing appear as the disorder progresses.[20] These are signs that the system in the brain that is responsible for movement has been affected.[21] Psychomotor functions become increasingly impaired, such that any action that requires muscle control is affected. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, swallowing, and speaking.[20] Sleep disturbances and weight loss are also associated symptoms.[22] Eating difficulties commonly cause weight loss and may lead to malnutrition.[23][24] Juvenile HD generally progresses at a faster rate with greater cognitive decline, and chorea is exhibited briefly, if at all; the Westphal variant of slowness of movement, rigidity and tremors is more typical in juvenile HD, as are seizures.[20][22]
Cognitive abilities are progressively impaired and tend to generally decline into dementia.[3] Especially affected are executive functions, which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiation of appropriate actions, and inhibition of inappropriate actions.[21] As the disease progresses, memory deficits tend to appear. Reported impairments range from short-term memory deficits to long-term memory difficulties, including deficits in episodic (memory of one's life), procedural (memory of the body of how to perform an activity) and working memory.[21]
Reported neuropsychiatric signs are anxiety, depression, a reduced display of emotions, egocentrism, aggression, and compulsive behavior, the latter of which can cause or worsen addictions, including alcoholism, gambling, and hypersexuality.[25] Difficulties in recognizing other people's negative expressions have also been observed.[21] The prevalence of these symptoms is highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33% and 76%.[25] For many sufferers and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for institutionalization.[25] Early behavioral changes in HD result in an increased risk of suicide.[19] Often individuals have reduced awareness of chorea, cognitive and emotional impairments.[26]
Mutant huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.[27]
## Genetics[edit]
Everyone has two copies of the huntingtin gene (HTT), which codes for the huntingtin protein (htt). HTT is also called the HD gene, and the IT15 gene, (interesting transcript 15). Part of this gene is a repeated section called a trinucleotide repeat expansion – a short repeat which varies in length between individuals and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein (mhtt). The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully penetrant: mutation of either of a person's HTT alleles causes the disease. It is not inherited according to sex, but by the length of the repeated section of the gene and hence its severity can be influenced by the sex of the affected parent.[20]
### Genetic mutation[edit]
HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range.[20] The HTT gene is located on the short arm of chromosome 4[20] at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat.[20] CAG is the three-letter genetic code (codon) for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region.[28]
Graphic showing at top normal range of repeats, and disease-causing range of repeats.
Classification of trinucleotide repeats, and resulting disease status, depending on the number of CAG repeats[20] Repeat count Classification Disease status Risk to offspring
<27 Normal Will not be affected None
27–35 Intermediate Will not be affected Elevated, but <50%
36–39 Reduced Penetrance May or may not be affected 50%
40+ Full Penetrance Will be affected 50%
Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein huntingtin.[20] However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics.[20] This altered form, called mutant huntingtin (mhtt), increases the decay rate of certain types of neurons. Regions of the brain have differing amounts and reliance on these types of neurons, and are affected accordingly.[20] Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to environment and other genes that modify the mechanism of HD.[20] 36 to 39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases the onset may be so late that symptoms are never noticed.[20] With very large repeat counts (more than 60) HD onset can occur below the age of 20 known as juvenile HD. Juvenile HD is typically of the Westphal variant that is characterised by slowness of movement, rigidity and tremors. This accounts for about 7% of HD carriers.[29][30]
### Inheritance[edit]
Huntington's disease is inherited in an autosomal dominant fashion. The probability of each offspring inheriting an affected gene is 50%. Inheritance is independent of gender, and the phenotype does not skip generations.
Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent.[20] Since penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele and therefore being affected with the disorder (see figure). This probability is sex-independent.[31]
Trinucleotide CAG repeats over 28 are unstable during replication, and this instability increases with the number of repeats present.[20] This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat.[20] This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD.[20] Such increases in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation.[1] Instability is greater in spermatogenesis than oogenesis;[20] maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length.[20][32] It is rare for Huntington's disease to be caused by a new mutation, where neither parent has over 36 CAG repeats.[33]
In the rare situations where both parents have an expanded HD gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100% (all children will be affected). Individuals with both genes affected are rare. For some time HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression,[34] but it has since been found that it can affect the phenotype and the rate of progression.[20][35]
## Mechanisms[edit]
The huntingtin protein interacts with over 100 other proteins, and appears to have multiple functions.[36] The behavior of the mutated protein (mhtt) is not completely understood, but it is toxic to certain cell types, particularly in the brain. Early damage is most evident in the striatum, but as the disease progresses, other areas of the brain are also more conspicuously affected. Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood and higher cognitive function.[20] DNA methylation also appears to be changed in HD.[37]
### Huntingtin function[edit]
See also: Huntingtin
Huntingtin (HTT) is expressed in all cells, with the highest concentrations found in the brain and testes, and moderate amounts in the liver, heart, and lungs. However, its function is unclear.[20] It interacts with proteins which are involved in transcription, cell signaling, and intracellular transporting.[20][38] In animals genetically modified to exhibit HD, several functions of HTT have been identified.[39] In these animals, HTT is important for embryonic development, as its absence is related to embryonic death. Caspase, an enzyme which plays a role in catalyzing apoptosis, is thought to be activated by the mutated gene through damaging the ubiquitin-protease system. It also acts as an anti-apoptotic agent preventing programmed cell death and controls the production of brain-derived neurotrophic factor, a protein which protects neurons and regulates their creation during neurogenesis. HTT also facilitates vesicular transport and synaptic transmission and controls neuronal gene transcription.[39] If the expression of HTT is increased and more HTT produced, brain cell survival is improved and the effects of mhtt are reduced, whereas when the expression of HTT is reduced, the resulting characteristics are more as seen in the presence of mhtt.[39] Accordingly it is thought that the disease is not caused by inadequate production of HTT, but by a toxic gain-of-function of mhtt in the body.[20]
### Cellular changes[edit]
A microscope image of a neuron with an inclusion body (stained orange) caused by HD, image width 250 µm
There are multiple cellular changes through which the toxic action of mhtt may manifest and produce the HD pathology.[40][41] In its mutant (i.e. polyglutamine expanded) form, the protein is more prone to cleavage that creates shorter fragments containing the polyglutamine expansion.[40] These protein fragments have a propensity to undergo misfolding and aggregation, yielding fibrillar aggregates in which non-native polyglutamine β-strands from multiple proteins are bonded together via hydrogen bonds.[8] These aggregates share the same fundamental cross-β amyloid architecture seen in other protein deposition diseases. Over time, the aggregates accumulate to form inclusion bodies within cells, ultimately interfering with neuron function.[40][8] Neuronal inclusions run indirect interference. Inclusion bodies have been found in both the cell nucleus and cytoplasm.[40] Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be toxic for the cell, but other experiments have shown that they may form as part of the body's defense mechanism and help protect cells.[40]
Several pathways by which mhtt may cause cell death have been identified. These include: effects on chaperone proteins, which help fold proteins and remove misfolded ones; interactions with caspases, which play a role in the process of removing cells; the toxic effects of glutamine on nerve cells; impairment of energy production within cells; and effects on the expression of genes.[8][42]
Mutant huntingtin protein has been found to play a key role in mitochondrial dysfunction.[43] The impairment of mitochondrial electron transport can result in higher levels of oxidative stress and release of reactive oxygen species.[44]
Glutamine is known to be excitotoxic when present in large amounts, and excitotoxins cause damage to numerous cellular structures. Glutamine is not found in excessively high amounts in HD, but the interactions of the altered huntingtin protein with numerous proteins in neurons lead to an increased vulnerability to glutamine. It has been postulated that the increased vulnerability results in excitotoxic effects from normal glutamine levels.[8]
### Macroscopic changes[edit]
See also: Basal ganglia disease
The area of brain most damaged in early Huntington's disease is the striatum made up of the caudate nucleus and the putamen.
HD affects the whole brain, but certain areas are more vulnerable than others. The most prominent early effects are in a part of the basal ganglia called the striatum, which is composed of the caudate nucleus and putamen.[20] Other areas affected include the substantia nigra, cortical layers 3, 5, and 6 of the neocortex, the hippocampus, Purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus.[20] These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells.[20] Striatal medium spiny neurons are the most vulnerable, particularly ones with projections towards the external globus pallidus, with interneurons and spiny cells projecting to the internal globus pallidus being less affected.[20][45] HD also causes an abnormal increase in astrocytes and activation of the brain's immune cells, microglia.[46]
The basal ganglia—the part of the brain most prominently affected in early HD—play a key role in movement and behavior control. Their functions are not fully understood, but current theories propose that they are part of the cognitive executive system[21] and the motor circuit.[47] The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to motion or motions to be unintentionally initiated, or a motion to be halted before, or beyond, its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with HD known as chorea, a dyskinesia.[47] Because of the basal ganglia's inability to inhibit movements, individuals affected by it will inevitably experience a reduced ability to produce speech and swallow foods and liquids (dysphagia).[48]
### Transcriptional dysregulation[edit]
CREB-binding protein (CBP), a transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways.[42] Furthermore, the amino acids that form CBP include a strip of 18 glutamines. Thus, the glutamines on CBP interact directly with the increased numbers of glutamine on the HTT chain and CBP gets pulled away from its typical location next to the nucleus.[49] Specifically, CBP contains an acetyltransferase domain to which HTT binds through its polyglutamine-containing domain.[50] Autopsied brains of those who had Huntington's disease also have been found to have incredibly reduced amounts of CBP.[49] In addition, when CBP is overexpressed, polyglutamine-induced death is diminished, further demonstrating that CBP plays an important role in Huntington's disease and neurons in general.[42]
## Diagnosis[edit]
Diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease.[20] Genetic testing can be used to confirm a physical diagnosis if there is no family history of HD. Even before the onset of symptoms, genetic testing can confirm if an individual or embryo carries an expanded copy of the trinucleotide repeat (CAG) in the HTT gene that causes the disease. Genetic counseling is available to provide advice and guidance throughout the testing procedure, and on the implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, family planning decisions, relatives and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.[20]
### Clinical[edit]
Coronal section from an MR brain scan of a patient with HD, showing atrophy of the heads of the caudate nuclei, enlargement of the frontal horns of the lateral ventricles (hydrocephalus ex vacuo), and generalized cortical atrophy[51]
A physical examination, sometimes combined with a psychological examination, can determine whether the onset of the disease has begun.[20] Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or behavioral symptoms are rarely the first symptoms diagnosed; they are usually only recognized in hindsight or when they develop further. How far the disease has progressed can be measured using the unified Huntington's disease rating scale, which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments.[52][53] Medical imaging, such as a CT scan or MRI scan, can show atrophy of the caudate nuclei early in the disease, as seen in the illustration to the right, but these changes are not, by themselves, diagnostic of HD. Cerebral atrophy can be seen in the advanced stages of the disease. Functional neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), can show changes in brain activity before the onset of physical symptoms, but they are experimental tools, and are not used clinically.[20]
### Predictive genetic testing[edit]
Because HD follows an autosomal dominant pattern of inheritance, there is a strong motivation for individuals who are at risk of inheriting it to seek a diagnosis. The genetic test for HD consists of a blood test which counts the numbers of CAG repeats in each of the HTT alleles.[54] Cutoffs are given as follows:
* 40 or more CAG repeats: full penetrance allele (FPA).[55] A "positive test" or "positive result" generally refers to this case. A positive result is not considered a diagnosis, since it may be obtained decades before the symptoms begin. However, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD.[20] The test will tell a person who originally had a 50 percent chance of inheriting the disease if their risk goes up to 100 percent or is eliminated. A person who tests positive for the disease will develop HD sometime within their lifetime, provided he or she lives long enough for the disease to appear.[20]
* 36 to 39 repeats: incomplete or reduced penetrance allele (RPA). It may cause symptoms, usually later in the adult life.[55] There is a maximum risk of 60% that a person with an RPA will be symptomatic at the age of 65 years, and a 70% risk of being symptomatic at the age of 75 years.[55]
* 27 to 35 repeats: intermediate allele (IA), or large normal allele. It is not associated with symptomatic disease in the tested individual, but may expand upon further inheritance to give symptoms in offspring.[55]
* 26 or fewer repeats: Not associated with HD.[55]
Testing before the onset of symptoms is a life-changing event and a very personal decision.[20] The main reason given for choosing testing for HD is to aid in career and family decisions.[20] Before 1993 there was not an available test for individuals to learn if they carried the Huntington's gene. At that time surveys indicated that 50–70% of at-risk individuals would have been interested in receiving testing, but since predictive testing has been offered far fewer choose to be tested.[56] Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because there is no treatment.[20] A key issue is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result.[20] Irrespective of the result, stress levels have been found to be lower two years after being tested, but the risk of suicide is increased after a positive test result.[20] Individuals found to have not inherited the disorder may experience survivor guilt with regard to family members who are affected.[20] Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individual's siblings will be at risk of inheriting it.[20] In one study genetic discrimination was found in 46% of individuals at risk for Huntington's disease. It occurred at higher rates within personal relationships than health insurance or employment relations.[57] Genetic counseling in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process.[58] Because of the implications of this test, patients who wish to undergo testing must complete three counseling sessions which provide information about Huntington's.[59]
Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant cerebellar ataxia.[20][60][61] Presymptomatic testing for HD has also influenced testing for other illnesses with genetic variants such as polycystic kidney disease, familial Alzheimer's disease and breast cancer.[60] The European Molecular Genetics Quality Network have published yearly external quality assessment scheme for molecular genetic testing for this disease and have developed best practice guidelines for genetic testing for HD to assist in testing and reporting of results.[62]
### Preimplantation genetic diagnosis[edit]
Embryos produced using in vitro fertilization may be genetically tested for HD using preimplantation genetic diagnosis (PGD). This technique, where one or two cells are extracted from a typically 4- to 8-cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos affected with HD genes are not implanted, and therefore any offspring will not inherit the disease. Some forms of preimplantation genetic diagnosis—non-disclosure or exclusion testing—allow at-risk people to have HD-free offspring without revealing their own parental genotype, giving no information about whether they themselves are destined to develop HD. In exclusion testing, the embryos' DNA is compared with that of the parents and grandparents to avoid inheritance of the chromosomal region containing the HD gene from the affected grandparent. In non-disclosure testing, only disease-free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed.[63][64]
### Prenatal testing[edit]
It is also possible to obtain a prenatal diagnosis for an embryo or fetus in the womb, using fetal genetic material acquired through chorionic villus sampling. An amniocentesis can be performed if the pregnancy is further along, within 14–18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation.[65] This, too, can be paired with exclusion testing to avoid disclosure of parental genotype. Prenatal testing can be done when a parent has been diagnosed with HD, when they have had genetic testing showing the expansion of the HTT gene, or when they have a 50% chance of inheriting the disease. The parents can be counseled on their options, which include termination of pregnancy, and on the difficulties of a child with the identified gene.[66][67]
In addition, in at-risk pregnancies due to an affected male partner, non-invasive prenatal diagnosis can be performed by analyzing cell-free fetal DNA in a blood sample taken from the mother (via venipuncture) between six and twelve weeks of pregnancy.[55] It has no procedure-related risk of miscarriage[55]
### Differential diagnosis[edit]
About 99% of HD diagnoses based on the typical symptoms and a family history of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of the remaining are called HD-like (HDL) syndromes.[20][68] The cause of most HDL diseases is unknown, but those with known causes are due to mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited unknown gene (HDL3—only found in two families and poorly understood), and the gene encoding the TATA box-binding protein (SCA17, sometimes called HDL4). Other autosomal dominant diseases that can be misdiagnosed as HD are dentatorubral-pallidoluysian atrophy and neuroferritinopathy. There are also autosomal recessive disorders that resemble sporadic cases of HD. These include chorea acanthocytosis and pantothenate kinase-associated neurodegeneration. One X-linked disorder of this type is McLeod syndrome.[68]
## Management[edit]
Illustration from a case report in 1977 of a person with Huntington's disease.
