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## Clinical Features
Heterotaxy results from failure to establish normal left-right (L-R) asymmetry during embryonic development. Other than X-linked visceral heterotaxy (306955), most familial cases are thought to be autosomal recessive. Casey et al. (1996) identified a family in which 4 individuals from 3 generations showed laterality defects. Two had complete reversal of normal laterality (situs inversus) (270100), while 2 others had asplenia, midline liver, and complex cardiac malformations (situs ambiguus). Two obligate gene carriers were anatomically normal (situs solitus). Male-to-male transmission confirmed autosomal inheritance.
Vitale et al. (2001) reported a 5-generation family with abnormality of laterality. Seven individuals were affected, with situs inversus present in 4 and situs ambiguus in 3. There was no male-to-male transmission, but males and females appeared to be similarly affected and linkage analysis excluded an X chromosome locus. Vitale et al. (2001) suggested that an autosomal dominant pattern of inheritance was likely; under this model, 4 apparently normal individuals were obligate gene carriers. Two additional family members had isolated cardiac defects without any other L/R abnormality: one had ventricular inversion in combination with transposition of the great arteries, whereas the other had hypoplastic left heart syndrome.
Maclean and Dunwoodie (2004) reviewed the evidence that mutations in genes and pathways critical for L-R patterning are involved in common isolated congenital malformations such as congenital heart disease, biliary tract anomalies, renal polycystic disease, and malrotation of the intestine, indicating that disorders of L-R development are far more common than a 1 in 10,000 incidence of heterotaxia might suggest. They reviewed data from mammalian (human and mouse) L-R patterning disorders to provide a clinically oriented perspective useful in this 'diagnostically challenging area.'
Wessels et al. (2008) described 9 affected members of a 3-generation family with a combination of cardiac abnormalities and left isomerism, inherited in an autosomal dominant pattern. The cardiac abnormalities included noncompaction of the ventricular myocardium, bradycardia, pulmonary valve stenosis, and secundum atrial septal defect; the laterality sequence anomalies included left bronchial isomerism, azygous continuation of the inferior vena cava, polysplenia, and intestinal malrotation. The common finding in all affected members was ventricular noncompaction with conduction abnormalities.
Inheritance
Male-to-male transmission of laterality defects in the family reported by Casey et al. (1996) confirmed autosomal dominant inheritance.
Mapping
Vitale et al. (2001) performed linkage analysis in a 5-generation family with abnormality of laterality and obtained a maximum lod score of 2.95 at theta = 0 for marker D6S426 on 6p21. Recombination events defined an interval of 32 cM bounded by markers D6S105 and D6S1960.
Wessels et al. (2008) performed linkage analysis in a 3-generation family with cardiac abnormalities and left isomerism and found linkage to chromosome 6p24.3-p21.2 between D6S470 (telomeric) and D6S1610 (centromeric), with a maximum lod score of 2.7 at D6S276. This linkage interval overlapped with that previously reported by Vitale et al. (2001) in a family with abnormality of laterality; the smallest region of overlap was a 9.4-cM (12-Mb) interval between D6S105 and D6S1610.
Cardiac \- Complex cardiac malformations Growth \- Heterotaxy \- Situs inversus Abdomen \- Asplenia \- Midline liver Inheritance \- Autosomal dominant ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| LATERALITY DEFECTS, AUTOSOMAL DOMINANT | c3178805 | 2,600 | omim | https://www.omim.org/entry/601086 | 2019-09-22T16:15:26 | {"mesh": ["D059446"], "omim": ["601086"], "orphanet": ["450"]} |
Fasciola hepatica
Egg of Dicrocoelium sp.
Liver fluke is a collective name of a polyphyletic group of parasitic trematodes under the phylum Platyhelminthes.[1] They are principally parasites of the liver of various mammals, including humans. Capable of moving along the blood circulation, they can occur also in bile ducts, gallbladder, and liver parenchyma. In these organs, they produce pathological lesions leading to parasitic diseases. They have complex life cycles requiring two or three different hosts, with free-living larval stages in water.[2]
## Contents
* 1 Biology
* 2 Pathogenicity
* 3 Species
* 4 See also
* 5 References
## Biology[edit]
The body of liver flukes is leaf-like and flattened. The body is covered with a tegument. They are hermaphrodites having complete sets of both male and female reproductive systems. They have simple digestive systems and primarily feed on blood. The anterior end is the oral sucker opening into the mouth. Inside, mouth lead to a small pharynx which is followed by an extended intestine that runs through the entire length of the body. The intestine is heavily branched and anus is absent. Instead, the intestine runs along an excretory canal that opens at the posterior end. Adult flukes produce eggs that are passed out through the excretory pore. The eggs infect different species of snails (as intermediate hosts) in which they grow into larvae. The larvae are released into the environment from where the definitive hosts (humans and other mammals) get the infection. In some species, another intermediate host is required, generally a cyprinid fish. In this case, the definitive hosts are infected from eating infected fish. Hence, they are food-borne parasites.[3][4]
## Pathogenicity[edit]
Liver fluke infections cause serious medical and veterinary diseases. Fasciolosis of sheep, goats and cattle, is the major cause of economic losses in dairy and meat industry.[5] Fasciolosis of humans produces clinical symptoms such as fever, nausea, swollen liver, extreme abdominal pain, jaundice and anemia.[6]
Clonorchiasis and opisthorchiasis (due to Opisthorchis viverrini) are particularly dangerous. They can survive for several decades in humans causing chronic inflammation of the bile ducts, epithelial hyperplasia, periductal fibrosis and bile duct dilatation. In many infections these symptoms cause further complications such as stone formation, recurrent pyogenic cholangitis and cancer (cholangiocarcinoma).[7] Opisthorchiasis is particularly the leading cause of cholangiocarcinoma in Thailand and the Lao People's Democratic Republic.[8] Both clonorchiasis and opisthorchiasis are classified as Group 1 human biological agents (carcinogens) by International Agency of Research on Cancer (IARC).[9]
## Species[edit]
Species of liver fluke include:
* Clonorchis sinensis (the Chinese liver fluke, or the Oriental liver fluke)
* Dicrocoelium dendriticum (the lancet liver fluke)
* Dicrocoelium hospes
* Fasciola hepatica (the sheep liver fluke)
* Fascioloides magna (the giant liver fluke)
* Fasciola gigantica
* Fasciola jacksoni
* Metorchis conjunctus
* Metorchis albidus
* Protofasciola robusta
* Parafasciolopsis fasciomorphae
* Opisthorchis viverrini (Southeast Asian liver fluke)
* Opisthorchis felineus (Cat liver fluke)
* Opisthorchis guayaquilensis
## See also[edit]
* The Integrated Opisthorchiasis Control Program
## References[edit]
1. ^ Lotfy, WM; Brant, SV; DeJong, RJ; Le, TH; Demiaszkiewicz, A; Rajapakse, RP; Perera, VB; Laursen, JR; Loker, ES (2008). "Evolutionary origins, diversification, and biogeography of liver flukes (Digenea, Fasciolidae)". The American Journal of Tropical Medicine and Hygiene. 79 (2): 248–255. doi:10.4269/ajtmh.2008.79.248. PMC 2577557. PMID 18689632.
2. ^ Diseases and Disorders Volume 2. Tarrytown, NY: Marshall Cavendish COrporation. 2008. p. 525. ISBN 978-0-7614-7772-3.
3. ^ Xiao, Lihua; Ryan, Una; Feng, Yaoyu (2015). Biology of Foodborne Parasites. Boca Raton, Florida: CRC Press. pp. 276–282. ISBN 978-1-4665-6885-3.
4. ^ Mas-Coma, S.; Bargues, M.D.; Valero, M.A. (2005). "Fascioliasis and other plant-borne trematode zoonoses". International Journal for Parasitology. 35 (11–12): 1255–1278. doi:10.1016/j.ijpara.2005.07.010. PMID 16150452.
5. ^ Piedrafita, D; Spithill, TW; Smith, RE; Raadsma, HW (2010). "Improving animal and human health through understanding liver fluke immunology". Parasite Immunology. 32 (8): 572–581. doi:10.1111/j.1365-3024.2010.01223.x. PMID 20626812.
6. ^ Carnevale, Silvana; Malandrini, Jorge Bruno; Pantano, María Laura; Sawicki, Mirna; Soria, Claudia Cecilia; Kuo, Lein Hung; Kamenetzky, Laura; Astudillo, Osvaldo Germán; Velásquez, Jorge Néstor (2016). "Fasciola hepatica infection in humans: overcoming problems for the diagnosis". Acta Parasitologica. 61 (4): 776–783. doi:10.1515/ap-2016-0107. PMID 27787223.
7. ^ Lim, Jae Hoon (2011). "Liver Flukes: the Malady Neglected". Korean Journal of Radiology. 12 (3): 269–79. doi:10.3348/kjr.2011.12.3.269. PMC 3088844. PMID 21603286.
8. ^ Sripa, Banchob; Bethony, Jeffrey M.; Sithithaworn, Paiboon; Kaewkes, Sasithorn; Mairiang, Eimorn; Loukas, Alex; Mulvenna, Jason; Laha, Thewarach; Hotez, Peter J.; Brindley, Paul J. (September 2011). "Opisthorchiasis and Opisthorchis-associated cholangiocarcinoma in Thailand and Laos". Acta Tropica. 120 (Suppl): S158–S168. doi:10.1016/j.actatropica.2010.07.006. PMC 3010517. PMID 20655862.
9. ^ Kim, TS; Pak, JH; Kim, JB; Bahk, YY (2016). "Clonorchis sinensis, an oriental liver fluke, as a human biological agent of cholangiocarcinoma: a brief review". BMB Reports. 49 (11): 590–597. doi:10.5483/BMBRep.2016.49.11.109. PMC 5346318. PMID 27418285.
* v
* t
* e
Parasitic disease caused by helminthiases
Flatworm/
platyhelminth
infection
Fluke/trematode
(Trematode infection)
Blood fluke
* Schistosoma mansoni / S. japonicum / S. mekongi / S. haematobium / S. intercalatum
* Schistosomiasis
* Trichobilharzia regenti
* Swimmer's itch
Liver fluke
* Clonorchis sinensis
* Clonorchiasis
* Dicrocoelium dendriticum / D. hospes
* Dicrocoeliasis
* Fasciola hepatica / F. gigantica
* Fasciolosis
* Opisthorchis viverrini / O. felineus
* Opisthorchiasis
Lung fluke
* Paragonimus westermani / P. kellicotti
* Paragonimiasis
Intestinal fluke
* Fasciolopsis buski
* Fasciolopsiasis
* Metagonimus yokogawai
* Metagonimiasis
* Heterophyes heterophyes
* Heterophyiasis
Cestoda
(Tapeworm infection)
Cyclophyllidea
* Echinococcus granulosus / E. multilocularis
* Echinococcosis
* Taenia saginata / T. asiatica / T. solium (pork)
* Taeniasis / Cysticercosis
* Hymenolepis nana / H. diminuta
* Hymenolepiasis
Pseudophyllidea
* Diphyllobothrium latum
* Diphyllobothriasis
* Spirometra erinaceieuropaei
* Sparganosis
* Diphyllobothrium mansonoides
* Sparganosis
Roundworm/
Nematode
infection
Secernentea
Spiruria
Camallanida
* Dracunculus medinensis
* Dracunculiasis
Spirurida
Filarioidea
(Filariasis)
* Onchocerca volvulus
* Onchocerciasis
* Loa loa
* Loa loa filariasis
* Mansonella
* Mansonelliasis
* Dirofilaria repens
* D. immitis
* Dirofilariasis
* Wuchereria bancrofti / Brugia malayi / |B. timori
* Lymphatic filariasis
Thelazioidea
* Gnathostoma spinigerum / G. hispidum
* Gnathostomiasis
* Thelazia
* Thelaziasis
Spiruroidea
* Gongylonema
Strongylida
(hookworm)
* Hookworm infection
* Ancylostoma duodenale / A. braziliense
* Ancylostomiasis / Cutaneous larva migrans
* Necator americanus
* Necatoriasis
* Angiostrongylus cantonensis
* Angiostrongyliasis
* Metastrongylus
* Metastrongylosis
Ascaridida
* Ascaris lumbricoides
* Ascariasis
* Anisakis
* Anisakiasis
* Toxocara canis / T. cati
* Visceral larva migrans / Toxocariasis
* Baylisascaris
* Dioctophyme renale
* Dioctophymosis
* Parascaris equorum
Rhabditida
* Strongyloides stercoralis
* Strongyloidiasis
* Trichostrongylus spp.
* Trichostrongyliasis
* Halicephalobus gingivalis
Oxyurida
* Enterobius vermicularis
* Enterobiasis
Adenophorea
* Trichinella spiralis
* Trichinosis
* Trichuris trichiura (Trichuriasis / Whipworm)
* Capillaria philippinensis
* Intestinal capillariasis
* C. hepatica
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Liver fluke | None | 2,601 | wikipedia | https://en.wikipedia.org/wiki/Liver_fluke | 2021-01-18T18:50:06 | {"wikidata": ["Q1326939"]} |
Abdominal or chest wall after operations for septic condition.
Chronic undermining burrowing ulcer
Other namesMeleney gangrene, or Meleney's ulcer
SpecialtyDermatology
Chronic undermining burrowing ulcer is a cutaneous condition that is a postoperative, progressive bacterial gangrene.[1]:269 It is seen in immunocompromised individuals, mostly after post abdominal surgery and rapidly spreads to involve a large area.[citation needed]
## 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 0-7216-2921-0.
This infection-related 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
| Chronic undermining burrowing ulcer | c0343023 | 2,602 | wikipedia | https://en.wikipedia.org/wiki/Chronic_undermining_burrowing_ulcer | 2021-01-18T19:06:52 | {"umls": ["C0343023"], "wikidata": ["Q5114006"]} |
Medulloepithelioma of the central nervous system is a rare, primitive neuroectodermal tumor characterized by papillary, tubular and trabecular arrangements of neoplastic neuroepithelium, mimicking the embryonic neural tube, most commonly found in the periventricular region within the cerebral hemispheres, but has also been reported in brainstem and cerebellum. It usually presents in childhood with headache, nausea, vomiting, facial nerve paresis, and/or cerebellar ataxia, and typically has a progressive course, highly malignant behavior and poor prognosis. Hearing and visual loss have also been observed.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Medulloepithelioma of the central nervous system | c0334596 | 2,603 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251883 | 2021-01-23T17:48:39 | {"mesh": ["D018242"], "umls": ["C0334596"]} |
Part of a series on
Discrimination
General forms
* Age
* Class (Caste)
* Physical Disability
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* Hair texture
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Specific forms
Social
* Acephobia
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Manifestations
* Blood libel
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* Eliminationism
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* examples
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* Hate group
* Hate speech
* online
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* Lynching
* Mortgage
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* Religious war
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* Segregation academy
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Policies
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* Nonpersons
* Numerus clausus (as religious or racial quota)
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* Racial quota
* Racial steering
* Redlining
* Same-sex marriage (laws and issues prohibiting)
* Segregation
* age
* racial
* religious
* sexual
* Sodomy law
* State atheism
* State religion
* Ugly law
* Voter suppression
Countermeasures
* Affirmative action
* Anti-discrimination law
* Cultural assimilation
* Cultural pluralism
* Diversity training
* Empowerment
* Feminism
* Fighting Discrimination
* Hate speech laws by country
* Human rights
* Intersex rights
* LGBT rights
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* Multiculturalism
* Nonviolence
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* Reappropriation
* Self-determination
* Social integration
* Toleration
Related topics
* Allophilia
* Anti-cultural, anti-national, and anti-ethnic terms
* Bias
* Christian privilege
* Civil liberties
* Cultural assimilation
* Dehumanization
* Diversity
* Ethnic penalty
* Eugenics
* Internalized oppression
* Intersectionality
* Male privilege
* Masculism
* Medical model of disability
* autism
* Multiculturalism
* Net bias
* Neurodiversity
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* Oppression
* Police brutality
* Political correctness
* Polyculturalism
* Power distance
* Prejudice
* Prisoner abuse
* Racial bias in criminal news
* Racism by country
* Religious intolerance
* Second-generation gender bias
* Snobbery
* Social exclusion
* Social model of disability
* Social stigma
* Stereotype
* threat
* The talk
* White privilege
* v
* t
* e
Gerontophobia is the fear of age-related self-degeneration (similar to Gerascophobia), or a hatred or fear of the elderly due to memento mori. The term comes from the Greek γέρων – gerōn, "old man"[1] and φόβος – phobos, "fear".[2]
## Contents
* 1 Ageism
* 2 See also
* 3 References
* 4 External links
## Ageism[edit]
Discriminatory aspects of ageism have been strongly linked to gerontophobia.[3] This irrational fear or hatred of the elderly is associated with the fact that someday all young people including oneself will be old inevitably and suffer from the irreversible health decline that comes with old age, which is associated with disability, disease and death. The sight of aged people is a reminder of death (memento mori) and inevitable biological vulnerability. This unwillingness to accept these manifests in feelings of hostility and discriminatory acts towards the elderly.[4]
## See also[edit]
* Gerascophobia
* Gerontocracy
* List of phobias
## References[edit]
1. ^ γέρων, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus
2. ^ φόβος, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus
3. ^ Bunzel, J. H. "Note on the history of a concept-gerontophobia." Gerontologist 12:116-203.
4. ^ Levin, J., & Levin, W. C. (1980). Ageism, prejudice and discrimination against the elderly (p. 94). Belmont, Calif.: Wadsworth Pub. Co..
## External links[edit]
* AGEISM AND AGING UP: A Q and A with Mariah
* MedFriendly
* Age Wave
* v
* t
* e
Discrimination
General forms
* Age
* Caste
* Class
* Disability
* Education
* Economic
* Employment
* Genetic
* Hair texture
* Height
* Housing
* Language
* Looks
* Race / Ethnicity / Nationality
* Rank
* Sanity
* Sex
* Sexual orientation
* Size
* Skin color
Social
* Acephobia
* Adultism
* Amatonormativity
* Anti-albinism
* Anti-autism
* Anti-homelessness
* Anti-intellectualism
* Anti-intersex
* Anti-left handedness
* Anti-Masonry
* Antisemitism (Judeophobia)
* Aporophobia
* Audism
* Biphobia
* Clannism
* Cronyism
* Drug use
* Elitism
* Ephebiphobia
* Fatism
* Gerontophobia
* Heteronormativity
* Heterosexism
* HIV/AIDS stigma
* Homophobia
* Leprosy stigma
* Lesbophobia
* Misandry
* Misogyny
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* Category
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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
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*[BMI]: body mass index
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*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Gerontophobia | None | 2,604 | wikipedia | https://en.wikipedia.org/wiki/Gerontophobia | 2021-01-18T18:41:00 | {"wikidata": ["Q2427390"]} |
A catastrophic illness is a severe illness requiring prolonged hospitalization or recovery. Examples would include[1] cancer, leukemia, heart attack or stroke. These illnesses usually involve high costs for hospitals, doctors and medicines and may incapacitate the person from working, creating a financial hardship. They are the type intended to be covered by high-deductible health plans. Research indicates that the unusual economic environment of the delivery of catastrophic illness care encourages the use of innovative therapies.[2] Medicare contains a benefit for catastrophic illness.[3]
## References[edit]
1. ^ MR Gillick; NA Serrell; LS Gillick (1982), "Adverse consequences of hospitalization in the elderly", Social Science & Medicine, 16 (10): 1033–1038, doi:10.1016/0277-9536(82)90175-7, PMID 6955965
2. ^ Warner, Kenneth E. (January 1977), "Treatment Decision Making in Catastrophic Illness", Medical Care, XV (1): 19–33, JSTOR 3763281
3. ^ John K. Iglehart (March 2001), Medicare's New Benefits: "Catastrophic" Health Insurance, 10, Journal of Research in Pharmaceutical Economics, pp. 213–228
This article about a disease, disorder, or medical condition is a stub. You can help Wikipedia by expanding it.
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| Catastrophic illness | c0007397 | 2,605 | wikipedia | https://en.wikipedia.org/wiki/Catastrophic_illness | 2021-01-18T18:41:01 | {"mesh": ["D002388"], "wikidata": ["Q5051575"]} |
The association of amelogenesis imperfecta and a microscopically typical hair dysplasia has been found in several members of a family in two generations. Transmission is X-linked.
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*[CREB]: cAMP response element-binding protein
| Trichodysplasia-amelogenesis imperfecta syndrome | None | 2,606 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79129 | 2021-01-23T17:22:26 | {} |
Discrete papular lichen myxedematosus is a rare chronic, slowly progressive form of localized lichen myxedematosus (see this term) characterized by the development of a few to multiple small symmetrical skin-coloured mucinous papules on the limbs and trunk.
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*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Discrete papular lichen myxedematosus | c4273967 | 2,607 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90394 | 2021-01-23T18:31:18 | {"icd-10": ["L98.5"]} |
## Clinical Features
Leroy et al. (2004) described 2 families with a novel form of spondyloepiphyseal dysplasia tarda. The first family consisted of 4 brothers (3 affected), and the second family consisted of an affected brother and sister. Consanguinity in the first family suggested autosomal recessive inheritance. Clinical features included late-onset, short-trunk type of short stature (height ranging from less than the 3rd percentile to the 50th percentile), abnormal spinal curvature (scoliosis, thoracic kyphosis, and lumbar hyperlordosis), and minor leg deformities. Spinal mobility was restricted, and knee pain developed in adolescence. Onset occurred in late childhood. Radiologically, skeletal abnormalities were limited mainly to the spine and proximal femora. The thoracic and lumbar vertebral bodies were flattened with anterior wedging in the thoracic spine. Irregularities of the upper and lower endplates became more conspicuous with age, and there was progressive narrowing of intervertebral spaces. The proximal femoral epiphyses were flattened. The femoral necks were broad, slightly short, and in the valgus position. Genu varum and genu valgum were described in 4 individuals.
Inheritance
The transmission pattern of SED in the families reported by Leroy et al. (2004) was consistent with autosomal recessive inheritance.
INHERITANCE \- Autosomal recessive GROWTH Height \- Short trunk short stature (<3rd - 50th percentile) CHEST External Features \- Pectus carinatum SKELETAL \- Spondyloepiphyseal dysplasia, mild Spine \- Lumbar hyperlordosis \- Scoliosis \- Thoracic kyphosis \- Flattened vertebral bodies \- Irregular vertebral endplates \- Narrow intervertebral spaces Pelvis \- Decreased hip abduction \- Broad femoral neck \- Flattened capital femoral epiphyses Limbs \- Genua vara \- Genua valga MISCELLANEOUS \- Onset late childhood ▲ Close
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*[AA]: Adrenergic agonist
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*[nM]: nanomolars
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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
| SPONDYLOEPIPHYSEAL DYSPLASIA TARDA, AUTOSOMAL RECESSIVE, LEROY-SPRANGER TYPE | c1836584 | 2,608 | omim | https://www.omim.org/entry/609223 | 2019-09-22T16:06:29 | {"mesh": ["C563772"], "omim": ["609223"]} |
Fournier gangrene refers to the death of body tissue of the genitals and/or perineum. Signs and symptoms of the condition include genital pain, tenderness, redness, and swelling with a rapid progression to gangrene. Although the condition can affect men and women of all ages, it is most commonly diagnosed in adult males. Most cases of Fournier gangrene are caused by an infection in the genital area or urinary tract. People with impaired immunity (i.e. due to diabetes or HIV) have an increased susceptibility to the condition. Treatment generally includes surgery and medications such as antibiotics and/or antifungal therapy.
*[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
| Fournier gangrene | c0238419 | 2,609 | gard | https://rarediseases.info.nih.gov/diseases/10912/fournier-gangrene | 2021-01-18T18:00:26 | {"mesh": ["D018934"], "synonyms": ["Fournier's gangrene"]} |
A number sign (#) is used with this entry because of evidence that hypotrichosis, or woolly hair with or without hypotrichosis, can be caused by homozygous or compound heterozygous mutation in the P2RY5 gene (LPAR6; 609239) on chromosome 13q14.
Description
Hypotrichosis simplex refers to a group of hereditary isolated alopecias characterized by diffuse and progressive hair loss, usually beginning in early childhood (Pasternack et al., 2008). Localized autosomal recessive hypotrichosis (LAH) is characterized by fragile hairs that break easily, leaving short, sparse scalp hairs. The disorder affects the trunk and extremities as well as the scalp, and the eyebrows and eyelashes may also be involved, whereas beard, pubic, and axillary hairs are largely spared. In addition, patients can develop hyperkeratotic follicular papules, erythema, and pruritus in affected areas (summary by Schaffer et al., 2006).
Woolly hair (WH) refers to a group of hair shaft disorders that are characterized by fine and tightly curled hair. Compared to normal curly hair that is observed in some populations, WH grows slowly and stops growing after a few inches. Under light microscopy, WH shows some structural anomalies, including trichorrhexis nodosa and tapered ends (summary by Petukhova et al., 2009). Several families have been reported in which some affected individuals exhibit features of hypotrichosis and others have woolly scalp hair (Khan et al., 2011).
Woolly hair is also a feature of several syndromes, such as Naxos disease (601214) and cardiofaciocutaneous syndrome (115150) (Petukhova et al., 2009), or the palmoplantar keratoderma and cardiomyopathy syndrome (601214) (Carvajal-Huerta, 1998).
### Genetic Heterogeneity of Hypotrichosis and Woolly Hair
For a discussion of genetic heterogeneity of nonsyndromic hypotrichosis, see HYPT1 (605389).
For a discussion of genetic heterogeneity of localized hypotrichosis, see LAH1 (HYPT6; 607903).
Another form of autosomal recessive woolly hair with or without hypotrichosis (ARWH2; 604379) is caused by mutation in the LIPH gene (607365) and is allelic to autosomal recessive localized hypotrichosis (LAH2). ARWH3 (616760) is caused by mutation in the KRT25 gene (616646) on chromosome 17q21.
An autosomal dominant form of woolly hair with hypotrichosis (HYPT13; 615896) is caused by mutation in the KRT71 gene (608245) on chromosome 12q13. Another autosomal dominant form of woolly hair (ADWH; 194300) with normal hair density is caused by mutation in the KRT74 gene (608248) on chromosome 12q13, and is allelic to an autosomal dominant form of hypotrichosis simplex of the scalp (HYPT3; 613981) as well as an ectodermal dysplasia of the hair/nail type (ECTD7; 614929).
Clinical Features
In addition to the better known autosomal dominant form of woolly hair (194300), Hutchinson et al. (1974) suggested the existence of a recessive form. The hair is blond and the diameter of the hair shaft is reduced. All the cases to that time had, it seemed, been sporadic, and the recessive hypothesis was suggested by the parents of 1 patient being second cousins.
Wali et al. (2007) described 2 related consanguineous Pakistani families in which 10 men and 6 women demonstrated typical features of hereditary hypotrichosis, including absent to sparse scalp hair, eyebrows, eyelashes, axillary hair, and body hair. At birth, scalp hair was present but regrew sparsely following ritual shaving, which occurred at 1 week of age. Affected males had sparse beards. Teeth, nails, sweating, and hearing were normal in all affected family members.
Shimomura et al. (2008) identified several Pakistani families that included consanguineous marriages and had multiple individuals showing features consistent with recessively inherited woolly hair that was present at birth. The hair over the entire scalp region was coarse, lusterless, dry, and tightly curled, leading to a diffuse woolly hair phenotype with varying degrees of hypotrichosis or sparse hair. Most of the plucked hairs showed dystrophic features without root sheath components in the bulb portion. Eyebrow, eyelash, and beard hairs appeared normal. Affected individuals in all families showed normal teeth, nails, and sweating and did not show palmoplantar hyperkeratosis or keratosis pilaris.
Shimomura et al. (2008) identified several consanguineous Pakistani families segregating autosomal recessive woolly hair with variable hypotrichosis. In affected individuals, woolly hair was present at birth, and the hair over the entire scalp region was coarse, lusterless, dry, and tightly curled, leading to a diffuse woolly hair phenotype with varying degrees of hypotrichosis or sparse hair. Most of the plucked hairs showed dystrophic features without root sheath components in the bulb portion. Eyebrow, eyelash, and beard hairs appeared normal. Affected individuals in all families showed normal teeth, nails, and sweating and did not show palmoplantar hyperkeratosis or keratosis pilaris.
Pasternack et al. (2008) studied a consanguineous Saudi Arabian family in which 4 of 10 sibs presented with progressive hair loss, thinning of scalp hair since early childhood (3 to 6 years), and sparse body hair. The oldest and the youngest of the affected individuals were almost completely bald. Eyebrows, eyelashes, and pubic and axillary hair were normal in all but 1 individual; the oldest affected sib showed a mild thinning of the eyebrows. This family had been described in detail by Al Aboud et al. (2002).
Azeem et al. (2008) reported 14 Pakistani families with LAH3. Affected individuals had sparse or absent scalp hair, sparse eyebrows and eyelashes, and sparse axillary and body hair. Affected adult males had normal beard hair. Teeth, nails, and sweating were normal in all affected individuals. Scalp skin biopsy from 1 affected individual revealed the complete absence of normal hair follicle structures and comedo-like remnants of the hair follicle. The remnants of the hair follicle infundibulum showed hyperkeratinization. Sebaceous glands appeared morphologically normal but had lost connections to the remnants of the hair follicle infundibulum.
Nahum et al. (2010) identified a consanguineous family of Turkish extraction with autosomal recessive hypotrichosis. The proband was born with normal hair that, over the first year of life, progressively became thin, sparse, short, and fair. Sparse eyebrows and eyelashes and nail pitting and longitudinal ridging were also present. Under light microscopy, dystrophic hair shafts with irregular cuticles and banding were seen. Teeth and sweating were normal, hyperkeratosis was absent, and there were no other skin, neurologic, skeletal, or cardiac abnormalities. His younger brother and sister had similar symptoms. An older sister and both parents had normal hair. The family history included hypotrichosis in a maternal cousin.
Khan et al. (2011) studied 17 families with the hypotrichosis/woolly hair phenotype belonging to different ethnic groups living in Pakistan. At birth, affected individuals had sparse scalp hair. Affected members of 8 of the families had features of hypotrichosis, with sparse fragile hair on the scalp and sparse to absent eyebrows, eyelashes, and axillary, pubic, and body hair. Affected members of 6 other families exhibited features of woolly hair on the scalp and sparse to absent hair on the rest of the body. In the remaining 3 families, some affected individuals had features of hypotrichosis whereas others had woolly scalp hair. All male members in all 17 families had normal hair in the beard and mustache area.