There is no cure for HD, but there are treatments available to reduce the severity of some of its symptoms.[69] For many of these treatments, evidence to confirm their effectiveness in treating symptoms of HD specifically are incomplete.[20][70] As the disease progresses the ability to care for oneself declines, and carefully managed multidisciplinary caregiving becomes increasingly necessary.[20] Although there have been relatively few studies of exercises and therapies that help rehabilitate cognitive symptoms of HD, there is some evidence for the usefulness of physical therapy, occupational therapy, and speech therapy.[20]
### Therapy[edit]
Weight loss and problems in eating due to swallowing difficulties, and other muscle discoordination are common, making nutrition management increasingly important as the disease advances.[20] Thickening agents can be added to liquids as thicker fluids are easier and safer to swallow.[20] Reminding the affected person to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking.[20] If eating becomes too hazardous or uncomfortable, the option of using a percutaneous endoscopic gastrostomy is available. This is a feeding tube, permanently attached through the abdomen into the stomach, which reduces the risk of aspirating food and provides better nutritional management.[71] Assessment and management by speech-language pathologists with experience in Huntington's disease is recommended.[20]
People with Huntington's disease may see a physical therapist for non-invasive and non-medication-based ways of managing the physical symptoms. Physical therapists may implement fall risk assessment and prevention, as well as strengthening, stretching, and cardiovascular exercises. Walking aids may be prescribed as appropriate. Physical therapists also prescribe breathing exercises and airway clearance techniques with the development of respiratory problems.[72] Consensus guidelines on physiotherapy in Huntington's disease have been produced by the European HD Network.[72] Goals of early rehabilitation interventions are prevention of loss of function. Participation in rehabilitation programs during early to middle stage of the disease may be beneficial as it translates into long term maintenance of motor and functional performance. Rehabilitation during the late stage aims to compensate for motor and functional losses.[73] For long-term independent management, the therapist may develop home exercise programs for appropriate people.[74]
Additionally, an increasing number of people with Huntington's disease are turning to palliative care, which aims to improve quality of life through the treatment of the symptoms and stress of serious illness, in addition to their other treatments.[75]
### Medications[edit]
Chemical structure of tetrabenazine, an approved compound for the management of chorea in HD
Tetrabenazine was approved in 2000 for treatment of chorea in Huntington's disease in the EU, and in 2008 in the US.[76] Other drugs that help to reduce chorea include antipsychotics and benzodiazepines.[15] Compounds such as amantadine or remacemide are still under investigation but have shown preliminary positive results.[20] Hypokinesia and rigidity, especially in juvenile cases, can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia can be treated with valproic acid.[15] Tentative evidence has found ethyl eicosapentaenoic acid to improve motor symptoms at one year.[77] In 2017 Deutetrabenazine a heavier form of tetrabenazine medication for the treatment of chorea in HD was approved by the FDA.[78] This is marketed as Austedo and is the first small molecule drug to receive FDA approval.[79]
Psychiatric symptoms can be treated with medications similar to those used in the general population.[20][70] Selective serotonin reuptake inhibitors and mirtazapine have been recommended for depression, while atypical antipsychotics are recommended for psychosis and behavioral problems.[70] Specialist neuropsychiatric input is recommended as people may require long-term treatment with multiple medications in combination.[20]
### Education[edit]
The families of individuals, and society at large, who have inherited or are at risk of inheriting HD have generations of experience of HD, but may be unaware of recent breakthroughs in understanding the disease, and of the availability of genetic testing. Genetic counseling benefits these individuals by updating their knowledge, seeking to dispel any unfounded beliefs that they may have, and helping them consider their future options and plans. Also covered is information concerning family planning choices, care management, and other considerations.[20][80]
## Prognosis[edit]
The length of the trinucleotide repeat accounts for 60% of the variation of the age of symptoms onset and their rate of progress. A longer repeat results in an earlier age of onset and a faster progression of symptoms.[20][81] Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may remain asymptomatic.[82] The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease.[20]
Life expectancy in HD is generally around 20 years following the onset of visible symptoms.[20] Most life-threatening complications result from muscle coordination and, to a lesser extent, behavioral changes induced by declining cognitive function. The largest risk is pneumonia, which causes death in one third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs and an increased risk of aspirating food or drink both increase the risk of contracting pneumonia. The second greatest risk is heart disease, which causes almost a quarter of fatalities of those with HD.[20] Suicide is the third greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. It is unclear to what extent suicidal thoughts are influenced by behavioral symptoms, as they signify sufferers' desires to avoid the later stages of the disease.[83][84][85] Other associated risks include choking, physical injury from falls, and malnutrition.[20]
## Epidemiology[edit]
The late onset of Huntington's disease means it does not usually affect reproduction.[20] The worldwide prevalence of HD is 5–10 cases per 100,000 persons,[86][87] but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns.[20] Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around 7 per 100,000 people, and is lower in the rest of the world; e.g., one per million people of Asian and African descent. A 2013 epidemiological study of the prevalence of Huntington's disease in the UK between 1990 and 2010 found that the average prevalence for the UK was 12.3 per 100,000.[20][88] Additionally, some localized areas have a much higher prevalence than their regional average.[20] One of the highest incidences is in the isolated populations of the Lake Maracaibo region of Venezuela, where HD affects up to 700 per 100,000 persons.[20][89] Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden.[85] Increased prevalence in some cases occurs due to a local founder effect, a historical migration of carriers into an area of geographic isolation.[85][90] Some of these carriers have been traced back hundreds of years using genealogical studies.[85] Genetic haplotypes can also give clues for the geographic variations of prevalence.[85][91] Iceland, on the contrary, has a rather low prevalence of 1 per 100,000, despite the fact that Icelanders as a people are descended of the early Germanic tribes of Scandinavia which also gave rise to the Swedes; all cases with the exception of one going back nearly two centuries having derived from the offspring of a couple living early in the 19th century.[92] Finland, as well, has a low incidence of only 2.2 per 100,000 people.[93]
Until the discovery of a genetic test, statistics could only include clinical diagnosis based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics; and, as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.[85][94]
## History[edit]
In 1872 George Huntington described the disorder in his first paper "On Chorea" at the age of 22.[95]
Although Huntington's has been recognized as a disorder since at least the Middle Ages, the cause has been unknown until fairly recently. Huntington's was given different names throughout this history as understanding of the disease changed. Originally called simply 'chorea' for the jerky dancelike movements associated with the disease, HD has also been called "hereditary chorea" and "chronic progressive chorea".[96] The first definite mention of HD was in a letter by Charles Oscar Waters, published in the first edition of Robley Dunglison's Practice of Medicine in 1842. Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease.[97] In 1846 Charles Gorman observed how higher prevalence seemed to occur in localized regions.[97] Independently of Gorman and Waters, both students of Dunglison at Jefferson Medical College in Philadelphia,[98] Johan Christian Lund also produced an early description in 1860.[97] He specifically noted that in Setesdalen, a secluded mountain valley in Norway, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that ran in families.[99]
The first thorough description of the disease was by George Huntington in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.
> Of its hereditary nature. When either or both the parents have shown manifestations of the disease ... one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.[95][100]
Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating that "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described."[97][101] Osler's continued interest in HD, combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge of the disorder throughout the medical community.[97] Great interest was shown by scientists in Europe, including Louis Théophile Joseph Landouzy, Désiré-Magloire Bourneville, Camillo Golgi, and Joseph Jules Dejerine, and until the end of the century, much of the research into HD was European in origin.[97] By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.[97]
During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance.[97] The English biologist William Bateson used the pedigrees of affected families to establish that HD had an autosomal dominant inheritance pattern.[98] The strong inheritance pattern prompted several researchers, including Smith Ely Jelliffe, to attempt to trace and connect family members of previous studies.[97] Jelliffe collected information from across New York and published several articles regarding the genealogy of HD in New England.[102] Jelliffe's research roused the interest of his college friend, Charles Davenport, who commissioned Elizabeth Muncey to produce the first field study on the East Coast of the United States of families with HD and to construct their pedigrees.[103] Davenport used this information to document the variable age of onset and range of symptoms of HD; he claimed that most cases of HD in the USA could be traced back to a handful of individuals.[103] This research was further embellished in 1932 by P. R. Vessie, who popularized the idea that three brothers who left England in 1630 bound for Boston were the progenitors of HD in the USA.[104] The claim that the earliest progenitors had been established and eugenic bias of Muncey's, Davenport's, and Vessie's work contributed to misunderstandings and prejudice about HD.[98] Muncey and Davenport also popularized the idea that in the past some HD sufferers may have been thought to be possessed by spirits or victims of witchcraft, and were sometimes shunned or exiled by society.[105][106] This idea has not been proven. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.[98][105]
The search for the cause of this condition was enhanced considerably in 1968, when the Hereditary Disease Foundation (HDF) was created by Milton Wexler, a psychoanalyst based in Los Angeles, California, whose wife Leonore Sabin had been diagnosed earlier that year with Huntington's disease.[107] The three brothers of Wexler's wife also suffered from this disease.
The foundation was involved in the recruitment of more than 100 scientists in the US-Venezuela Huntington's Disease Collaborative Project who over a 10-year period from 1979, worked to locate the genetic cause.[108] This was achieved in 1983 when a causal gene was approximately located,[90] and in 1993 the gene was precisely located at chromosome 4 (4p16.3).[109] The study had focused on the populations of two isolated Venezuelan villages, Barranquitas and Lagunetas, where there was an unusually high prevalence of the disease. It involved over 18,000 people, mostly from a single extended family, and resulted in making HD the first autosomal disease locus found using genetic linkage analysis.[109][110] Among other innovations, the project developed DNA-marking methods which were an important step in making the Human Genome Project possible.[108]
In the same time frame, key discoveries concerning the mechanisms of the disorder were being made, including the findings by Anita Harding's research group on the effects of the gene's length.[111]
Modelling the disease in various types of animals, such as the transgenic mouse developed in 1996, enabled larger scale experiments. As these animals have faster metabolisms and much shorter lifespans than humans, results from experiments are received sooner, speeding research. The 1997 discovery that mhtt fragments misfold led to the discovery of the nuclear inclusions they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.[97][112]
The condition was formerly called 'Huntington's chorea' but this term has been replaced by 'Huntington's disease' because not all patients develop chorea and due to the importance of cognitive and behavioral problems.[113]
## Society and culture[edit]
See also: List of Huntington's disease media depictions
### Ethics[edit]
See also: In vitro fertilisation § Ethics, and Stem cell controversy
Huntington's disease, particularly the application of the genetic test for the disease, has raised several ethical issues. The issues for genetic testing include defining how mature an individual should be before being considered eligible for testing, ensuring the confidentiality of results, and whether companies should be allowed to use test results for decisions on employment, life insurance or other financial matters. There was controversy when Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be used for people with certain diseases, including HD, as part of the eugenics movement.[114] In vitro fertilization has some issues regarding its use of embryos. Some HD research has ethical issues due to its use of animal testing and embryonic stem cells.[115][116]
The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access to and use of a person's results.[117][118] Many guidelines and testing procedures have strict procedures for disclosure and confidentiality to allow individuals to decide when and how to receive their results and also to whom the results are made available.[20] Financial institutions and businesses are faced with the question of whether to use genetic test results when assessing an individual, such as for life insurance or employment. The United Kingdom's insurance companies agreed with the Department of Health and Social Care that until 2017 customers would not need to disclose predictive genetics tests to them, but this agreement explicitly excluded the government-approved test for Huntington's when writing policies with a value over GB£500,000.[119][120] As with other untreatable genetic conditions with a later onset, it is ethically questionable to perform pre-symptomatic testing on a child or adolescent, as there would be no medical benefit for that individual. There is consensus for testing only individuals who are considered cognitively mature, although there is a counter-argument that parents have a right to make the decision on their child's behalf. With the lack of an effective treatment, testing a person under legal age who is not judged to be competent is considered unethical in most cases.[41][121][122]
There are ethical concerns related to prenatal genetic testing or preimplantation genetic diagnosis to ensure a child is not born with a given disease.[123] For example, prenatal testing raises the issue of selective abortion, a choice considered unacceptable by some.[123] As it is a dominant disease, there are difficulties in situations in which a parent does not want to know his or her own diagnosis. This would require parts of the process to be kept secret from the parent.[123]
### Support organizations[edit]
The death of Woody Guthrie led to the foundation of the Committee to Combat Huntington's Disease
In 1968, after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF), with the aim of curing genetic illnesses by coordinating and supporting research.[11] The foundation and Wexler's daughter, Nancy Wexler, were key parts of the research team in Venezuela which discovered the HD gene.[11]
At roughly the same time as the HDF formed, Marjorie Guthrie helped to found the Committee to Combat Huntington's Disease (now the Huntington's Disease Society of America), after her husband Woody Guthrie died from complications of HD.[12]
Since then, support and research organizations have formed in many countries around the world and have helped to increase public awareness of HD. A number of these collaborate in umbrella organizations, like the International Huntington Association and the European HD network.[124] Many support organizations hold an annual HD awareness event, some of which have been endorsed by their respective governments. For example, 6 June is designated "National Huntington's Disease Awareness Day" by the US Senate.[125]
The largest funder of Huntington's disease research globally,[126] is the Cure Huntington's Disease Initiative Foundation (CHDI), a US non-profit biomedical foundation that aims to "rapidly discover and develop drugs that delay or slow Huntington's disease".[127] CHDI was formerly known as the High Q Foundation. In 2006, it spent $50 million on Huntington's disease research.[126] CHDI collaborates with many academic and commercial laboratories globally and engages in oversight and management of research projects as well as funding.[128] Many organizations exist to support and inform those affected by HD, including the Huntington's Disease Association in the UK.
## Research directions[edit]
Research into the mechanism of HD is focused on identifying the functioning of HTT, how mhtt differs or interferes with it, and the brain pathology that the disease produces.[129] Research is conducted using in vitro methods, animal models and human volunteers. Animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development.[112] Animals with chemically induced brain injury exhibit HD-like symptoms and were initially used, but they did not mimic the progressive features of the disease.[130] The identification of the causative gene has enabled the development of many transgenic animal models including nematode worms, Drosophila fruit flies, mice, rats, sheep, pigs and monkeys that express mutant huntingtin and develop progressive neurodegeneration and HD-like symptoms.[112]
Research is being conducted on many different approaches to prevent Huntington's disease or slow its progression.[129] Disease-modifying strategies can be broadly grouped into three categories: reducing the level of the mutant huntingtin protein (including gene splicing and gene silencing); approaches aimed at improving neuronal survival by reducing the harm caused by the protein to specific cellular pathways and mechanisms (including protein homeostasis and histone deacetylase inhibition); and strategies to replace lost neurons. In addition, novel therapies to improve brain functioning are under development; these seek to produce symptomatic rather than disease-modifying therapies, and include phosphodiesterase inhibitors.[131][132]
In 2020 the CHDI Foundation began a small-molecule computational research collaboration with OpenEye Scientific focusing on small-molecule treatments, using a molecular design platform of OpenEye's known as Orion.[127]
### Reducing huntingtin production[edit]
Gene silencing aims to reduce the production of the mutant protein, since HD is caused by a single dominant gene encoding a toxic protein. Gene silencing experiments in mouse models have shown that when the expression of mhtt is reduced, symptoms improve.[133] The safety of RNA interference, and allele-specific oligonucleotide (ASO) methods of gene silencing has been demonstrated in mice and the larger primate macaque brain.[134][135] Allele-specific silencing attempts to silence mutant htt while leaving wild-type HTT untouched. One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele.[136] The first gene silencing trial involving humans with HD began in 2015, testing the safety of IONIS-HTTRx, produced by Ionis Pharmaceuticals and led by UCL Institute of Neurology.[137][138] Mutant huntingtin was detected and quantified for the first time in cerebrospinal fluid from Huntington's disease mutation-carriers in 2015 using a novel "single-molecule counting" immunoassay,[139] providing a direct way to assess whether huntingtin-lowering treatments are achieving the desired effect.[140][141] Similarly, gene splicing techniques are being looked at to try to repair a genome with the erroneous gene that causes HD, using tools such as CRISPR/Cas9.[132]
### Increasing huntingtin clearance[edit]
Another strategy to reduce the levels of mutant huntingtin is to increase the rate at which cells are able to clear the mutant protein.[142] As mutant huntingtin protein (and many other aggregate prone proteins) is degraded by autophagy, increasing levels of autophagy have the potential to reduce levels of the toxic protein and thereby ameliorate disease.[143] Pharmacological and genetic inducers of autophagy have been tested in a variety of Huntington's disease models, and many have been shown to reduce mHTT levels and decrease toxicity.[142]
### Improving cell survival[edit]
Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of transcriptional regulation using histone deacetylase inhibitors, modulating aggregation of huntingtin, improving metabolism and mitochondrial function and restoring function of synapses.[133]
### Neuronal replacement[edit]
Stem-cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments have yielded mixed results using this technique in animal models and preliminary human clinical trials.[144] Whatever their future therapeutic potential, stem cells are already a valuable tool for studying Huntington's disease in the laboratory.[145]
### Clinical trials[edit]
In 2020 there were 197 clinical trials related to varied therapies and biomarkers for Huntington's disease listed as either underway, recruiting or newly completed.[146]
Compounds trialled, that have failed to prevent or slow the progression of Huntington's disease include remacemide, coenzyme Q10, riluzole, creatine, minocycline, ethyl-EPA, phenylbutyrate and dimebon.[147]
## See also[edit]
* Medicine portal
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## External links[edit]
Huntington's diseaseat Wikipedia's sister projects
* Definitions from Wiktionary
* Media from Wikimedia Commons
* News from Wikinews
* Texts from Wikisource
* Textbooks from Wikibooks
* Resources from Wikiversity
* Huntington's disease at Curlie
* HOPES project – Stanford University's HD information project
* HDBuzz – HD research news written by scientists in plain language
* HD Drug Works – news about current treatments and planned trials
Classification
D
* ICD-10: G10, F02.2
* ICD-9-CM: 333.4, 294.1
* OMIM: 143100
* MeSH: D006816
* DiseasesDB: 6060
External resources
* MedlinePlus: 000770
* eMedicine: article/1150165 article/792600 article/289706
* Patient UK: Huntington's disease
* GeneReviews: Huntington Disease
* Orphanet: 399
* 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
* t
* e
Diseases of the nervous system, primarily CNS
Inflammation
Brain
* Encephalitis
* Viral encephalitis
* Herpesviral encephalitis
* Limbic encephalitis
* Encephalitis lethargica
* Cavernous sinus thrombosis
* Brain abscess
* Amoebic
Brain and spinal cord
* Encephalomyelitis
* Acute disseminated
* Meningitis
* Meningoencephalitis
Brain/
encephalopathy
Degenerative
Extrapyramidal and
movement disorders
* Basal ganglia disease
* Parkinsonism
* PD
* Postencephalitic
* NMS
* PKAN
* Tauopathy
* PSP
* Striatonigral degeneration
* Hemiballismus
* HD
* OA
* Dyskinesia
* Dystonia
* Status dystonicus
* Spasmodic torticollis
* Meige's
* Blepharospasm
* Athetosis
* Chorea
* Choreoathetosis
* Myoclonus
* Myoclonic epilepsy
* Akathisia
* Tremor
* Essential tremor
* Intention tremor
* Restless legs
* Stiff-person
Dementia
* Tauopathy
* Alzheimer's
* Early-onset
* Primary progressive aphasia
* Frontotemporal dementia/Frontotemporal lobar degeneration
* Pick's
* Dementia with Lewy bodies
* Posterior cortical atrophy
* Vascular dementia
Mitochondrial disease
* Leigh syndrome
Demyelinating
* Autoimmune
* Inflammatory
* Multiple sclerosis
* For more detailed coverage, see Template:Demyelinating diseases of CNS
Episodic/
paroxysmal
Seizures and epilepsy
* Focal
* Generalised
* Status epilepticus
* For more detailed coverage, see Template:Epilepsy
Headache
* Migraine
* Cluster
* Tension
* For more detailed coverage, see Template:Headache
Cerebrovascular
* TIA
* Stroke
* For more detailed coverage, see Template:Cerebrovascular diseases
Other
* Sleep disorders
* For more detailed coverage, see Template:Sleep
CSF
* Intracranial hypertension
* Hydrocephalus
* Normal pressure hydrocephalus
* Choroid plexus papilloma
* Idiopathic intracranial hypertension
* Cerebral edema
* Intracranial hypotension
Other
* Brain herniation
* Reye syndrome
* Hepatic encephalopathy
* Toxic encephalopathy
* Hashimoto's encephalopathy
Both/either
Degenerative
SA
* Friedreich's ataxia
* Ataxia–telangiectasia
MND
* UMN only:
* Primary lateral sclerosis
* Pseudobulbar palsy
* Hereditary spastic paraplegia
* LMN only:
* Distal hereditary motor neuronopathies
* Spinal muscular atrophies
* SMA
* SMAX1
* SMAX2
* DSMA1
* Congenital DSMA
* Spinal muscular atrophy with lower extremity predominance (SMALED)
* SMALED1
* SMALED2A
* SMALED2B
* SMA-PCH
* SMA-PME
* Progressive muscular atrophy
* Progressive bulbar palsy
* Fazio–Londe
* Infantile progressive bulbar palsy
* both:
* Amyotrophic lateral sclerosis
* v
* t
* e
Non-Mendelian inheritance: anticipation
Trinucleotide
Polyglutamine (PolyQ), CAG
* Dentatorubral-pallidoluysian atrophy
* Huntington's disease
* Kennedy disease
* Spinocerebellar ataxia 1, 2, 3, 6, 7, 17 (Machado-Joseph disease)
Non-polyglutamine
* CGG (Fragile X syndrome)
* GAA (Friedreich's ataxia)
* CTG (Myotonic dystrophy type 1)
* CTG (Spinocerebellar ataxia 8)
* CAG (Spinocerebellar ataxia 12)
Tetranucleotide
* CCTG (Myotonic dystrophy type 2)
Pentanucleotide
* ATTCT (Spinocerebellar ataxia 10)
Authority control
* GND: 4026223-6
* NKC: ph195819
*[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 inhibitors
*[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
| Huntington's disease | c0020179 | 4,891 | wikipedia | https://en.wikipedia.org/wiki/Huntington%27s_disease | 2021-01-18T18:45:08 | {"gard": ["6677"], "mesh": ["D006816"], "umls": ["C0020179"], "icd-9": ["333.4333.4,294.1294.1"], "icd-10": ["F02.2", "G10"], "orphanet": ["399", "248111"], "wikidata": ["Q190564"]} |
Damage caused to the lung by mechanical ventilation
Atelectasis occurs when distending pressure of the alveolus is overcome by surface tension of fluid within the alveolus. Repeated atelectasis and re-inflation leads to atelectotrauma.