Inheritance
Localized hypotrichosis-3 is an autosomal recessive disorder (Wali et al., 2007; Pasternack et al., 2008), as is the ARWH1 phenotype (Shimomura et al., 2008).
Mapping
Using polymorphic microsatellite markers in a genome scan of the Pakistani families segregating hereditary hypotrichosis, Wali et al. (2007) mapped the locus for the disorder on chromosome 13q14.11-q21.32, with a maximum 2-point lod score of 4.79. Haplotype analysis defined a 17.35-cM linkage interval flanked by markers D13S325 and D13S1231.
Using homozygosity mapping and linkage studies in a consanguineous Pakistani family, Shimomura et al. (2008) mapped a woolly hair phenotype to chromosome 13q14.2-q14.3.
Using homozygosity mapping in a consanguineous Saudi Arabian family, Pasternack et al. (2008) mapped an autosomal recessive form of hypotrichosis to 13q14.11-q21.33. They noted that the critical interval overlapped the hypotrichosis simplex-associated region mapped by Wali et al. (2007).
Using homozygosity mapping, Nahum et al. (2010) determined that the hypotrichosis phenotype in affected members of a consanguineous Turkish family was linked to the region surrounding the LPAR6 (P2RY5) gene (609239) on chromosome 13q.
Molecular Genetics
Shimomura et al. (2008) sequenced genes in the critical mapping region related to autosomal recessive woolly hair and found pathogenic mutations in P2RY5 (609239), which encodes a G protein-coupled receptor and is a nested gene residing within intron 17 of the RB1 gene (614041). P2RY5 is expressed in both the Henle and the Huxley layers of the inner root sheath of the hair follicle. In 2 of 6 families different mutations predicted to result in frameshift and premature termination were found. In the remaining 4 families, 3 missense mutations were found.
In a consanguineous Saudi Arabian family with hypotrichosis simplex, Pasternack et al. (2008) identified a homozygous truncating mutation in the P2RY5 (LPAR6) gene (609239.0001), which encodes a G protein-coupled receptor. They detected an additional homozygous truncating mutation in P2RY5 (609239.0002) in 2 other affected families.
In 6 Pakistani families with woolly hair and hair density that varied from normal to sparse, Shimomura et al. (2008) sequenced genes in the critical mapping region related to autosomal recessive woolly hair and found homozygosity for pathogenic mutations in the P2RY5 gene in all 6 families (see, e.g., 609239.0003; 609239.0004; 609239.0006). Immunofluorescence analysis of human hair follicles showed that P2RY5 is expressed in both the Henle and the Huxley layers of the inner root sheath of the hair follicle. In 2 of 6 families different mutations predicted to result in frameshift and premature termination were found; in the remaining 4 families, 3 missense mutations were found.
In affected individuals from 14 Pakistani families with LAH3, Azeem et al. (2008) identified 7 different homozygous mutations in the P2RY5 gene (see, e.g., 609239.0003; 609239.0005; 609239.0006). Three of the mutations had been reported by Shimomura et al. (2008) in individuals with woolly hair. However, none of the individuals reported by Azeem et al. (2008) had the woolly hair phenotype.
In affected members of a consanguineous Turkish family segregating localized hypotrichosis, Nahum et al. (2010) identified homozygosity for a missense mutation in the LPAR6 (P2RY5) gene (P196L; 609239.0007). The mutation segregated with the disease in the family and was absent from 100 population-matched controls. Nahum et al. (2010) noted that mutations in LIPH (607365) result in impaired signaling through LPAR6 and in a phenotype (LAH2; 604379) indistinguishable from that displayed by individuals carrying mutations in LPAR6.
Khan et al. (2011) performed microsatellite genotyping in 17 Pakistani families with the hypotrichosis/woolly hair phenotype and found linkage to the LIPH gene in 9 families (see HYPT7, 604379) and to the LPAR6 gene in 8 families. Sequence analysis of LPAR6 in the 8 linked families revealed 4 recurrent homozygous mutations (see, e.g., 609239.0003-609239.0005), in families with hypotrichosis, woolly hair with or without hypotrichosis, or a mixed phenotype. Khan et al. (2011) observed no difference in severity of hair loss in patients carrying different mutations in either LIPH or LPAR6, and there were no clear genotype/phenotype correlations.
Nomenclature
Wali et al. (2007) noted that this form of autosomal recessive hypotrichosis is clinically similar to 2 other forms of hereditary hypotrichosis: LAH, mapped to chromosome 18q, and AH, mapped to chromosome 3q27. They proposed that the LAH locus be renamed as LAH1 (607903), the AH locus as LAH2 (604379), and the locus identified in their families on chromosome 13q as LAH3.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Sparse eyebrows (in some patients) \- Sparse eyelashes (in some patients) Teeth \- Normal teeth SKIN, NAILS, & HAIR Skin \- Normal sweating \- Normal sweating Skin Histology \- Absent root sheath components in bulb portion of plucked hair \- Comedo-like remnant hair follicles Nails \- Normal nails (in most patients) \- Pitted nails (rare) \- Longitudinal ridging (rare) Hair \- Normal hair at birth (in some patients) \- Beard and moustache hair normal (in most patients) \- Hair stops growing at a few inches \- Hypotrichosis, varying degrees of \- Sparse scalp hair (in some patients) \- Sparse to absent eyebrows (in some patients) \- Sparse to absent eyelashes (in some patients) \- Sparse to absent axillary hair (in some patients) \- Sparse to absent body hair (in some patients) \- Coarse hair (in some patients) \- Tightly curled or woolly hair (in some patients) \- Dry hair (in some patients) \- Fair/blond hair (in some patients) \- Small hair shaft diameter \- Irregular cuticles on hair shafts \- Twisted hair shaft \- Tapered distal end of hair \- Banded hair shafts \- HISTOLOGY: \- Absent root sheath components in bulb portion of plucked hair \- Comedo-like remnant hair follicles MISCELLANEOUS \- Variable phenotype within families ranging from woolly hair to hypotrichosis MOLECULAR BASIS \- Caused by mutation in the lysophosphatidic acid receptor 6 gene (P2RY5, 609239.0001 ) ▲ Close
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*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| HYPOTRICHOSIS 8 | c1854310 | 2,610 | omim | https://www.omim.org/entry/278150 | 2019-09-22T16:21:09 | {"doid": ["0110705"], "mesh": ["C537160"], "omim": ["278150"], "orphanet": ["55654", "170"], "synonyms": ["Alternative titles", "HYPOTRICHOSIS, LOCALIZED, AUTOSOMAL RECESSIVE 3"]} |
A rare, potentially fatal , epileptic encephalopathy characterized by explosive-onset of recurrent multifocal and bilateral tonic-clonic seizures following an unspecific febrile illness. The syndrome develops without a clear acute structural, toxic or metabolic cause, in a patient without previous epilepsy. FIRES is a subgroup of new-onset refractory status epilepticus (NORSE), and requires a preceding febrile infection as a mandatory feature.
## Epidemiology
In Germany, the prevalence is estimated at 1/100,000 and annual incidence at 1/1,000,000 in children and adolescents. For adults, prevalence and incidence are unknown. In pediatric cases there is a male predominance, while females seem to be more frequently affected in adulthood. Familial cases have not been reported.
## Clinical description
Febrile infection-related epilepsy syndrome (FIRES) is most common in school-age children. Typically, a previously healthy individual manifests with a sudden onset of recurrent multifocal and bilateral tonic-clonic seizures, following an unspecific febrile illness. Refractory, and usually superrefractory, status epilepticus develops. The acute phase can last for weeks or months. A chronic phase follows, without a latent period, characterized by refractory focal epilepsy along with, often severe, impairments in memory, cognition and behavior. Motor disability is less common.
## Etiology
The etiology is not fully known. Most likely FIRES is an immune-inflammatory-mediated epileptic encephalopathy, with a vicious circle of inflammation and hyperexcitability. Findings in cerebrospinal fluid (CSF), and the poor response to immune therapies, point to the innate immune system and autoinflammatory rather than autoimmune mechanisms. Variants in known epilepsy genes do not seem to predispose to FIRES.
## Diagnostic methods
An extensive work-up is needed to exclude treatable conditions. Initial magnetic resonance imaging is normal or shows temporal lobe signal abnormalities. Diffuse brain atrophy and mesial temporal lobe changes are common in the chronic phase. Analysis of CSF shows normal findings or mild pleocytosis but no presence of pathogens and usually no oligoclonal bands or neuronal antibodies. Metabolic investigations are negative. Genetic investigations to exclude genetic epilepsies such as those related to POLG. Continuous electroencephalogram (cEEG) is required to monitor seizures and depth of anesthesia. Beta-delta complexes resembling extreme delta brush is recorded in some patients in the early phase.
## Differential diagnosis
Differential diagnoses include, but are not limited to, infectious or autoimmune encephalitis (e.g. anti-NMDAR encephalitis and other antineuronal antibody-related encephalitides, acute disseminated encephalomyelitis), primary angiitis of the central nervous system, acute necrotizing encephalopathy, other infection-induced encephalopathies, metabolic diseases (e.g. mitochondrial disorders, citrillunemia, thiamin metabolism disorders) and genetic epilepsies (e.g. Dravet syndrome, PCDH19 epilepsy).
## Management and treatment
Monitoring in intensive care during the acute phase is mandatory. Anti-seizure medications are often ineffective. High-dose benzodiazepines can have a transient efficacy. Usually, general anesthesia with barbiturates (titrated to burst suppression) are needed to stop seizures, even if prolonged burst-suppression can be associated with a worse cognitive outcome. Recurrence is common on awakening, necessitating repeated anesthesia. Immune therapy is usually disappointing but anakinra or tocilizumab has been highly effective in a few cases. So far, the ketogenic diet has seemed most beneficial, especially if initiated early, but no controlled trials exist. Ketamine, inhalation anesthetics, cannabidiol, hypothermia and neurostimulation have shown transient efficacy in a few cases.
## Prognosis
FIRES has a poor prognosis with a high risk of chronic drug-resistant epilepsy and significant cognitive impairment, but a few patients have fully recovered. The mortality rate is around 12% in children.
* European Reference Network
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Febrile infection-related epilepsy syndrome | c4049262 | 2,611 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=163703 | 2021-01-23T18:44:42 | {"gard": ["11005"], "icd-10": ["G40.5"], "synonyms": ["AERRPS", "Acute encephalitis with refractory repetitive partial seizures", "Acute non-herpetic encephalitis with severe refractory status epilepticus", "DESC syndrome", "Devastating epileptic encephalopathy in school-aged children", "FIRES", "Fever-induced refractory epileptic encephalopathy in school-aged children", "Idiopathic catastrophic epileptic encephalopathy", "Severe refractory status epilepticus owing to presumed encephalitis"]} |
Progressive encephalopathy with leukodystrophy due to DECR deficiency is a rare mitochondrial disease, which presents with neonatal hypotonia, central nervous system abnormalities (ventriculomegaly, corpus callosum hypoplasia, cerebellar atrophy), acquired microcephaly, failure to thrive, developmental delay and intermittent lactic acidosis provoked by catabolic stress (e.g. infection). Hyperlysinemia and elevated C10:2 carnitine can be detected in plasma. Later on, epilepsy, cerebellar ataxia, renal tubular acidosis, severe encephalopathy, dystonia, spastic quadriplegia and other complications may develop.
*[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
| Progressive encephalopathy with leukodystrophy due to DECR deficiency | c1857252 | 2,612 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=431361 | 2021-01-23T19:09:52 | {"gard": ["10327"], "mesh": ["C565624"], "omim": ["616034"], "umls": ["C1857252"], "icd-10": ["G31.8"], "synonyms": ["2,4-dienoyl-CoA reductase deficiency", "DECR deficiency with hyperlysinemia"]} |
Schwannoma
Other namesneurilemoma,[1]:621 neuroma,[2] neurolemoma,[2] Schwann cell tumor[2]
Micrograph of a schwannoma showing both a cellular Antoni A area (top) and a loose paucicellular Antoni B area (bottom). HE stain.
SpecialtyOncology
A schwannoma is a usually benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves.
## Contents
* 1 Overview
* 2 Gallery
* 3 See also
* 4 References
* 5 External links
## Overview[edit]
Schwannomas are homogeneous tumors, consisting only of Schwann cells. The tumor cells always stay on the outside of the nerve, but the tumor itself may either push the nerve aside and/or up against a bony structure (thereby possibly causing damage). Schwannomas are relatively slow-growing. For reasons not yet understood, schwannomas are mostly benign and less than 1% become malignant, degenerating into a form of cancer known as neurofibrosarcoma. These masses are generally contained within a capsule, so surgical removal is often successful.[3]
Schwannomas can be associated with neurofibromatosis type II, which may be due to a loss-of-function mutation in the protein merlin.[4] They are universally S-100 positive, which is a marker for cells of neural crest cell origin.
Schwannomas of the head and neck are a fairly common occurrence and can be found incidentally in 3–4% of patients at autopsy.[4] Most common of these is a vestibular schwannoma, a tumor of the vestibulocochlear nerve that may lead to tinnitus and hearing loss on the affected side. Outside the cranial nerves, schwannomas may present on the flexor surfaces of the limbs. Rare occurrences of these tumors in the penis have been documented in the literature.[5]
Verocay bodies are seen histologically in schwannomas.
## Gallery[edit]
* * * Subcutaneous schwannoma
* Antoni A area of schwannoma with Verocay bodies (one annotated by circle)
* * *
## See also[edit]
* Intranodal palisaded myofibroblastoma
* List of inclusion bodies that aid in diagnosis of cutaneous conditions
* Neurofibroma
* Palisaded encapsulated neuroma
## References[edit]
1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
2. ^ a b c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
3. ^ Biswas, Deb (September 2007). "Extracranial head and neck schwannomas—A 10-year review". Auris Nasus Larynx. 34 (3): 353–359. doi:10.1016/j.anl.2007.01.006. PMID 17376620.
4. ^ a b Hanemann, CO (December 2006). "News on the genetics, epidemiology, medical care and translational research of Schwannomas". Journal of Neurology. 253 (12): 1533–1541. doi:10.1007/s00415-006-0347-0. PMID 17219030.
5. ^ Nguyen, Austin Huy; Smith, Megan; Maranda, Eric; Punnen, Sanoj (24 December 2015). "Clinical Features and Treatment of Penile Schwannoma: A Systematic Review". Clinical Genitourinary Cancer. 14 (3): 198–202. doi:10.1016/j.clgc.2015.12.018. PMID 26797586.
## External links[edit]
Classification
D
* ICD-10: C72.4
* ICD-9-CM: 225.1
* ICD-O: M9560/0
* MeSH: D009442
* DiseasesDB: 33713
* v
* t
* e
Tumours of the nervous system
Endocrine
Sellar:
* Craniopharyngioma
* Pituicytoma
Other:
* Pinealoma
CNS
Neuroepithelial
(brain tumors,
spinal tumors)
Glioma
Astrocyte
* Astrocytoma
* Pilocytic astrocytoma
* Pleomorphic xanthoastrocytoma
* Subependymal giant cell astrocytoma
* Fibrillary astrocytoma
* Anaplastic astrocytoma
* Glioblastoma multiforme
Oligodendrocyte
* Oligodendroglioma
* Anaplastic oligodendroglioma
Ependyma
* Ependymoma
* Subependymoma
Choroid plexus
* Choroid plexus tumor
* Choroid plexus papilloma
* Choroid plexus carcinoma
Multiple/unknown
* Oligoastrocytoma
* Gliomatosis cerebri
* Gliosarcoma
Mature
neuron
* Ganglioneuroma: Ganglioglioma
* Retinoblastoma
* Neurocytoma
* Dysembryoplastic neuroepithelial tumour
* Lhermitte–Duclos disease
PNET
* Neuroblastoma
* Esthesioneuroblastoma
* Ganglioneuroblastoma
* Medulloblastoma
* Atypical teratoid rhabdoid tumor
Primitive
* Medulloepithelioma
Meninges
* Meningioma
* Hemangiopericytoma
Hematopoietic
* Primary central nervous system lymphoma
PNS:
* Nerve sheath tumor
* Cranial and paraspinal nerves
* Neurofibroma
* Neurofibromatosis
* Neurilemmoma/Schwannoma
* Acoustic neuroma
* Malignant peripheral nerve sheath tumor
Other
* WHO classification of the tumors of the central nervous system
Note: Not all brain tumors are of nervous tissue, and not all nervous tissue tumors are in the brain (see brain metastasis).
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Schwannoma | c0027809 | 2,613 | wikipedia | https://en.wikipedia.org/wiki/Schwannoma | 2021-01-18T19:04:09 | {"gard": ["4767"], "mesh": ["D009442"], "umls": ["C0027809"], "icd-9": ["225.8"], "icd-10": ["D36.1"], "wikidata": ["Q369148"]} |
A number sign (#) is used with this entry because osteogenesis type III (OI3) is caused by heterozygous mutation in one of the genes for type I collagen, COL1A1 (120150) or COL1A2 (120160).
Clinical Features
In Victoria, Australia, Sillence et al. (1979) found type III OI to be about one-eighth as frequent as dominantly inherited OI with blue sclerae. Scleral hue, which may be bluish at birth, usually normalizes with age. Patients reported in the literature with normal sclerae have shown progressive deformity of the limbs in childhood and of the spine in late childhood and adolescence. Dentinogenesis imperfecta is particularly striking, especially in the primary dentition. Sillence et al. (1979) observed 2 families with consanguineous parents. Some of the cases referenced in 166210 presumably represent this type.
Peltonen et al. (1980) studied procollagen synthesis by fibroblasts from a male patient who died at age 18 years after a fall from his wheelchair. He was born with multiple fractures. He had blue sclerae, but normal dentition. He developed severe kyphoscoliosis and multiple limb deformities. Whether this represented Sillence's type III OI or new mutation for Sillence's type I OI (166200) was not clear. When fibroblasts were incubated with tritiated-mannose, type I procollagen contained 2 to 3 times more labeled-mannose than that from normal fibroblasts, although type III procollagen produced simultaneously by the patient's fibroblasts was not abnormal. The type I collagen synthesized by the patient's fibroblasts was secreted into the medium abnormally slowly. The patient's procollagen formed insoluble aggregates with abnormal facility. The findings were interpreted as indicating an amino acid change, presumably in the COOH-terminal propeptide because this was the site of the mannose, which altered the protein's glycosylation. Unfortunately, it was not possible to study the collagen of the parents of this case; this might have permitted conclusions as to whether the patient was homozygous for an amino acid substitution or heterozygous.
Nicholls et al. (1979, 1984) described absence of alpha-2 chains in a child of a third-cousin marriage who they suggested had Sillence type III OI, although the sclerae were described as 'significantly blue.' Type I collagen consisted only of alpha-1 chains, i.e., was an alpha-1 trimer. The child had remarkably mild manifestations. The first recognized fracture, of the humerus, occurred at age 5 weeks. Following another break 2 weeks later, x-rays showed normal width of bones with signs of several earlier fractures. Nicholls et al. (1984) concluded that the child was homozygous for an abnormal pro-alpha-2(I) chain (120160) which does not associate with pro-alpha-1(I) chains and therefore is not incorporated into triple helical trimers of type I procollagen. In a child with type III OI, Pope et al. (1985) showed an abnormality of the alpha-2 chain of type I collagen, specifically a 4-bp deletion which led to frame shift at the carboxyl end of the protein. Because of this, the normal type I helix could not be assembled and the alpha-2 gene product was degraded intracellularly.
Tenni et al. (1988) reported a male infant with type III OI in whom biochemical analysis of the alpha-1(I) chains was consistent with a mutation towards the C-terminus of the triple helix or within the C-propeptide.
Byers et al. (2006) published practice guidelines for the genetic evaluation of suspected OI.
Heterogeneity
Among 345 pedigrees with OI, Sillence et al. (1986) found 7 that had autosomal recessive inheritance suggested by segregation pattern or parental consanguinity and answering to the other criteria of type III OI: normal sclerae and teeth, fractures or deformability present from birth. They described 'popcorn calcification' in the growth plates found radiographically in OI III, but not specific for this form of OI or indeed for any form of OI, being seen also in Strudwick spondylometaepiphyseal dysplasia (184250), Jansen metaphyseal dysplasia (156400), and parastremmatic dysplasia (168400). They concluded that OI III is probably heterogeneous.
Population Genetics
Beighton and Versfeld (1985) suggested that type III OI is relatively high in the black population of South Africa. The high frequency did not seem to be limited to one tribe. Whereas in Australian whites the ratio of OI I to OI III is about 7 to 1 (Sillence et al., 1979), in South African blacks it is about 1 to 6. The authors cited a report of a relatively high frequency of OI III in Nigeria. In Zimbabwe, Viljoen and Beighton (1987) identified 58 cases of OI in institutions for crippled persons; 42 of the patients had the rare OI type III. The Shona and the Ndebele, both major tribal groups, had a similar and relatively high gene frequency for this disorder. Both tribes were derived from common progenitors, but until 150 years earlier had been geographically separated for 2 millennia; they remain culturally and socially distinct. Viljoen and Beighton (1987) inferred that the mutation for OI III in Africa occurred at least 2000 years ago.
Molecular Genetics
Starman et al. (1989) reported a family in which the OI III phenotype was caused by a dominant mutation in the COL1A1 gene that resulted in substitution of cysteine for glycine at position 526 of the triple helix (120150.0005). This and other experience suggested to Starman et al. (1989) that a significant proportion of individuals with the OI III phenotype have a dominant mutation which, in some families, is inherited. Pruchno et al. (1991) found a heterozygous de novo mutation, gly154-to-arg, in 2 unrelated individuals with a progressive deforming variety of OI compatible with OI type III (see 120150.0030). Dominant inheritance of OI III was also supported by Cohen-Solal et al. (1991), who found biochemical evidence of heterozygosity. The parents were nonconsanguineous. Parental gonadal mosaicism was presumed. Molyneux et al. (1993) also presented molecular evidence of heterozygosity for a new dominant mutation in a child with progressive deforming OI. They concluded with the statement that 'in the majority of instances, the phenotype results from heterozygosity for mutations in one of the genes that encode chains of type I collagen.'
De Paepe et al. (1997) identified homozygosity for a gly751-to-ser mutation of the COL1A2 gene (120160.0039) in 2 sibs; the 2 parents, who were first cousins, and 2 other sibs were heterozygous and had manifestations consistent with type I OI (166200).
Cabral et al. (2001) reported a 13-year-old girl with severe type III OI in whom they identified heterozygosity for a gly76-to-glu substitution in the COL1A1 gene (120150.0065). The authors stated that this was the first delineation of a glutamic acid substitution in the alpha-1(I) chain causing nonlethal osteogenesis imperfecta.
Autosomal dominant inheritance of OI type III is represented by a family in which the affected member of the first generation had molecularly proven mosaicism for a heterozygous 562-bp deletion in the COL1A1 gene (120150.0054) (Cabral and Marini, 2004).
Genotype/Phenotype Correlations
Faqeih et al. (2009) reported 3 unrelated patients with OI type III, brachydactyly, and intracranial hemorrhage, 1 of whom was previously described by Cole and Lam (1996), who all had glycine mutations involving exon 49, in the most C-terminal part of the triple helical domain of COL1A2 (120160.0037, 120160.0054, and 120160.0055, respectively). Faqeih et al. (2009) suggested that mutations in this region of COL1A2 carry a high risk of abnormal limb development and intracranial bleeding.
Clinical Management
Plotkin et al. (2000) studied 9 severely affected OI patients under 2 years of age (2.3 to 20.7 months at entry), 8 of whom had type III OI and 1 of whom had type IV OI (166220), for a period of 12 months. Pamidronate was administered intravenously in cycles of 3 consecutive days. Patients received 4 to 8 cycles during the treatment period, with cumulative doses averaging 12.4 mg/kg. Clinical changes were evaluated regularly during treatment, and radiologic changes were assessed after 6 to 12 months of treatment. The control group consisted of 6 age-matched, severely affected OI patients who had not received pamidronate treatment. During treatment bone mineral density (BMD) increased between 86% and 227%. The deviation from normal, as indicated by the z-score, diminished from -6.5 +/- 2.1 to -3.0 +/- 2.1 (P less than 0.001). In the control group, the BMD z-score worsened significantly. Vertebral coronal area increased in all treated patients (11.4 +/- 3.4 to 14.9 +/- 1.8 cm2; P less than 0.001), but decreased in the untreated group (P less than 0.05). In the treated patients, fracture rate was lower than in control patients (2.6 +/- 2.5 vs 6.3 +/- 1.6 fractures/year; P less than 0.01). No adverse side effects were noted, apart from the well-known acute phase reaction during the first infusion cycle. The authors concluded that pamidronate treatment in severely affected OI patients under 3 years of age is safe, increases BMD, and decreases fracture rate.
Astrom and Soderhall (2002) performed a prospective observational study using disodium pamidronate (APD) in 28 children and adolescents (aged 0.6 to 18 years) with severe OI or a milder form of the disease, but with spinal compression fractures. All bone metabolism variables in serum (alkaline phosphatase, osteocalcin, procollagen-1 C-terminal peptide, collagen-1 teleopeptide) and urine (deoxypyridinoline) indicated that there was a decrease in bone turnover. All patients experienced beneficial effects, and the younger patients showed improvement in well-being, pain, and mobility without significant side effects. Vertebral remodeling was also seen. They concluded that APD seemed to be an efficient symptomatic treatment for children and adolescents with OI.
Rauch et al. (2002) compared parameters of iliac bone histomorphometry in 45 patients (23 girls, 22 boys) with OI type I, III, or IV before and after 2.4 +/- 0.6 years of treatment with cyclical intravenous pamidronate (age at the time of the first biopsy, 1.4 to 17.5 years). There was an increase in bone mass due to increases in cortical width and trabecular number. The bone surface-based indicators of cancellous bone remodeling, however, were decreased. There was no evidence of a mineralization defect in any of the patients.
Lindsay (2002) reviewed the mechanism, effects, risks, and benefits of bisphosphonate therapy in children with OI. He stated that the clinical course and attendant morbidity for many children with severe OI is clearly improved with its judicious use. Nevertheless, since bisphosphonates accumulate in the bone and residual levels are measurable after many years, the long-term safety of this approach was unknown. He recommended that until long-term safety data were available, pamidronate intervention be reserved for those for whom the benefits clearly outweighed the risks.
Rauch et al. (2003) evaluated the effect of cyclic intravenous therapy with pamidronate on bone and mineral metabolism in 165 patients with OI types I, III, and IV. All patients received intravenous pamidronate infusions on 3 successive days, administered at age-dependent intervals of 2 to 4 months. During the 3 days of the first infusion cycle, serum concentrations of ionized calcium dropped and serum PTH levels transiently almost doubled. Two to 4 months later, ionized calcium had returned to pretreatment levels. During 4 years of pamidronate therapy ionized calcium levels remained stable, but PTH levels increased by about 30%. In conclusion, serum calcium levels can decrease considerably during and after pamidronate infusions, requiring close monitoring especially at the first infusion cycle. In long-term therapy, bone turnover is suppressed to levels lower than those in healthy children. The authors stated that consequences of chronically low bone turnover in children with OI were unknown.
Zeitlin et al. (2003) analyzed longitudinal growth during cyclical intravenous pamidronate treatment in children and adolescents (ages .04 to 15.6 years at baseline) with moderate to severe forms of OI types I, III, and IV and found that 4 years of treatment led to a significant height gain.
Rauch et al. (2006) studied the effect of pamidronate discontinuation in pediatric patients with moderate to severe OI types I, III, and IV. In the controlled study, 12 pairs of patients were matched for age, OI severity, and duration of pamidronate treatment. Pamidronate was stopped in one patient of each pair; the other continued to receive treatment. In the observational study, 38 OI patients were examined (mean age, 13.8 years). The intervention was discontinuation of pamidronate treatment for 2 years. The results indicated that bone mass gains continue after treatment is stopped, but that lumbar spine areal bone mineral density (aBMD) increases less than in healthy subjects. The size of these effects is growth dependent.
In a cohort of 540 individuals with OI studied longitudinally, Bellur et al. (2016) conducted a study to address whether cesarean delivery has an effect on at-birth fracture rates and whether an antenatal diagnosis of OI influences the choice of delivery method. They compared self-reported at-birth fracture rates among individuals with OI types I, III, and IV. When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was vaginal or by cesarean section. Increased birth weight conferred conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing cesarean delivery. The authors recommended that cesarean delivery should not be performed for the sole purpose of fracture prevention in OI, but only for other maternal or fetal indications.
### Gene Therapy
Chamberlain et al. (2004) used adeno-associated virus vectors to disrupt dominant-negative mutant COL1A1 (120150) collagen genes in mesenchymal stem cells, also known as marrow stromal cells, from individuals with severe OI, demonstrating successful gene targeting in adult human stem cells.
INHERITANCE \- Autosomal dominant GROWTH Height \- Short limb dwarfism recognizable at birth \- Adult height 92-108 cm HEAD & NECK Face \- Triangular face \- Frontal bossing \- Micrognathia Ears \- Hearing loss Eyes \- Blue sclerae at birth becoming normal with age Teeth \- Dentinogenesis imperfecta (both primary and secondary teeth) RESPIRATORY Lung \- Pulmonary hypertension CHEST Ribs Sternum Clavicles & Scapulae \- Thin gracile ribs SKELETAL \- Severe, generalized osteoporosis \- Multiple fractures present at birth Skull \- Wormian bones \- Large anterior fontanelle \- Undermineralized calvarium Spine \- Scoliosis \- Kyphosis \- Codfish vertebrae Pelvis \- Protrusio acetabuli Limbs \- Long bone deformity evident at birth or in the first 2 years of life \- Bowing of limbs due to multiple fractures \- Thin gracile long bones \- Tibial bowing \- Short deformed femurs \- Evidence of in utero fracture \- "Popcorn" calcification NEUROLOGIC Central Nervous System \- Basilar impression MISCELLANEOUS \- Some mutations have been found in homozygosity and the phenotype is more severe than that of the heterozygous parents MOLECULAR BASIS \- Caused by mutation in the collagen I, alpha-1 polypeptide gene (COL1A1, 120150.0005 ) \- Caused by mutation in the collagen I, alpha-2 polypeptide gene (COL1A2, 120160.0005 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| OSTEOGENESIS IMPERFECTA, TYPE III | c0268362 | 2,614 | omim | https://www.omim.org/entry/259420 | 2019-09-22T16:23:53 | {"doid": ["0110339"], "mesh": ["C536044"], "omim": ["259420"], "orphanet": ["216812", "666"], "synonyms": ["Alternative titles", "OI, TYPE III", "OSTEOGENESIS IMPERFECTA, PROGRESSIVELY DEFORMING, WITH NORMAL SCLERAE"], "genereviews": ["NBK1295"]} |
A rare, genetic form of pontocerebellar hypoplasia characterized by pontocerebellar hypoplasia and progressive neocortical atrophy that manifests clinically with uncoordinated sucking and swallowing, and generalized clonus in the neonate. In early childhood, spasticity, chorea/dyskinesia, seizures and progressive microcephaly develop. Voluntary motor development is lacking.
## Epidemiology
Pontocerebellar hypoplasia type 2 (PCH2) is reported in at least 81 families to date. It is the most common form of pontocerebellar hypoplasia.
## Clinical description
After an uneventful pregnancy and birth without dysmorphic features, affected neonates present usually, but not always, with dysphagia due to bucco-pharyngeal incoordination, respiratory and feeding difficulties and generalized clonus. Extrapyramidal dyskinesia with mixed spasticity such as chorea, athetosis and dystonia develop later. From infancy onward, affected children develop progressive microcephaly, central visual impairment, seizures and a severe impairment of cognitive and motor development, marked by an impaired motor development with failing head control, lack of voluntary hand control and the absence of speech and communication. PCH2 is often fatal in early childhood.
## Etiology
PCH2 is generally caused by homozygous mutations in the TSEN54 gene (17q25.1), most frequently a founder mutation, prevalent in families of European extraction: p.A307S/A307S or and missense mutations. Rarely mutations in the TSEN2 (3p25.2), TSEN34 (19q13.42), TSEN15 (1q25.3),
## Diagnostic methods
Diagnosis is made is based on a combination of neuroradiologic and clinical findings : MRI demonstrates variable neocortical atrophy, progressive in time, flattening of the caudate nuclear heads, and pontocerebellar hypoplasia with a typical dragonfly-like cerebellar pattern on coronal sections caused by the flat hemispheres heavily reduced in size together with a comparatively spared vermis. Genetic testing is recommended to confirm the diagnosis.
## Differential diagnosis
Due to phenotypic overlap, other subtypes of PCH should be considered, as well as mutations in the CASK gene. Congenital Disorder of Glycosylation type 1A (CDG1A) caused by mutations in the PMM2 gene can resemble PCH. Extreme prematurity (gestational age <32 weeks) can cause cerebellar hypoplasia of variable degrees.
## Antenatal diagnosis
In case of risk for recurrence of PCH2, genetic prenatal diagnosis, by amniocentesis or chorionic villus sampling and cytogenetic analysis, may be offered. Prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal testing or pre-implantation genetic diagnosis (PGD) should be offered.
## Genetic counseling
PCH2 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH2. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.
## Management and treatment
Treatment is symptomatic in PCH and involves medication for treatment of dystonia, dyskinesia and seizures and percutaneous endoscopic gastrostomy tube feeding.
## Prognosis
Prognosis is variable; the majority of patients will not reach puberty. Life threatening complications include sleep apnea, rhabdomyolysis and malignant hyperthermia. Cot death is possible.
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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
| Pontocerebellar hypoplasia type 2 | c2932714 | 2,615 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2524 | 2021-01-23T17:20:03 | {"gard": ["10705"], "mesh": ["C548070"], "omim": ["277470", "612389", "612390", "613811", "617026"], "umls": ["C2932714"], "icd-10": ["Q04.3"], "synonyms": ["PCH2"]} |
Microphthalmia-ankyloblepharon-intellectual disability syndrome is characterized by microphthalmia, ankyloblepharon and intellectual deficit. It has been described in seven male patients from two generations of a Northern Ireland family. The causative gene is localized to the Xq27-q28 region. The syndrome is transmitted as an X-linked recessive trait.
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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
| Microphthalmia-ankyloblepharon-intellectual disability syndrome | c1844948 | 2,616 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85275 | 2021-01-23T17:56:49 | {"gard": ["5066"], "mesh": ["C564457"], "omim": ["301590"], "umls": ["C1844948"], "icd-10": ["Q11.2"], "synonyms": ["MCOPS4", "Syndromic microphthalmia type 4"]} |
A number sign (#) is used with this entry because of evidence that selective tooth agenesis-3 (STHAG3) is caused by heterozygous mutation in the PAX9 gene (167416) on chromosome 14q13.
For a general phenotypic description and a discussion of genetic heterogeneity of selective tooth agenesis, see STHAG1 (106600).
Clinical Features
Stockton et al. (2000) studied a family segregating a seemingly unique form of oligodontia in an autosomal dominant manner. The affected individuals had normal primary dentition but lacked most permanent molars. Some individuals also lacked maxillary and/or mandibular second premolars as well as mandibular central incisors.
Frazier-Bowers et al. (2002) described a large family with autosomal dominant oligodontia. Affected individuals showed predominantly molar oligodontia but it was not limited to posterior teeth.
Lammi et al. (2003) described a Finnish family segregating autosomal dominant oligodontia with a distinct phenotype involving missing premolars, canines, and incisors in addition to permanent molars, as well as reduced size of both deciduous and permanent teeth. Several second premolars were missing, even though the neighboring first molars were present.
Mostowska et al. (2006) described a 3-generation family with severe autosomal dominant oligodontia. Those affected lacked all permanent molars, second premolars, and mandibular central incisors.
Inheritance
Selective tooth agenesis-3 is an autosomal dominant anomaly (Stockton et al., 2000; Frazier-Bowers et al., 2002).
Mapping
By a genomewide search using microsatellite markers spaced at an average interval of 10 cM throughout the autosomes in a family with oligodontia, Stockton et al. (2000) demonstrated a 2-point lod score of 6.83 at theta = 0.0 with marker D14S288, and the phenotype was localized to an 18.9-cM interval between D14S1060 and D14S276. PAX9 (167416) had previously been mapped to 14q12-q13 by fluorescence in situ hybridization and analysis of somatic cell hybrids. Using radiation hybrid mapping, Stockton et al. (2000) placed PAX9 within the nonrecombinant region for the oligodontia phenotype.
Molecular Genetics
Nieminen et al. (1995) excluded involvement of the MSX1 (142983) and MSX2 (123101) genes in some families with hypodontia involving both second premolars and lateral incisors.
In a family segregating autosomal dominant oligodontia, Stockton et al. (2000) identified heterozygosity for an insertion of a guanine at nucleotide 219 of the PAX9 gene (167416.0001) in affected individuals.
Das et al. (2002) noted that mutations in the PAX9 gene had been found to cause both oligodontia (e.g., 167416.0002) and hypodontia (e.g., 167416.0003). They suggested that the disorders may not be fundamentally different.
Frazier-Bowers et al. (2002) identified a novel insertion mutation in the PAX9 gene (167416.0010) in a large family with autosomal dominant oligodontia.
Lammi et al. (2003) identified a novel missense mutation in the PAX9 gene (167416.0008) in affected members of a Finnish family segregating autosomal dominant oligodontia.
Mostowska et al. (2006) detected a mutation in the PAX9 gene (167416.0012) in all affected individuals in a 3-generation family with severe autosomal dominant oligodontia.
In affected members of a family segregating molar oligodontia, Kapadia et al. (2006) identified a heterozygous missense mutation in the PAX9 gene (167416.0009). Based on functional studies of the mutant and wildtype proteins, Kapadia et al. (2006) suggested that the pathogenesis of oligodontia in this family involves a loss-of-function mechanism that contributes to haploinsufficiency of PAX9.
Genotype/Phenotype Correlations
Kim et al. (2006) analyzed the pattern of tooth agenesis in several kindreds with defined MSX1 and PAX9 mutations. They found that the probability of missing a particular type of tooth is always bilaterally symmetrical, but differences exist between the maxilla and mandible. MSX1-associated tooth agenesis (STHAG1; 106600) typically includes missing maxillary and mandibular second premolars and maxillary first premolars. The most distinguishing feature of MSX1-associated tooth agenesis is the frequent (75%) absence of maxillary first premolars, whereas the most distinguishing feature of PAX9-associated tooth agenesis is the frequent (over 80%) absence of maxillary and mandibular second molars.
Animal Model
Kist et al. (2005) described a hypomorphic Pax9 allele, which they termed Pax9-neo, producing decreased levels of Pax9 wildtype mRNA and showed that this caused oligodontia in mice. Homozygous Pax9 neo/neo mice exhibited hypoplastic or missing lower incisors and third molars. When combined with a Pax9 null allele, the Pax9 neo/null compound mutants developed severe forms of oligodontia. The missing molars were arrested at different developmental stages and posterior molars were consistently arrested at an earlier stage, suggesting that a reduction of Pax9 gene dosage may affect the dental field as a whole. Pax9 neo/neo and neo/null mice also showed defects in enamel formation of the continuously growing incisors, whereas molars exhibited increased attrition and reparative dentin formation.
INHERITANCE \- Autosomal dominant HEAD & NECK Teeth \- Normal primary dentition (in some patients) \- Agenesis of 6 or more permanent teeth \- Missing secondary dentition (including molars, premolars, or mandibular central incisors) \- Small teeth (in some patients) MOLECULAR BASIS \- Caused by mutation in the paired box gene 9 (PAX9, 176416 ) ▲ 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
| TOOTH AGENESIS, SELECTIVE, 3 | c1970291 | 2,617 | omim | https://www.omim.org/entry/604625 | 2019-09-22T16:11:51 | {"doid": ["0050591"], "mesh": ["C567036"], "omim": ["604625"], "orphanet": ["99798"], "synonyms": ["Alternative titles", "HYPODONTIA/OLIGODONTIA 3", "Selective tooth agenesis"]} |
Hypertension due to gain-of-function mutations in the mineralocorticoid receptor is a rare genetic hypertension characterized by a familial severe hypertension with an onset before age 20 years, associated with suppressed plasma renin and low aldosterone levels in the presence of low or normal levels of the mineralocorticoid aldosterone, that is highly resistant to antihypertensive medication. During pregnancy, there is a marked exacerbation of hypertension, accompanied by low serum potassium levels and undetectable aldosterone levels, but without signs of preeclampsia, requiring early delivery.
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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
| Hypertension due to gain-of-function mutations in the mineralocorticoid receptor | c1854631 | 2,618 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=88660 | 2021-01-23T19:06:02 | {"mesh": ["C565359"], "umls": ["C1854631"], "icd-10": ["I15.1"], "synonyms": ["Early-onset hypertension with exacerbation in pregnancy", "Pseudohyperaldosteronism type 2"]} |
Chronic active Epstein-Barr virus infection (CAEBV) is a very rare complication of an Epstein Barr virus (EBV) infection. Symptoms of CAEBV may include fever, swollen lymph nodes, and an enlarged liver and/or spleen. More serious complications may include anemia, nerve damage, liver failure, and/or interstitial pneumonia. Symptoms may be constant or come and go, and tend to get worse over time. CAEBV occurs when the virus remains ‘active’ and the symptoms of an EBV infection do not go away. It is diagnosed based on the symptoms, clinical exam, and blood tests that show EBV DNA remaining at high levels for at least 3 months. Treatment is focused on managing the symptoms. The most well-documented, effective treatment for CAEBV is hematopoietic stem cell transplantation.
Some people with fatigue alone are mistakenly thought to have CAEBV. Very specific testing looking for the level of EBV DNA is necessary to diagnose CAEBV.
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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
| Chronic active Epstein-Barr virus infection | c4016741 | 2,619 | gard | https://rarediseases.info.nih.gov/diseases/9534/chronic-active-epstein-barr-virus-infection | 2021-01-18T18:01:18 | {"omim": ["226990"], "synonyms": ["CEBV", "CAEBV infection", "Chronic active Epstein-Barr disease"]} |
A number sign (#) is used with this entry because Seckel syndrome-1 (SCKL1) is caused by homozygous or compound heterozygous mutation in the ATR gene (601215) on chromosome 3q23.
Description
Seckel syndrome is a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly with mental retardation, and a characteristic 'bird-headed' facial appearance (Shanske et al., 1997).
### Genetic Heterogeneity of Seckel Syndrome
Other forms of Seckel syndrome include SCKL2 (606744), caused by mutation in the RBBP8 gene (604124) on chromosome 18q11; SCKL4 (613676), caused by mutation in the CENPJ gene (609279) on chromosome 13q12; SCKL5 (613823), caused by mutation in the CEP152 gene (613529) on chromosome 15q21; SCKL6 (614728), caused by mutation in the CEP63 gene (614724) on chromosome 3q22; SCKL7 (614851), caused by mutation in the NIN gene (608684) on chromosome 14q22; SCKL8 (615807), caused by mutation in the DNA2 gene (601810) on chromosome 10q21; SCKL9 (616777), caused by mutation in the TRAIP gene (605958) on chromosome 3p21; and SCKL10 (617253), caused by mutation in the NSMCE2 gene (617246) on chromosome 8q24.
The report of a Seckel syndrome locus on chromosome 14q, designated SCKL3, by Kilinc et al. (2003) was found to be in error; see History section.
Clinical Features
This condition was given the 2 names bird-headed dwarfism and nanocephaly by Virchow. Seckel (1960) produced the definitive publication based on 2 personally observed cases and 13 reliable plus 11 less reliable cases from the literature. In addition to dwarfism of 'low birth weight' type, the features are small head, large eyes, beak-like protrusion of the nose, narrow face, and receding lower jaw. Mental retardation is not as marked as might be expected in view of the very small brain. Multiple occurrence in the same sibship, increased frequency of parental consanguinity, occurrence in both sexes, and normal parents suggest autosomal recessive inheritance. Affected sisters were reported by Black (1961). Harper et al. (1967) reported brother and sister who strikingly resembled Seckel's cases 1 and 2, 2 other reported cases, and the 3 sibs reported by McKusick et al. (1967). Majewski and Goecke (1982) picked out 17 cases that agreed with Seckel's case 1 and 43 others (including the cases of McKusick et al., 1967) that they felt were not identical to that case. Butler et al. (1987) raised the question of whether there may be a subgroup of Seckel syndrome patients who have chromosome instability and/or hematologic problems. Chromosome breakage was demonstrated in 2 patients, one of whom had pancytopenia. Sugio et al. (1993) suggested that only 19 patients with classic Seckel syndrome had been reported--17 reviewed by Majewski and Goecke (1982) and 2 reported by Butler et al. (1987). They reported a Japanese case in which severe brain dysplasia was present.
Hayani et al. (1994) described a female who was diagnosed with Seckel syndrome at 2 years of age. She was dwarfed (at 26 years of age she weighed 14.8 kg and was 113 cm tall), had severe microcephaly, and was mentally retarded. At age 26 years, she was diagnosed with acute myeloid leukemia (AML) by the study of blood marrow and peripheral blood. Chemotherapy produced severe toxicity with profound bone marrow aplasia. She died 2 months later. Although some patients with Seckel syndrome manifest anemia and other hematologic abnormalities, AML had not previously been reported. Hayani et al. (1994) suggested that patients with Seckel syndrome may be at risk of developing myelodysplasia and AML.
Shanske et al. (1997) reported a family of Yemeni-Arab extraction in which 3 sibs out of 8, the offspring of consanguineous parents, had this disorder. Imaging studies of the central nervous system were reported. Shanske et al. (1997) stated that only 6 families with 2 or more children affected with this disorder had previously been reported; however, they appeared to have overlooked the family reported by McKusick et al. (1967) with 3 affected sibs. In that family, neuroimaging studies were not performed but detailed anatomical studies of the brain at autopsy were reported.
In 2 unrelated Arabic patients with Seckel syndrome, Abou-Zahr et al. (1999) tested for hematologic abnormalities and chromosome breakage, suggesting Fanconi anemia. By Western analysis, they determined the expression of FAA (607139) and FAC (227645), 2 Fanconi anemia disease gene products that together account for approximately 80% of Fanconi anemia, and found that they were expressed at similar levels to those of normal cell lines. Furthermore, the cells from the patients were resistant to the effects of mitomycin C.
In a consanguineous Pakistani family, Goodship et al. (2000) found that the proband with Seckel syndrome weighed 1.1 kg at birth, with a head circumference of 24 cm. At age 9 years his height was 106 cm and head circumference 37 cm. He had moderate mental retardation and did not walk until the age of 7 years. He had striking microcephaly, receding forehead, and micrognathia with a prominent nose. The teeth were crowded, with dental malocclusion.
Seckel syndrome shows phenotypic overlap with type II microcephalic osteodysplastic primordial dwarfism (MOPD2; 210720). Both are characterized by intrauterine growth retardation, severe proportionate short stature, and microcephaly; MOPD2 is distinct from SCKL by more severe growth retardation, radiologic abnormalities, and milder mental retardation.
Can et al. (2010) reported a male infant with characteristic features of Seckel syndrome, who also had tetralogy of Fallot, ventricular septal defect, pulmonary stenosis, patent foramen ovale, left arcus aorta, dextroposition of the aorta, and increased intraventricular septal thickening. The authors stated that although cardiac malformation has previously been described in patients with Seckel syndrome, this was the first case involving tetralogy of Fallot.
Ogi et al. (2012) reported 2 unrelated English patients with Seckel syndrome-1 resulting from compound heterozygous mutations in the ATR gene (601215.0004 and 601215.0005). The patients had severe microcephaly (-10 SD), micrognathia, dental crowding, and small ears with absent lobes. Skeletal anomalies were also prominent, including symmetric dwarfism, small/poorly ossified patellae, and clinodactyly or small tapering fingers. Brain imaging of 1 patient showed an area of abnormal gyration and hypoplastic corpus callosum.
Mokrani-Benhelli et al. (2013) described a 9.5-year-old French girl who had intrauterine growth retardation and dwarfism at birth, with severe microcephaly and mental retardation that worsened with age. Examination revealed a triangular face, high-set slightly beaked nose, micrognathia, upslanting palpebral fissures, thick eyebrows with synophrys, slightly posteriorly rotated ears lacking lobes, and a narrow palate. Her hands were thin and flat with abnormally positioned thumbs. She had pes cavus with retracted toes, and a growth disorder of the nails. Puberty occurred early. Radiography revealed right convex lumbar scoliosis, slight dorsal kyphosis, and hyperlordosis; in addition, her long bones were very slender. She had severe anemia at birth, which after initial transfusions spontaneously corrected and was normal thereafter. There was no obvious immunologic defect, but analysis of immunoglobulin class switch recombination (CSR) junctions resulting from in vivo class switching between S-mu and S-alpha-1 regions showed a significant decrease in blunt-end joining and an increased usage of microhomology (MH) at the S-mu/S-alpha-1 switch junctions in patient cells compared to controls. This increase in MH-mediated CSR junctions suggested a defect in a DNA repair factor involved in the CSR process.
Mapping
Goodship et al. (2000) studied 2 consanguineous families with Seckel syndrome from the same village in Pakistan who were not known to be related to each other. By a genome screen and homozygosity mapping, they assigned the Seckel syndrome locus to 3q22.1-q24, between loci D3S1316 and D3S3710; maximum lod score = 8.72. All 5 affected individuals were homozygous for the same allele.
Heterogeneity
Faivre et al. (2002) confirmed the heterogeneity of Seckel syndrome by excluding the previously mapped loci on chromosomes 3 and 18 in 5 consanguineous and 1 multiplex nonconsanguineous Seckel syndrome families.
Molecular Genetics
O'Driscoll et al. (2003) showed that affected individuals in the Pakistani families studied by Goodship et al. (2000) had a mutation in the gene encoding ataxia-telangiectasia and RAD3-related protein (ATR; 601215.0001).
In a 9.5-year-old French girl with Seckel syndrome, Mokrani-Benhelli et al. (2013) identified compound heterozygosity for a missense mutation in the ATR gene (D1879Y; 601215.0003) and a 540-kb deletion on chromosome 3 encompassing ATR as well as 3 other genes, XRN1 (607994), PLS1 (602734), and TRPC1 (602343). Her unaffected parents were each heterozygous for 1 of the mutations.
### Associations Pending Confirmation
For discussion of a possible association between Seckel syndrome and variation in the ATRIP gene, see 606605.0001.
Animal Model
Murga et al. (2009) developed a mouse model of Seckel syndrome by replacing exons 8, 9, and 10 of the mouse Atr gene with those from human, and then introducing the A-to-G transition in exon 9 into the humanized gene (601215.0001). ATR Seckel homozygous mice were born at submendelian ratios and showed severe dwarfism that was already noticeable at birth. Mutant placentas showed an accumulation of necrotic areas and overall loss of cellularity. In addition to the overall dwarfism, Seckel mice showed microcephaly and facial dysmorphism including micrognathia and receding foreheads. Seckel mice also had small brains, cysts, and agenesis of the corpus callosum. Seckel mice showed high levels of replicative stress during embryogenesis, when proliferation is widespread, but this was reduced to marginal amounts in postnatal life. In spite of this decrease, adult Seckel mice showed accelerated aging, which was further aggravated in the absence of p53 (191170). Murga et al. (2009) concluded that their results supported a model whereby replicative stress, particularly in utero, contributes to the onset of aging in postnatal life, and this is balanced by the replicative stress-limiting role of the checkpoint proteins ATR and p53.
History
Kilinc et al. (2003) performed linkage analysis by a microsatellite genome scan in a study of 13 unrelated Turkish families with Seckel syndrome and identified a novel locus (SCKL3) on chromosome 14q in 5 of the families. In an erratum, the authors stated that this finding was incorrect and that one of the families they had studied was found to have a mutation in the LIG4 gene (601837). In their original article, the authors noted that there was great variation in the phenotypes of the patients in the 5 'linked' families.
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature, proportionate Weight \- Average birth weight 1540g Other \- Prenatal growth retardation \- Postnatal growth retardation (-7 S.D.) HEAD & NECK Head \- Microcephaly, severe \- Small anterior fontanel Face \- Sloping forehead \- Micrognathia \- Facial asymmetry Ears \- Low-set, malformed ears \- Absence of earlobe Eyes \- Relatively large eyes \- Downslanting palpebral fissures \- Strabismus \- Blepharophimosis Nose \- Prominent nose \- Beaked nose Mouth \- Cleft palate \- High-arched palate Teeth \- Selective tooth agenesis \- Enamel hypoplasia \- Class II malocclusion \- Dental crowding CHEST Ribs Sternum Clavicles & Scapulae \- 11 pairs of ribs GENITOURINARY External Genitalia (Male) \- Hypospadias External Genitalia (Female) \- Clitoromegaly Internal Genitalia (Male) \- Cryptorchidism SKELETAL \- Delayed bone age Spine \- Scoliosis Pelvis \- Hip dislocation Limbs \- Hypoplasia of proximal radius \- Radial head dislocation \- Hypoplasia of proximal fibula \- Elbow flexion contracture \- Aberrant patellae Hands \- Fifth finger clinodactyly \- Transverse palmar creases \- Ivory epiphyses (phalanges) \- Cone-shaped epiphyses (phalanges) \- Abnormal finger flexion creases Feet \- Gap between first and second toes \- Talipes \- Pes planus SKIN, NAILS, & HAIR Skin \- Abnormal finger flexion creases \- Transverse palmar creases NEUROLOGIC Central Nervous System \- Mental retardation \- Seizures \- Pachygyria \- Arachnoidal cysts \- Large basal ganglia \- Hypoplasia of the cerebellar vermis Behavioral Psychiatric Manifestations \- Hyperactivity HEMATOLOGY \- Pancytopenia \- Increased sister chromatid exchange MISCELLANEOUS \- Half of cases show retarded head circumference equal to height retardation \- Other half show head circumference more retarded than height MOLECULAR BASIS \- Caused by mutation in the ataxia-telangiectasia and Rad3-related gene (ATR, 601215.0001 ) ▲ 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
| SECKEL SYNDROME 1 | c0265202 | 2,620 | omim | https://www.omim.org/entry/210600 | 2019-09-22T16:30:31 | {"doid": ["0070007"], "omim": ["210600"], "orphanet": ["808"], "synonyms": ["Alternative titles", "SCKL", "SECKEL-TYPE DWARFISM", "NANOCEPHALIC DWARFISM", "MICROCEPHALIC PRIMORDIAL DWARFISM I", "BIRD-HEADED DWARFISM"]} |
A rare, genetic organic aciduria affecting ketone body metabolism and the catabolism of isoleucine and characterized by intermittent ketoacidotic episodes associated with vomiting, dyspnea, tachypnoea, hypotonia, lethargy and coma, with an onset during infancy and usually ceasing by adolescence.
## Epidemiology
The estimated birth prevalence ranges between 1/100,000 to 230,000 worldwide.
## Clinical description
Children often appear normal at birth with disease presentation typically between the ages of 5 months to 2 years; however, presentation may occur anywhere between birth and childhood. The onset of symptoms usually occurs in the form of a ketoacidotic crisis, most often brought on by stress, fasting, acute illness and/or infections (i.e. gastroenteritis), and rarely by increased dietary protein intake. An acetone or fruity odor on the breath often signals ketoacidosis. These episodes are associated with vomiting, dyspnea, lethargy and unconsciousness, and can lead to coma and death if not treated. Neurological sequelae (such as developmental delay) following severe episodes are common. Rarely, patients present with signs of metabolic encephalopathy (hypotonia, dysarthria, chorea, developmental delay). The occurrence of developmental delay or neurological manifestations before a first ketoacidotic crisis, however, is rare. The frequency of episodes decreases with age, eventually stopping before adolescence. In between episodes, patients are often asymptomatic.
## Etiology
This disease is caused by mutations (over 100 described) in the gene, ACAT1 (11q22.3). This gene encodes the enzyme acetyl-CoA acetyltransferase which, when its activity is reduced or absent, impairs the breakdown of isoleucine and acetoacetyl- CoA, hampering the utilization of ketone bodies and leading to toxic accumulations of isoleucine derived acyl-CoA esters in the body.
## Diagnostic methods
Most patients are diagnosed by demonstrating metabolic acidosis and ketosis, by urinary organic acid analysis (2-methyl-3-hydroxybutyrate (the most reliable marker), 2- methylacetoacetate and tiglylglycine), or by acylcarnitine analysis during metabolic decompensation. Diagnosis can be confirmed by cultured fibroblast enzyme assays (reduced potassium-dependent acetoacetyl-CoA thiolase activity) and molecular genetic testing. Computed tomography of the brain may reveal basal ganglia lesions that have been reported in some patients. Newborn screening programs are available in certain countries including the U.S. and Australia.
## Differential diagnosis
The differential diagnosis includes sepsis, other organic acidurias, HSD10 disease and succinyl-CoA:3-ketoacid CoA transferase deficiency, and other conditions that cause ketoacidosis in childhood.
## Antenatal diagnosis
In families with a known disease causing mutation, prenatal testing is possible by molecular genetic testing or enzyme activity assays using cultured amniocytes.
## Genetic counseling
The pattern of inheritance is autosomal recessive. The risk of inheriting the disease is 25% where both parents are unaffected carriers.
## Management and treatment
During a ketoacidotic crisis, intravenous fluids with glucose and electrolytes should be administered immediately. Bicarbonate (initially as 1mmol/kg over 10 minutes followed by continuous infusion) should be given to treat acidosis. Carnitine supplementation may be helpful. Dialysis is effective but usually not necessary. Unconscious patients and those with severe dyspnea may require mechanical ventilation. Long-term management involves avoidance of fasting (and intravenous glucose in cases of fever or vomiting) and, in children, a mildly restricted protein intake (1.5-2g/kg/day), avoidance of fat-rich (ketogenic) diet, and L-carnitine therapy in those with low carnitine levels. Avoidance of isoleucine overload might prevent neurological complications, but currently there is no evidence to support this.
## Prognosis
The prognosis is often good if detected early and treated properly so as to prevent ketoacidotic attacks.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Beta-ketothiolase deficiency | c1536500 | 2,621 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=134 | 2021-01-23T19:09:29 | {"gard": ["872"], "mesh": ["C535434"], "omim": ["203750"], "umls": ["C1536500"], "icd-10": ["E71.1"], "synonyms": ["3-ketothiolase deficiency", "3-oxothiolase deficiency", "Alpha methylacetoacetic aciduria", "Alpha-methyl-acetoacetyl-CoA thiolase deficiency", "Mitochondrial acetoacetyl-coenzyme A thiolase deficiency", "T2 deficiency"]} |
Low back pain
Other namesLower back pain, lumbago
Low back pain is a common and costly complaint.