Atelectotrauma, atelectrauma, cyclic atelectasis or repeated alveolar collapse and expansion (RACE) are medical terms for the damage caused to the lung by mechanical ventilation under certain conditions. When parts of the lung collapse at the end of expiration, due to a combination of a diseased lung state and a low functional residual capacity, then reopen again on inspiration, this repeated collapsing and reopening causes shear stress which has a damaging effect on the alveolus.[1][2] Clinicians attempt to reduce atelectotrauma by ensuring adequate positive end-expiratory pressure (PEEP) to maintain the alveoli open in expiration. This is known as open lung ventilation. High frequency oscillatory ventilation (HFOV) with its use of 'super CPAP' is especially effective in preventing atelectotrauma since it maintains a very high mean airway pressure (MAP), equivalent to a very high PEEP. Atelectotrauma is one of several means by which mechanical ventilation may damage the lungs leading to ventilator-associated lung injury. The other means are volutrauma, barotrauma, rheotrauma and biotrauma. Attempts have been made to combine these factors in an all encompassing term: mechanical power.
## References[edit]
1. ^ Shi C., Boehme S., Hartmann E. K., Markstaller K. Novel technologies to detect atelectotrauma in the injured lung. Exp Lung Res. 2011 Feb;37(1):18-25. PMID 20860539 [1]
2. ^ Attar MA, Donn SM. Mechanisms of ventilator-induced lung injury in premature infants. Semin Neonatol. 2002 Oct;7(5):353-60. PMID 12464497 [2]
* v
* t
* e
Mechanical ventilation
Fundamentals
* Modes of mechanical ventilation
* Mechanical ventilation in emergencies
* Nomenclature of mechanical ventilation
Modes
* IMV/SIMV
* CMV
* ACV
* CSV
* PAP
* BPAP/NIV
* CPAP
* APRV
* MMV
* PAV
* ASV
* HFV
Related illness
* ARDS
* Atelectotrauma
* Biotrauma
* Pulmonary barotrauma
* Pulmonary volutrauma
* Rheotrauma
* Ventilator-associated pneumonia
* Oxygen toxicity
* Ventilator-associated lung injury
Pressure
* PEEP
* FiO2
* ΔP
* PIP
* PS
* PAW
* Pplat
Volumes
* VT
* VE
* Vf
Other
* Cdyn
* Cstatic
* PAO2
* VD/VT
* OI
* A-a gradient
* Mechanical power
*[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 inhibitors
*[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
| Atelectotrauma | None | 4,892 | wikipedia | https://en.wikipedia.org/wiki/Atelectotrauma | 2021-01-18T18:51:37 | {"wikidata": ["Q48844417"]} |
Congenital absence of thigh and lower leg with foot present is a rare, non-syndromic, intercalary limb reduction defect characterized by unilateral or bilateral absence of femoral and tibio-fibular components, with the presence of intact foot elements.
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*[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 inhibitors
*[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
| Congenital absence of thigh and lower leg with foot present | c0265626 | 4,893 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=294977 | 2021-01-23T18:32:11 | {"icd-10": ["Q72.1"], "synonyms": ["Femorotibiofibular intercalary transverse meromelia"]} |
For a general phenotypic description and a discussion of genetic heterogeneity of Wilms tumor, see WT1 (194070).
Mapping
With loss of heterozygosity studies, Maw et al. (1992) concluded that a third Wilms tumor locus (WT3) is on 16q. In addition to loss on chromosome 11p (11 of 25 informative Wilms tumors), there was significant loss on 16q (9 of 45 informative tumors), while the total frequency of allele loss excluding these loci was low (9 of 426 total informative loci). They screened loci on 33 autosomal arms. The parental origin of the lost chromosome 16q allele was paternal in 4 and maternal in 4 sporadic tumors tested. Thus, unlike chromosome 11p, alleles of either parental origin are lost on 16q.
INHERITANCE \- Autosomal dominant GENITOURINARY Kidneys \- Nephroblastoma (Wilms tumor) NEOPLASIA \- Nephroblastoma (Wilms tumor) MISCELLANEOUS \- Familial form MOLECULAR BASIS \- Linked to a locus at 16q. ▲ 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 inhibitors
*[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
| WILMS TUMOR 3 | c0027708 | 4,894 | omim | https://www.omim.org/entry/194090 | 2019-09-22T16:31:45 | {"mesh": ["D009396"], "omim": ["194090"], "orphanet": ["654"], "genereviews": ["NBK1294"]} |
Juvenile dermatomyositis (JDM) is the early-onset form of dermatomyositis (DM, see this term), a systemic, autoimmune inflammatory muscle disorder, characterized by proximal muscle weakness, evocative skin lesion, and systemic manifestations.
## Epidemiology
The exact prevalence of JDM is not known. Estimated annual incidence rates range from 1/520,000 to 1/250,000. Females are affected more frequently than males (2.3:1 ratio).
## Clinical description
Dermatomyositis occurring before the age of 18 years is considered to be JDM. The average age of onset is 5 to 14 years of age (median = 7 years). Patients commonly have the signs of DM, i.e symmetrical proximal muscle weakness and erythematous rash (heliotrope rash, Gottron papules, sunexposed areas erythema), that is sometimes pruritic, along with cutaneous vasculitis and ulcerations, calcinosis of soft tissue (20-40%), and vasculopathy affecting the digestive tract (with bowel ischemia and/or infarction, abdominal pain, and melena). Muscle weakness leads to variable impairment of physical function. Commonly reported signs also include myalgia and arthralgia. Other associated extramuscular features include dysphagia, sometimes dysphonia, hoarseness, pneumonitis, cardiac manifestations (conduction defects, myocarditis, dilated cardiomyopathy, see this term). Raynaud's phenomenon and inflammatory arthritis. The course of JDM is highly variable: some patients go into remission within 2 to 3 years, others have a cyclic course marked by relapse, while some have ulcerative or chronic disease. Macrophage activation syndrome, a severe sometimes life-threatening condition, has been described in some children diagnosed with JDM. Malignancy and interstitial lung disease are uncommon. Reported malignancies include lymphoma and leukemia.
## Etiology
The exact pathogenesis of JDM has not yet been elucidated. It is thought to be related to complement-mediated changes in small vessels in muscle tissue leading to vascular damage. Viruses (e.g. coxsackie virus, parvovirus, and echovirus) and Toxoplasma and Borrelia species, have been suggested as possible triggers.
## Diagnostic methods
Diagnosis is based on the clinical signs and magnetic resonance imaging (MRI) of muscle. Muscle biopsy and electromyographic (EMG) testing may also be used but are more invasive. Muscle enzymes are elevated. Nailfold capillaroscopy can be used to predict disease severity and disease course. Antinuclear antibody (ANA), extractable nuclear antigens (ENA); and myositis-specific antibodies (anti-Jo-1, anti-SRP, and anti-Mi-2) should be tested.
## Differential diagnosis
Differential diagnosis in JDM may include mitochondrial myopathies, infectious myopathies, other forms of inflammatory myopathies, particularly autoimmune necrotizing myopathy (see this term), as well as Duchenne muscular dystrophy or Becker muscular dystrophy, systemic lupus erythematosus, and juvenile idiopathic arthritis (see these terms).
## Management and treatment
The aim of treatment is to reduce long-term morbidity and to restore physical function. High-dose corticosteroids are the mainstay of treatment, with dose tapering after a few weeks of therapy depending on patient response. Methotrexate may also be used, and for severe disease, intravenous methylprednisolone (IVMP). Physical therapy is important to maintain or restore muscle strength. Topical corticosteroids and tacrolimus have been used to treat skin manifestations. Patients should avoid direct UV light and use high-factor sunscreen. No effective treatment is currently available for calcinosis cutis.
## Prognosis
Treatment is generally effective, with very low mortality rates reported. The disorder may however be associated with significant morbidity.
*[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 inhibitors
*[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
| Juvenile dermatomyositis | c0263666 | 4,895 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93672 | 2021-01-23T18:22:50 | {"gard": ["6805"], "mesh": ["D003882", "C538250"], "umls": ["C0263666", "C2931785"], "icd-10": ["M33.0"], "synonyms": ["Juvenile DM"]} |
Hereditary spastic paraplegia
SpecialtyNeurology
Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder. The disease presents with progressive stiffness (spasticity) and contraction in the lower limbs.[1] HSP is also known as hereditary spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell disease, or Strumpell-Lorrain disease. The symptoms are a result of dysfunction of long axons in the spinal cord. The affected cells are the primary motor neurons; therefore, the disease is an upper motor neuron disease.[2] HSP is not a form of cerebral palsy even though it physically may appear and behave much the same as spastic diplegia. The origin of HSP is different from cerebral palsy. Despite this, some of the same anti-spasticity medications used in spastic cerebral palsy are sometimes used to treat HSP symptoms.
HSP is caused by defects in transport of proteins, structural proteins, cell maintaining proteins, lipids, and other substances through the cell. Long nerve fibers (axons) are affected because long distances make nerve cells particularly sensitive to defects in these mentioned mechanisms.[3][4]
The disease was first described in 1880 by the German neurologist Adolph Strümpell.[5] It was described more extensively in 1888 by Maurice Lorrain, a French physician.[6] Due to their contribution in describing the disease, it is still called Strümpell-Lorrain disease in French-speaking countries. The term hereditary spastic paraplegia was coined by Anita Harding in 1983.[7]
## Contents
* 1 Signs and symptoms
* 1.1 Age of onset
* 2 Cause
* 2.1 Genotypes
* 3 Pathophysiology
* 3.1 Axon pathfinding
* 3.2 Lipid metabolism
* 3.3 Endosomal trafficking
* 3.4 Mitochondrial function
* 4 Diagnosis
* 4.1 Classification
* 5 Treatment
* 6 Prognosis
* 7 Epidemiology
* 8 References
* 9 Further reading
* 10 External links
## Signs and symptoms[edit]
Symptoms depend on the type of HSP inherited. The main feature of the disease is progressive spasticity in the lower limbs due to pyramidal tract dysfunction. This also results in brisk reflexes, extensor plantar reflexes, muscle weakness, and variable bladder disturbances. Furthermore, among the core symptoms of HSP are also included abnormal gait and difficulty in walking, decreased vibratory sense at the ankles, and paresthesia.[8] Individuals with HSP can experience extreme fatigue associated with central nervous system and neuromuscular disorders, which can be disabling.[9][10][11] Initial symptoms are typically difficulty with balance, stubbing the toe or stumbling. Symptoms of HSP may begin at any age, from infancy to older than 60 years. If symptoms begin during the teenage years or later, then spastic gait disturbance usually progresses over many years. Canes, walkers, and wheelchairs may eventually be required, although some people never require assistance devices.[12] Disability has been described as progressing more rapidly in adult onset forms.[13]
More specifically, patients with the autosomal dominant pure form of HSP reveal normal facial and extraocular movement. Although jaw jerk may be brisk in older subjects, there is no speech disturbance or difficulty of swallowing. Upper extremity muscle tone and strength are normal. In the lower extremities, muscle tone is increased at the hamstrings, quadriceps and ankles. Weakness is most notable at the iliopsoas, tibialis anterior, and to a lesser extent, hamstring muscles.[13] In the complex form of the disorder, additional symptoms are present. These include: peripheral neuropathy, amyotrophy, ataxia, intellectual disability, ichthyosis, epilepsy, optic neuropathy, dementia, deafness, or problems with speech, swallowing or breathing.[14]
Anita Harding[7] classified the HSP in a pure and complicated form. Pure HSP presents with spasticity in the lower limbs, associated with neurogenic bladder disturbance as well as lack of vibration sensitivity (pallhypesthesia). On the other hand, HSP is classified as complex when lower limb spasticity is combined with any additional neurological symptom.[citation needed]
This classification is subjective and patients with complex HSPs are sometimes diagnosed as having cerebellar ataxia with spasticity, mental retardation (with spasticity), or leukodystrophy.[7] Some of the genes listed below have been described in other diseases than HSP before. Therefore, some key genes overlap with other disease groups.[citation needed]
### Age of onset[edit]
In the past, HSP has been classified as early onset beginning in early childhood or later onset in adulthood. The age of onsets has two points of maximum at age 2 and around age 40.[15] New findings propose that an earlier onset leads to a longer disease duration without loss of ambulation or the need for the use of a wheelchair.[15] This was also described earlier, that later onset forms evolve more rapidly.[13]
## Cause[edit]
HSP is a group of genetic disorders. It follows general inheritance rules and can be inherited in an autosomal dominant, autosomal recessive or X-linked recessive manner. The mode of inheritance involved has a direct impact on the chances of inheriting the disorder. Over 70 genotypes had been described, and over 50 genetic loci have been linked to this condition.[16] Ten genes have been identified with autosomal dominant inheritance. One of these, SPG4, accounts for ~50% of all genetically solved cases, or approximately 25% of all HSP cases.[15] Twelve genes are known to be inherited in an autosomal recessive fashion. Collectively this latter group account for ~1/3 cases.[citation needed]
Most altered genes have known function, but for some the function haven't been identified yet. All of them are listed in the gene list below, including their mode of inheritance. Some examples are spastin (SPG4) and paraplegin (SPG7) are both AAA ATPases.[17]
### Genotypes[edit]
The genes are designated SPG (Spastic gait gene). The gene locations are in the format: chromosome - arm (short or p: long or q) - band number. These designations are for the human genes only. The locations may (and probably will) vary in other organisms. Despite the number of genes known to be involved in this condition ~40% of cases have yet to have their cause identified.[18] In the table below SPG? is used to indicate a gene that has been associated with HSP but has not yet received an official HSP gene designation.