Pronunciation
* Lumbago /lʌmˈbeɪɡoʊ/
SpecialtyOrthopedics, rheumatology, rehabilitation medicine
Usual onset20 to 40 years of age[1]
Duration~65% get better in 6 weeks[2]
TypesAcute (less than 6 weeks), sub-chronic (6 to 12 weeks), chronic (more than 12 weeks)[3]
CausesUsually non-specific, occasionally significant underlying cause[1][4]
Diagnostic methodMedical imaging (if red flags )[5]
TreatmentContinued normal activity, non-medication based treatments, NSAIDs[2][6]
Frequency~25% in any given month[7][8]
Low back pain (LBP) is a common disorder involving the muscles, nerves, and bones of the back.[4] Pain can vary from a dull constant ache to a sudden sharp feeling.[4] Low back pain may be classified by duration as acute (pain lasting less than 6 weeks), sub-chronic (6 to 12 weeks), or chronic (more than 12 weeks).[3] The condition may be further classified by the underlying cause as either mechanical, non-mechanical, or referred pain.[5] The symptoms of low back pain usually improve within a few weeks from the time they start, with 40–90% of people completely better by six weeks.[2]
In most episodes of low back pain, a specific underlying cause is not identified or even looked for, with the pain believed to be due to mechanical problems such as muscle or joint strain.[1][4] If the pain does not go away with conservative treatment or if it is accompanied by "red flags" such as unexplained weight loss, fever, or significant problems with feeling or movement, further testing may be needed to look for a serious underlying problem.[5] In most cases, imaging tools such as X-ray computed tomography are not useful and carry their own risks.[9][10] Despite this, the use of imaging in low back pain has increased.[11] Some low back pain is caused by damaged intervertebral discs, and the straight leg raise test is useful to identify this cause.[5] In those with chronic pain, the pain processing system may malfunction, causing large amounts of pain in response to non-serious events.[12]
Initial management with non-medication based treatments is recommended.[6] NSAIDs are recommended if these are not sufficiently effective.[6] Normal activity should be continued as much as the pain allows.[2] Medications are recommended for the duration that they are helpful.[13] A number of other options are available for those who do not improve with usual treatment. Opioids may be useful if simple pain medications are not enough, but they are not generally recommended due to side effects.[4][13] Surgery may be beneficial for those with disc-related chronic pain and disability or spinal stenosis.[14][15] No clear benefit has been found for other cases of non-specific low back pain.[14] Low back pain often affects mood, which may be improved by counseling or antidepressants.[13][16] Additionally, there are many alternative medicine therapies, including the Alexander technique and herbal remedies, but there is not enough evidence to recommend them confidently.[17] The evidence for chiropractic care[18] and spinal manipulation is mixed.[17][19][20][21]
Approximately 9–12% of people (632 million) have LBP at any given point in time, and nearly 25% report having it at some point over any one-month period.[7][8] About 40% of people have LBP at some point in their lives,[7] with estimates as high as 80% among people in the developed world.[22] Difficulty most often begins between 20 and 40 years of age.[1] Men and women are equally affected.[4] Low back pain is more common among people aged between 40 and 80 years, with the overall number of individuals affected expected to increase as the population ages.[7]
Play media
Video explanation
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Pathophysiology
* 3.1 Back structures
* 3.2 Pain sensation
* 4 Diagnosis
* 4.1 Classification
* 4.2 Red flags
* 4.3 Tests
* 5 Prevention
* 6 Management
* 6.1 Physical management
* 6.2 Medications
* 6.3 Surgery
* 6.4 Alternative medicine
* 6.5 Education
* 7 Prognosis
* 8 Epidemiology
* 9 History
* 10 Society and culture
* 11 Research
* 12 References
* 13 External links
## Signs and symptoms
In the common presentation of acute low back pain, pain develops after movements that involve lifting, twisting, or forward-bending. The symptoms may start soon after the movements or upon waking up the following morning. The description of the symptoms may range from tenderness at a particular point to diffuse pain. It may or may not worsen with certain movements, such as raising a leg, or positions, such as sitting or standing. Pain radiating down the legs (known as sciatica) may be present. The first experience of acute low back pain is typically between the ages of 20 and 40. This is often a person's first reason to see a medical professional as an adult.[1] Recurrent episodes occur in more than half of people[23] with the repeated episodes being generally more painful than the first.[1]
Other problems may occur along with low back pain. Chronic low back pain is associated with sleep problems, including a greater amount of time needed to fall asleep, disturbances during sleep, a shorter duration of sleep, and less satisfaction with sleep.[24] In addition, a majority of those with chronic low back pain show symptoms of depression[13] or anxiety.[17]
## Causes
A herniated disc as seen on MRI, one possible cause of low back pain
Low back pain is not a specific disease but rather a complaint that may be caused by a large number of underlying problems of varying levels of seriousness.[25] The majority of LBP does not have a clear cause[1] but is believed to be the result of non-serious muscle or skeletal issues such as sprains or strains.[26] Obesity, smoking, weight gain during pregnancy, stress, poor physical condition, poor posture and poor sleeping position may also contribute to low back pain.[26] A full list of possible causes includes many less common conditions.[5] Physical causes may include osteoarthritis, degeneration of the discs between the vertebrae or a spinal disc herniation, broken vertebra(e) (such as from osteoporosis) or, rarely, an infection or tumor of the spine.[27]
Women may have acute low back pain from medical conditions affecting the female reproductive system, including endometriosis, ovarian cysts, ovarian cancer, or uterine fibroids.[28] Nearly half of all pregnant women report pain in the lower back or sacral area during pregnancy, due to changes in their posture and center of gravity causing muscle and ligament strain.[29]
Low back pain can be broadly classified into four main categories:
* Musculoskeletal – mechanical (including muscle strain, muscle spasm, or osteoarthritis); herniated nucleus pulposus, herniated disk; spinal stenosis; or compression fracture
* Inflammatory – HLA-B27 associated arthritis including ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and inflammatory bowel disease
* Malignancy – bone metastasis from lung, breast, prostate, thyroid, among others
* Infectious – osteomyelitis; abscess
Low back pain can also be caused by an urinary tract infection.[30]
## Pathophysiology
### Back structures
The five lumbar vertebrae define the lower back region.
The structures surrounding and supporting the vertebrae can be sources of low back pain.
The lumbar (or lower back) region is made up of five vertebrae (L1–L5), sometimes including the sacrum. In between these vertebrae are fibrocartilaginous discs, which act as cushions, preventing the vertebrae from rubbing together while at the same time protecting the spinal cord. Nerves come from and go to the spinal cord through specific openings between the vertebrae, providing the skin with sensations and messages to muscles. Stability of the spine is provided by the ligaments and muscles of the back and abdomen. Small joints called facet joints limit and direct the motion of the spine.[31]
The multifidus muscles run up and down along the back of the spine, and are important for keeping the spine straight and stable during many common movements such as sitting, walking and lifting.[12] A problem with these muscles is often found in someone with chronic low back pain, because the back pain causes the person to use the back muscles improperly in trying to avoid the pain.[32] The problem with the multifidus muscles continues even after the pain goes away, and is probably an important reason why the pain comes back.[32] Teaching people with chronic low back pain how to use these muscles is recommended as part of a recovery program.[32]
An intervertebral disc has a gelatinous core surrounded by a fibrous ring.[33] When in its normal, uninjured state, most of the disc is not served by either the circulatory or nervous systems – blood and nerves only run to the outside of the disc.[33] Specialized cells that can survive without direct blood supply are in the inside of the disc.[33] Over time, the discs lose flexibility and the ability to absorb physical forces.[25] This decreased ability to handle physical forces increases stresses on other parts of the spine, causing the ligaments of the spine to thicken and bony growths to develop on the vertebrae.[25] As a result, there is less space through which the spinal cord and nerve roots may pass.[25] When a disc degenerates as a result of injury or disease, the makeup of a disc changes: blood vessels and nerves may grow into its interior and/or herniated disc material can push directly on a nerve root.[33] Any of these changes may result in back pain.[33]
### Pain sensation
Pain is generally an unpleasant feeling in response to an event that either damages or can potentially damage the body's tissues. There are four main steps in the process of feeling pain: transduction, transmission, perception, and modulation.[12] The nerve cells that detect pain have cell bodies located in the dorsal root ganglia and fibers that transmit these signals to the spinal cord.[34] The process of pain sensation starts when the pain-causing event triggers the endings of appropriate sensory nerve cells. This type of cell converts the event into an electrical signal by transduction. Several different types of nerve fibers carry out the transmission of the electrical signal from the transducing cell to the posterior horn of spinal cord, from there to the brain stem, and then from the brain stem to the various parts of the brain such as the thalamus and the limbic system. In the brain, the pain signals are processed and given context in the process of pain perception. Through modulation, the brain can modify the sending of further nerve impulses by decreasing or increasing the release of neurotransmitters.[12]
Parts of the pain sensation and processing system may not function properly; creating the feeling of pain when no outside cause exists, signaling too much pain from a particular cause, or signaling pain from a normally non-painful event. Additionally, the pain modulation mechanisms may not function properly. These phenomena are involved in chronic pain.[12]
## Diagnosis
As the structure of the back is complex and the reporting of pain is subjective and affected by social factors, the diagnosis of low back pain is not straightforward.[5] While most low back pain is caused by muscle and joint problems, this cause must be separated from neurological problems, spinal tumors, fracture of the spine, and infections, among others.[3][1]
### Classification
There are a number of ways to classify low back pain with no consensus that any one method is best.[5] There are three general types of low back pain by cause: mechanical back pain (including nonspecific musculoskeletal strains, herniated discs, compressed nerve roots, degenerative discs or joint disease, and broken vertebra), non-mechanical back pain (tumors, inflammatory conditions such as spondyloarthritis, and infections), and referred pain from internal organs (gallbladder disease, kidney stones, kidney infections, and aortic aneurysm, among others).[5] Mechanical or musculoskeletal problems underlie most cases (around 90% or more),[5][35] and of those, most (around 75%) do not have a specific cause identified, but are thought to be due to muscle strain or injury to ligaments.[5][35] Rarely, complaints of low back pain result from systemic or psychological problems, such as fibromyalgia and somatoform disorders.[35]
Low back pain may be classified based on the signs and symptoms. Diffuse pain that does not change in response to particular movements, and is localized to the lower back without radiating beyond the buttocks, is classified as nonspecific, the most common classification.[5] Pain that radiates down the leg below the knee, is located on one side (in the case of disc herniation), or is on both sides (in spinal stenosis), and changes in severity in response to certain positions or maneuvers is radicular, making up 7% of cases.[5] Pain that is accompanied by red flags such as trauma, fever, a history of cancer or significant muscle weakness may indicate a more serious underlying problem and is classified as needing urgent or specialized attention.[5]
The symptoms can also be classified by duration as acute, sub-chronic (also known as sub-acute), or chronic. The specific duration required to meet each of these is not universally agreed upon, but generally pain lasting less than six weeks is classified as acute, pain lasting six to twelve weeks is sub-chronic, and more than twelve weeks is chronic.[3] Management and prognosis may change based on the duration of symptoms.
### Red flags
Red flags are warning signs that may indicate a more serious problem Red flag[36] Possible cause[1]
Previous history of cancer Cancer
Unintentional weight loss
Loss of bladder or bowel control Cauda
equina
syndrome
Significant motor weakness
or sensory problems
Loss of sensation in the
buttocks (saddle anesthesia)
Significant trauma related to age Fracture
Chronic corticosteroid use
Osteoporosis
Severe pain after lumbar
surgery in past year Infection
Fever
Urinary tract infection
Immunosuppression
Intravenous drug use
The presence of certain signs, termed red flags, indicate the need for further testing to look for more serious underlying problems, which may require immediate or specific treatment.[5][37] The presence of a red flag does not mean that there is a significant problem. It is only suggestive,[38][39] and most people with red flags have no serious underlying problem.[3][1] If no red flags are present, performing diagnostic imaging or laboratory testing in the first four weeks after the start of the symptoms has not been shown to be useful.[5]
The usefulness of many red flags are poorly supported by evidence.[40][41] The most useful for detecting a fracture are: older age, corticosteroid use, and significant trauma especially if it results in skin markings.[40] The best determinant of the presence of cancer is a history of the same.[40]
With other causes ruled out, people with non-specific low back pain are typically treated symptomatically, without exact determination of the cause.[3][1] Efforts to uncover factors that might complicate the diagnosis, such as depression, substance abuse, or an agenda concerning insurance payments may be helpful.[5]
### Tests
The straight leg raise test can detect pain originating from a herniated disc. When warranted, imaging such as MRI can provide clear detail about disc related causes of back pain (L4–L5 disc herniation shown)
Imaging is indicated when there are red flags, ongoing neurological symptoms that do not resolve, or ongoing or worsening pain.[5] In particular, early use of imaging (either MRI or CT) is recommended for suspected cancer, infection, or cauda equina syndrome.[5] MRI is slightly better than CT for identifying disc disease; the two technologies are equally useful for diagnosing spinal stenosis.[5] Only a few physical diagnostic tests are helpful.[5] The straight leg raise test is almost always positive in those with disc herniation.[5] Lumbar provocative discography may be useful to identify a specific disc causing pain in those with chronic high levels of low back pain.[42] Similarly, therapeutic procedures such as nerve blocks can be used to determine a specific source of pain.[5] Some evidence supports the use of facet joint injections, transforminal epidural injections and sacroilliac injections as diagnostic tests.[5] Most other physical tests, such as evaluating for scoliosis, muscle weakness or wasting, and impaired reflexes, are of little use.[5]
Complaints of low back pain are one of the most common reasons people visit doctors.[9][43] For pain that has lasted only a few weeks, the pain is likely to subside on its own.[44] Thus, if a person's medical history and physical examination do not suggest a specific disease as the cause, medical societies advise against imaging tests such as X-rays, CT scans, and MRIs.[43] Individuals may want such tests but, unless red flags are present,[10][45] they are unnecessary health care.[9][44] Routine imaging increases costs, is associated with higher rates of surgery with no overall benefit,[46][47] and the radiation used may be harmful to one's health.[46] Fewer than 1% of imaging tests identify the cause of the problem.[9] Imaging may also detect harmless abnormalities, encouraging people to request further unnecessary testing or to worry.[9] Even so, MRI scans of the lumbar region increased by more than 300% among United States Medicare beneficiaries from 1994 to 2006.[11]
## Prevention
Exercise appears to be useful for preventing low back pain.[48] Exercise is also probably effective in preventing recurrences in those with pain that has lasted more than six weeks.[1][49] Medium-firm mattresses are more beneficial for chronic pain than firm mattresses.[50] There is little to no evidence that back belts are any more helpful in preventing low back pain than education about proper lifting techniques.[48][51] There is no quality data that supports medium firm mattresses over firm mattresses. A few studies that have contradicted this notion have also failed to include sleep posture and mattress firmness. The most comfortable sleep surface may be preferred.[52] Shoe insoles do not help prevent low back pain.[48][53]
## Management
Most people with acute or subacute low back pain improve over time no matter the treatment.[6] There is often improvement within the first month.[6] Recommendations include remaining active, avoiding activity that worsen the pain, and understanding self-care of the symptoms.[6] Management of low back pain depends on which of the three general categories is the cause: mechanical problems, non-mechanical problems, or referred pain.[54] For acute pain that is causing only mild to moderate problems, the goals are to restore normal function, return the individual to work, and minimize pain. The condition is normally not serious, resolves without much being done, and recovery is helped by attempting to return to normal activities as soon as possible within the limits of pain.[3] Providing individuals with coping skills through reassurance of these facts is useful in speeding recovery.[1] For those with sub-chronic or chronic low back pain, multidisciplinary treatment programs may help.[55] Initial management with non–medication based treatments is recommended, with NSAIDs used if these are not sufficiently effective.[6] Non–medication based treatments include superficial heat, massage, acupuncture, or spinal manipulation.[6] Acetaminophen and systemic steroids are not recommended as both medications are not effective at improving pain outcomes in acute or subacute low back pain.[6]
### Physical management
Increasing general physical activity has been recommended, but no clear relationship to pain or disability has been found when used for the treatment of an acute episode of pain.[49][56] For acute pain, low- to moderate-quality evidence supports walking.[57] Treatment according to McKenzie method is somewhat effective for recurrent acute low back pain, but its benefit in the short term does not appear significant.[1] There is tentative evidence to support the use of heat therapy for acute and sub-chronic low back pain[58] but little evidence for the use of either heat or cold therapy in chronic pain.[59] Weak evidence suggests that back belts might decrease the number of missed workdays, but there is nothing to suggest that they will help with the pain.[51] Ultrasound and shock wave therapies do not appear effective and therefore are not recommended.[60][61] Lumbar traction lacks effectiveness as an intervention for radicular low back pain.[62] It is also unclear whether lumbar supports are an effective treatment intervention.[63] Aerobic exercises like progressive walking appears useful for subacute and acute low back pain, is strongly recommended for chronic low back pain, and is recommended after surgery.[52] In terms of directional exercise which try to limit low back pain is recommended in sub-acute, chronic and radicular low back pain. These exercises only work if they are limiting low back pain.[52] Exercise programs that incorporate stretching only are not recommended for low back pain. Generic or non specific stretching has also been found to not help with acute low back pain. Stretching, especially with limited range of motion, can impede future progression of treatment like limiting strength and limiting exercises.[52]
Exercise therapy is effective in decreasing pain and improving physical function, trunk muscle strength and mental health for those with chronic low back pain.[64] It also appears to reduce recurrence rates for as long as six months after the completion of program[65] and improves long-term function.[59] There is no evidence that one particular type of exercise therapy is more effective than another.[66][67] The Alexander technique appears useful for chronic back pain,[68] and there is tentative evidence to support the use of yoga.[69] If a person is motivated with chronic low back pain, it is recommended to use yoga and tai chi as a form of treatment, but not recommended to treat acute or subacute low back pain.[52] Transcutaneous electrical nerve stimulation (TENS) has not been found to be effective in chronic low back pain.[70] Evidence for the use of shoe insoles as a treatment is inconclusive.[53] Motor control exercise involves guided movement and use of normal muscles during simple tasks which then builds to more complex tasks improves pain and function up to 20 weeks but was little different from manual therapy and other forms of exercise.[71] Motor control exercise accompanied by manual therapy also produces similar reductions in pain intensity when compared to general strength and condition exercise training, yet only the latter also improved muscle endurance and strength, whilst concurrently decreased self-reported disability.[72] Peripheral nerve stimulation, a minimally-invasive procedure, may be useful in cases of chronic low back pain that do not respond to other measures, although the evidence supporting it is not conclusive, and it is not effective for pain that radiates into the leg.[73] Aquatic therapy is recommended as an option in those with other preexisting conditions like extreme obesity, degenerative joint disease, or other conditions that limit progressive walking. Aquatic therapy is recommended for chronic and subacute low back pain in those with a preexisting condition. Aquatic therapy is not recommended for people that have no preexisting condition that limits their progressive walking.[52] There has been little research that supports the use of lumbar extension machines and thus they are not recommended.[52] There is no quality evidence that supports pilates in low back pain.[52]
### Medications
The management of low back pain often includes medications for the duration that they are beneficial. With the first episode of low back pain the hope is a complete cure; however, if the problem becomes chronic, the goals may change to pain management and the recovery of as much function as possible. As pain medications are only somewhat effective, expectations regarding their benefit may differ from reality, and this can lead to decreased satisfaction.[13]
The medication typically recommended first are acetaminophen (paracetamol), NSAIDs (though not aspirin), or skeletal muscle relaxants and these are enough for most people.[13][6][74] Benefits with NSAIDs; however, is often small.[75] High-quality reviews have found acetaminophen (paracetamol) to be no more effective than placebo at improving pain, quality of life, or function.[76][77] NSAIDs are more effective for acute episodes than acetaminophen; however, they carry a greater risk of side effects, including kidney failure, stomach ulcers and possibly heart problems. Thus, NSAIDs are a second choice to acetaminophen, recommended only when the pain is not handled by the latter. NSAIDs are available in several different classes; there is no evidence to support the use of COX-2 inhibitors over any other class of NSAIDs with respect to benefits.[75][13][78] With respect to safety naproxen may be best.[79] Muscle relaxants may be beneficial.[13]
If the pain is still not managed adequately, short term use of opioids such as morphine may be useful.[80][13] These medications carry a risk of addiction, may have negative interactions with other drugs, and have a greater risk of side effects, including dizziness, nausea, and constipation.[13] The effect of long term use of opioids for lower back pain is unknown.[81] Opioid treatment for chronic low back pain increases the risk for lifetime illicit drug use.[82] Specialist groups advise against general long-term use of opioids for chronic low back pain.[13][83] As of 2016, the CDC has released a guideline for prescribed opioid use in the management of chronic pain.[84] It states that opioid use is not the preferred treatment when managing chronic pain due to the excessive risks involved. If prescribed, a person and their clinician should have a realistic plan to discontinue its use in the event that the risks outweigh the benefit.[84]
For older people with chronic pain, opioids may be used in those for whom NSAIDs present too great a risk, including those with diabetes, stomach or heart problems. They may also be useful for a select group of people with neuropathic pain.[85]
Antidepressants may be effective for treating chronic pain associated with symptoms of depression, but they have a risk of side effects.[13] Although the antiseizure drugs gabapentin, pregabalin, and topiramate are sometimes used for chronic low back pain evidence does not support a benefit.[86] Systemic oral steroids have not been shown to be useful in low back pain.[1][13] Facet joint injections and steroid injections into the discs have not been found to be effective in those with persistent, non-radiating pain; however, they may be considered for those with persistent sciatic pain.[87] Epidural corticosteroid injections provide a slight and questionable short-term improvement in those with sciatica but are of no long term benefit.[88] There are also concerns of potential side effects.[89]
### Surgery
Surgery may be useful in those with a herniated disc that is causing significant pain radiating into the leg, significant leg weakness, bladder problems, or loss of bowel control.[14] It may also be useful in those with spinal stenosis.[15] In the absence of these issues, there is no clear evidence of a benefit from surgery.[14]
Discectomy (the partial removal of a disc that is causing leg pain) can provide pain relief sooner than nonsurgical treatments.[14] Discectomy has better outcomes at one year but not at four to ten years.[14] The less invasive microdiscectomy has not been shown to result in a different outcome than regular discectomy.[14] For most other conditions, there is not enough evidence to provide recommendations for surgical options.[14] The long-term effect surgery has on degenerative disc disease is not clear.[14] Less invasive surgical options have improved recovery times, but evidence regarding effectiveness is insufficient.[14]
For those with pain localized to the lower back due to disc degeneration, fair evidence supports spinal fusion as equal to intensive physical therapy and slightly better than low-intensity nonsurgical measures.[15] Fusion may be considered for those with low back pain from acquired displaced vertebra that does not improve with conservative treatment,[14] although only a few of those who have spinal fusion experience good results.[15] There are a number of different surgical procedures to achieve fusion, with no clear evidence of one being better than the others.[90] Adding spinal implant devices during fusion increases the risks but provides no added improvement in pain or function.[11]
### Alternative medicine
It is unclear if among those with non-chronic back pain alternative treatments are useful.[91] Chiropractic care or spinal manipulation therapy (SMT) appears similar to other recommended treatments.[92] National guidelines reach different conclusions, with some not recommending spinal manipulation, some describing manipulation as optional, and others recommending a short course for those who do not improve with other treatments.[3] A 2017 review recommended spinal manipulation based on low quality evidence.[6] Manipulation under anaesthesia, or medically assisted manipulation, has not enough evidence to make any confident recommendation.[93] Spinal manipulative does not have a significant benefits over motor control exercises.[94]
Acupuncture is no better than placebo, usual care, or sham acupuncture for nonspecific acute pain or sub-chronic pain.[95] For those with chronic pain, it improves pain a little more than no treatment and about the same as medications, but it does not help with disability.[95] This pain benefit is only present right after treatment and not at follow-up.[95] Acupuncture may be a reasonable method to try for those with chronic pain that does not respond to other treatments like conservative care and medications.[1][96]
Massage therapy does not appear to provide much benefit for acute low back pain.[1] A 2015 Cochrane review found that for acute low back pain massage therapy was better than no treatment for pain only in the short-term.[97] There was no effect for improving function.[97] For chronic low back pain massage therapy was no better than no treatment for both pain and function, though only in the short-term.[97] The overall quality of the evidence was low and the authors conclude that massage therapy is generally not an effective treatment for low back pain.[97] Massage therapy is recommended for selected people with subacute and chronic low back pain, but it should be paired with another form of treatment like aerobic or strength exercises. For acute or chronic radicular pain syndromes massage therapy is recommended only if low back pain is considered a symptom. Mechanical massage tools are not recommended for the treatment of any form of low back pain.[52]
Prolotherapy – the practice of injecting solutions into joints (or other areas) to cause inflammation and thereby stimulate the body's healing response – has not been found to be effective by itself, although it may be helpful when added to another therapy.[17]
Herbal medicines, as a whole, are poorly supported by evidence.[98] The herbal treatments Devil's claw and white willow may reduce the number of individuals reporting high levels of pain; however, for those taking pain relievers, this difference is not significant.[17] Capsicum, in the form of either a gel or a plaster cast, has been found to reduce pain and increase function.[17]
Behavioral therapy may be useful for chronic pain.[16] There are several types available, including operant conditioning, which uses reinforcement to reduce undesirable behaviors and increase desirable behaviors; cognitive behavioral therapy, which helps people identify and correct negative thinking and behavior; and respondent conditioning, which can modify an individual's physiological response to pain.[17] The benefit however is small.[99] Medical providers may develop an integrated program of behavioral therapies.[17] The evidence is inconclusive as to whether mindfulness-based stress reduction reduces chronic back pain intensity or associated disability, although it suggests that it may be useful in improving the acceptance of existing pain.[100][101]
Tentative evidence supports neuroreflexotherapy (NRT), in which small pieces of metal are placed just under the skin of the ear and back, for non-specific low back pain.[102][103][17] Multidisciplinary biopsychosocial rehabilitation (MBR), targeting physical and psychological aspects, may improve back pain but evidence is limited.[104] There is a lack of good quality evidence to support the use of radiofrequency denervation for pain relief.[105]
KT Tape has been found to be no different for management of chronic non-specific low back pain than other established pain management strategies.[106]
### Education
There is strong evidence that education may improve low back pain, with a 2.5 hour educational session more effective than usual care for helping people return to work in the short- and long-term. This was more effective for people with acute rather than chronic back pain.[107]
## Prognosis
Overall, the outcome for acute low back pain is positive. Pain and disability usually improve a great deal in the first six weeks, with complete recovery reported by 40 to 90%.[2] In those who still have symptoms after six weeks, improvement is generally slower with only small gains up to one year. At one year, pain and disability levels are low to minimal in most people. Distress, previous low back pain, and job satisfaction are predictors of long-term outcome after an episode of acute pain.[2] Certain psychological problems such as depression, or unhappiness due to loss of employment may prolong the episode of low back pain.[13] Following a first episode of back pain, recurrences occur in more than half of people.[23]
For persistent low back pain, the short-term outcome is also positive, with improvement in the first six weeks but very little improvement after that. At one year, those with chronic low back pain usually continue to have moderate pain and disability.[2] People at higher risk of long-term disability include those with poor coping skills or with fear of activity (2.5 times more likely to have poor outcomes at one year),[108] those with a poor ability to cope with pain, functional impairments, poor general health, or a significant psychiatric or psychological component to the pain (Waddell's signs).[108]
Prognosis may be influenced by expectations, with those having positive expectations of recovery related to higher likelihood of returning to work and overall outcomes.[109]
## Epidemiology
Low back pain that lasts at least one day and limits activity is a common complaint.[7] Globally, about 40% of people have LBP at some point in their lives,[7] with estimates as high as 80% of people in the developed world.[22] Approximately 9 to 12% of people (632 million) have LBP at any given point in time, and nearly one quarter (23.2%) report having it at some point over any one-month period.[7][8] Difficulty most often begins between 20 and 40 years of age.[1] Low back pain is more common among people aged 40–80 years, with the overall number of individuals affected expected to increase as the population ages.[7]
It is not clear whether men or women have higher rates of low back pain.[7][8] A 2012 review reported a rate of 9.6% among males and 8.7% among females.[8] Another 2012 review found a higher rate in females than males, which the reviewers felt was possibly due to greater rates of pains due to osteoporosis, menstruation, and pregnancy among women, or possibly because women were more willing to report pain than men.[7] An estimated 70% of women experience back pain during pregnancy with the rate being higher the further along in pregnancy.[110] Current smokers – and especially those who are adolescents – are more likely to have low back pain than former smokers, and former smokers are more likely to have low back pain than those who have never smoked.[111]
## History
Harvey Williams Cushing, 1920s
Low back pain has been with humans since at least the Bronze Age. The oldest known surgical treatise – the Edwin Smith Papyrus, dating to about 1500 BCE – describes a diagnostic test and treatment for a vertebral sprain. Hippocrates (c. 460 BCE – c. 370 BCE) was the first to use a term for sciatic pain and low back pain; Galen (active mid to late second century CE) described the concept in some detail. Physicians through the end of the first millennium did not attempt back surgery and recommended watchful waiting. Through the Medieval period, folk medicine practitioners provided treatments for back pain based on the belief that it was caused by spirits.[112]
At the start of the 20th century, physicians thought low back pain was caused by inflammation of or damage to the nerves,[112] with neuralgia and neuritis frequently mentioned by them in the medical literature of the time.[113] The popularity of such proposed causes decreased during the 20th century.[113] In the early 20th century, American neurosurgeon Harvey Williams Cushing increased the acceptance of surgical treatments for low back pain.[14] In the 1920s and 1930s, new theories of the cause arose, with physicians proposing a combination of nervous system and psychological disorders such as nerve weakness (neurasthenia) and female hysteria.[112] Muscular rheumatism (now called fibromyalgia) was also cited with increasing frequency.[113]
Emerging technologies such as X-rays gave physicians new diagnostic tools, revealing the intervertebral disc as a source for back pain in some cases. In 1938, orthopedic surgeon Joseph S. Barr reported on cases of disc-related sciatica improved or cured with back surgery.[113] As a result of this work, in the 1940s, the vertebral disc model of low back pain took over,[112] dominating the literature through the 1980s, aiding further by the rise of new imaging technologies such as CT and MRI.[113] The discussion subsided as research showed disc problems to be a relatively uncommon cause of the pain. Since then, physicians have come to realize that it is unlikely that a specific cause for low back pain can be identified in many cases and question the need to find one at all as most of the time symptoms resolve within 6 to 12 weeks regardless of treatment.[112]
## Society and culture
Low back pain results in large economic costs. In the United States, it is the most common type of pain in adults, responsible for a large number of missed work days, and is the most common musculoskeletal complaint seen in the emergency department.[25] In 1998, it was estimated to be responsible for $90 billion in annual health care costs, with 5% of individuals incurring most (75%) of the costs.[25] Between 1990 and 2001 there was a more than twofold increase in spinal fusion surgeries in the US, despite the fact that there were no changes to the indications for surgery or new evidence of greater usefulness.[11] Further costs occur in the form of lost income and productivity, with low back pain responsible for 40% of all missed work days in the United States.[114] Low back pain causes disability in a larger percentage of the workforce in Canada, Great Britain, the Netherlands and Sweden than in the US or Germany.[114]
Workers who experience acute low back pain as a result of a work injury may be asked by their employers to have x-rays.[115] As in other cases, testing is not indicated unless red flags are present.[115] An employer's concern about legal liability is not a medical indication and should not be used to justify medical testing when it is not indicated.[115] There should be no legal reason for encouraging people to have tests which a health care provider determines are not indicated.[115]
## Research
Total disc replacement is an experimental option,[33] but no significant evidence supports its use over lumbar fusion.[14] Researchers are investigating the possibility of growing new intervertebral structures through the use of injected human growth factors, implanted substances, cell therapy, and tissue engineering.[33]
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66. ^ van Middelkoop M, Rubinstein SM, Verhagen AP, Ostelo RW, Koes BW, van Tulder MW (April 2010). "Exercise therapy for chronic nonspecific low-back pain". Best Practice & Research. Clinical Rheumatology. 24 (2): 193–204. doi:10.1016/j.berh.2010.01.002. PMID 20227641.