Genotype OMIM Gene symbol Gene locus Inheritance Age of onset Other names and characteristics
SPG1 303350 L1CAM Xq28 X-linked recessive Early MASA syndrome
SPG2 312920 PLP1 Xq22.2 X-linked recessive Variable Pelizaeus–Merzbacher disease
SPG3A 182600 ATL1 14q22.1 Autosomal dominant Early Strumpell disease (this Wiki)
SPG4 182601 SPAST 2p22.3 Autosomal dominant Variable
SPG5A 270800 CYP7B1 8q12.3 Autosomal recessive Variable
SPG6 600363 NIPA1 15q11.2 Autosomal dominant Variable
SPG7 607259 SPG7 16q24.3 Autosomal dominant Variable
SPG8 603563 KIAA0196 8q24.13 Autosomal dominant Adult
SPG9A 601162 ALDH18A1 10q24.1 Autosomal dominant Teenage Cataracts with motor neuronopathy, short stature and skeletal abnormalities
SPG9B 616586 ALDH18A1 10q24.1 Autosomal recessive Early
SPG10 604187 KIF5A 12q13.3 Autosomal dominant Early
SPG11 604360 SPG11 15q21.1 Autosomal recessive Variable
SPG12 604805 RTN2 19q13.32 Autosomal dominant Early
SPG13 605280 HSP60 2q33.1 Autosomal dominant Variable
SPG14 605229 ? 3q27–q28 Autosomal recessive Adult
SPG15 270700 ZFYVE26 14q24.1 Autosomal recessive Early
SPG16 300266 ? Xq11.2 X-linked recessive Early
SPG17 270685 BSCL2 11q12.3 Autosomal dominant Teenage
SPG18 611225 ERLIN2 8p11.23 Autosomal recessive Early
SPG19 607152 ? 9q Autosomal dominant Adult onset
SPG20 275900 SPG20 13q13.3 Autosomal recessive Early onset Troyer syndrome
SPG21 248900 ACP33 15q22.31 Autosomal recessive Early onset MAST syndrome
SPG22 300523 SLC16A2 Xq13.2 X-linked recessive Early onset Allan–Herndon–Dudley syndrome
SPG23 270750 RIPK5 1q32.1 Autosomal recessive Early onset Lison syndrome
SPG24 607584 ? 13q14 Autosomal recessive Early onset
SPG25 608220 ? 6q23–q24.1 Autosomal recessive Adult
SPG26 609195 B4GALNT1 12q13.3 Autosomal recessive Early onset
SPG27 609041 ? 10q22.1–q24.1 Autosomal recessive Variable
SPG28 609340 DDHD1 14q22.1 Autosomal recessive Early onset
SPG29 609727 ? 1p31.1–p21.1 Autosomal dominant Teenage
SPG30 610357 KIF1A 2q37.3 Autosomal recessive Teenage
SPG31 610250 REEP1 2p11.2 Autosomal dominant Early onset
SPG32 611252 ? 14q12–q21 Autosomal recessive Childhood
SPG33 610244 ZFYVE27 10q24.2 Autosomal dominant Adult
SPG34 300750 ? Xq24–q25 X-linked recessive Teenage/Adult
SPG35 612319 FA2H 16q23.1 Autosomal recessive Childhood
SPG36 613096 ? 12q23–q24 Autosomal dominant Teenage/Adult
SPG37 611945 ? 8p21.1–q13.3 Autosomal dominant Variable
SPG38 612335 ? 4p16–p15 Autosomal dominant Teenage/Adult
SPG39 612020 PNPLA6 19p13.2 Autosomal recessive Childhood
SPG41 613364 ? 11p14.1–p11.2 Autosomal dominant Adolescence
SPG42 612539 SLC33A1 3q25.31 Autosomal dominant Variable
SPG43 615043 C19orf12 19q12 Autosomal recessive Childhood
SPG44 613206 GJC2 1q42.13 Autosomal recessive Childhood/teenage
SPG45 613162 NT5C2 10q24.32–q24.33 Autosomal recessive Infancy
SPG46 614409 GBA2 9p13.3 Autosomal recessive Variable
SPG47 614066 AP4B1 1p13.2 Autosomal recessive Childhood
SPG48 613647 AP5Z1 7p22.1 Autosomal recessive 6th decade
SPG49 615041 TECPR2 14q32.31 Autosomal recessive Infancy
SPG50 612936 AP4M1 7q22.1 Autosomal recessive Infancy
SPG51 613744 AP4E1 15q21.2 Autosomal recessive Infancy
SPG52 614067 AP4S1 14q12 Autosomal recessive Infancy
SPG53 614898 VPS37A 8p22 Autosomal recessive Childhood
SPG54 615033 DDHD2 8p11.23 Autosomal recessive Childhood
SPG55 615035 C12orf65 12q24.31 Autosomal recessive Childhood
SPG56 615030 CYP2U1 4q25 Autosomal recessive Childhood
SPG57 615658 TFG 3q12.2 Autosomal recessive Early
SPG58 611302 KIF1C 17p13.2 Autosomal recessive Within first two decades Spastic ataxia 2
SPG59 603158 USP8 15q21.2 ?Autosomal recessive Childhood
SPG60 612167 WDR48 3p22.2 ?Autosomal recessive Infancy
SPG61 615685 ARL6IP1 16p12.3 Autosomal recessive Infancy
SPG62 615681 ERLIN1 10q24.31 Autosomal recessive Childhood
SPG63 615686 AMPD2 1p13.3 Autosomal recessive Infancy
SPG64 615683 ENTPD1 10q24.1 Autosomal recessive Childhood
SPG66 610009 ARSI 5q32 ?Autosomal dominant Infancy
SPG67 615802 PGAP1 2q33.1 Autosomal recessive Infancy
SPG68 609541 KLC2 11q13.1 Autosomal recessive Childhood SPOAN syndrome
SPG69 609275 RAB3GAP2 1q41 Autosomal recessive Infancy Martsolf syndrome, Warburg Micro syndrome
SPG70 156560 MARS 12q13 ?Autosomal dominant Infancy
SPG71 615635 ZFR 5p13.3 ?Autosomal recessive Childhood
SPG72 615625 REEP2 5q31 Autosomal recessive;
autosomal dominant Infancy
SPG73 616282 CPT1C 19q13.33 Autosomal dominant Adult
SPG74 616451 IBA57 1q42.13 Autosomal recessive Childhood
SPG75 616680 MAG 19q13.12 Autosomal recessive Childhood
SPG76 616907 CAPN1 11q13 Autosomal recessive Adult
SPG77 617046 FARS2 6p25 Autosomal recessive Childhood
SPG78 617225 ATP13A2 1p36 Autosomal recessive Adult Kufor–Rakeb syndrome
SPG79 615491 UCHL1 4p13 Autosomal recessive Childhood
HSNSP 256840 CCT5 5p15.2 Autosomal recessive Childhood Hereditary sensory neuropathy with spastic paraplegia
SPG? SERAC1 6q25.3 Juvenile MEGDEL syndrome
SPG? 605739 KY 3q22.2 Autosomal recessive Infancy
SPG? PLA2G6 22q13.1 Autosomal recessive Childhood
SPG? ATAD3A 1p36.33 Autosomal dominant Childhood Harel-Yoon syndrome
SPG? KCNA2 1p13.3 Autosomal dominant Childhood
SPG? Granulin 17q21.31
SPG? POLR3A 10q22.3 Autosomal recessive
## Pathophysiology[edit]
The major feature of HSP is a length-dependent axonal degeneration.[19] These include the crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis. The spinocerebellar tract is involved to a lesser extent. Neuronal cell bodies of degenerating axons are preserved and there is no evidence of primary demyelination.[16] Loss of anterior horn cells of the spinal cord are observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are not directly affected.[citation needed]
HSP affects several pathways in motor neurons. Many genes were identified and linked to HSP. It remains a challenge to accurately define the key players in each of the affected pathways, mainly because many genes have multiple functions and are involved in more than one pathway[citation needed].
Overview of HSP pathogenesis on cellular level. Identified affected genes in each pathway are depicted.
### Axon pathfinding[edit]
Pathfinding is important for axon growth to the right destination (e.g. another nerve cell or a muscle). Significant for this mechanism is the L1CAM gene, a cell surface glycoprotein of the immunoglobulin superfamily. Mutations leading to a loss-of-function in L1CAM are also found in other X-linked syndromes. All of these disorders display corticospinal tract impairment (a hallmark feature of HSP). L1CAM participates in a set of interactions, binding other L1CAM molecules as well as extracellular cell adhesion molecules, integrins, and proteoglycans or intracellular proteins like ankyrins.[citation needed]
The pathfinding defect occurs via the association of L1CAM with neuropilin-1. Neuropilin-1 interacts with Plexin-A proteins to form the Semaphorin-3A receptor complex. Semaphorin-a3A is then released in the ventral spinal cord to steer corticospinal neurons away from the midline spinal cord / medullary junction. If L1CAM does not work correctly due to a mutation, the cortiocospinal neurons are not directed to the correct position and the impairment occurs.[3]
### Lipid metabolism[edit]
Axons in the central and peripheral nervous system are coated with an insulation, the myelin layer, to increase the speed of action potential propagation. Abnormal myelination in the CNS is detected in some forms of hsp HSP.[20] Several genes were linked to myelin malformation, namely PLP1, GFC2 and FA2H.[3] The mutations alter myelin composition, thickness and integrity.[citation needed]
Endoplasmic reticulum (ER) is the main organelle for lipid synthesis. Mutations in genes encoding proteins that have a role in shaping ER morphology and lipid metabolism were linked to HSP. Mutations in ATL1, BSCL2 and ERLIN2 alter ER structure, specifically the tubular network and the formation of three-way junctions in ER tubules. Many mutated genes are linked to abnormal lipid metabolism. The most prevalent effect is on arachidonic acid (CYP2U1) and cholesterol (CYP7B1) metabolism, phospholipase activity (DDHD1 and DDHD2), ganglioside formation (B4GALNT-1) and the balance between carbohydrate and fat metabolism (SLV33A1).[3][21][20]
### Endosomal trafficking[edit]
Neurons take in substances from their surrounding by endocytosis. Endocytic vesicles fuse to endosomes in order to release their content. There are three main compartments that have endosome trafficking: Golgi to/from endosomes; plasma membrane to/from early endosomes (via recycling endosomes) and late endosomes to lysosomes. Dysfunction of endosomal trafficking can have severe consequences in motor neurons with long axons, as reported in HSP. Mutations in AP4B1 and KIAA0415 are linked to disturbance in vesicle formation and membrane trafficking including selective uptake of proteins into vesicles. Both genes encode proteins that interact with several other proteins and disrupt the secretory and endocytic pathways.[20]
### Mitochondrial function[edit]
Mitochondrial dysfunctions have been connected with developmental and degenerative neurological disorders. Only a few HSP genes encode for mitochondrial proteins. Two mitochondrial resident proteins are mutated in HSP: paraplegin and chaperonin 60. Paraplegin is a m-AAA metalloprotease of the inner mitochondrial membrane. It functions in ribosomal assembly and protein quality control. The impaired chaperonin 60 activity leads to impaired mitochondrial quality control. Two genes DDHD1 and CYP2U1 have shown alteration of mitochondrial architecture in patient fibroblasts. These genes encode enzymes involved in fatty-acid metabolism.[citation needed]
## Diagnosis[edit]
Initial diagnosis of HSPs relies upon family history, the presence or absence of additional signs and the exclusion of other nongenetic causes of spasticity, the latter being particular important in sporadic cases.[7]
Cerebral and spinal MRI is an important procedure performed in order to rule out other frequent neurological conditions, such as multiple sclerosis, but also to detect associated abnormalities such as cerebellar or corpus callosum atrophy as well as white matter abnormalities. Differential diagnosis of HSP should also exclude spastic diplegia which presents with nearly identical day-to-day effects and even is treatable with similar medicines such as baclofen and orthopedic surgery; at times, these two conditions may look and feel so similar that the only perceived difference may be HSP's hereditary nature versus the explicitly non-hereditary nature of spastic diplegia (however, unlike spastic diplegia and other forms of spastic cerebral palsy, HSP cannot be reliably treated with selective dorsal rhizotomy).[citation needed]
Ultimate confirmation of HSP diagnosis can only be provided by carrying out genetic tests targeted towards known genetic mutations.[citation needed]
### Classification[edit]
Hereditary spastic paraplegias can be classified based on the symptoms; mode of inheritance; the patient's age at onset; the affected genes; and biochemical pathways involved.[citation needed]
## Treatment[edit]
No specific treatment is known that would prevent, slow, or reverse HSP. Available therapies mainly consist of symptomatic medical management and promoting physical and emotional well-being. Therapeutics offered to HSP patients include:
* Baclofen – a voluntary muscle relaxant to relax muscles and reduce tone. This can be administered orally or intrathecally. (Studies in HSP [22][23][24])
* Tizanidine – to treat nocturnal or intermittent spasms (studies available [25][26])
* Diazepam and clonazepam – to decrease intensity of spasms[citation needed]
* Oxybutynin chloride – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems[citation needed]
* Tolterodine tartrate – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems[citation needed]
* Cro System – to reduce muscle overactivity (existing studies for spasticity [27][28][29])
* Botulinum toxin – to reduce muscle overactivity (existing studies for HSP patients[30][31])
* Antidepressants (such as selective serotonin re-uptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors) – for patients experiencing clinical depression[citation needed]
* Physical therapy – to restore and maintain the ability to move; to reduce muscle tone; to maintain or improve range of motion and mobility; to increase strength and coordination; to prevent complications, such as frozen joints, contractures, or bedsores.[citation needed]
## Prognosis[edit]
Although HSP is a progressive condition, the prognosis for individuals with HSP varies greatly. It primarily affects the legs although there can be some upperbody involvement in some individuals. Some cases are seriously disabling while others are less disabling and are compatible with a productive and full life. The majority of individuals with HSP have a normal life expectancy.[14]
## Epidemiology[edit]
Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people.[32] A Norwegian study of more than 2.5 million people published in March 2009 has found an HSP prevalence rate of 7.4/100,000 of population – a higher rate, but in the same range as previous studies. No differences in rate relating to gender were found, and average age at onset was 24 years.[33] In the United States, Hereditary Spastic Paraplegia is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health which means that the disorder affects less than 200,000 people in the US population.[32]
## References[edit]
1. ^ Fink, John K. (2003-08-01). "The hereditary spastic paraplegias: nine genes and counting". Archives of Neurology. 60 (8): 1045–1049. doi:10.1001/archneur.60.8.1045. ISSN 0003-9942. PMID 12925358.
2. ^ Depienne, Christel; Stevanin, Giovanni; Brice, Alexis; Durr, Alexandra (2007-12-01). "Hereditary spastic paraplegias: an update". Current Opinion in Neurology. 20 (6): 674–680. doi:10.1097/WCO.0b013e3282f190ba. ISSN 1350-7540. PMID 17992088. S2CID 35343501.
3. ^ a b c d Blackstone, Craig (21 July 2012). "Cellular Pathways of Hereditary Spastic Paraplegia". Annual Review of Neuroscience. 35 (1): 25–47. doi:10.1146/annurev-neuro-062111-150400. PMC 5584684. PMID 22540978.
4. ^ De Matteis, Maria Antonietta; Luini, Alberto (2011-09-08). "Mendelian disorders of membrane trafficking". The New England Journal of Medicine. 365 (10): 927–938. doi:10.1056/NEJMra0910494. ISSN 1533-4406. PMID 21899453. S2CID 14772080.
5. ^ Faber I, Pereira ER, Martinez AR, França M Jr, Teive HA (November 2013). "Hereditary spastic paraplegia from 1880 to 2017: an historical review". Arquivos de Neuro-Psiquiatria. Brazilian Academy of Neurology. 75 (11): 813–818. doi:10.1590/0004-282X20170160. PMID 29236826.
6. ^ Lorrain, Maurice. Contribution à l'étude de la paraplégie spasmodique familiale: travail de la clinique des maladies du système nerveux à la Salpêtrière. G. Steinheil, 1898.
7. ^ a b c d Harding, AE (1983). "Classification of the hereditary ataxias and paraplegias". Lancet. New York: Lancet. 1 (8334): 1151–5. doi:10.1016/s0140-6736(83)92879-9. PMID 6133167. S2CID 6780732.
8. ^ McAndrew CR, Harms P (2003). "Paraesthesias during needle-through-needle combined spinal epidural versus single-shot spinal for elective caesarean section". Anaesthesia and Intensive Care. 31 (5): 514–517. doi:10.1177/0310057X0303100504. PMID 14601273.
9. ^ Fjermestad, Krister W.; Kanavin, Øivind J.; Næss, Eva E.; Hoxmark, Lise B.; Hummelvoll, Grete (2016-07-13). "Health survey of adults with hereditary spastic paraparesis compared to population study controls". Orphanet Journal of Rare Diseases. 11 (1): 98. doi:10.1186/s13023-016-0469-0. ISSN 1750-1172. PMC 4944497. PMID 27412159.
10. ^ Chaudhuri, Abhijit; Behan, Peter O. (2004-03-20). "Fatigue in neurological disorders". Lancet. 363 (9413): 978–988. doi:10.1016/S0140-6736(04)15794-2. ISSN 1474-547X. PMID 15043967. S2CID 40500803.
11. ^ "Hereditary spastic paraplegia". nhs.uk. 2017-10-18. Retrieved 2018-01-28.
12. ^ Fink JK (2003). "The Hereditary Spastic Paraplegias". Archives of Neurology. 60 (8): 1045–1049. doi:10.1001/archneur.60.8.1045. PMID 12925358.
13. ^ a b c Harding AE (1981). "Hereditary "pure" spastic paraplegia: a clinical and genetic study of 22 families". Journal of Neurology, Neurosurgery, and Psychiatry. 44 (10): 871–883. doi:10.1136/jnnp.44.10.871. PMC 491171. PMID 7310405.
14. ^ a b Depienne C, Stevanin G, Brice A, Durr A (2007). "Hereditary Spastic Paraplegia: An Update". Current Opinion in Neurology. 20 (6): 674–680. doi:10.1097/WCO.0b013e3282f190ba. PMID 17992088. S2CID 35343501.
15. ^ a b c Schüle, Rebecca; Wiethoff, Sarah; Martus, Peter; Karle, Kathrin N.; Otto, Susanne; Klebe, Stephan; Klimpe, Sven; Gallenmüller, Constanze; Kurzwelly, Delia (2016-04-01). "Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients". Annals of Neurology. 79 (4): 646–658. doi:10.1002/ana.24611. ISSN 1531-8249. PMID 26856398. S2CID 10558032.
16. ^ a b Schüle R, Schöls L (2011) Genetics of hereditary spastic paraplegias. Semin Neurol 31(5):484-493
17. ^ Wang YG, Shen L (2009) AAA ATPases and hereditary spastic paraplegia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 26(3):298-301
18. ^ Helbig KL, Hedrich UB, Shinde DN, Krey I, Teichmann AC, Hentschel J, Schubert J, Chamberlin AC, Huether R, Lu HM4, Alcaraz WA, Tang S, Jungbluth C, Dugan SL, Vainionpää L, Karle KN, Synofzik M, Schöls L, Schüle R, Lehesjoki AE, Helbig I, Lerche H, Lemke JR (2016) A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia. Ann Neurol 80(4)
19. ^ Wharton SB, McDermott CJ, Grierson AJ, Wood JD, Gelsthorpe C, Ince PG, Shaw PJ (2003) The cellular and molecular pathology of the motor system in hereditary spastic paraparesis due to mutation of the spastin gene. J Neuropathol Exp Neurol 62:1166–1177
20. ^ a b c Noreau, A., Dion, P.A. & Rouleau, G.A., 2014. Molecular aspects of hereditary spastic paraplegia. Experimental Cell Research, 325(1), pp.18–26
21. ^ Lo Giudice, T. et al., 2014. Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms. Experimental Neurology, 261, pp.518–539.
22. ^ Margetis K, Korfias S, Boutos N, Gatzonis S, Themistocleous M, Siatouni A, et al. Intrathecal baclofen therapy for the symptomatic treatment of hereditary spastic paraplegia. Clinical Neurology and Neurosurgery. 2014;123:142-5.
23. ^ Heetla HW, Halbertsma JP, Dekker R, Staal MJ, van Laar T. Improved Gait Performance in a Patient With Hereditary Spastic Paraplegia After a Continuous Intrathecal Baclofen Test Infusion and Subsequent Pump Implantation: A Case Report. Archives of Physical Medicine and Rehabilitation. 2015;96(6):1166-9.
24. ^ Klebe S, Stolze H, Kopper F, Lorenz D, Wenzelburger R, Deuschl G, et al. Objective assessment of gait after intrathecal baclofen in hereditary spastic paraplegia. Journal of Neurology. 2005;252(8):991-3.
25. ^ Knutsson E, Mårtensson A, Gransberg L. Antiparetic and antispastic effects induced by tizanidine in patients with spastic paresis. Journal of the Neurological Sciences. 1982;53(2):187-204.
26. ^ Bes A, Eyssette M, Pierrot-Deseilligny E, Rohmer F, Warter JM. A multi-centre, double-blind trial of tizanidine, a new antispastic agent, in spasticity associated with hemiplegia. Current Medical Research and Opinion. 1988;10(10):709-18.
27. ^ Celletti C, Camerota F. Preliminary evidence of focal muscle vibration effects on spasticity due to cerebral palsy in a small sample of Italian children. Clin Ter. 162(5): 125-8. 2011
28. ^ Caliandro P, Celletti C, Padua L, Minciotti I, Russo G, Granata G, La Torre G, Granieri E, Camerota F. Focal muscle vibration in the treatment of upper limb spasticity: a pilot randomized controlled trial in patients with chronic stroke. Arch Phys Med Rehabil. 93(9):1656-61. 2012.
29. ^ . Casale R1, Damiani C, Maestri R, Fundarò C, Chimento P, Foti C. Focalized 100 Hz vibration improves function and reduces upper limb spasticity: a double-blind controlled study. Eur J Phys Rehabil Med. 2014 Oct;50(5):495-504. 2014.
30. ^ Hecht MJ, Stolze H, Auf Dem Brinke M, Giess R, Treig T, Winterholler M, et al. Botulinum neurotoxin type A injections reduce spasticity in mild to moderate hereditary spastic paraplegia— Report of 19 cases. Movement Disorders. 2008;23(2):228-33.
31. ^ de Niet M, de Bot ST, van de Warrenburg BP, Weerdesteyn V, Geurts AC. Functional effects of botulinum toxin type-A treatment and subsequent stretching of spastic calf muscles: A study in patients with hereditary spastic paraplegia. Journal of rehabilitation medicine. 2015;47(2):147-53.
32. ^ a b National Institute of Health (2008). "Hereditary Spastic Paraplegia Information Page". Archived from the original on 2014-02-21. Retrieved 2008-04-30.
33. ^ Erichsen, AK; Koht, J; Stray-Pedersen, A; Abdelnoor, M; Tallaksen, CM (June 2009). "Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study" (PDF). Brain. 132 (Pt 6): 1577–88. doi:10.1093/brain/awp056. PMID 19339254.
## Further reading[edit]
* GeneReviews/NCBI/NIH/UW entry on Spastic Paraplegia 3A
* GeneReviews/NCBI/NIH/UW entry on Hereditary Spastic Paraplegia Overview
* Warner, Tom (January–February 2007). "Hereditary Spastic Paraplegia" (PDF). Advances in Clinical Neuroscience and Rehabilitation. 6 (6): 16–17.