67. ^ Wewege, Michael A.; Booth, John; Parmenter, Belinda J. (25 October 2018). "Aerobic vs. resistance exercise for chronic non-specific low back pain: A systematic review and meta-analysis". Journal of Back and Musculoskeletal Rehabilitation. 31 (5): 889–899. doi:10.3233/BMR-170920. PMID 29889056.
68. ^ Woodman JP, Moore NR (January 2012). "Evidence for the effectiveness of Alexander Technique lessons in medical and health-related conditions: a systematic review". International Journal of Clinical Practice. 66 (1): 98–112. doi:10.1111/j.1742-1241.2011.02817.x. PMID 22171910. S2CID 7579458.
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70. ^ Dubinsky RM, Miyasaki J (January 2010). "Assessment: efficacy of transcutaneous electric nerve stimulation in the treatment of pain in neurologic disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology". Neurology. 74 (2): 173–6. doi:10.1212/WNL.0b013e3181c918fc. PMID 20042705.
71. ^ Saragiotto BT, Maher CG, Yamato TP, Costa LO, Menezes Costa LC, Ostelo RW, Macedo LG (January 2016). "Motor control exercise for chronic non-specific low-back pain". The Cochrane Database of Systematic Reviews (1): CD012004. doi:10.1002/14651858.cd012004. PMID 26742533.
72. ^ Tagliaferri, Scott D; Miller, Clint T; Ford, Jon J; Hahne, Andrew J; Main, Luana C; Rantalainen, Timo; Connell, David A; Simson, Katherine J; Owen, Patrick J; Belavy, Daniel L (3 June 2020). "Randomized Trial of General Strength and Conditioning Versus Motor Control and Manual Therapy for Chronic Low Back Pain on Physical and Self-Report Outcomes". Journal of Clinical Medicine. 9 (6): 1726. doi:10.3390/jcm9061726. PMC 7355598. PMID 32503243.
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94. ^ Macedo LG, Saragiotto BT, Yamato TP, Costa LO, Menezes Costa LC, Ostelo RW, Maher CG (February 2016). "Motor control exercise for acute non-specific low back pain". The Cochrane Database of Systematic Reviews. 2: CD012085. doi:10.1002/14651858.cd012085. PMID 26863390.
95. ^ a b c Furlan AD, Yazdi F, Tsertsvadze A, Gross A, Van Tulder M, Santaguida L, et al. (2012). "A systematic review and meta-analysis of efficacy, cost-effectiveness, and safety of selected complementary and alternative medicine for neck and low-back pain". Evidence-Based Complementary and Alternative Medicine. 2012: 953139. doi:10.1155/2012/953139. PMC 3236015. PMID 22203884.
96. ^ Lin CW, Haas M, Maher CG, Machado LA, van Tulder MW (July 2011). "Cost-effectiveness of guideline-endorsed treatments for low back pain: a systematic review". European Spine Journal. 20 (7): 1024–38. doi:10.1007/s00586-010-1676-3. PMC 3176706. PMID 21229367.
97. ^ a b c d Furlan AD, Giraldo M, Baskwill A, Irvin E, Imamura M (September 2015). "Massage for low-back pain". The Cochrane Database of Systematic Reviews (9): CD001929. doi:10.1002/14651858.CD001929.pub3. PMID 26329399.
98. ^ Gagnier JJ, Oltean H, van Tulder MW, Berman BM, Bombardier C, Robbins CB (January 2016). "Herbal Medicine for Low Back Pain: A Cochrane Review". Spine. 41 (2): 116–33. doi:10.1097/brs.0000000000001310. PMID 26630428.
99. ^ Cherkin DC, Herman PM (April 2018). "Cognitive and Mind-Body Therapies for Chronic Low Back Pain and Neck Pain: Effectiveness and Value". JAMA Internal Medicine. 178 (4): 556–557. doi:10.1001/jamainternmed.2018.0113. PMID 29507946. S2CID 3680364.
100. ^ Cramer H, Haller H, Lauche R, Dobos G (September 2012). "Mindfulness-based stress reduction for low back pain. A systematic review". BMC Complementary and Alternative Medicine. 12: 162. doi:10.1186/1472-6882-12-162. PMC 3520871. PMID 23009599.
101. ^ Anheyer D, Haller H, Barth J, Lauche R, Dobos G, Cramer H (June 2017). "Mindfulness-Based Stress Reduction for Treating Low Back Pain: A Systematic Review and Meta-analysis". Annals of Internal Medicine. 166 (11): 799–807. doi:10.7326/M16-1997. PMID 28437793. S2CID 1157568.
102. ^ Urrútia G, Burton AK, Morral A, Bonfill X, Zanoli G (19 April 2004). "Neuroreflexotherapy for non-specific low-back pain". The Cochrane Database of Systematic Reviews (2): CD003009. doi:10.1002/14651858.cd003009.pub2. PMID 15106186.
103. ^ Urrútia G, Burton K, Morral A, Bonfill X, Zanoli G (March 2005). "Neuroreflexotherapy for nonspecific low back pain: a systematic review". Spine. 30 (6): E148-53. doi:10.1097/01.brs.0000155575.85223.14. PMID 15770167. S2CID 31140257.
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## External links
Classification
D
* ICD-10: M54.5
* ICD-9-CM: 724.2
* MeSH: D017116
External resources
* MedlinePlus: 007422
* eMedicine: pmr/73
* Back and spine at Curlie
* "Back Pain". MedlinePlus. U.S. National Library of Medicine.
* v
* t
* e
Spinal disease
Deforming
Spinal curvature
* Kyphosis
* Lordosis
* Scoliosis
Other
* Scheuermann's disease
* Torticollis
Spondylopathy
inflammatory
* Spondylitis
* Ankylosing spondylitis
* Sacroiliitis
* Discitis
* Spondylodiscitis
* Pott disease
non inflammatory
* Spondylosis
* Spondylolysis
* Spondylolisthesis
* Retrolisthesis
* Spinal stenosis
* Facet syndrome
Back pain
* Neck pain
* Upper back pain
* Low back pain
* Coccydynia
* Sciatica
* Radiculopathy
Intervertebral disc disorder
* Schmorl's nodes
* Degenerative disc disease
* Spinal disc herniation
* Facet joint arthrosis
* v
* t
* e
Pain
By region/system
Head and neck
* Headache
* Neck
* Odynophagia (swallowing)
* Toothache
Respiratory system
* Sore throat
* Pleurodynia
Musculoskeletal
* Arthralgia (joint)
* Bone pain
* Myalgia (muscle)
* Acute
* Delayed-onset
Neurologic
* Neuralgia
* Pain asymbolia
* Pain disorder
* Paroxysmal extreme pain disorder
* Allodynia
* Chronic pain
* Hyperalgesia
* Hypoalgesia
* Hyperpathia
* Phantom pain
* Referred pain
* Congenital insensitivity to pain
* congenital insensitivity to pain with anhidrosis
* congenital insensitivity to pain with partial anhidrosis
Other
* Pelvic pain
* Proctalgia
* Back
* Low back pain
Measurement and testing
* Pain scale
* Cold pressor test
* Dolorimeter
* Grimace scale (animals)
* Hot plate test
* Tail flick test
* Visual analogue scale
Pathophysiology
* Nociception
* Anterolateral system
* Posteromarginal nucleus
* Substance P
Management
* Analgesia
* Anesthesia
* Cordotomy
* Pain eradication
Related concepts
* Pain threshold
* Pain tolerance
* Suffering
* SOCRATES
* Philosophy of pain
* Cancer pain
* Drug-seeking behavior
Authority control
* GND: 4036631-5
* NDL: 00574378
* NSK: 000054109
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Low back pain | c0024031 | 2,622 | wikipedia | https://en.wikipedia.org/wiki/Low_back_pain | 2021-01-18T19:00:32 | {"mesh": ["D017116"], "umls": ["C0024031"], "icd-9": ["724.2"], "icd-10": ["M54.5"], "wikidata": ["Q852163"]} |
## Description
Restless legs syndrome (RLS) is a neurologic sleep/wake disorder characterized by uncomfortable and unpleasant sensations in the legs that appear at rest, usually at night, inducing an irresistible desire to move the legs. The disorder results in nocturnal insomnia and chronic sleep deprivation (Bonati et al., 2003).
For additional information and a discussion of genetic heterogeneity of restless legs syndrome (RLS), see RLS1 (102300).
Clinical Features
Levchenko et al. (2006) reported a French Canadian pedigree in which 17 individuals had restless legs syndrome inherited in an autosomal dominant pattern.
Mapping
By genomewide linkage analysis in a French Canadian pedigree segregating restless legs syndrome, Levchenko et al. (2006) identified a 5.2-Mb candidate region, referred to as RLS5, on chromosome 20p13 (maximum multipoint lod score of 3.86 at D20S849).
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| RESTLESS LEGS SYNDROME, SUSCEPTIBILITY TO, 5 | c1970010 | 2,623 | omim | https://www.omim.org/entry/611242 | 2019-09-22T16:03:35 | {"omim": ["611242"]} |
A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type XVIII (OI18) is caused by homozygous mutation in the FAM46A gene (611357) on chromosome 6q14.
Description
Osteogenesis imperfecta type XVIII (OI18) is characterized by congenital bowing of the long bones, wormian bones, blue sclerae, vertebral collapse, and multiple fractures in the first years of life (Doyard et al., 2018).
Clinical Features
Doyard et al. (2018) reported 2 sibs and 2 unrelated patients with osteogenesis imperfecta and mutations in the FAM46A gene. The first patient was an Italian boy who was born with bowing of the femora and tibia, but also experienced swallowing difficulties and hyperthermic episodes in the first 6 months of life. He was originally diagnosed with Stuve-Wiedemann syndrome (601559), but his symptoms later became more consistent with a diagnosis of OI, with 4 spontaneous fractures and vertebral collapses in the first 2 years of life. He also had blue sclerae and abnormal teeth. He died suddenly and inexplicably at 4 years of age. A French brother and sister, born to first-cousin parents, showed bowing of the femora, poor mineralization, thin cortical bone, and numerous wormian bones at birth. They sustained numerous fractures in the first years of life, and also exhibited blue sclerae and joint hyperlaxity. The girl and her mother both had a marfanoid habitus, with arachnodactyly and joint hyperlaxity, but no cardiovascular abnormalities; the mother had no ocular abnormalities. The fourth patient was an Egyptian girl born to double-first-cousin parents, who presented at 5 years of age with a history of recurrent spontaneous fractures, approximately 7 per year. Dysmorphic features included high broad forehead, long eyelashes, wide palpebral fissures, blue sclerae, grooved philtrum, broad nasal root, and micrognathia. She also had joint laxity and an umbilical hernia. X-ray examination showed generalized osteoporotic texture, collapse of the lower 3 thoracic and first lumbar vertebral bodies with biconcave endplates (codfish vertebrae), thin ribs, bowing of long bones, thin cortex, multiple fractures, and wormian bones at the skull base. An older sister who was born with severe bowing of upper and lower limbs died of pneumonia at 3 months of age. The French sibs showed developmental delay, with speech delay in the brother and global hypotonia and motor delay in the sister; the Egyptian girl had motor developmental delay.
Molecular Genetics
In an Italian boy who exhibited features of Stuve-Wiedemann syndrome but was negative for mutation in the LIFR gene (151443), and who later developed symptoms consistent with OI, Doyard et al. (2018) performed exome sequencing and identified homozygosity for a frameshift mutation in the FAM46A gene (611357.0001). Screening the FAM46A gene in 25 patients with OI who were negative for mutation in known OI-associated genes revealed homozygosity for missense mutations in a French brother and sister (H127R; 611357.0002) and an Egyptian girl (D231G; 611357.0003).
INHERITANCE \- Autosomal recessive HEAD & NECK Face \- High broad forehead \- Grooved philtrum \- Micrognathia Eyes \- Blue sclerae \- Long eyelashes Nose \- Broad nasal root Teeth \- Abnormal teeth (rare) CHEST Ribs Sternum Clavicles & Scapulae \- Thin ribs \- Clavicular fractures ABDOMEN External Features \- Umbilical hernia (rare) SKELETAL \- Poor mineralization \- Multiple spontaneous fractures \- Thin cortex of bones Skull \- Wormian bones Spine \- Vertebral collapse \- Codfish vertebrae Limbs \- Bowing of long bones \- Joint laxity NEUROLOGIC Central Nervous System \- Motor developmental delay \- Speech delay MOLECULAR BASIS \- Caused by mutation in the family with sequence similarity 46, member A gene (FAM46A, 611357.0001 ) ▲ 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
| OSTEOGENESIS IMPERFECTA, TYPE XVIII | c4693736 | 2,624 | omim | https://www.omim.org/entry/617952 | 2019-09-22T15:44:26 | {"omim": ["617952"]} |
A number sign (#) is used with this entry because of a clear genetic heterogeneity and demonstration of specific genetic causes in a number of instances. These include mutations of keratin 8 (KRT8; 148060) and keratin 18 (KRT18; 148070), which cause cryptogenic cirrhosis as well as susceptibility to noncryptogenic cirrhosis.
Aside from Wilson disease (277900), type IV glycogen storage disease (232500), and galactosemia (230400), which are well-known causes of familial cirrhosis, families with multiple affected sibs and normal parents have been observed (Iber and Maddrey, 1965). The group is probably heterogeneous and in some instances nongenetic factors may be responsible for the familial aggregation. Iber and Maddrey (1965) reviewed 13 reported families and 8 of their own, each with 2 or more affected members. They pointed out that with 1 exception the multiple cases were in the same generation. Within a given family, age of onset, clinical course, and biopsy findings were very similar, but there were wide differences between families. Baber (1956) described cases of congenital cirrhosis with generalized amino aciduria. Some of these patients may be examples of Wilson disease. Others may have tyrosinemia (Zetterstrom, 1963; Gentz et al., 1965). See tyrosinemia (276700). In India, so-called Indian childhood cirrhosis (Sen syndrome) affects multiple sibs (Chaudhuri and Chaudhuri, 1965). The disorder usually has its onset between ages 6 and 18 months and is said to be several times more frequent in males than in females; familial cases are frequent (Srivastava, 1956). Lefkowitch et al. (1982) described 4 white American sibs who died between ages 4.5 and 6 years of cirrhosis. Progressive lethargy, abdominal swelling, jaundice, and fever developed 4 to 7 months before death. The liver histopathology closely resembled that of the childhood cirrhosis of Asiatic Indians and included severe panlobular liver-cell swelling with Mallory body formation, prominent pericellular fibrosis, 'micro-micronodular' cirrhosis, and marked deposits of copper and copper-binding protein. Hepatic copper levels were as much as 40 times normal. The parents were apparently not related. The father was adopted. The mother, of Scottish and Irish extraction, had a single sib, a brother who died at the age of 10 years of cirrhosis. Copper-overload is a feature of the Indian childhood cirrhosis also. Before the report by Lefkowitch et al. (1982), the clinical syndrome had been described only in children in India, Pakistan, Sri Lanka, and Burma (Mowat, 1979) and rarely in immigrants to Britain from India (Tanner et al., 1978). The family history is said to be positive in about 30% of cases. Although one might suspect (in view of the population distribution) autosomal recessive inheritance with an occult selectively advantageous polymorphism in heterozygotes, no formal proof is available.
Kalra et al. (1982) studied the families of 220 cases of Indian childhood cirrhosis and 70 families of age-matched controls. The hypotheses of autosomal recessive, partial sex-linkage, and doubly recessive inheritance were found untenable. Multifactorial inheritance was found more plausible. In a review of the subject, Kumar (1984) concluded that multifactorial inheritance is likely. Gahl et al. (1988) pointed out that the use of brass cooking utensils in Indian families with ICC suggests an environmental source of copper toxicity; however, the 25% frequency of familial disease points to a genetic basis as well. Gahl et al. (1988) studied a 2-year-old boy with features of ICC whose parents were third cousins of European descent. He was normal at birth but had poor growth in infancy. At 18 months he developed nephrogenic diabetes insipidus. At 21 months liver enzymes were elevated and biopsy showed mild fibrosis and electron-dense granules, which electron probe analysis showed to contain sulfur and copper. By 29 months progressive liver failure and advanced micronodular cirrhosis with occasional Mallory bodies were found. The remaining hepatocytes stained strongly with rhodamine (for copper) and with orcein (for copper-binding proteins). The patient died at 32 months of an esophageal variceal bleed. The patient's disease was manifest in cultured fibroblasts. This may represent a lysosomal storage disorder. Yet another cause of congenital cirrhosis is alpha-1-antitrypsin deficiency (613490). Familial aggregation of chronic active hepatitis due to hepatitis B virus is discussed elsewhere (118900). The coincidence of liver disease and 'primary' pulmonary hypertension was indicated by 2 brothers in a family originally reported by Maddrey and Iber (1964), according to follow-up information from Summer and Herlong (1982); 3 brothers, 2 of them identical twins, were by then affected.
Muller et al. (1996) described 138 cases of endemic Tyrolean infantile cirrhosis (ETIC) which was clinically and pathologically indistinguishable from Indian childhood cirrhosis (ICC) and idiopathic copper toxicosis (ICT) (Scheinberg and Sternlieb, 1996). It also resembled the early-onset form of Wilson disease. Although ETIC, ICC, and ICT require copper-enriched diets to become manifest (Tanner et al., 1983), it was thought that these disorders might represent allelic variants of Wilson disease. ETIC, like Wilson disease, shows autosomal recessive inheritance. In contrast to the 30 isolated cases described worldwide, the high frequency of ETIC in the Tyrol (Muller et al., 1996) suggested a founder effect. Wijmenga et al. (1998) published a pedigree with 11 affected children in 6 sibships, all of consanguineous parents and all with both parents tracing back to a common ancestral couple 10 generations ago. The lethality of the disease meant that no living children were available, but 8 pairs of parents were identified with at least 1 ETIC child. Wijmenga et al. (1998) studied the possible role of the ATP7B gene, mutant in Wilson disease, in ETIC by investigating association and haplotype sharing in obligate gene carriers. Haplotypes in ETIC carriers did not demonstrate sharing and the association studies did not detect linkage disequilibrium between ETIC and the individual markers at 13q14.3 where the ATP7B gene maps.
Muller et al. (1999) encountered 8 cases of infantile liver cirrhosis in 5 families in Emsland, a circumscribed and predominantly rural area of Northern Germany; ICT was definitely proven in 2 cases. Clinical presentation and liver pathology in 6 additional cases were consistent with the diagnosis of ICT. Pedigrees of affected families revealed complex relationships with occasional consanguinity of parents, suggesting autosomal recessive inheritance. The households were served by private wells with water of low pH flowing through copper pipes, suggesting the possibility of increased alimentary copper exposure. These findings supported an earlier conclusion that ICT develops when an infant with a genetic predisposition is exposed to a copper-enriched diet.
Pulmonary hypertension can develop as a complication of portal hypertension (Krowka, 1993). Hadengue et al. (1991) suggested that the pulmonary endothelial damage in this hepatopulmonary syndrome may be caused by nonmetabolized substances in the portal blood that reach the pulmonary vasculature through portal systemic shunting.
Patel and Parekh (1997) reported that parents and social workers observed an absence of rigor mortis for a minimum of 12 hours to a maximum of 30 hours postmortem in 37 children who died of ICC between the ages of 10 months and 2 years; the authors observed absence of rigor mortis for 22 to 36 hours after death in 5 hospitalized patients. Children who died from other causes developed body stiffness within 4 to 6 hours. Patel and Parekh (1997) noted that the absence of rigor mortis had not been mentioned in previous studies of ICC and postulated that excess glycogen in the muscles of these patients would facilitate postmortem ATP resynthesis and so delay the development of rigor.
Neuro \- Lethargy Lab \- Liver histopathology shows severe panlobular liver-cell swelling with Mallory body formation, prominent pericellular fibrosis, 'micro-micronodular' cirrhosis, and marked deposits of copper and copper-binding protein \- Hepatic copper increased Inheritance \- Autosomal recessive cases, probably heterogeneous Skin \- Jaundice Vascular \- 'Primary' pulmonary hypertension Misc \- Fever Abdomen \- Swelling GI \- Congenital cirrhosis \- Childhood cirrhosis \- Esophageal varices ▲ 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
| CIRRHOSIS, FAMILIAL | c0268074 | 2,625 | omim | https://www.omim.org/entry/215600 | 2019-09-22T16:29:33 | {"mesh": ["C562580"], "omim": ["215600"], "icd-10": ["K74.69"], "orphanet": ["209919"], "synonyms": ["Non-Wilsonian hepatic copper toxicosis of infancy and childhood"]} |
Spinocerebellar ataxia type 18 (SCA18) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by sensory neuropathy and cerebellar ataxia.
## Epidemiology
Prevalence is unknown. Only 26 cases in a 5-generation American family of Irish ancestry have been reported to date.
## Clinical description
Onset is in the 2nd and 3rd decades of life with symptomatic onset ranging from 13 to 27 years. Patients initially present with axonal sensory neuropathy, while cerebellar ataxia and motor neuron dysfunction develop later.
## Etiology
SCA18 has been linked to chromosome 7q22-q23 but the responsible gene mutation has not yet been identified. Both SCA3 and SCA4 are also associated with a peripheral neuropathy and should be taken into account in the differential diagnosis.
## Prognosis
Prognosis is unclear. However, mean disease duration from age at onset of illness to age at last examination is about 24 years in the reported cases.
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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
| Spinocerebellar ataxia type 18 | c1843884 | 2,626 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98771 | 2021-01-23T17:32:01 | {"gard": ["9976"], "mesh": ["C537197"], "omim": ["607458"], "umls": ["C1843884"], "icd-10": ["G11.8"], "synonyms": ["SCA18"]} |
Hyperprolinemia is when there is an excess of a particular protein building block (amino acid), called proline, in the blood. This condition generally occurs when proline is not broken down properly by the body. There are two inherited forms: hyperprolinemia type 1 and hyperprolinemia type 2. People with hyperprolinemia type I often do not show any symptoms, although they have proline levels in their blood between 3 and 10 times the normal level. Less commonly, affected individuals can experience seizures, intellectual disability, or other neurological or psychiatric problems. Hyperprolinemia is caused by mutations in the PRODH gene and is inherited in an autosomal recessive pattern.
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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
| Hyperprolinemia | c0268529 | 2,627 | gard | https://rarediseases.info.nih.gov/diseases/2847/hyperprolinemia | 2021-01-18T17:59:54 | {"omim": ["239500"], "orphanet": ["419"], "synonyms": ["Proline oxidase deficiency", "Proline hydrogenase deficiency", "Hyperprolinemia type 1"]} |
Smith-Magenis syndrome (SMS) is a developmental disorder that affects many parts of the body. The major features of this condition include mild to moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems. Most people with SMS have a deletion of genetic material in each cell from a specific region of chromosome 17. Although this region contains multiple genes, researchers believe that the loss of one particular gene, RAI1, is responsible for most of the features of the condition. In most of these cases, the deletion is not inherited, occurring randomly during the formation of eggs or sperm, or in early fetal development. In rare cases, the deletion is due to a chromosomal balanced translocation in one of the parents. In about 10% of cases, SMS is caused by a mutation in the RAI1 gene. These mutations may occur randomly, or may be inherited from a parent in an autosomal dominant manner. Treatment for SMS depends on the symptoms present in each person.
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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
| Smith-Magenis syndrome | c0795864 | 2,628 | gard | https://rarediseases.info.nih.gov/diseases/8197/smith-magenis-syndrome | 2021-01-18T17:57:01 | {"mesh": ["D058496"], "omim": ["182290"], "umls": ["C0795864"], "orphanet": ["819"], "synonyms": ["SMS", "Chromosome 17p11.2 deletion syndrome"]} |
Multiple mitochondrial dysfunctions syndrome describes a group of rare inborn errors of energy metabolism due to defects in mitochondrial [4Fe-4S] protein assembly. Patients present with a neonatal/infancy onset of metabolic lactic acidosis (that may be associated with hyperglycinemia and other abnormal metabolic testing results), muscular hypotonia, absence of psychomotor development or developmental regression, as well as abnormal neuroimaging findings (including leukodystrophy, brain developmental defects, white matter abnormalities, cerebral atrophy), and other variable clinical features (e.g., optic atrophy, cardiomyopathy, pulmonary hypertension, seizures, and dysmorphic features). Early fatal outcome is usual.
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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
| Multiple mitochondrial dysfunctions syndrome | c3502075 | 2,629 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=289573 | 2021-01-23T17:01:55 | {"gard": ["12632"], "mesh": ["C565304"]} |
The morning glory disc anomaly (MGDA) is a congenital deformity resulting from failure of the optic nerve to completely form in utero.[1] The term was coined in 1970 by Kindler, noting a resemblance of the malformed optic nerve to the morning glory flower.[2] The condition is usually unilateral.[3]
## Contents
* 1 Presentation
* 1.1 Complications
* 1.2 Associated conditions
* 2 Diagnosis
* 3 See also
* 4 References
## Presentation[edit]
### Complications[edit]
Serous retinal detachment can occur in the affected eye.[4]
### Associated conditions[edit]
Although the finding itself is rare, MGDA can be associated with midline cranial defects and abnormal carotid circulation, such as carotid stenosis/aplasia or progressive vascular obstruction with collateralization (also known as moyamoya disease).[4] The vascular defects may lead to ischemia, stroke, or seizures and so a finding of MGDA should be further investigated with radiographic imaging.
## Diagnosis[edit]
On fundoscopic examination, there are three principal findings comprising the anomaly:[5]
1. an enlarged, funnel-shaped excavation in optic disc
2. an annulus or ring of chorioretinal pigmentary changes surrounding the optic disc excavation
3. a central glial tuft overlying the optic disc
## See also[edit]
* Coloboma of optic nerve
## References[edit]
1. ^ Magrath, GN; Cheeseman EW; Sarrica RA (2013). "Morning Glory Disc Anomaly". Pediatric Neurology. 49 (6): 517. doi:10.1016/j.pediatrneurol.2013.05.015.
2. ^ Kindler (1970). "Morning glory syndrome: unusual congenital optic disk anomaly". Am J Ophthalmol. 69 (3): 376–84. doi:10.1016/0002-9394(70)92269-5.
3. ^ Barnard, Simon. "An Introduction to Diseases of the Optic nerve". Retrieved 30 May 2014.
4. ^ a b Quah, BL; Hamilton J; Blaser S; et al. (2005). "Morning glory disc anomaly, midline cranial defects and abnormal carotid circulation: an association worth looking for". Pediatr Radiol. 35 (5): 525–528. doi:10.1007/s00247-004-1345-y.
5. ^ Auber, AE; O’Hara M (1999). "Morning glory syndrome. MR imaging". Clin Imaging. 23: 152–158. doi:10.1016/s0899-7071(99)00118-7.
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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
| Morning glory disc anomaly | c0393782 | 2,630 | wikipedia | https://en.wikipedia.org/wiki/Morning_glory_disc_anomaly | 2021-01-18T18:33:10 | {"gard": ["13354", "8502"], "mesh": ["C535970"], "umls": ["C0393782"], "icd-10": ["Q14.2"], "orphanet": ["35737"], "wikidata": ["Q18070807"]} |
Polydactyly of a triphalangeal thumb or PPD2 is a form of preaxial polydactyly of fingers (see this term), a limb malformation syndrome, that is characterized by the presence of a usually opposable triphalangeal thumb with or without additional duplication of one or more skeletal components of the thumb. The thumb appearance can differ widely in shape (wedge to rectangular) or it can be deviated in the radio-ulnar plane (clinodactyly). PPD2 is also associated with systemic syndromes, including Holt-Oram syndrome and Fanconi anemia (see these terms).
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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
| Polydactyly of a triphalangeal thumb | c1868114 | 2,631 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93336 | 2021-01-23T17:04:48 | {"gard": ["5289"], "mesh": ["C536311"], "omim": ["174500"], "umls": ["C1868114"], "icd-10": ["Q69.1"], "synonyms": ["PPD2", "Preaxial polydactyly type 2"]} |
Experience of intense sexual arousal to atypical objects, situations, or individuals
Paraphilia
SpecialtyPsychiatry
CausesSexual attraction
Paraphilia (previously known as sexual perversion and sexual deviation[1]) is the experience of intense sexual arousal to atypical objects, situations, fantasies, behaviors, or individuals.[2][3]
No consensus has been found for any precise border between unusual sexual interests and paraphilic ones.[4][5] There is debate over which, if any, of the paraphilias should be listed in diagnostic manuals, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases (ICD).
The number and taxonomy of paraphilia is under debate; one source lists as many as 549 types of paraphilia.[6] The DSM-5 has specific listings for eight paraphilic disorders.[2] Several sub-classifications of the paraphilias have been proposed, and some argue that a fully dimensional, spectrum or complaint-oriented approach would better reflect the evidence.[7][8]
## Contents
* 1 Terminology
* 1.1 Homosexuality and non-heterosexuality
* 2 Causes
* 3 Diagnosis
* 3.1 Typical versus atypical interests
* 3.2 Intensity and specificity
* 3.3 Diagnostic and Statistical Manual of Mental Disorders
* 3.3.1 DSM-I and DSM-II
* 3.3.2 DSM-III through DSM-IV
* 3.3.3 DSM-IV-TR
* 3.3.4 DSM-5
* 4 Management
* 4.1 Medications
* 4.1.1 SSRIs
* 4.1.2 Antiandrogens
* 5 Epidemiology
* 6 Legal issues
* 7 See also
* 8 References
* 9 Further reading
* 10 External links
## Terminology[edit]
Many terms have been used to describe atypical sexual interests, and there remains debate regarding technical accuracy and perceptions of stigma. Sexologist John Money popularized the term paraphilia as a non-pejorative designation for unusual sexual interests.[9][10][11][12] Money described paraphilia as "a sexuoerotic embellishment of, or alternative to the official, ideological norm."[13] Psychiatrist Glen Gabbard writes that despite efforts by Stekel and Money, "the term paraphilia remains pejorative in most circumstances."[14]
Coinage of the term paraphilia (paraphilie) has been credited to Friedrich Salomon Krauss in 1903, and it entered the English language in 1913, in reference to Krauss by urologist William J. Robinson.[15] It was used with some regularity by Wilhelm Stekel in the 1920s.[16] The term comes from the Greek παρά (para) "beside" and φιλία (-philia) "friendship, love".
In the late 19th century, psychologists and psychiatrists started to categorize various paraphilias as they wanted a more descriptive system than the legal and religious constructs of sodomy[17] and perversion.[18] Before the introduction of the term paraphilia in the DSM-III (1980), the term sexual deviation was used to refer to paraphilias in the first two editions of the manual.[19] In 1981, an article published in American Journal of Psychiatry described paraphilia as "recurrent, intense sexually arousing fantasies, sexual urges, or behaviors generally involving" the following:[20]
* Non-human objects
* The suffering or humiliation of oneself or one's partner
* Children
* Non-consenting persons
### Homosexuality and non-heterosexuality[edit]
Homosexuality, now widely accepted to be a normal variant of human sexuality, was at one time discussed as a sexual deviation.[21] Sigmund Freud and subsequent psychoanalytic thinkers considered homosexuality and paraphilias to result from psychosexual non-normative relations to the Oedipal complex.[22] As such, the term sexual perversion or the epithet pervert have historically referred to gay men, as well as other non-heterosexuals (people who fall out of the perceived norms of sexual orientation).[21][22][23][24]
By the mid-20th century, mental health practitioners began formalizing "deviant sexuality" classifications into categories. Originally coded as 000-x63, homosexuality was the top of the classification list (Code 302.0) until the American Psychiatric Association removed homosexuality from the DSM in 1973. Martin Kafka writes, "Sexual disorders once considered paraphilias (e.g., homosexuality) are now regarded as variants of normal sexuality."[23]
A 2012 literature study by clinical psychologist James Cantor, when comparing homosexuality with paraphilias, found that both share "the features of onset and course (both homosexuality and paraphilia being life-long), but they appear to differ on sex ratio, fraternal birth order, handedness, IQ and cognitive profile, and neuroanatomy". The research then concluded that the data seemed to suggest paraphilias and homosexuality as two distinct categories, but regarded the conclusion as "quite tentative" given the current limited understanding of paraphilias.[24]
## Causes[edit]
The causes of paraphilic sexual preferences in people are unclear, although a growing body of research points to a possible prenatal neurodevelopmental correlation. A 2008 study analyzing the sexual fantasies of 200 heterosexual men by using the Wilson Sex Fantasy Questionnaire exam determined that males with a pronounced degree of fetish interest had a greater number of older brothers, a high 2D:4D digit ratio (which would indicate excessive prenatal estrogen exposure), and an elevated probability of being left-handed, suggesting that disturbed hemispheric brain lateralization may play a role in deviant attractions.[25]
Behavioral explanations propose that paraphilias are conditioned early in life, during an experience that pairs the paraphilic stimulus with intense sexual arousal.[26] Susan Nolen-Hoeksema suggests that, once established, masturbatory fantasies about the stimulus reinforce and broaden the paraphilic arousal.[26]
## Diagnosis[edit]
There is scientific and political controversy regarding the continued inclusion of sex-related diagnoses such as the paraphilias in the DSM, due to the stigma of being classified as a mental illness.[27]
Some groups, seeking greater understanding and acceptance of sexual diversity, have lobbied for changes to the legal and medical status of unusual sexual interests and practices. Charles Allen Moser, a physician and advocate for sexual minorities, has argued that the diagnoses should be eliminated from diagnostic manuals.[28]
### Typical versus atypical interests[edit]
Albert Eulenburg (1914) noted a commonality across the paraphilias, using the terminology of his time, "All the forms of sexual perversion...have one thing in common: their roots reach down into the matrix of natural and normal sex life; there they are somehow closely connected with the feelings and expressions of our physiological erotism. They are...hyperbolic intensifications, distortions, monstrous fruits of certain partial and secondary expressions of this erotism which is considered 'normal' or at least within the limits of healthy sex feeling."[29]
The clinical literature contains reports of many paraphilias, only some of which receive their own entries in the diagnostic taxonomies of the American Psychiatric Association or the World Health Organization.[30][31] There is disagreement regarding which sexual interests should be deemed paraphilic disorders versus normal variants of sexual interest. For example, as of May 2000, per DSM-IV-TR, "Because some cases of Sexual Sadism may not involve harm to a victim (e.g., inflicting humiliation on a consenting partner), the wording for sexual sadism involves a hybrid of the DSM-III-R and DSM-IV wording (i.e., "the person has acted on these urges with a non-consenting person, or the urges, sexual fantasies, or behaviors cause marked distress or interpersonal difficulty").[32]
The DSM-IV-TR also acknowledges that the diagnosis and classification of paraphilias across cultures or religions "is complicated by the fact that what is considered deviant in one cultural setting may be more acceptable in another setting”.[33] Some argue that cultural relativism is important to consider when discussing paraphilias, because there is wide variance concerning what is sexually acceptable across cultures.[34]
Consensual adult activities and adult entertainment involving sexual roleplay, novel, superficial, or trivial aspects of sexual fetishism, or incorporating the use of sex toys are not necessarily paraphilic.[33] Paraphilial psychopathology is not the same as psychologically normative adult human sexual behaviors, sexual fantasy, and sex play.[35]
### Intensity and specificity[edit]
Clinicians distinguish between optional, preferred and exclusive paraphilias,[36] though the terminology is not completely standardized. An "optional" paraphilia is an alternative route to sexual arousal. In preferred paraphilias, a person prefers the paraphilia to conventional sexual activities, but also engages in conventional sexual activities.
The literature includes single-case studies of exceedingly rare and idiosyncratic paraphilias. These include an adolescent male who had a strong fetishistic interest in the exhaust pipes of cars, a young man with a similar interest in a specific type of car, and a man who had a paraphilic interest in sneezing (both his own and the sneezing of others).[37][38]
### Diagnostic and Statistical Manual of Mental Disorders[edit]
Main article: Diagnostic and Statistical Manual of Mental Disorders
#### DSM-I and DSM-II[edit]
In American psychiatry, prior to the publication of the DSM-I, paraphilias were classified as cases of "psychopathic personality with pathologic sexuality". The DSM-I (1952) included sexual deviation as a personality disorder of sociopathic subtype. The only diagnostic guidance was that sexual deviation should have been "reserved for deviant sexuality which [was] not symptomatic of more extensive syndromes, such as schizophrenic or obsessional reactions". The specifics of the disorder were to be provided by the clinician as a "supplementary term" to the sexual deviation diagnosis; there were no restrictions in the DSM-I on what this supplementary term could be.[39] Researcher Anil Aggrawal writes that the now-obsolete DSM-I listed examples of supplementary terms for pathological behavior to include "homosexuality, transvestism, pedophilia, fetishism, and sexual sadism, including rape, sexual assault, mutilation."[40]
The DSM-II (1968) continued to use the term sexual deviations, but no longer ascribed them under personality disorders, but rather alongside them in a broad category titled "personality disorders and certain other nonpsychotic mental disorders". The types of sexual deviations listed in the DSM-II were: sexual orientation disturbance (homosexuality), fetishism, pedophilia, transvestitism (sic), exhibitionism, voyeurism, sadism, masochism, and "other sexual deviation". No definition or examples were provided for "other sexual deviation", but the general category of sexual deviation was meant to describe the sexual preference of individuals that was "directed primarily toward objects other than people of opposite sex, toward sexual acts not usually associated with coitus, or toward coitus performed under bizarre circumstances, as in necrophilia, pedophilia, sexual sadism, and fetishism."[41] Except for the removal of homosexuality from the DSM-III onwards, this definition provided a general standard that has guided specific definitions of paraphilias in subsequent DSM editions, up to DSM-IV-TR.[42]
#### DSM-III through DSM-IV[edit]
The term paraphilia was introduced in the DSM-III (1980) as a subset of the new category of "psychosexual disorders."
The DSM-III-R (1987) renamed the broad category to sexual disorders, renamed atypical paraphilia to paraphilia NOS (not otherwise specified), renamed transvestism as transvestic fetishism, added frotteurism, and moved zoophilia to the NOS category. It also provided seven nonexhaustive examples of NOS paraphilias, which besides zoophilia included exhibitionism, necrophilia, partialism, coprophilia, klismaphilia, and urophilia.[43]
The DSM-IV (1994) retained the sexual disorders classification for paraphilias, but added an even broader category, "sexual and gender identity disorders," which includes them. The DSM-IV retained the same types of paraphilias listed in DSM-III-R, including the NOS examples, but introduced some changes to the definitions of some specific types.[42]
#### DSM-IV-TR[edit]
The DSM-IV-TR describes paraphilias as "recurrent, intense sexually arousing fantasies, sexual urges or behaviors generally involving nonhuman objects, the suffering or humiliation of oneself or one's partner, or children or other nonconsenting persons that occur over a period of six months" (criterion A), which "cause clinically significant distress or impairment in social, occupational, or other important areas of functioning" (criterion B). DSM-IV-TR names eight specific paraphilic disorders (exhibitionism, fetishism, frotteurism, pedophilia, sexual masochism, sexual sadism, voyeurism, and transvestic fetishism, plus a residual category, paraphilia—not otherwise specified).[44] Criterion B differs for exhibitionism, frotteurism, and pedophilia to include acting on these urges, and for sadism, acting on these urges with a nonconsenting person.[36] Sexual arousal in association with objects that were designed for sexual purposes is not diagnosable.[36]
Some paraphilias may interfere with the capacity for sexual activity with consenting adult partners.[36]
In the current version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), a paraphilia is not diagnosable as a psychiatric disorder unless it causes distress to the individual or harm to others.[3]
#### DSM-5[edit]
The DSM-5 adds a distinction between paraphilias and paraphilic disorders, stating that paraphilias do not require or justify psychiatric treatment in themselves, and defining paraphilic disorder as "a paraphilia that is currently causing distress or impairment to the individual or a paraphilia whose satisfaction has entailed personal harm, or risk of harm, to others".[2]
The DSM-5 Paraphilias Subworkgroup reached a "consensus that paraphilias are not ipso facto psychiatric disorders", and proposed "that the DSM-V make a distinction between paraphilias and paraphilic disorders. [...] One would ascertain a paraphilia (according to the nature of the urges, fantasies, or behaviors) but diagnose a paraphilic disorder (on the basis of distress and impairment). In this conception, having a paraphilia would be a necessary but not a sufficient condition for having a paraphilic disorder." The 'Rationale' page of any paraphilia in the electronic DSM-5 draft continues: "This approach leaves intact the distinction between normative and non-normative sexual behavior, which could be important to researchers, but without automatically labeling non-normative sexual behavior as psychopathological. It also eliminates certain logical absurdities in the DSM-IV-TR. In that version, for example, a man cannot be classified as a transvestite—however much he cross-dresses and however sexually exciting that is to him—unless he is unhappy about this activity or impaired by it. This change in viewpoint would be reflected in the diagnostic criteria sets by the addition of the word 'Disorder' to all the paraphilias. Thus, Sexual Sadism would become Sexual Sadism Disorder; Sexual Masochism would become Sexual Masochism Disorder, and so on."[45]
Bioethics professor Alice Dreger interpreted these changes as "a subtle way of saying sexual kinks are basically okay – so okay, the sub-work group doesn't actually bother to define paraphilia. But a paraphilic disorder is defined: that's when an atypical sexual interest causes distress or impairment to the individual or harm to others." Interviewed by Dreger, Ray Blanchard, the Chair of the Paraphilias Sub-Work Group, stated, "We tried to go as far as we could in depathologizing mild and harmless paraphilias, while recognizing that severe paraphilias that distress or impair people or cause them to do harm to others are validly regarded as disorders."[46]
Charles Allen Moser stated that this change is not really substantive, as the DSM-IV already acknowledged a difference between paraphilias and non-pathological but unusual sexual interests, a distinction that is virtually identical to what was being proposed for DSM-5, and it is a distinction that, in practice, has often been ignored.[47] Linguist Andrew Clinton Hinderliter argued that "including some sexual interests—but not others—in the DSM creates a fundamental asymmetry and communicates a negative value judgment against the sexual interests included," and leaves the paraphilias in a situation similar to ego-dystonic homosexuality, which was removed from the DSM because it was realized not to be a mental disorder.[48]
The DSM-5 acknowledges that many dozens of paraphilias exist, but only has specific listings for eight that are forensically important and relatively common. These are voyeuristic disorder, exhibitionistic disorder, frotteuristic disorder, sexual masochism disorder, sexual sadism disorder, pedophilic disorder, fetishistic disorder, and transvestic disorder.[2] Other paraphilias can be diagnosed under the Other Specified Paraphilic Disorder or Unspecified Paraphilic Disorder listings, if accompanied by distress or impairment.[49]
## Management[edit]
Most clinicians and researchers believe that paraphilic sexual interests cannot be altered,[50] although evidence is needed to support this.[50] Instead, the goal of therapy is normally to reduce the person's discomfort with their paraphilia and limit any criminal behavior.[50] Both psychotherapeutic and pharmacological methods are available to these ends.[50]
Cognitive behavioral therapy, at times, can help people with paraphilias develop strategies to avoid acting on their interests.[50] Patients are taught to identify and cope with factors that make acting on their interests more likely, such as stress.[50] It is currently the only form of psychotherapy for paraphilias supported by randomized double-blind trials, as opposed to case studies and consensus of expert opinion.[51]
### Medications[edit]
Pharmacological treatments can help people control their sexual behaviors, but do not change the content of the paraphilia.[51] They are typically combined with cognitive behavioral therapy for best effect.[52]
#### SSRIs[edit]
Selective serotonin reuptake inhibitors (SSRIs) are used, especially with exhibitionists, non-offending pedophiles, and compulsive masturbators. They are proposed to work by reducing sexual arousal, compulsivity, and depressive symptoms.[52] They have been well received and are considered an important pharmacological treatment of paraphilia.[53]
#### Antiandrogens[edit]
Antiandrogens are used in more severe cases.[52] Similar to physical castration, they work by reducing androgen levels, and have thus been described as chemical castration.[52] The antiandrogen cyproterone acetate has been shown to substantially reduce sexual fantasies and offending behaviors.[52] Medroxyprogesterone acetate and gonadotropin-releasing hormone agonists (such as leuprorelin) have also been used to lower sex drive.[52] Due to the side effects, the World Federation of Societies of Biological Psychiatry recommends that hormonal treatments only be used when there is a serious risk of sexual violence, or when other methods have failed.[51] Surgical castration has largely been abandoned because these pharmacological alternatives are similarly effective and less invasive.[54]
## Epidemiology[edit]
Research has shown that paraphilias are rarely observed in women.[55][56] However, there have been some studies on females with paraphilias.[57] Sexual masochism has been found to be the most commonly observed paraphilia in women, with approximately 1 in 20 cases of sexual masochism being female.[36][56]
Many acknowledge the scarcity of research on female paraphilias.[58] The majority of paraphilia studies are conducted on people who have been convicted of sex crimes.[59] Since the number of male convicted sex offenders far exceeds the number of female convicted sex offenders, research on paraphilic behavior in women is consequently lacking.[59] Some researchers argue that an underrepresentation exists concerning pedophilia in females.[60] Due to the low number of women in studies on pedophilia, most studies are based from "exclusively male samples".[60] This likely underrepresentation may also be attributable to a "societal tendency to dismiss the negative impact of sexual relationships between young boys and adult women".[60] Michele Elliott has done extensive research on child sexual abuse committed by females, publishing the book Female Sexual Abuse of Children: The Last Taboo in an attempt to challenge the gender-biased discourse surrounding sex crimes.[61] John Hunsley states that physiological limitations in the study of female sexuality must also be acknowledged when considering research on paraphilias. He states that while a man's sexual arousal can be directly measured from his erection (see penile plethysmograph), a woman's sexual arousal cannot be measured as clearly (see vaginal photoplethysmograph), and therefore research concerning female sexuality is rarely as conclusive as research on men.[58]
## Legal issues[edit]
In the United States, since 1990 a significant number of states have passed sexually violent predator laws.[62] Following a series of landmark cases in the Supreme Court of the United States, persons diagnosed with paraphilias, particularly pedophilia (Kansas v. Hendricks, 1997) and exhibitionism (Kansas v. Crane, 2002), with a history of anti-social behavior and related criminal history, can be held indefinitely in civil confinement under various state legislation generically known as sexually violent predator laws[63][64] and the federal Adam Walsh Act (United States v. Comstock, 2010).[65][66]
## See also[edit]
* Psychology portal
* Human sexuality portal
* Psychiatry portal
* List of paraphilias
* Perversion
* -phil- (list of philias)
* Courtship disorder
* Dorian Gray syndrome
* Erotic target location error
* Human sexuality
* Lovemap
* Object sexuality
* Psychosexual development
* Richard von Krafft-Ebing
* Sex and the law
* Sexual ethics
## References[edit]
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Bibliography
* D. Richard Laws, William T. O'Donohue (ed.), Sexual Deviance: Theory, Assessment, and Treatment, 2nd ed., Guilford Press, 2008, ISBN 978-1-59385-605-2
## Further reading[edit]
* Kenneth Plummer, Sexual stigma: an interactionist account, Routledge, 1975, ISBN 0-7100-8060-3
* Elisabeth Roudinesco, Our Dark Side, a History of Perversion, Polity Press, 2009, ISBN 0-7456-4593-3
* David Morgan (psychoanalyst), Married to the Eiffel Tower. [1]
* "Deviance or Normalcy? The Relationship Among Paraphilic Thoughts and Behaviors, Hypersexuality, and Psychopathology in a Sample of University Students" (PDF). Journal of Sexual Medicine. Archived from the original (PDF) on 24 March 2020.
## External links[edit]
Classification
D
* ICD-10: F65
* MeSH: D010262
Look up paraphilia in Wiktionary, the free dictionary.
Wikimedia Commons has media related to Paraphilias.
* DSM-IV and DSM-IV-TR list of paraphilias
* Proposed diagnostic criteria for sex and gender section of DSM5
* 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
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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
| Paraphilia | c1527307 | 2,632 | wikipedia | https://en.wikipedia.org/wiki/Paraphilia | 2021-01-18T19:06:48 | {"mesh": ["D010262"], "icd-9": ["302.0"], "icd-10": ["F65"], "wikidata": ["Q178059"]} |
Homocystinuria without methylmalonic aciduria is an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, encephalopathy and, sometimes, developmental delay, and associated with homocystinuria and hyperhomocysteinemia. There are three types of homocystinuria without methylmalonic aciduria; cblE, cblG and cblD-variant 1 (cblDv1).
## Epidemiology
Prevalence is unknown. To date, about 30 cases of cblE, about 38 cases of cblG, and 5 cases of cblDv1 have been reported.
## Clinical description
Homocystinuria without methylmalonic aciduria manifests mainly in early childhood with failure to thrive, megaloblastic anemia, developmental delay, hypotonia, seizures and cerebral atrophy with white matter abnormalities. Some patients may have an acute expression in the first few months of life, with vomiting, poor feeding and lethargy. Patients develop homocystinuria, hyperhomocysteinemia and, sometimes, hypomethioninemia. A mild clinical phenotype and late-onset disease in the absence of neurological involvement have also been described for the cblE disorder. Presentation in adulthood with ataxia, dementia or psychosis has been observed in cblG.
## Etiology
These disorders are caused by a functional deficiency of the cytoplasmic enzyme methionine synthase (MS), which catalyzes remethylation of homocysteine to form methionine. cblG is caused by mutations of the MTR gene (1q43), which encodes MS, while cblE is caused by mutations of the MTRR gene (5p15.3-15.2), which encodes methionine synthase reductase, an accessory protein required to maintain MS-bound cobalamin in its active form. The cblDv1 disorder results in decreased provision of the cobalamin coenzyme required for MS activity.
## Diagnostic methods
Diagnosis is based on evidence of increased levels of homocystine in urine, and homocysteine or homocystine in plasma, and presence of megaloblastic anemia. Plasma methionine is frequently low. Genetic complementation analysis or identification of mutations in the MTR, MTRR or MMADHC genes can confirm the diagnosis.
## Differential diagnosis
Differential diagnosis includes multiple sclerosis, particularly for cblG. The forms of homocystinuria without methylmalonic aciduria can be distinguished on the basis of complementation analysis in cultured cells. In contrast to patients with classical homocystinuria due to cystathionine synthase deficiency, methionine is not elevated.
## Antenatal diagnosis
Prenatal diagnosis is possible by identification of elevated homocysteine in amniotic fluid or by biochemical studies of cultured amniocytes. Mutation analysis is possible when the disease causing mutations have been identified in the index case. Treatment of the mother of an affected fetus with cobalamin during pregnancy has been carried out, and appears to have been successful in preventing development of disease.
## Genetic counseling
All three types of methylcobalamin deficiency are inherited in an autosomal recessive manner.
## Management and treatment
Treatment is based on daily intramuscular injections of 1 mg hydroxycobalamin (OHCbl), tapering the frequency of injections over time to one dose, one to three times a week. A few patients with cblG have required additional treatment with folates and betaine.
## Prognosis
With treatment, biochemical parameters rapidly normalize and clinical symptoms of hypotonia, lethargy and impaired responsiveness improve within 24-48 hours. Hematologic parameters also improve. The improvement in psychomotor status is slow and often incomplete.
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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
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*[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
| Homocystinuria without methylmalonic aciduria | c1856057 | 2,633 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=622 | 2021-01-23T17:55:54 | {"mesh": ["C565510"], "omim": ["236270", "250940", "277410"], "icd-10": ["E72.1"], "synonyms": ["Functional methionine synthase deficiency", "Methylcobalamin deficiency"]} |
A number sign (#) is used with this entry because of the demonstration that Dejerine-Sottas syndrome (DSS) can be caused by mutations in the MPZ gene (159440), the PMP22 gene (601097), the PRX gene (605725), and the EGR2 (129010) gene.
There is also evidence that mutations in the GJB1 gene (304040) may contribute to the phenotype.
See also severe congenital hypomyelination (605253), which shows phenotypic overlap with DSS.
Description
Dejerine-Sottas neuropathy is a demyelinating peripheral neuropathy with onset in infancy. It can show autosomal dominant or recessive inheritance. Affected individuals have delayed motor development due to severe distal motor and sensory impairment, resulting in difficulties in gait. Some patients have generalized hypotonia in infancy. Other features may include pes cavus, scoliosis, and sensory ataxia. Nerve conduction velocities are severely decreased (sometimes less than 10 m/s), and sural nerve biopsy shows severe loss of myelinated fibers (summary by Baets et al., 2011).
Clinical Features
Andermann et al. (1962) described Dejerine-Sottas hypertrophic neuropathy in grandfather, father, and 4-year-old daughter. Features included nystagmus, distal muscular weakness, distal sensory change, pes cavus and exacerbations and remissions. Isaacs (1960) described a family in which paralysis of the extremities was precipitated by cold weather. No sensory changes occurred in the family of Russell and Garland (1930), restudied by Croft and Wadia (1957) with tracing of the disorder through 5 generations. On the other hand Andermann et al. (1962) described sensory changes. They also demonstrated advanced involvement of cranial and spinal nerves. Spinal nerve root enlargement was demonstrable by myelography. Elevated spinal fluid protein is often found in this condition and in Refsum syndrome (266500). Bedford and James (1956) also observed a family with affected members in 5 generations. The onset is usually with weakness and deformity of the feet and lower limbs. 'Onion bulb' formation makes the histologic diagnosis.
In the original cases described by Dejerine and Sottas (1893), 2 sibs of presumably unaffected parents were affected. Onset was in infancy in Fanny Roy and at age 14 in Henri Roy. The patients showed clubfoot, kyphoscoliosis, generalized weakness and muscular atrophy with fasciculations beginning first in the leg muscles, decreased reactivity to electric stimulation, areflexia, marked distal sensory loss in all four extremities, incoordination in the arms, Romberg sign, miosis, decreased pupillary reaction to light, and nystagmus. Fanny died at age 45. Autopsy showed the peripheral nerves to be increased in size, firm and gelatinous. Only rare nerve fibers contained myelin. Dyck et al. (1970) found changes in nerves and liver suggesting a systemic defect in the metabolism of ceramide hexosides and ceramide hexoside sulfates.
Thomas et al. (1972) studied 9 kindreds in which 2 types of the disorder were suggested. In one type, onset was in childhood with leg weakness, foot deformity, and only mild sensory changes. In the other type, sensory loss was severe and often associated with chronic ulceration of the feet.
Joosten (1982) described 8 patients with Dejerine-Sottas disease. Two of the patients were sibs and 2 others had sibs with a similar disorder, suggesting autosomal recessive inheritance. In 6 cases the parents were studied clinically and electroneurographically, and no signs of polyneuropathy were found. In 1 family, the parents were related.
Ionasescu et al. (1996) reported a 55-year-old black male with Dejerine-Sottas neuropathy who belonged to a family with 9 severely affected DSN patients in an autosomal dominant pedigree pattern. Onset had occurred at 2 years of age with steppage gait. He showed pes cavus, hammertoes, progressive severe weakness and atrophy of the legs, and claw hands. He developed Charcot joints at both shoulders. A brother, aged 47, had similar neurologic findings and demonstrated Charcot joints with degeneration of the interphalangeal joints of the fourth and fifth fingers.
Mapping
Roa et al. (1993) identified mutations in the PMP22 gene, located on chromosome 17p11, in patients with Dejerine-Sottas neuropathy.
Hayasaka et al. (1993) identified mutations in the MPZ gene, located on chromosome 1q22, in patients with Dejerine-Sottas neuropathy.
In family studies, Boerkoel et al. (2001) found linkage of recessive Dejerine-Sottas neuropathy to 19q13.1-q13.2.
Ionasescu et al. (1996) performed family studies showing linkage of DSN to microsatellite markers in the 8q23-q24 region. Positive lod scores were obtained for D8S257, D8S284, D8S256, and D8S274 with values between 1.81 and 2.11. Linkage to both PMP22 and MPZ was excluded and no duplication of PMP22 was demonstrated.
Molecular Genetics
Hayasaka et al. (1993) investigated the MPZ gene as a candidate gene in 2 sporadic cases of Dejerine-Sottas neuropathy. They found 2 different mutations in the patients (159440.0004, 159440.0005). Roa et al. (1993) demonstrated that 2 point mutations in the PMP22 gene on 17p11.2 also caused Dejerine-Sottas neuropathy. Two unrelated patients were heterozygous for different mutations (601097.0006, 601097.0007).
In 3 sibs with Dejerine-Sottas syndrome, Parman et al. (1999) identified a homozygous mutation in the PMP22 gene (601097.0018). The unaffected parents were related as first cousins and both were heterozygous for the mutation. Parman et al. (1999) commented that DSS caused by mutation in the PMP22 gene is usually autosomal dominant, caused by a heterozygous mutation, and that the findings in this family demonstrate autosomal recessive inheritance.
In 3 unrelated patients with Dejerine-Sottas neuropathy, Boerkoel et al. (2001) identified recessive mutations in the PRX gene; see 605725.0001-605725.0004.
Timmerman et al. (1999) screened 170 unrelated neuropathy patients and identified 2 with Dejerine-Sottas neuropathy who had a heterozygous R359W mutation (129010.0004) in the alpha-helix domain of the first zinc finger of EGR2. Sural nerve biopsy showed severe demyelination, classic onion bulbs, and focally folded myelin sheaths. Boerkoel et al. (2001) reported 2 additional DSN patients with the R359W mutation and suggested that it is the most common neuropathy-associated EGR2 mutation and consistently causes DSN. The expressivity ranged from that typical for DSN to a more rapidly progressive neuropathy that can cause death by age 6 years. Furthermore, in contrast to patients with typical DSN, patients with the EGR2 R359W mutation had more respiratory compromise and cranial nerve involvement.
Takashima et al. (2002) reported a patient, born of consanguineous parents, with Dejerine-Sottas neuropathy due to a homozygous deletion in the PRX gene (605725.0007). Neuropathology showed demyelination, onion bulb and occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate-like junctions between the terminal loops and axon.
Chung et al. (2005) reported an unusual case of a Korean girl with DSS who had mutations in 2 different genes: EGR2 (R359W; 129010.0004) and GJB1 (V136A; 304040.0021). She inherited a heterozygous R359W mutation from her father, who had Charcot-Marie-Tooth disease-1D (607678). The GJB1 mutation was de novo. The father had pes cavus and developed difficulty walking at age 8 years, but had a milder phenotype than the daughter, who had experienced gait difficulties since infancy and facial weakness. She also had bilateral hand muscle weakness and atrophy and had sensory impairment of both upper and lower extremities. Chung et al. (2005) concluded that the more severe phenotype in the daughter was caused by an additive effect of the 2 mutations.
Al-Thihli et al. (2008) reported a 7-year-old boy with autosomal recessive Dejerine-Sottas disease associated with compound heterozygous deletions in the PMP2 gene: the common 1.5-Mb deletion (601097.0004), inherited from the mother, and a deletion encompassing exons 2 and 3 (601097.0020), inherited from the father. The nonconsanguineous parents were each heterozygous for a deletion and showed a phenotype consistent with hereditary neuropathy with liability to pressure palsies (HNPP; 162500). The boy had a severe phenotype with significantly delayed motor development, pes cavus, scoliosis, hyporeflexia, hearing deficits, severe demyelination on sural nerve biopsy, and gastroesophageal reflux. Al-Thihli et al. (2008) commented that the deletions in this patient were the largest compound heterozygous PMP22 deletions reported in the literature.
Animal Model
Low (1976, 1976) suggested that the Trembler mouse may be a mouse model of Dejerine-Sottas syndrome. Suter et al. (1992) identified a mutation in the Pmp22 gene in the Trembler mouse.