## External links[edit]
Classification
D
* ICD-10: G11.4
* ICD-9-CM: 334.1
* OMIM: 312920 PS303350
* MeSH: D015419
* DiseasesDB: 33207
External resources
* eMedicine: pmr/45
* Orphanet: 685
* v
* t
* e
Diseases of the nervous system, primarily CNS
Inflammation
Brain
* Encephalitis
* Viral encephalitis
* Herpesviral encephalitis
* Limbic encephalitis
* Encephalitis lethargica
* Cavernous sinus thrombosis
* Brain abscess
* Amoebic
Brain and spinal cord
* Encephalomyelitis
* Acute disseminated
* Meningitis
* Meningoencephalitis
Brain/
encephalopathy
Degenerative
Extrapyramidal and
movement disorders
* Basal ganglia disease
* Parkinsonism
* PD
* Postencephalitic
* NMS
* PKAN
* Tauopathy
* PSP
* Striatonigral degeneration
* Hemiballismus
* HD
* OA
* Dyskinesia
* Dystonia
* Status dystonicus
* Spasmodic torticollis
* Meige's
* Blepharospasm
* Athetosis
* Chorea
* Choreoathetosis
* Myoclonus
* Myoclonic epilepsy
* Akathisia
* Tremor
* Essential tremor
* Intention tremor
* Restless legs
* Stiff-person
Dementia
* Tauopathy
* Alzheimer's
* Early-onset
* Primary progressive aphasia
* Frontotemporal dementia/Frontotemporal lobar degeneration
* Pick's
* Dementia with Lewy bodies
* Posterior cortical atrophy
* Vascular dementia
Mitochondrial disease
* Leigh syndrome
Demyelinating
* Autoimmune
* Inflammatory
* Multiple sclerosis
* For more detailed coverage, see Template:Demyelinating diseases of CNS
Episodic/
paroxysmal
Seizures and epilepsy
* Focal
* Generalised
* Status epilepticus
* For more detailed coverage, see Template:Epilepsy
Headache
* Migraine
* Cluster
* Tension
* For more detailed coverage, see Template:Headache
Cerebrovascular
* TIA
* Stroke
* For more detailed coverage, see Template:Cerebrovascular diseases
Other
* Sleep disorders
* For more detailed coverage, see Template:Sleep
CSF
* Intracranial hypertension
* Hydrocephalus
* Normal pressure hydrocephalus
* Choroid plexus papilloma
* Idiopathic intracranial hypertension
* Cerebral edema
* Intracranial hypotension
Other
* Brain herniation
* Reye syndrome
* Hepatic encephalopathy
* Toxic encephalopathy
* Hashimoto's encephalopathy
Both/either
Degenerative
SA
* Friedreich's ataxia
* Ataxia–telangiectasia
MND
* UMN only:
* Primary lateral sclerosis
* Pseudobulbar palsy
* Hereditary spastic paraplegia
* LMN only:
* Distal hereditary motor neuronopathies
* Spinal muscular atrophies
* SMA
* SMAX1
* SMAX2
* DSMA1
* Congenital DSMA
* Spinal muscular atrophy with lower extremity predominance (SMALED)
* SMALED1
* SMALED2A
* SMALED2B
* SMA-PCH
* SMA-PME
* Progressive muscular atrophy
* Progressive bulbar palsy
* Fazio–Londe
* Infantile progressive bulbar palsy
* both:
* Amyotrophic lateral sclerosis
* v
* t
* e
Diseases relating to the peripheral nervous system
Mononeuropathy
Arm
median nerve
* Carpal tunnel syndrome
* Ape hand deformity
ulnar nerve
* Ulnar nerve entrapment
* Froment's sign
* Ulnar tunnel syndrome
* Ulnar claw
radial nerve
* Radial neuropathy
* Wrist drop
* Cheiralgia paresthetica
long thoracic nerve
* Winged scapula
* Backpack palsy
Leg
lateral cutaneous nerve of thigh
* Meralgia paraesthetica
tibial nerve
* Tarsal tunnel syndrome
plantar nerve
* Morton's neuroma
superior gluteal nerve
* Trendelenburg's sign
sciatic nerve
* Piriformis syndrome
Cranial nerves
* See Template:Cranial nerve disease
Polyneuropathy and Polyradiculoneuropathy
HMSN
* Charcot–Marie–Tooth disease
* Dejerine–Sottas disease
* Refsum's disease
* Hereditary spastic paraplegia
* Hereditary neuropathy with liability to pressure palsy
* Familial amyloid neuropathy
Autoimmune and demyelinating disease
* Guillain–Barré syndrome
* Chronic inflammatory demyelinating polyneuropathy
Radiculopathy and plexopathy
* Brachial plexus injury
* Thoracic outlet syndrome
* Phantom limb
Other
* Alcoholic polyneuropathy
Other
General
* Complex regional pain syndrome
* Mononeuritis multiplex
* Peripheral neuropathy
* Neuralgia
* Nerve compression syndrome
* v
* t
* e
Inherited disorders of trafficking / vesicular transport proteins
Vesicle formation
Lysosome/Melanosome:
* HPS1–HPS7
* Hermansky–Pudlak syndrome
* LYST
* Chédiak–Higashi syndrome
COPII:
* SEC23A
* Cranio-lenticulo-sutural dysplasia
* COG7
* CDOG IIE
APC:
* AP1S2
* X-linked intellectual disability
* AP3B1
* Hermansky–Pudlak syndrome 2
* AP4M1
* CPSQ3
Rab
* ARL6
* BBS3
* RAB27A
* Griscelli syndrome 2
* CHM
* Choroideremia
* MLPH
* Griscelli syndrome 3
Cytoskeleton
Myosin:
* MYO5A
* Griscelli syndrome 1
Microtubule:
* SPG4
* Hereditary spastic paraplegia 4
Kinesin:
* KIF5A
* Hereditary spastic paraplegia 10
Spectrin:
* SPTBN2
* Spinocerebellar ataxia 5
Vesicle fusion
Synaptic vesicle:
* SNAP29
* CEDNIK syndrome
* STX11
* Hemophagocytic lymphohistiocytosis 4
Caveolae:
* CAV1
* Congenital generalized lipodystrophy 3
* CAV3
* Limb-girdle muscular dystrophy 2B, Long QT syndrome 9
Vacuolar protein sorting:
* VPS33B
* ARC syndrome
* VPS13B
* Cohen syndrome
* DYSF
* Distal muscular dystrophy
See also vesicular transport proteins
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[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
| Hereditary spastic paraplegia | c2931355 | 4,896 | wikipedia | https://en.wikipedia.org/wiki/Hereditary_spastic_paraplegia | 2021-01-18T18:43:06 | {"gard": ["6637"], "mesh": ["D015419", "C536864"], "umls": ["C2931355"], "orphanet": ["685"], "wikidata": ["Q657516"]} |
Inflammatory process affecting the mediastinum
Mediastinitis
Mediastinum
SpecialtyPulmonology
Mediastinitis is inflammation of the tissues in the mid-chest, or mediastinum. It can be either acute or chronic. It is thought to be due to four different etiologies:[1]
* direct contamination
* hematogenous or lymphatic spread
* extension of infection from the neck or retroperitoneum
* extension from the lung or pleura
Acute mediastinitis is usually caused by bacteria and is most often due to perforation of the esophagus. As the infection can progress rapidly, this is considered a serious condition.
Chronic sclerosing (or fibrosing) mediastinitis, while potentially serious, is caused by a long-standing inflammation of the mediastinum, leading to growth of acellular collagen and fibrous tissue within the chest and around the central vessels and airways. It has a different cause, treatment, and prognosis than acute infectious mediastinitis.
Space infections: Pretracheal space – lies anterior to trachea. Pretracheal space infection leads to mediastinitis. Here, the fascia fuses with the pericardium and the parietal pleura, which explains the occurrence of empyema and pericardial effusion in mediastinitis. However, infectious of other spaces can also lead to mediastinitis.
## Contents
* 1 Causes
* 1.1 Acute
* 1.2 Chronic
* 2 Symptoms
* 2.1 Acute
* 2.2 Chronic
* 3 Diagnosis
* 3.1 Acute
* 3.2 Chronic
* 4 Treatment
* 5 Etiology
* 6 Prognosis
* 7 References
* 8 External links
## Causes[edit]
Mediastinum Anatomy
### Acute[edit]
CT scan of a patient with Descending Necrotizing Mediastinitis.
Esophageal perforation, a form of direct contamination, accounts for 90% of acute mediastinal infections.[1] Esophageal perforation can arise from vomiting, incidental trauma from a procedure or operation, external trauma, ingestion of corrosive substances, malignancy, or other esophageal disease.[1]
Other causes of acute mediastinitis include infection secondary to cervical disease which arises from dental procedures, skin infections of the neck, neck trauma, or neck procedures.[1]
Descending necrotizing mediastinitis (DNM) was first described by Herman E. Pearse Jr., M.D. in 1938 and he stated, "the term 'mediastinitis' means little unless qualified by a description of its type and kind."[2] Although Descending Necrotizing Mediastinitis is an acute mediastinitis, it is distinct because it does not originate from structures within the mediastinum. Therefore, the term Descending Necrotizing Mediastinitis implies that the infection of the mediastinum originated from a primary site in the head or neck and descended through fascial spaces into the mediastinum.[citation needed]
### Chronic[edit]
There are two types of fibrosing mediastinitis: granulomatous and non-granulomatous. Granulomatous mediastinitis is due to a granulomatous process of the mediastinal lymph nodes leading to fibrosis and chronic abscesses in the mediastinum. The most common causes are histoplasmosis and tuberculosis infections. Non-granulomatous fibrosing mediastinitis is caused by an idiopathic reaction to drugs and radiation therapy.[3] Autoimmune disease and Behcet's disease are also causes.[4]
## Symptoms[edit]
### Acute[edit]
Acute mediastinitis is an infectious process and can cause fever, chills, tachycardia. Pain can occur with mediastinitis but the location of the pain depends on which part of the mediastinum is involved. When the upper mediastinum is involved, the pain is typically retro-sternal pain. When the lower mediastinum is involved, pain can be located between in the scapulae and radiate around to the chest.[5]
### Chronic[edit]
Symptoms depend on what organs of the mediastinum the disease is affecting. They might be caused by a constricted airway, constricted esophagus, or constricted blood vessels. Symptoms also depend on how mush fibrosis has occurred. There may be cough, shortness of breath, coughing up blood, pain in the chest, and difficulty in swallowing.[4]
## Diagnosis[edit]
### Acute[edit]
Acute mediastinitis can be confirmed by contrast x-rays since most cases of acute mediastinitis are due to esophageal perforation. Other studies that can be used include endoscopic visualization, Chest CT scan with oral and intravenous contrast.
With regards to CT Imaging, the extent of involvement of the mediastinum can be evaluated. Therefore, acute mediastinitis can be classified into three categories:[6]
1. diffuse mediastinitis
2. isolated mediastinal abscess
3. mediastinitis or mediastinal abscess complicated by empyema or subphrenic abscess.
### Chronic[edit]
Most cases of granulomatous mediastinitis (75%) are incidentally found on chest x-rays which show a mediastinal mass, or widening of the mediastinum.[3]
## Treatment[edit]
Treatment for acute mediastinitis usually involves aggressive intravenous antibiotic therapy and hydration. If discrete fluid collections or grossly infected tissue have formed (such as abscesses), they may have to be surgically drained or debrided.[1]
Treatment for DNM usually requires an operation to remove and drain infected necrotic tissue. Broad spectrum intravenous antibiotics are also given to treat the infection. Patients are typically managed in the intensive care unit due to the severity of the disease.[7]
Treatment for chronic fibrosing mediastinitis is somewhat controversial, and may include steroids or surgical decompression of affected vessels.
## Etiology[edit]
An observational retrospective study of 17 patients diagnosed with DNM found that the infections most often originated from neck infections including tonsillar abscess, pharyngitis, and epiglottitis. The study also found that most infections are poly-microbial.[7] Often the culprits are usually Gram-positive bacteria and anaerobes, though rarely, Gram-negative bacteria are also present. This severe form represents 20% of acute mediastinitis cases.[8]
## Prognosis[edit]
Fibrosing mediastinitis can lead to entrapment of mediastinal structures.The mortality of DNM ranges from 10-40% due to sepsis and multi-organ failure if not recognized and intervened upon early.[citation needed]
## References[edit]
1. ^ a b c d e Deatrick, K. Barrett; Long, Jason; Chang, Andrew C. (2015), Doherty, Gerard M. (ed.), "Thoracic Wall, Pleura, Mediastinum, & Lung", CURRENT Diagnosis & Treatment: Surgery (14 ed.), McGraw-Hill Education, retrieved 2018-12-14
2. ^ Pearse, Herman E. (1938-10-01). "Mediastinitis Following Cervical Suppuration". Annals of Surgery. 108 (4): 588–611. doi:10.1097/00000658-193810000-00009. ISSN 0003-4932. PMC 1387034. PMID 17857255.
3. ^ a b Jain, Neeraj; Chauhan, Udit; Puri, Sunil Kumar; Agrawal, Sachin; Garg, Lalit (2015-11-16). "Fibrosing mediastinitis: when to suspect and how to evaluate?". BJR Case Reports. 2 (1): 20150274. doi:10.1259/bjrcr.20150274. PMC 6195926. PMID 30364448.
4. ^ a b "Fibrosing mediastinitis | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2019-01-31.
5. ^ Goodwin, R.A. (1998). Pulmonary Disease and Disorders (3rd Edition). New York: McGraw-Hill. pp. 1479–1490.
6. ^ Carrol, Clark L.; Jeffrey, R. Brooke; Federle, Michael P.; Vernacchia, Fred S. (May 1987). "CT Evaluation of Mediastinal Infections". Journal of Computer Assisted Tomography. 11 (3): 449–454. doi:10.1097/00004728-198705000-00015. ISSN 0363-8715. PMID 3571587.
7. ^ a b Schmid, Ralph A.; Wiegand, Jan; Caversaccio, Marco; Hoksch, Beatrix; Kocher, Gregor J. (2012-10-01). "Diffuse descending necrotizing mediastinitis: surgical therapy and outcome in a single-centre series". European Journal of Cardio-Thoracic Surgery. 42 (4): e66–e72. doi:10.1093/ejcts/ezs385. ISSN 1010-7940. PMID 22761501.
8. ^ Pota, Vincenzo; Passavanti, Maria Beatrice; Sansone, Pasquale; Pace, Maria Caterina; Peluso, Filomena; Fiorelli, Alfonso; Aurilio, Caterina (2018-03-03). "Septic shock from descending necrotizing mediastinitis – combined treatment with IgM-enriched immunoglobulin preparation and direct polymyxin B hemoperfusion: a case report". Journal of Medical Case Reports. 12 (1): 55. doi:10.1186/s13256-018-1611-5. ISSN 1752-1947. PMC 5834850. PMID 29499757.