INHERITANCE \- Autosomal dominant \- Autosomal recessive HEAD & NECK Eyes \- Nystagmus (in some patients) SKELETAL Spine \- Kyphoscoliosis may occur Hands \- Claw hand deformities (in severe cases) Feet \- Pes cavus \- Hammer toes \- Foot deformities NEUROLOGIC Peripheral Nervous System \- Delayed motor development \- Hypotonia \- Distal limb muscle weakness due to peripheral neuropathy \- Distal limb muscle atrophy due to peripheral neuropathy \- 'Steppage' gait \- Foot drop \- Distal sensory impairment \- Sensory ataxia \- Hyporeflexia \- Areflexia \- Increased CSF protein \- Severely decreased motor nerve conduction velocity (NCV) (less than 38 m/s) \- Hypertrophic nerve changes \- 'Onion bulb' formations on nerve biopsy \- Segmental demyelination/remyelination on nerve biopsy \- Decreased number of myelinated fibers MISCELLANEOUS \- Onset in infancy or early childhood \- Usually begins in feet and legs (peroneal distribution) \- Upper limb involvement occur later \- Variable severity \- Genetic heterogeneity \- Clinical overlap with demyelinating Charcot-Marie-Tooth disease type 1 (see CMT1B, 118200 ), but much more severe phenotype \- Clinical overlap with congenital hypomyelinating neuropathy (CHN, 605253 ) MOLECULAR BASIS \- Caused by mutation in the myelin protein zero gene (MPZ, 159440.0004 ) \- Caused by mutation in the peripheral myelin protein-22 gene (PMP22, 601097.0006 ) \- Caused by mutation in the periaxin gene (PRX, 605725.0001 ) \- Caused by mutation in the early growth response-2 gene (EGR2, 129010.0004 ) ▲ 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
| HYPERTROPHIC NEUROPATHY OF DEJERINE-SOTTAS | c0011195 | 2,634 | omim | https://www.omim.org/entry/145900 | 2019-09-22T16:39:49 | {"doid": ["0050540"], "mesh": ["D015417"], "omim": ["145900"], "icd-10": ["G60.0"], "orphanet": ["64748"], "synonyms": ["Alternative titles", "DEJERINE-SOTTAS SYNDROME", "CHARCOT-MARIE-TOOTH DISEASE, TYPE 3", "HEREDITARY MOTOR AND SENSORY NEUROPATHY TYPE III", "DEJERINE-SOTTAS NEUROPATHY"]} |
A number sign (#) is used with this entry because of evidence that cerebellar, ocular, craniofacial, and genital syndrome (COFG) is caused by homozygous mutation in the MAB21L1 gene (601280) on chromosome 13q13.
Description
Cerebellar, ocular, craniofacial, and genital syndrome (COFG) is characterized by moderate to severe developmental delay and impaired intellectual development, severe cerebellar hypoplasia, a noticeably short forehead, medially sparse/flared and laterally extended eyebrows, corneal dystrophy, underdeveloped labioscrotal folds, and tufts of hair extruding from the lactiferous ducts with breast and nipple underdevelopment. Additional features such as pontine involvement, retinal degeneration, anteverted nares, and low-set ears have been variably observed (Rad et al., 2019).
Clinical Features
Silay et al. (2013) reported a 7-year-old Turkish boy, born of consanguineous parents, who had bilateral undescended testes and agenesis of the scrotum. His 16-year-old and 6-month-old sisters had complete agenesis of the labia majora. All 3 sibs had visual impairment and moderate hearing loss, and the boy was reported to have various dysmorphic features, significant cognitive impairment, and corneal dystrophy. Endocrinologic evaluation was normal in the sibs. The authors stated that this was the first report of sibs with absence of scrotum and labia majora, and noted that the additional findings suggested the presence of a genetic syndrome.
Kayserili et al. (2016) restudied the 3 Turkish sibs reported by Silay et al. (2013) and described a similarly affected 19-year-old Turkish man. All 4 patients exhibited microcephaly with distinctive facial features, including short forehead and laterally extended, medially flared eyebrows, as well as central corneal opacities, underdevelopment of labioscrotal folds, and nonprogressive pontocerebellar hypoplasia. In addition, the patients exhibited the unusual finding of hair extruding from the lactiferous ducts.
Bruel et al. (2017) described an 8-year-old Algerian boy with scrotal agenesis, dysmorphic facial features, corneal dystrophy, Dandy-Walker malformation, and global developmental delay.
Molecular Genetics
In an 8-year-old Algerian boy with cerebellar malformation, ocular anomalies, facial dysmorphism, and scrotal agenesis, Bruel et al. (2017) identified homozygosity for a 1-bp duplication in the MAB21L1 gene (601280.0001) that was present in heterozygosity in his unaffected first-cousin parents and not carried by his unaffected sisters.
Rad et al. (2019) studied 10 patients from 5 unrelated families with a strikingly similar syndromic labioscrotal aplasia phenotype, including the 2 Turkish families (families 4 and 5) reported by Kayserili et al. (2016), who were all homozygous for mutations in the MAB21L1 gene (see, e.g., 601280.0002-601280.0005) that were inherited from unaffected consanguineous parents. Rad et al. (2019) designated the disorder 'cerebellar, ocular, craniofacial, and genital syndrome (COFG).'
INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly (in some patients) Face \- Short forehead \- Low anterior hairline \- Long philtrum \- Tented philtrum \- Smooth philtrum Ears \- Low-set ears \- Posteriorly rotated ears \- Protruding ears \- Helical abnormalities Eyes \- Horizontal nystagmus \- Central corneal opacities, bilateral \- Poor vision \- Strabismus \- Medially sparse, flared eyebrows \- Laterally extended eyebrows \- Synophrys \- Long eyelashes \- Buphthalmos \- Dry eyes \- Retinal degeneration Nose \- Anteverted nares CHEST Breasts \- Absent or underdeveloped nipples \- No discernable areola \- Tufts of hair extruding from lactiferous ducts \- Widely spaced nipples \- Lack of postpubertal breast development GENITOURINARY External Genitalia (Male) \- Absent scrotum \- Flat, nonrugose perineal skin \- Glanular hypospadias External Genitalia (Female) \- Absent labia majora \- Small labia minora SKIN, NAILS, & HAIR Hair \- Hirsutism MUSCLE, SOFT TISSUES \- Muscular build \- Prominent trapezius muscles NEUROLOGIC Central Nervous System \- Intellectual disability, moderate to severe \- Neurodevelopmental delay, moderate to severe \- Ataxic gait \- Cerebellar hypoplasia, nonprogressive \- Pontine hypoplasia (in some patients) \- Dandy-Walker malformation Peripheral Nervous System \- Brisk deep tendon reflexes \- Absent plantar reflexes Behavioral Psychiatric Manifestations \- Timid, shy, or anxious behavior \- Autism spectrum behaviors \- Aggressive behavior \- Attention-deficit/hyperactivity disorder MISCELLANEOUS \- Medial sparseness of eyebrows less prominent with advancing age MOLECULAR BASIS \- Caused by mutation in the mab-21 like 1 gene (MAB21L1, 601280.0001 ) ▲ 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
| CEREBELLAR, OCULAR, CRANIOFACIAL, AND GENITAL SYNDROME | None | 2,635 | omim | https://www.omim.org/entry/618479 | 2019-09-22T15:41:42 | {"omim": ["618479"]} |
Human disease: joints that stretch further than normal
Hypermobility
Other nameshyperlaxity, benign joints hypermobility syndrome (BJHS), hypermobility syndrome (HMS)[1]
Hypermobile fingers and thumb
SpecialtyRheumatology
Hypermobility, also known as double-jointedness, describes joints that stretch farther than normal. For example, some hypermobile people can bend their thumbs backwards to their wrists, bend their knee joints backwards, put their leg behind the head or perform other contortionist "tricks." It can affect one or more joints throughout the body.
Hypermobile joints are common and occur in about 10 to 25% of the population,[2] but in a minority of people, pain and other symptoms are present. This may be a sign of what is known as joint hypermobility syndrome (JMS)[3] or, more recently, hypermobility spectrum disorder (HSD). Hypermobile joints are a feature of genetic connective tissue disorders such as hypermobility spectrum disorder (HSD) or Ehlers–Danlos syndromes. Until new diagnostic criteria were introduced, hypermobility syndrome was sometimes considered identical to Ehlers–Danlos syndrome hypermobile type/EDS Type 3. As no genetic test can identify or separate either conditions and because of the similarity of the diagnostic criteria and recommended treatments, many experts recommend they should be recognized as the same condition until further research is carried out.[4][5]
In 2016 the diagnostic criteria for EDS Type 3 were re-written to be more restrictive, with the intent of narrowing the pool of EDS Type 3 patients in the hope of making it easier to identify a common genetic mutation, EDS Type 3 being the only EDS variant without a diagnostic DNA test. At the same time hypermobility spectrum disorder was redefined as a hypermobility disorder that does not meet the diagnostic criteria for EDS Type 3 (or Marfans, OI, or other collagen disorders) and renamed as hypermobility spectrum disorder (HSD).
## Contents
* 1 Signs and symptoms
* 1.1 Associated conditions
* 2 Causes
* 2.1 Syndromes
* 2.2 Ehlers–Danlos syndrome hypermobility type
* 3 Diagnosis
* 3.1 Beighton criteria
* 3.1.1 Major criteria
* 3.1.2 Minor criteria
* 3.2 Beighton score
* 3.3 Belavy-Owen-Mitchell (BOM) score
* 4 Treatments
* 4.1 Physical therapy
* 4.2 Medication
* 4.3 Lifestyle modification
* 4.4 Other treatments
* 5 Epidemiology
* 6 See also
* 7 References
* 8 External links
## Signs and symptoms[edit]
People with Joint Hypermobility Syndrome may develop other conditions caused by their unstable joints.[3][6] These conditions include:
* Joint instability causing frequent sprains, tendinitis, or bursitis when doing activities that would not affect others
* Joint pain
* Early-onset osteoarthritis (as early as during teen years)
* Subluxations or dislocations, especially in the shoulder (severe limits on one’s ability to push, pull, grasp, finger, reach, etc., is considered a disability by the US Social Security Administration)[7]
* Knee pain
* Fatigue, even after short periods of exercise
* Back pain, prolapsed discs or spondylolisthesis
* Joints that make clicking noises (also a symptom of osteoarthritis)
* Susceptibility to whiplash
* Temporomandibular Joint Syndrome also known as TMJ
* Increased nerve compression disorders (such as carpal tunnel syndrome)
* The ability of finger locking
* Poor response to anaesthetic or pain medication
* "Growing pains" as described in children in late afternoon or night
### Associated conditions[edit]
Those with hypermobile joints are more likely to have fibromyalgia, mitral valve prolapse, and anxiety disorders such as panic disorder.[2]
## Causes[edit]
Hypermobility generally results from one or more of the following:
* Abnormally shaped ends of one or more bones at a joint
* A Type 1 collagen or other connective tissue defect (as found in Ehlers–Danlos syndrome, Loeys–Dietz syndrome and Marfan syndrome) resulting in weakened ligaments/ligamentous laxity, muscles and tendons. This same defect also results in weakened bones, which may result in osteoporosis and fractures.
* Abnormal joint proprioception (an impaired ability to locate body parts in space and/or monitor an extended joint)
These abnormalities cause abnormal joint stress, meaning that the joints can wear out, leading to osteoarthritis.
The condition tends to run in families, suggesting a genetic basis for at least some forms of hypermobility. The term double jointed is often used to describe hypermobility; however, the name is a misnomer and should not be taken literally, as hypermobile joints are not doubled/extra in any sense.
Most people have hypermobility with no other symptoms. Approximately 5% of the healthy population have one or more hypermobile joints. However, people with "joint hypermobility syndrome" are subject to many difficulties. For example, their joints may be easily injured, be more prone to complete dislocation due to the weakly stabilized joint and they may develop problems from muscle fatigue (as muscles must work harder to compensate for weakness in the ligaments that support the joints). Hypermobility syndrome can lead to chronic pain or even disability in severe cases. Musical instrumentalists with hypermobile fingers may have difficulties when fingers collapse into the finger locking position. Or, conversely, they may display superior abilities due to their increased range of motion for fingering, such as in playing a violin or cello.
Hypermobility may be symptomatic of a serious medical condition, such as Stickler syndrome, Ehlers–Danlos syndrome,[8] Marfan syndrome,[8] Loeys–Dietz syndrome, rheumatoid arthritis, osteogenesis imperfecta,[8] lupus, polio, Down syndrome,[8] morquio syndrome, cleidocranial dysostosis or myotonia congenita.
Hypermobility has been associated with chronic fatigue syndrome and fibromyalgia. Hypermobility causes physical trauma (in the form of joint dislocations, joint subluxations, joint instability, sprains, etc.). These conditions often, in turn, cause physical and/or emotional trauma and are possible triggers for conditions such as fibromyalgia.[9]
Women with hypermobility may experience particular difficulties when pregnant. During pregnancy, the body releases certain hormones that alter ligament physiology, easing the stretching needed to accommodate fetal growth as well as the birthing process. The combination of hypermobility and pregnancy-related pelvic girdle during pregnancy can be debilitating. The pregnant woman with hypermobile joints will often be in significant pain as muscles and joints adapt to the pregnancy. Pain often inhibits such women from standing or walking during pregnancy. The pregnant patient may be forced to use a bedpan and/or a wheelchair during pregnancy and may experience permanent disability.
Symptoms of hypermobility include a dull but intense pain around the knee and ankle joints and the soles of the feet. The pain and discomfort affecting these body parts can be alleviated by using custom orthoses.
### Syndromes[edit]
Hypermobile metacarpo-phalangeal joints
Hyperextension thumb
Hypermobility syndrome is generally considered to comprise hypermobility together with other symptoms, such as myalgia and arthralgia. It is relatively common among children and affects more females than males.
Current thinking suggests four causative factors:
* The shape of the ends of the bones—Some joints normally have a large range of movement, such as the shoulder and hip. Both are ball-and-socket joints. If a shallow rather than a deep socket is inherited, a relatively large range of movement will be possible. If the socket is particularly shallow, then the joint may dislocate easily.
* Protein deficiency or hormone problems—Ligaments are made up of several types of protein fibre. These proteins include elastin, which gives elasticity and which may be altered in some people. Female sex hormones alter collagen proteins. Women are generally more supple just before a period and even more so in the latter stages of pregnancy, because of a hormone called relaxin that allows the pelvis to expand so the head of the baby can pass. Joint mobility differs by race, which may reflect differences in collagen protein structure. People from the Indian sub-continent, for example, often have more supple hands than Caucasians.[10]
* Muscle tone—The tone of muscles is controlled by the nervous system, and influences range of movement. Special techniques can change muscle tone and increase flexibility. Yoga, for example, can help to relax muscles and make the joints more supple. However, please note that Yoga is not recommended by most medical professionals for people with Joint Hypermobility Syndrome, due to the likelihood of damage to the joints. Gymnasts and athletes can sometimes acquire hypermobility in some joints through activity.
* Proprioception—Compromised ability to detect exact joint/body position with closed eyes, may lead to overstretching and hypermobile joints.[11]
Hypermobility can also be caused by connective tissue disorders, such as Ehlers–Danlos syndrome (EDS) and Marfan syndrome. Joint hypermobility is a common symptom for both. EDS has numerous sub-types; most include hypermobility in some degree. When hypermobility is the main symptom, then EDS/hypermobility type is likely. People with EDS-HT suffer frequent joint dislocations and subluxations (partial/incomplete dislocations), with or without trauma, sometimes spontaneously. Commonly, hypermobility is dismissed by medical professionals as nonsignificant.[12]
### Ehlers–Danlos syndrome hypermobility type[edit]
Joint hypermobility is often correlated with hypermobile Ehlers–Danlos syndrome (hEDS, known also by EDS type III or Ehlers–Danlos syndrome hypermobility type (EDS-HT)). Ehlers–Danlos syndrome is a genetic disorder caused by mutations or hereditary genes, but the genetic defect that produced hEDS is largely unknown. In conjunction with joint hypermobility, a common symptom for hEDS is smooth, velvety, and stretchy skin; a symptom largely unique to the syndrome. When diagnosing hEDS, the Beighton Criteria are used, but are not always able to distinguish between generalized hypermobility and hEDS.[13]
Ehlers–Danlos hypermobility type can have severe musculoskeletal affects including:
* Jaw laxity that may make an individual's jaw open and close like a hinge, as well as open further than the average.
* Neck pain that can lead to chronic headaches and is usually associated with a crackling or grinding sensation (crepitus).
* The spine may end up in a "round back" or inversely may extend too much into hyperlordosis. Individuals may also experience scoliosis.
* Joints commonly associated with hypermobility (wrists, knees, ankles, elbows, shoulders) may be at more severe risk to dislocate or strain.
## Diagnosis[edit]
Joint hypermobility syndrome shares symptoms with other conditions such as Marfan syndrome, Ehlers-Danlos Syndrome, and osteogenesis imperfecta. Experts in connective tissue disorders formally agreed that severe forms of Hypermobility Syndrome and mild forms of Ehlers-Danlos Syndrome Hypermobility Type are the same disorder.[citation needed]
Generalized hypermobility is a common feature in all these hereditary connective tissue disorders and many features overlap, but often features are present that enable differentiating these disorders.[14] The inheritance pattern of Ehlers-Danlos syndrome varies by type. The arthrochalasia, classic, hypermobility and vascular forms usually have an autosomal dominant pattern of inheritance. Autosomal dominant inheritance occurs when one copy of a gene in each cell is sufficient to cause a disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new (sporadic) gene mutations. Such cases can occur in people with no history of the disorder in their family.
The dermatosparaxis and kyphoscoliosis types of EDS and some cases of the classic and hypermobility forms, are inherited in an autosomal recessive pattern. In autosomal recessive inheritance, two copies of the gene in each cell are altered. Most often, both parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.
### Beighton criteria[edit]
Beighton score criteria: one point for each elbow and knee that hyperextends by 10 degrees or more (4 points), one for each little finger that bends back by 90 degrees (2 points), one for each thumb which can be touched to the forearm (2 points), and one for touching the floor with the palms.[15]
As of July 2000, hypermobility was diagnosed using the Beighton criteria. In 2017, the criteria changed, but still involve the Beighton score. [16] The Beighton criteria do not replace the Beighton score but instead use the previous score in conjunction with other symptoms and criteria. HMS is diagnosed in the presence of either two major criteria, one major and two minor criteria, or four minor criteria. The criteria are:
#### Major criteria[edit]
* A Beighton score of 5/9 or more (either current or historic)
* Arthralgia for more than three months in four or more joints
this has been edited
#### Minor criteria[edit]
* A Beighton score of 1, 2 or 3/9 (0, 1, 2 or 3 if aged 50+)
* Arthralgia (> 3 months) in one to three joints or back pain (> 3 months), spondylosis, spondylolysis/spondylolisthesis.
* Dislocation/subluxation in more than one joint, or in one joint on more than one occasion.
* Soft tissue rheumatism. > 3 lesions (e.g. epicondylitis, tenosynovitis, bursitis).
* Marfanoid habitus (tall, slim, span/height ratio >1.03, upper: lower segment ratio less than 0.89, arachnodactyly; positive Steinberg finger / Walker wrist signs).
* Abnormal skin: striae, hyperextensibility, thin skin, papyraceous scarring.
### Beighton score[edit]
The Beighton score is an edited version of the Carter/Wilkinson scoring system which was used for many years as an indicator of widespread hyper-mobility. Medical professionals varied in their interpretations of the results; some accepting as low as 1/9 and some 4/9 as a diagnosis of HMS. Therefore, it was incorporated, with clearer guidelines, into the Brighton Criteria. The Beighton score is measured by adding 1 point for each of the following:
* Placing flat hands on the floor with straight legs
* Left knee bending backward
* Right knee bending backward
* Left elbow bending backward
* Right elbow bending backward
* Left thumb touching the forearm
* Right thumb touching the forearm
* Left little finger bending backward past 90 degrees
* Right little finger bending backward past 90 degrees
### Belavy-Owen-Mitchell (BOM) score[edit]
The Belavy-Owen-Mitchell (BOM) score is a quantitative version of the Beighton scoring system that is calculated as a sum of nine variables on a continuous scale, as opposed to a sum of nine categories.[17] This method allows for greater sensitivity for change within or between individuals and warrants consideration in future studies examining general joint laxity.
## Treatments[edit]
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### Physical therapy[edit]
It is important that hypermobile individuals remain fit - even more so than the average individual - to prevent recurrent injuries. Regular exercise and exercise that is supervised by a physician and physical therapist can reduce symptoms because strong muscles increase dynamic joint stability. Low-impact exercise such as closed chain kinetic exercises are usually recommended as they are less likely to cause injury when compared to high-impact exercise or contact sports.
Heat and cold treatment can help temporarily to relieve the pain of aching joints and muscles but does not address the underlying problems.
### Medication[edit]
Medication is not the primary treatment for hypermobility, but can be used as an adjunct treatment for related joint pain. NSAIDs are the primary medications of choice. Narcotics are not recommended for primary or long term treatment and are reserved for short term use after acute injury.
### Lifestyle modification[edit]
For some people with hypermobility, lifestyle changes decrease symptom severity. In general, activity that increases pain is to be avoided. For example:
* Typing can reduce pain from writing.
* Voice control software or a more ergonomic keyboard can reduce pain from typing.
* Bent knees or sitting can reduce pain from standing.
* Unwanted symptoms are frequently produced by some forms of yoga and weightlifting.
* Use of low impact elliptical trainer machines can replace high-impact running.
* Pain-free swimming may require a kickboard or extra care to avoid hyperextending elbow and other joints.
* Weakened ligaments and muscles contribute to poor posture, which may contribute to other medical conditions.
* Isometric exercise avoids hyperextension and contributes to strength.
### Other treatments[edit]
* Bracing can be helpful for temporarily protecting unstable joints.
## Epidemiology[edit]
Hypermobile joints occur in about 10 to 25% of the population.[2]
## See also[edit]
* Ligamentous laxity
## References[edit]
1. ^ Federman CA, Dumesic DA, Boone WR, Shapiro SS (1990). "Relative efficiency of therapeutic donor insemination using a luteinizing hormone monitor". Fertil Steril. 54 (3): 489–92. doi:10.1016/S0015-0282(16)53767-4. PMID 2204553.
2. ^ a b c Garcia-Campayo, J; Asso, E; Alda, M (February 2011). "Joint hypermobility and anxiety: the state of the art". Current Psychiatry Reports. 13 (1): 18–25. doi:10.1007/s11920-010-0164-0. PMID 20963520. S2CID 24237928.
3. ^ a b "Joint hypermobility - NHS Choices". NHS choices. Retrieved 2016-12-02.
4. ^ "Hypermobility Syndromes Association » JHS v EDS Hypermobility- Same Thing?". hypermobility.org. Archived from the original on 2016-11-25. Retrieved 2016-11-24.
5. ^ "Ehlers Danlos UK - JHS vs EDS". www.ehlers-danlos.org. Archived from the original on 2016-11-25. Retrieved 2016-11-24.
6. ^ "Clinician's Guide to JHS". hypermobility.org. Hypermobility Syndromes Association. Archived from the original on 2016-11-15. Retrieved 2016-12-02.
7. ^ "1.00 Musculoskeletal System-Adult". SSA.gov. Social Security Administration. 2013-05-31. Retrieved 2014-03-06.
8. ^ a b c d Simpson, MR (September 2006). "Benign joint hypermobility syndrome: evaluation, diagnosis, and management". The Journal of the American Osteopathic Association. 106 (9): 531–536. PMID 17079522. Archived from the original on 2013-03-02.
9. ^ "Fibromyalgia: Possible Causes and Risk Factors". Webmd.com. 2008-05-21. Retrieved 2014-03-06.
10. ^ Keer, Rosemary; Rodney Grahame (2003). Hypermobility syndrome : recognition and management for physiotherapists. Edinburgh: Butterworth-Heinemann. p. 71. ISBN 978-0-7506-5390-9. "Asian Indians were found by Wordsworth et al. (1987) to be significantly more mobile than English Caucasians."
11. ^ "Joint hypermobility". Arthritis Research UK. Archived from the original on 2009-04-08.
12. ^ Levy, Howard (2004). “The Ehlers Danlos Syndrome, Hypermobility Type.” Archived 2013-10-19 at the Wayback Machine University of Washington: NIH. Retrieved from
13. ^ T., Tinkle, Brad (2010). Joint hypermobility handbook : a guide for the issues & management of Ehlers-Danlos syndrome hypermobility type and the hypermobility syndrome. Greens Fork, IN: Left Paw Press. ISBN 9780982577158. OCLC 672037902.
14. ^ Zweers MC, Kucharekova M, Schalkwijk J (March 2005). "Tenascin-X: a candidate gene for benign joint hypermobility syndrome and hypermobility type Ehlers-Danlos syndrome?". Ann. Rheum. Dis. 64 (3): 504–5. doi:10.1136/ard.2004.026559. PMC 1755395. PMID 15708907.
15. ^ File:Hiperlaxitud.jpg
16. ^ Grahame R. The revised (Beighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol. 2000;27:1777–1779
17. ^ Mitchell, Ulrike H.; Owen, Patrick J.; Rantalainen, Timo; Belavy, Daniel L. (12 August 2020). "Increased Joint Mobility Is Associated With Impaired Transversus Abdominis Contraction". Journal of Strength and Conditioning Research. doi:10.1519/JSC.0000000000003752. PMID 32796412.
## External links[edit]
Classification
D
* ICD-10: M35.7
* ICD-9-CM: 728.5
* OMIM: 147900
* MeSH: D007593
* DiseasesDB: 31101
External resources
* MedlinePlus: 003295
Wikimedia Commons has media related to Hypermobility.
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Systemic connective tissue disorders
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Systemic lupus erythematosus
* Drug-induced SLE
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upper limb
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Fibromatosis/contracture
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* Plantar fibromatosis
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* Knuckle pads
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Hypermobility (joints) | c0158359 | 2,636 | wikipedia | https://en.wikipedia.org/wiki/Hypermobility_(joints) | 2021-01-18T18:29:59 | {"umls": ["C0086437", "C0152093", "C0158359"], "wikidata": ["Q1641042"]} |
Salivary gland hyperplasia is hyperplasia of the terminal duct of salivary glands.[1]
There are two types:[1]
* Acinar adenomatoid hyperplasia
* Ductal adenomatoid hyperplasia
## References[edit]
1. ^ a b Eveson JW; Speight PM (February 2006). "Non-neoplastic lesions of the salivary glands: New entities and diagnostic problems". Current Diagnostic Pathology. 12 (1): 22–30. doi:10.1016/j.cdip.2005.10.007.
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* Torus mandibularis
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* Maxillary hypoplasia
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Salivary glands
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Other
* Eagle syndrome
* Hemifacial hypertrophy
* Facial hemiatrophy
* Oral manifestations of systemic 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
| Salivary gland hyperplasia | c0020569 | 2,637 | wikipedia | https://en.wikipedia.org/wiki/Salivary_gland_hyperplasia | 2021-01-18T18:52:32 | {"icd-10": ["K11.1"], "wikidata": ["Q25339418"]} |
Acquired idiopathic generalized anhidrosis
SpecialtyDermatology
Acquired idiopathic generalized anhidrosis (AIGA) is characterized by generalized absence of sweating without other autonomic and neurologic dysfunction.[1]
AIGA is classified into 3 subgroups: idiopathic pure sudomotor failure (IPSF), sweat gland failure (SGF), and sudomotor neuropathy, with each subgroup presenting a different pathogenesis.[2][3][4]
## Contents
* 1 Diagnosis
* 2 See also
* 3 References
* 4 External links
## Diagnosis[edit]
Quantitative sudomotor axon reflex test and microneurography are used in the diagnosis of AIGA. However, these refined methods are mostly used for research purposes and not generally available.[5]
Skin biopsy analysis may play a crucial role in the identification of AIGA subgroups.[1]
## See also[edit]
* Hypohidrosis
## References[edit]
1. ^ a b Chen, Y. C.; Wu, C. S.; Chen, G. S.; Khor, G. T.; Chen, C. H.; Huang, P. (2008). "Identification of Subgroups of Acquired Idiopathic Generalized Anhidrosis". The Neurologist. 14 (5): 318–320. doi:10.1097/NRL.0b013e318173e818. PMID 18784603.
2. ^ Nakazato, Y.; Tamura, N.; Ohkuma, A.; Yoshimaru, K.; Shimazu, K. (2004). "Idiopathic pure sudomotor failure: Anhidrosis due to deficits in cholinergic transmission". Neurology. 63 (8): 1476–1480. doi:10.1212/01.wnl.0000142036.54112.57. PMID 15505168.
3. ^ Donadio, V.; Montagna, P.; Nolano, M.; Cortelli, P.; Misciali, C.; Pierangeli, G.; Provitera, V.; Casano, A.; Baruzzi, A.; Liguori, R. (2005). "Generalised anhidrosis: Different lesion sites demonstrated by microneurography and skin biopsy". Journal of Neurology, Neurosurgery & Psychiatry. 76 (4): 588–591. doi:10.1136/jnnp.2004.039263. PMC 1739609. PMID 15774454.
4. ^ Miyazoe, S.; Matsuo, H.; Ohnishi, A.; Tajima, F.; Fujishita, S.; Ichinose, K.; Shibuya, N. (1998). "Acquired idiopathic generalized anhidrosis with isolated sudomotor neuropathy". Annals of Neurology. 44 (3): 378–381. doi:10.1002/ana.410440314. PMID 9749605.
5. ^ Hilz, M. J.; Dütsch, M. (2006). "Quantitative studies of autonomic function". Muscle & Nerve. 33 (1): 6–20. doi:10.1002/mus.20365. PMID 15965941.
## External links[edit]
Classification
D
* ICD-10: L74.8
*[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
| Acquired idiopathic generalized anhidrosis | c0393920 | 2,638 | wikipedia | https://en.wikipedia.org/wiki/Acquired_idiopathic_generalized_anhidrosis | 2021-01-18T19:10:57 | {"umls": ["C0393920"], "wikidata": ["Q16975956"]} |
Wiskott-Aldrich syndrome is characterized by abnormal immune system function (immune deficiency), eczema (an inflammatory skin disorder characterized by abnormal patches of red, irritated skin), and a reduced ability to form blood clots. This condition primarily affects males.
Individuals with Wiskott-Aldrich syndrome have microthrombocytopenia, which is a decrease in the number and size of blood cells involved in clotting (platelets). This platelet abnormality, which is typically present from birth, can lead to easy bruising, bloody diarrhea, or episodes of prolonged bleeding following nose bleeds or minor trauma. Microthrombocytopenia can also lead to small areas of bleeding just under the surface of the skin, resulting in purplish spots called purpura, or variably sized rashes made up of tiny red spots called petechiae. In some cases, particularly if a bleeding episode occurs within the brain, prolonged bleeding can be life-threatening.