## External links[edit]
Classification
D
* ICD-10: J98.5
* ICD-9-CM: 519.2
* MeSH: D008480
* DiseasesDB: 7909
External resources
* MedlinePlus: 000081
* eMedicine: med/2798
* Patient UK: Mediastinitis
* Mediastinitis at the US National Library of Medicine Medical Subject Headings (MeSH)
* v
* t
* e
Diseases of the respiratory system
Upper RT
(including URTIs,
common cold)
Head
sinuses
Sinusitis
nose
Rhinitis
Vasomotor rhinitis
Atrophic rhinitis
Hay fever
Nasal polyp
Rhinorrhea
nasal septum
Nasal septum deviation
Nasal septum perforation
Nasal septal hematoma
tonsil
Tonsillitis
Adenoid hypertrophy
Peritonsillar abscess
Neck
pharynx
Pharyngitis
Strep throat
Laryngopharyngeal reflux (LPR)
Retropharyngeal abscess
larynx
Croup
Laryngomalacia
Laryngeal cyst
Laryngitis
Laryngopharyngeal reflux (LPR)
Laryngospasm
vocal cords
Laryngopharyngeal reflux (LPR)
Vocal fold nodule
Vocal fold paresis
Vocal cord dysfunction
epiglottis
Epiglottitis
trachea
Tracheitis
Laryngotracheal stenosis
Lower RT/lung disease
(including LRTIs)
Bronchial/
obstructive
acute
Acute bronchitis
chronic
COPD
Chronic bronchitis
Acute exacerbation of COPD)
Asthma (Status asthmaticus
Aspirin-induced
Exercise-induced
Bronchiectasis
Cystic fibrosis
unspecified
Bronchitis
Bronchiolitis
Bronchiolitis obliterans
Diffuse panbronchiolitis
Interstitial/
restrictive
(fibrosis)
External agents/
occupational
lung disease
Pneumoconiosis
Aluminosis
Asbestosis
Baritosis
Bauxite fibrosis
Berylliosis
Caplan's syndrome
Chalicosis
Coalworker's pneumoconiosis
Siderosis
Silicosis
Talcosis
Byssinosis
Hypersensitivity pneumonitis
Bagassosis
Bird fancier's lung
Farmer's lung
Lycoperdonosis
Other
* ARDS
* Combined pulmonary fibrosis and emphysema
* Pulmonary edema
* Löffler's syndrome/Eosinophilic pneumonia
* Respiratory hypersensitivity
* Allergic bronchopulmonary aspergillosis
* Hamman-Rich syndrome
* Idiopathic pulmonary fibrosis
* Sarcoidosis
* Vaping-associated pulmonary injury
Obstructive / Restrictive
Pneumonia/
pneumonitis
By pathogen
* Viral
* Bacterial
* Pneumococcal
* Klebsiella
* Atypical bacterial
* Mycoplasma
* Legionnaires' disease
* Chlamydiae
* Fungal
* Pneumocystis
* Parasitic
* noninfectious
* Chemical/Mendelson's syndrome
* Aspiration/Lipid
By vector/route
* Community-acquired
* Healthcare-associated
* Hospital-acquired
By distribution
* Broncho-
* Lobar
IIP
* UIP
* DIP
* BOOP-COP
* NSIP
* RB
Other
* Atelectasis
* circulatory
* Pulmonary hypertension
* Pulmonary embolism
* Lung abscess
Pleural cavity/
mediastinum
Pleural disease
* Pleuritis/pleurisy
* Pneumothorax/Hemopneumothorax
Pleural effusion
Hemothorax
Hydrothorax
Chylothorax
Empyema/pyothorax
Malignant
Fibrothorax
Mediastinal disease
* Mediastinitis
* Mediastinal emphysema
Other/general
* Respiratory failure
* Influenza
* Common cold
* SARS
* Coronavirus disease 2019
* Idiopathic pulmonary haemosiderosis
* Pulmonary alveolar proteinosis
*[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 inhibitors
*[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
| Mediastinitis | c0025064 | 4,897 | wikipedia | https://en.wikipedia.org/wiki/Mediastinitis | 2021-01-18T18:38:58 | {"mesh": ["D008480"], "umls": ["C0025064"], "wikidata": ["Q1581845"]} |
Serum sickness
SpecialtyHematology
Serum sickness in humans is a reaction to proteins in antiserum derived from a non-human animal source, occurring 5–10 days after exposure. It is a type of hypersensitivity, specifically immune complex hypersensitivity (type III). The term serum sickness–like reaction (SSLR) is occasionally used to refer to similar illnesses that arise from the introduction of certain non-protein substances, such as penicillin.[1] It was first characterized by Clemens von Pirquet and Béla Schick in 1906.[2]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 2.1 Antitoxins and antisera
* 2.2 Drugs
* 2.3 Others
* 3 Diagnosis
* 4 Prevention
* 5 Treatment
* 6 See also
* 7 References
* 8 External links
## Signs and symptoms[edit]
Signs and symptoms can take as long as 14 days after exposure to appear, and may include signs and symptoms commonly associated with hypersensitivity or infections.
* rashes
* itching
* joint pain (arthralgia), especially finger and toe joints
* fever, as high as 40 °C and usually appears before rash
* lymphadenopathy (swelling of lymph nodes), particularly near the site of injection, head and neck
* malaise
* hypotension (decreased blood pressure)
* splenomegaly (enlarged spleen)
* glomerulonephritis
* protein in the urine
* blood in the urine
* shock
## Causes[edit]
When an antiserum is given, the human immune system can mistake the proteins present for harmful antigens. The body produces antibodies, which combine with these proteins to form immune complexes. These complexes precipitate, enter the walls of blood vessels, and activate the complement cascade, initiating an inflammatory response and consuming much of the available complement component 3 (C3). The result is a leukocytoclastic vasculitis. This results in hypocomplementemia, a low C3 level in serum. They can also cause more reactions resulting in typical symptoms of serum sickness.
### Antitoxins and antisera[edit]
Serum sickness can be developed as a result of exposure to antibodies derived from animals. These sera or antitoxins are generally administered to prevent or treat an infection or envenomation.
### Drugs[edit]
Some of the drugs associated with serum sickness are:
* allopurinol
* barbiturates
* captopril
* cephalosporins
* crofab
* griseofulvin
* penicillins
* phenytoin
* procainamide
* quinidine
* streptokinase
* sulfonamides
* rituximab
* ibuprofen
* infliximab
* oxycodone
### Others[edit]
Allergenic extracts, hormones and vaccines can also cause serum sickness. However, according to the Johns Hopkins Bloomberg School of Public Health, currently routinely recommended vaccinations to the general population in the U.S have not been shown to cause serum sickness. [1]
## Diagnosis[edit]
Diagnosis is based on history given by patient, including recent medications.
## Prevention[edit]
Avoidance of antitoxins that may cause serum sickness is the best way to prevent serum sickness. Although, sometimes, the benefits outweigh the risks in the case of a life-threatening bite or sting. Prophylactic antihistamines or corticosteroids may be used concomitant with the antitoxin. Skin testing may be done beforehand in order to identify individuals who may be at risk of a reaction. Physicians should make their patients aware of the drugs or antitoxins to which they are allergic if there is a reaction. The physician will then choose an alternate antitoxin if it's appropriate or continue with prophylactic measures.
## Treatment[edit]
With discontinuation of the offending agent(s), symptoms usually disappear within 4–5 days.
Corticosteroids, antihistamines, and analgesics are the main line of treatment. The choice depends on the severity of the reaction.
Use of plasmapheresis has also been described.[3]
## See also[edit]
* Hypersensitivity
* Arthus reaction
* Serum sickness-like reaction
## References[edit]
1. ^ Brucculeri M, Charlton M, Serur D (2006). "Serum sickness-like reaction associated with cefazolin". BMC Clin Pharmacol. 6: 3. doi:10.1186/1472-6904-6-3. PMC 1397863. PMID 16504095.
2. ^ Jackson R (October 2000). "Serum sickness". J Cutan Med Surg. 4 (4): 223–5. doi:10.1177/120347540000400411. PMID 11231202.
3. ^ Lundquist AL, Chari RS, Wood JH, et al. (May 2007). "Serum sickness following rabbit antithymocyte-globulin induction in a liver transplant recipient: case report and literature review". Liver Transpl. 13 (5): 647–50. doi:10.1002/lt.21098. PMID 17377915.
## External links[edit]
Classification
D
* ICD-10: T80.6
* ICD-9-CM: 999.5
* MeSH: D012713
* DiseasesDB: 11970
External resources
* MedlinePlus: 000820
* eMedicine: med/2105
* Serum sickness-like reactions
* v
* t
* e
Blood transfusion and transfusion medicine
Blood products
* Whole blood
* Platelets
* Platelet transfusion
* Red blood cells
* Plasma
* Fresh frozen plasma
* PF24
* Cryoprecipitate
* Cryosupernatant
* White blood cells
* Granulocyte transfusion
* Blood substitutes
General concepts
* Blood donation
* Methods
* Apheresis (plasmapheresis, plateletpheresis, leukapheresis)
* Exchange transfusion
* Intraoperative blood salvage
* Tests
* Blood typing
* Cross-matching
* Coombs test
* Blood bank
* International Society of Blood Transfusion
* ISBT 128
Transfusion reactions
and adverse effects
* Transfusion hemosiderosis
* Transfusion related acute lung injury
* Transfusion associated circulatory overload
* Transfusion-associated graft versus host disease
* Febrile non-hemolytic transfusion reaction
* Hemolytic reaction
* acute
* delayed
* Serum sickness
* Transfusion transmitted infection
Blood group systems
* Blood types
* ABO
* Secretor status
* Augustine
* CD59
* Chido-Rodgers
* Colton
* Cromer
* Diego
* Dombrock
* Duffy
* Er
* FORS
* Gerbich
* GIL
* GLOB
* Hh
* Ii
* Indian
* JR
* JMH
* KANNO
* Kell (Xk)
* Kidd
* Knops
* Lan
* Lewis
* Lutheran
* LW
* MNS
* OK
* P
* Raph
* Rh and RHAG
* Scianna
* Sid
* T-Tn
* Vel
* Xg
* Yt
* Other
* v
* t
* e
Hypersensitivity and autoimmune diseases
Type I/allergy/atopy
(IgE)
Foreign
* Atopic eczema
* Allergic urticaria
* Allergic rhinitis (Hay fever)
* Allergic asthma
* Anaphylaxis
* Food allergy
* common allergies include: Milk
* Egg
* Peanut
* Tree nut
* Seafood
* Soy
* Wheat
* Penicillin allergy
Autoimmune
* Eosinophilic esophagitis
Type II/ADCC
* * IgM
* IgG
Foreign
* Hemolytic disease of the newborn
Autoimmune
Cytotoxic
* Autoimmune hemolytic anemia
* Immune thrombocytopenic purpura
* Bullous pemphigoid
* Pemphigus vulgaris
* Rheumatic fever
* Goodpasture syndrome
* Guillain–Barré syndrome
"Type V"/receptor
* Graves' disease
* Myasthenia gravis
* Pernicious anemia
Type III
(Immune complex)
Foreign
* Henoch–Schönlein purpura
* Hypersensitivity vasculitis
* Reactive arthritis
* Farmer's lung
* Post-streptococcal glomerulonephritis
* Serum sickness
* Arthus reaction
Autoimmune
* Systemic lupus erythematosus
* Subacute bacterial endocarditis
* Rheumatoid arthritis
Type IV/cell-mediated
(T cells)
Foreign
* Allergic contact dermatitis
* Mantoux test
Autoimmune
* Diabetes mellitus type 1
* Hashimoto's thyroiditis
* Multiple sclerosis
* Coeliac disease
* Giant-cell arteritis
* Postorgasmic illness syndrome
* Reactive arthritis
GVHD
* Transfusion-associated graft versus host disease
Unknown/
multiple
Foreign
* Hypersensitivity pneumonitis
* Allergic bronchopulmonary aspergillosis
* Transplant rejection
* Latex allergy (I+IV)
Autoimmune
* Sjögren syndrome
* Autoimmune hepatitis
* Autoimmune polyendocrine syndrome
* APS1
* APS2
* Autoimmune adrenalitis
* Systemic autoimmune 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 inhibitors
*[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
| Serum sickness | c0036830 | 4,898 | wikipedia | https://en.wikipedia.org/wiki/Serum_sickness | 2021-01-18T18:55:28 | {"mesh": ["D012713"], "icd-9": ["999.5"], "icd-10": ["T80.6"], "wikidata": ["Q33121"]} |
Deafness-craniofacial syndrome is characterised by the association of congenital hearing loss and facial dysmorphism (facial asymmetry, a broad nasal root and small nasal alae). It has been described in two members (father and daughter) of one Jewish family. Temporal alopecia was also noted. Transmission appeared to be 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 inhibitors
*[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
| Deafness-craniofacial syndrome | c1852278 | 4,899 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3241 | 2021-01-23T19:03:08 | {"gard": ["1686"], "mesh": ["C565118"], "omim": ["125230"], "umls": ["C1852278"], "icd-10": ["Q87.0"], "synonyms": ["Hearing loss-craniofacial syndrome"]} |
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