Wiskott-Aldrich syndrome is also characterized by abnormal or nonfunctional immune system cells known as white blood cells. Changes in white blood cells lead to an increased risk of several immune and inflammatory disorders in people with Wiskott-Aldrich syndrome. These immune problems vary in severity and include an increased susceptibility to infection from bacteria, viruses, and fungi. People with Wiskott-Aldrich syndrome are at greater risk of developing autoimmune disorders, such as rheumatoid arthritis, vasculitis, or hemolytic anemia. These disorder occur when the immune system malfunctions and attacks the body's own tissues and organs. The chance of developing certain types of cancer, such as cancer of the immune system cells (lymphoma), is also increased in people with Wiskott-Aldrich syndrome.
Wiskott-Aldrich syndrome is often considered to be part of a disease spectrum with two other disorders: X-linked thrombocytopenia and severe congenital neutropenia. These conditions have overlapping signs and symptoms and the same genetic cause.
## Frequency
The estimated incidence of Wiskott-Aldrich syndrome is between 1 and 10 cases per million males worldwide; this condition is rarer in females.
## Causes
Mutations in the WAS gene cause Wiskott-Aldrich syndrome. The WAS gene provides instructions for making a protein called WASP. This protein is found in all blood cells. WASP is involved in relaying signals from the surface of blood cells to the actin cytoskeleton, which is a network of fibers that make up the cell's structural framework. WASP signaling triggers the cell to move and attach to other cells and tissues (adhesion). In white blood cells, this signaling allows the actin cytoskeleton to establish interactions between cells and the foreign invaders that they target (immune synapses).
WAS gene mutations that cause Wiskott-Aldrich syndrome lead to a lack of any functional WASP. Loss of WASP signaling disrupts the function of the actin cytoskeleton in developing blood cells. White blood cells that lack WASP have a decreased ability to respond to their environment and form immune synapses. As a result, white blood cells are less able to respond to foreign invaders, causing many of the immune problems related to Wiskott-Aldrich syndrome. Similarly, a lack of functional WASP in platelets impairs their development, leading to reduced size and early cell death. Additionally, the normal process of removing platelets from circulation and taking them to the spleen for destruction also likely contributes to microthrombocytopenia in individuals with Wiskott-Aldrich syndrome.
Because they all have the same genetic cause, Wiskott-Aldrich syndrome, X-linked thrombocytopenia, and severe congenital neutropenia are sometimes collectively referred to as WAS-related disorders.
### Learn more about the gene associated with Wiskott-Aldrich syndrome
* WAS
## Inheritance Pattern
This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males, who have only one X chromosome, a mutation in the only copy of the gene in each cell is sufficient to cause the condition. In females, who have two copies of the X chromosome, one altered copy of the gene in each cell can lead to less severe features of the condition or may cause no signs or symptoms at all. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
*[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
| Wiskott-Aldrich syndrome | c0043194 | 2,639 | medlineplus | https://medlineplus.gov/genetics/condition/wiskott-aldrich-syndrome/ | 2021-01-27T08:24:32 | {"gard": ["7895"], "mesh": ["D014923"], "omim": ["301000"], "synonyms": []} |
## Summary
### Clinical characteristics.
Infants with Duarte variant galactosemia who receive breast milk or a high galactose-containing formula (dairy milk-based formula) are typically asymptomatic and show the same prevalence of acute issues seen in the general newborn population. For decades it has been unclear whether Duarte variant galactosemia results in long-term developmental problems either with or without dietary intervention. However, a recent study of 350 children ages six to 12 years reported no detectable differences in developmental outcomes tested between children with Duarte variant galactosemia and controls, or among children with Duarte variant galactosemia as a function of galactose exposure in infancy. Premature ovarian insufficiency, which is common in classic galactosemia, also has not been reported for girls or women with Duarte variant galactosemia.
### Diagnosis/testing.
Duarte variant galactosemia is diagnosed by a combination of biochemical and genetic testing. Specifically, erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity is typically about 25% of control activity, and GALT genotyping reveals the presence of one heterozygous pathogenic GALT variant together with either a heterozygous or homozygous Duarte (D2) GALT variant.
### Management.
Treatment of manifestations: Currently, there is no uniform standard of care regarding restriction of dietary galactose for infants with Duarte variant galactosemia. Thus, some health care providers, or parents, may choose to restrict dietary galactose in the first year of life, while others may not. When dietary galactose is restricted in infancy, centers often perform a galactose challenge around age one year followed by measurement of the erythrocyte galactose-1-phosphate level. If the level is within the normal range (<1.0 mg/dL), dietary restriction of galactose is generally discontinued. When dietary galactose is not restricted in infancy, some health care providers may still choose to check the erythrocyte galactose-1-phosphate level at age one year to confirm that the level is approaching the normal range.
Surveillance: For infants on dietary restriction of galactose: if the erythrocyte galactose-1-phosphate level is >1.0 mg/dL following a galactose challenge at age one year, galactose restriction may be resumed. In this case, the galactose challenge and measurement of erythrocyte galactose-1-phosphate level may be repeated every four to six months until the erythrocyte galactose-1-phosphate level stabilizes at <1.0 mg/dL.
Agents/circumstances to avoid: Opinion varies as to whether avoidance of all dairy products (including breast milk and dairy milk-based formula) until age one year is warranted.
Evaluation of relatives at risk: If families with one child with Duarte variant galactosemia wish to evaluate their other children for Duarte variant galactosemia, molecular genetic testing for the GALT variants identified in the family can be performed.
### Genetic counseling.
Duarte variant galactosemia is inherited in an autosomal recessive manner. When one parent is heterozygous for the GALT D2 allele and the other parent is heterozygous for a GALT pathogenic variant, each child has a 25% chance of having Duarte variant galactosemia, a 25% chance of being an asymptomatic carrier of the D2 allele, a 25% chance of being an asymptomatic carrier of the GALT pathogenic variant, and a 25% chance of being unaffected and also not a carrier of either GALT variant. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk requires prior identification of the GALT variants in the family and determination of the parental origin of each allele.
## Diagnosis
Duarte variant galactosemia is defined by a combination of the following:
* One GALT pathogenic variant (G allele) present in the heterozygous state plus the GALT Duarte (D2) variant allele present in either the heterozygous state (in trans to the G allele) or in the homozygous state (both in cis and in trans to the G allele)
* Erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity that is typically about 25% of control activity
### Suggestive Findings
Duarte variant galactosemia, caused by a partial deficiency in erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme, should be suspected in infants with a positive newborn screening (NBS) result for galactosemia but few if any clinical findings when on a high-galactose diet (e.g., breast milk or a dairy milk-based formula).
Positive NBS result
* NBS for classic galactosemia and its variants (including Duarte variant galactosemia) is primarily based on quantification of erythrocyte GALT enzyme activity on dried blood spots.
Note: While all states in the US now include screening for classic galactosemia in their NBS panel, some states have set their newborn screening GALT enzyme activity cutoff level to ensure the detection of classic and clinical variant galactosemia while minimizing false positives and the detection of infants with Duarte variant galactosemia [Pyhtila et al 2015]. In those states, a NBS result for galactosemia that is not flagged as "abnormal" may not be informative for Duarte variant galactosemia.
* GALT enzyme activity below the cutoff defined by the screening program is considered positive and requires follow-up diagnostic testing (see Establishing the Diagnosis).
Note: GALT is a labile enzyme; exposure of the sample to heat and/or humidity in storage or transit (as sometimes occurs in hot climates especially during the summer months) can result in artifactual loss of activity and higher false positive rates.
Follow-up testing. Quantitative testing of erythrocyte GALT enzyme activity is the first recommended follow-up approach for a positive NBS result for galactosemia. Testing of erythrocyte galactose-1-phosphate and/or urinary galactitol may also be useful as a baseline or if the infant is on a high-galactose diet (e.g., breast milk or a dairy milk-based formula).
* Erythrocyte GALT enzyme activity that is typically about 25% of control activity is consistent with a diagnosis of Duarte variant galactosemia (reviewed in Carney et al [2009], Walter & Fridovich-Keil [2014], Pyhtila et al [2015]).
* The erythrocyte galactose-1-phosphate (Gal-1P) concentration may range from high (>30 mg/dL) to normal (<1.0 mg/dL) depending on the infant's recent dietary exposure to breast milk or galactose-containing formula.
Note: Dairy milk products contain lactose, which is metabolized to glucose and galactose by normal digestion. Therefore, any product that contains dairy milk and/or lactose also contains galactose.
* Erythrocyte galactose-1-phosphate concentrations may exceed 30 mg/dL within the first few weeks of life; however, even in infants with Duarte variant galactosemia who are not treated with a galactose-restricted diet the concentration tends to normalize (<1.0 mg/dL) within the first year [Ficicioglu et al 2008, Ficicioglu et al 2010, Pyhtila et al 2015].
* Erythrocyte galactose-1-phosphate concentration in infants placed on a galactose-restricted diet normalizes rapidly, decreasing to an almost undetectable level within one month [Ficicioglu et al 2008].
* Urinary galactitol may be elevated, but not to the same extent seen in classic galactosemia [Ficicioglu et al 2010].
* The mean urinary galactitol level in a cohort of young children with Duarte variant galactosemia on unrestricted (regular) diet at age one year was 46±14 mmol/mol creatinine [Ficicioglu et al 2008], and in a cohort of children with Duarte variant galactosemia on unrestricted galactose (regular) diet at ages one to six years was 31.6 mmol/mol creatinine.
* Mean urinary galactitol in controls (<1 year of age) was reported to range from 2-78 mmol/mol creatinine, and mean urinary galactitol in infants (<1 year) with classic galactosemia was 466±166 mmol/mol [Palmieri et al 1999].
Click here (pdf) for information on testing of historical interest.
### Establishing the Diagnosis
The diagnosis of Duarte variant galactosemia is established in a proband by a combination of: (1) erythrocyte GALT enzyme activity that is typically about 25% of control activity; and (2) molecular genetic test results that identify the presence of one heterozygous pathogenic GALT variant together with either a heterozygous or homozygous Duarte (D2) GALT variant (Table 1).
Duarte variant (D2) allele. Five sequence changes in cis configuration are found on the Duarte variant (D2) allele.
Of primary importance is a 4-bp deletion in the GALT promoter region (c.-119_-116delGTCA) that is considered to cause diminished transcription (reviewed in Carney et al [2009]). The four remaining variants unique to the D2 allele are described in Molecular Genetics, Benign variants and Table 3.
Pathogenic allele. A GALT pathogenic variant is one that results in absent or barely detectable GALT enzyme activity when it occurs in the homozygous state or the compound heterozygous state with another pathogenic variant; the resulting phenotypes are classic (<1% GALT activity) or clinical variant galactosemia (1%-10% GALT activity) (see Classic Galactosemia and Clinical Variant Galactosemia). Note: Pathogenic GALT variants are sometimes referred to collectively as G alleles.
Single-gene testing. Sequence analysis of GALT detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected by sequence analysis.
* Sequence analysis can detect the D2 GALT allele as well as most GALT pathogenic variants. However, a nearly whole-gene deletion of GALT that has been reported predominantly among affected individuals of Ashkenazi Jewish ancestry (see Classic Galactosemia and Clinical Variant Galactosemia) may not be detected by traditional sequencing technologies.
* If the D2 variant is identified in a sample in which GALT enzyme activity is about 25%, but no GALT pathogenic variant is identified by sequence analysis, deletion/duplication analysis should be considered. This is especially true if variants characteristic of the D2 allele appear homozygous; the other allele of GALT may be deleted.
Interpretation of molecular genetic test results. See Molecular Genetics for details.
### Table 1.
Molecular Genetic Testing Used in Duarte Variant Galactosemia
View in own window
Gene 1MethodProportion of Probands in Whom the Method Detects:
The Duarte (D2) variantA pathogenic variant 2
GALTSequence analysis 3100%>95%
Deletion/duplication analysis 40 5Estimated <1% 6
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants detected in this gene.
3\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
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.
5\.
Deletion/duplication analysis will not identify the D2 allele.
6\.
Exon and multiexon GALT deletions have been reported; while rare overall, such deletions may be common in specific populations. See Table A, Locus-Specific Databases.
## Clinical Characteristics
### Clinical Description
The neonatal period. Infants with Duarte variant galactosemia who are on breast milk or a high galactose-containing formula (here referred to as "diary milk-based formula") are typically asymptomatic. However, anecdotal reports suggest that some infants with Duarte variant galactosemia, like some infants who do not have any form of galactosemia, may experience jaundice or other acute symptoms that resolve over time following removal of breast milk or diary milk-based formula from the diet [Author, personal observation].
Note: Resolution of acute symptoms over time following removal of breast milk or diary milk-based formula from the diet does not confirm that the problem was related to galactose.
Neurodevelopment. A recent study by Carlock et al [2019] reported 73 outcomes representing five general domains of development (cognitive, physical, motor, socio-emotional, and speech/language) in 350 children, 206 with Duarte variant galactosemia and 144 controls. Cases and controls were derived from the same set of families and ascertained from 13 different states in the United States, so they were well-matched by geography, race, socioeconomic status, and other covariates.
* No significant difference in prevalence of complications was seen between affected individuals and controls for any of the outcomes tested.
* No significant difference was seen comparing developmental outcomes of children with Duarte variant galactosemia who consumed breast milk or dairy milk-based formula versus low-galactose formula in the first year of life.
* Combined, these results strongly support the assertion that Duarte variant galactosemia does not cause developmental complications in children with or without dietary restriction of galactose.
Note: The developmental outcomes of school-age children with Duarte variant galactosemia has been a point of controversy for some time, in part because a study by Powell et al [2009] reported that 3-10 year olds with Duarte variant galactosemia in metropolitan Atlanta were more likely than age-matched controls from the general population to receive speech-language intervention in public school. However, a reconsideration of these data in 2019 revealed a number of important confounding factors that may explain the results observed [Fridovich-Keil et al 2019].
Ovarian function in females. A study of anti-müllerian hormone in young girls with enzymatically and/or molecularly confirmed Duarte variant galactosemia demonstrated no evidence of premature ovarian insufficiency [Badik et al 2011]. Further, family studies of newly diagnosed infants with classic or Duarte variant galactosemia sometimes reveal that the mother herself has Duarte variant galactosemia, confirming that women with Duarte variant galactosemia can be fertile and carry a pregnancy successfully to term [Author, personal observation].
### Genotype-Phenotype Correlations
No significant genotype-phenotype relationships for Duarte variant galactosemia with regard to different pathogenic GALT alleles in trans with the D2 allele have been reported.
### Nomenclature
Duarte variant galactosemia may also be called Duarte galactosemia, DG, or biochemical variant galactosemia.
Sometimes, Duarte variant galactosemia is simply called variant galactosemia; however, this term is better reserved for individuals now said to have "clinical variant galactosemia," who do not have a GALT D2 allele but rather have biallelic GALT pathogenic variants of which at least one is hypomorphic, resulting in a low level of residual GALT enzyme activity. Of note, galactokinase deficiency and epimerase deficiency are also sometimes called "variant" galactosemia. Thus, unless the term Duarte, D, DG, or D2 is explicit, the reader should not assume that the term variant galactosemia implies Duarte variant galactosemia.
### Prevalence
The prevalence of Duarte variant galactosemia is difficult to confirm due to incomplete ascertainment. Duarte variant galactosemia is detected in as many as 1:3,500 screened births in some states and essentially zero in others, largely reflecting differences in NBS protocols [Pyhtila et al 2015] (see Diagnosis, Erythrocyte GALT enzyme activity).
The true prevalence of Duarte variant galactosemia in the US newborn population is estimated to be approximately tenfold the prevalence of classic galactosemia [Fernhoff 2010, Pyhtila et al 2015].
Among newborns diagnosed with Duarte variant galactosemia some patterns implicating differential prevalence by race are evident [Pyhtila et al 2015]. For example, Duarte variant galactosemia is more common among infants of European ancestry and less prevalent among infants of African, African American, or Asian ancestry. These differences parallel recognized differences among these populations in the prevalence of the D2 variant and/or other known GALT pathogenic variants [Pyhtila et al 2015].
## Differential Diagnosis
Most infants with Duarte variant galactosemia are diagnosed because of a positive NBS result for galactosemia. The differential diagnosis of a positive NBS for galactosemia is:
* Classic galactosemia and clinical variant galactosemia
* Duarte variant galactosemia
* GALE (epimerase) deficiency galactosemia
* GALK (galactokinase) deficiency (OMIM 230200)
* GALM deficiency galactosemia (OMIM 618881)
* Compromised galactose utilization not caused by a Leloir enzyme deficiency (e.g., Fanconi-Bickel syndrome [OMIM 227810] or portosystemic shunt [Bernard et al 2012]).
* A false positive result that includes:
* Heterozygotes (carriers) for a GALT pathogenic variant;
* Other combinations of partially impaired GALT alleles (e.g., D2 variant homozygotes);
* Individuals with completely normal GALT alleles and enzyme activity whose samples were technically compromised by exposure to heat and/or humidity in storage or transit.
Erythrocyte GALT enzyme activity. Measuring erythrocyte GALT enzyme activity is often the first step in differential diagnosis of a positive NBS result for galactosemia.
### Table 2.
Disorders to Consider Given a Newborn Screening Result Suggestive of Galactosemia
View in own window
Erythrocyte GALT Enzyme Activity 1Diagnosis
Very low to undetectableClassic galactosemia
1%-10%Clinical variant galactosemia
~15%-33%Duarte variant galactosemia 2
~50%Carrier of 1 pathogenic GALT allele or homozygous for the D2 variant
~75%Carrier of 1 D2 variant
IndistinguishableGALE (epimerase) deficiency or GALK (galactokinase) deficiency 3 or GALM (galactose mutarotase) deficiency 4
1\.
Compared with the erythrocyte GALT enzyme activity of controls
2\.
See Classic Galactosemia and Clinical Variant Galactosemia.
3\.
Carney et al [2009], Pyhtila et al [2015]
4\.
Iwasawa et al [2019], Wada et al [2019]
Erythrocyte galactose-1-phosphate levels in infants with Duarte variant galactosemia exposed to galactose may be elevated. Although these erythrocyte galactose-1-phosphate levels overlap those seen in classic galactosemia, they typically do not exceed 30 mg/dL [Ficicioglu et al 2008, Pyhtila et al 2015]. In contrast, in classic galactosemia levels >50 mg/dL are not uncommon, and in some samples erythrocyte galactose-1-phosphate exceeds 100 mg/dL [Walter & Fridovich-Keil 2014, Pyhtila et al 2015].
## Management
### Evaluations Following Initial Diagnosis
An infant who is symptomatic should be seen by a metabolic specialist for evaluation for other possible conditions.
To assist the family with understanding the genetic implications of a diagnosis of Duarte variant galactosemia for the child and family, a genetic counseling consultation is recommended.
### Treatment of Manifestations
Current data suggest that infants and children with Duarte variant galactosemia are not at increased risk for acute or long-term developmental [Carlock et al 2019] or ovarian [Badik et al 2011] complications regardless of dietary exposure to galactose in infancy. In light of these data, some healthcare providers may conclude that dietary intervention in Duarte variant galactosemia is neither required nor desirable [McCandless 2019]; however, other providers may disagree.
If the decision is made to restrict dietary galactose, health care providers may recommend one or more of the following [Fernhoff 2010, Pyhtila et al 2015]:
* Immediate dietary galactose restriction for infants with erythrocyte galactose-1-phosphate >10 mg/dL
* Full dietary restriction of galactose by feeding low-galactose formula, through age one year, at which time a galactose challenge is performed
* A compromise approach in which parents wishing to breastfeed alternate breast milk with a low-galactose formula
The galactose challenge. If dietary galactose is restricted, conducting a galactose challenge by age 12 months should be considered. For example:
* Obtain a baseline erythrocyte galactose-1-phosphate level at diagnosis and again around age six months (i.e., after the introduction of solid foods).
* At age 12 months, gradually liberalize the dietary intake of galactose, and obtain an erythrocyte galactose-1-phosphate level one month later.
* If the erythrocyte galactose-1-phosphate level is within the normal range (<1.0 mg/dL) despite dairy milk ingestion, dietary restriction of galactose is not resumed.
### Surveillance
Most individuals diagnosed with Duarte variant galactosemia as infants who are followed by a genetics or metabolic specialist are discharged from follow up after a successful galactose challenge at age one year (see Treatment of Manifestations).
Among children with Duarte variant galactosemia who have been restricted for dietary galactose as infants, if the erythrocyte galactose-1-phosphate level is >1.0 mg/dL following a galactose challenge at age one year, galactose restriction may be resumed, and the galactose challenge and measurement of erythrocyte galactose-1-phosphate level repeated every four to six months until the level stabilizes at <1.0 mg/dL.
### Agents/Circumstances to Avoid
Some health care providers recommend avoiding all high galactose foods (e.g., dairy milk products) until age one year; other health care providers argue that this precaution is neither warranted nor desirable [McCandless 2019].
### 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: As there are no negative health consequences documented for this condition, there may not be any clinical trials.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Duarte Variant Galactosemia | None | 2,640 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK258640/ | 2021-01-18T21:29:57 | {"synonyms": ["Duarte Galactosemia"]} |
A leukodystrophy is a type of rare genetic disorder that affects the brain, spinal cord, and other nerves in the body. It is caused by destruction of the white matter of the brain. The white matter degrades due to defects of the myelin, which is a fatty covering that insulates nerves in the brain. Myelin is needed to protect the nerves and the nerves can't function normally without it. These disorders are progressive, meaning they tend to get worse with time. The leukodystrophies are a group of disorders caused by spelling mistakes (mutations) in the genes involved in making myelin. Specific leukodystrophies include metachromatic leukodystrophy, Krabbe leukodystrophy, X-linked adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Canavan disease, and Alexander disease. The most common symptom of a leukodystrophy is a decline in functioning of an infant or child who previously appeared healthy. This gradual loss may be seen with issues in body tone, movements, gait, speech, ability to eat, vision, hearing, and behavior.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Leukodystrophy | c0023520 | 2,641 | gard | https://rarediseases.info.nih.gov/diseases/6895/leukodystrophy | 2021-01-18T17:59:26 | {"umls": ["C0023520"], "orphanet": ["68356"], "synonyms": []} |
A number sign (#) is used with this entry because Kabuki syndrome-1 (KABUK1) is caused by heterozygous mutation in the MLL2 gene (KMT2D; 602113) on chromosome 12q13.
Description
Kabuki syndrome is a congenital mental retardation syndrome with additional features, including postnatal dwarfism, a peculiar facies characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids (reminiscent of the make-up of actors of Kabuki, a Japanese traditional theatrical form), a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy (Niikawa et al., 1981).
### Genetic Heterogeneity
Kabuki syndrome-2 (300867) is caused by mutation in the KDM6A gene (300128) on chromosome Xp11.3.
Clinical Features
Niikawa et al. (1988) collected data from 62 patients with Kabuki syndrome from 33 institutions, almost all of them in Japan. Most of the patients had 5 cardinal manifestations: (1) a peculiar face in all cases, characterized by eversion of the lower lateral eyelid, arched eyebrows with sparse or dispersed lateral one-third, depressed nasal tip, and prominent ears; (2) skeletal anomalies in 92%, including brachydactyly V and spinal deformity with or without sagittal cleft vertebrae; (3) dermatoglyphic abnormalities in 93%, including increased digital ulnar loop and hypothenar loop patterns, absence of the digital triradius c and/or d, and presence of fingertip pads; (4) mild to moderate mental retardation in 92%; and (5) postnatal growth deficiency in 83%. Fetal finger pads, which are typical of Kabuki syndrome, occur also in the FG syndrome (305450). Early breast development occurred in 23% of infant girls. Congenital heart defects, including single ventricle with a common atrium, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of aorta, patent ductus arteriosus (see 607411), aneurysm of aorta, transposition of great vessels, and right bundle branch block, were observed in 31% of the patients. Of the 62 Kabuki syndrome patients, 58 were Japanese. The incidence of the disorder in Japanese newborns was estimated at 1 in 32,000. All cases were sporadic. The sex ratio was even, and there was no correlation with birth order. Consanguinity was not increased among the parents, and no exogenous agent could be incriminated. Three of the 62 patients had a Y chromosome abnormality involving Yp11.2. In general, the findings of Niikawa et al. (1988) were considered compatible with an autosomal dominant disorder in which each patient represents a fresh mutation. A mutation rate was calculated at 15.6 x 10(-6) per gamete per generation. (The abstract of Niikawa et al. (1988) incorrectly stated the rate to be 15.6 x 10(6).) The possibility of the location of the gene in the pseudoautosomal region of the X chromosome was also raised.
Clarke and Hall (1990) described 3 unrelated Caucasian children with this syndrome. Gillis et al. (1990) described the disorder in a child of Arab descent. Philip et al. (1992) studied 16 non-Japanese cases from Europe and North America. They concluded that the facial phenotype is specific and easily recognizable regardless of ethnic origin. Postnatal growth retardation and mild mental retardation were confirmed to be cardinal manifestations. Significant neurologic dysfunction other than mental retardation and joint hypermobility appeared to be more common in the non-Japanese patients.
Hughes and Davies (1994) presented 20 unselected cases with a definitive diagnosis of Kabuki syndrome: 6 boys and 14 girls, ranging in age from 10 months to 13 years. The incidence of heart abnormalities in these children was almost twice that previously reported (55%) and juxtaductal coarctation occurred with a frequency of 25%. One of the patients pictured by Hughes and Davies (1994) showed the accentuated depression that is often seen below the midpoint of the lower lip.
Ilyina et al. (1995) reported 10 patients of European ancestry from Byelorussia, Russia, and Moldavia. They emphasized prominent and broad philtrum as an important component. Some clinical manifestations were observed in parents and other relatives in 3 generations of 3 families. Ilyina et al. (1995) favored autosomal dominant inheritance with variable expressivity.
Burke and Jones (1995) reported 8 cases of Kabuki syndrome in non-Japanese patients. They commented that the phenotype appears to evolve over time, making the diagnosis difficult in infancy. They stated that cleft palate occurs in about 40% of patients. Galan-Gomez et al. (1995) described Kabuki syndrome in 5 Spanish children, 3 females and 2 males. Sagittal vertebral clefts and dermatoglyphic abnormalities were present in all 5; general heart defects were present in 4.
Halal et al. (1989) reported an instance of probable autosomal dominant inheritance of the Kabuki syndrome; a father and his 2 children were affected. The father had milder symptoms than the offspring, but had typical facial changes and was of normal intelligence. Kobayashi and Sakuragawa (1996) described a family in which a 45-year-old business man and his 17-year-old daughter, born to nonconsanguineous parents, were affected. The father had characteristic facial abnormalities of Kabuki syndrome, including long palpebral fissures, long eyelashes, and a prominent nose. He was of normal stature and there were no deformities of the fingers, feet, or ribs. However, he had all ulnar loop patterns on the fingertips, and lacked palmar triradii c and d. His mental status was above average. In the daughter, a ventricular septal defect had been surgically closed at age 6 years. Her psychomotor development was delayed and school performance was poor. She was 146.5 cm tall at the age of 17. She had epicanthic folds, long palpebral fissures, high-arched eyebrows sparse in the lateral one-third, a broad and depressed nasal tip, a short nasal septum, and large malformed ears. Her fingers were stubby with bilateral clinodactyly of the fifth fingers, and the first toes were hyperplastic. On fingertips she had an increased number of ulnar loops, and she lacked palmar triradii c and d. There was a hypothenar ulnar loop, and fingertip pads were found on all fingers, a common finding in Kabuki syndrome. Her IQ was estimated to be 60. The mother was of normal height and had no minor anomalies or abnormal dermatoglyphic patterns.
Silengo et al. (1996) reported an Italian girl with typical findings of Kabuki syndrome and a mildly affected mother. The fact that males and females are equally affected, that the consanguinity rate is not increased, that parents and other relatives of patients show a facial resemblance, and that the condition is transmitted vertically with variable clinical manifestations in familial cases are all compatible with autosomal dominant inheritance. Sporadic cases may represent new mutations.
Tsukahara et al. (1997) described 4 individuals with Kabuki syndrome in 2 families. In family 1, the proposita, a 2-year-old girl, and her mother had typical Kabuki syndrome. The proposita also had early breast development. In family 2, the proposita, a 6-month-old girl, and her mother had typical Kabuki syndrome. The proposita died at age 6 months as a result of complications of a cardiac malformation.
In a girl with Kabuki syndrome, Lerone et al. (1997) described conical incisors, hypodontia, hypoplastic nails, and brittle hair. Although abnormal teeth have commonly been described in this disorder, hair abnormalities have never been investigated.
Dominant inheritance with variable expressivity was supported by the mother and child reported by Courtens et al. (2000). The 18-month-old daughter had facial features characteristic of Kabuki syndrome, prominent fingertips, a midsagittal cleft of vertebral body thoracic-4, hypotonia, and psychomotor retardation. The mother had a similar facial appearance, prominent, cup-shaped ears, abnormal dentition, early breast development, and low normal intelligence. The maternal grandmother had the same facial appearance and 3 maternal aunts reportedly likewise showed these features. Microscopic examination of the hair of the proposita showed abnormalities consisting of trichorrhexis nodosa, twisting of the hair shafts, and irregularity of the diameter of the hair, all changes similar to those reported by Lerone et al. (1997).
Shotelersuk et al. (2002) described 6 Thai children with the Kabuki syndrome, including monozygotic twins who are discordant for the syndrome. In another family, a mother had a facial appearance similar to that of her affected son, suggesting autosomal dominant inheritance. Common findings included lower lip pits with or without symmetrical lower lip nodules and pilonidal sinuses. Early eruption of the 2 lower central incisors, transient hyperthyrotropinemia in infancy, and aplasia cutis were also observed.
Wilson (1998) compared 8 new and 5 previously illustrated cases of this syndrome with those in the literature, providing data on 183 cases. A total of 108 non-Asian patients had been reported.
Although hydronephrosis had been reported in a few cases of Kabuki syndrome, Ewart-Toland et al. (1998) reported the first cases of Kabuki syndrome with hepatic anomalies. They described 2 patients with renal and/or hepatic anomalies requiring transplantation. Both patients had the characteristic facial appearance of children with Kabuki syndrome, postnatal growth deficiency, and developmental delay. At birth, 1 patient presented with hypoglycemia, ileal perforation, right hydroureter, and hydronephrosis. The patient subsequently developed hyperbilirubinemia, hepatic abscess, and cholangitis. At age 8 months, he underwent a liver transplant. Hepatic pathology was interpreted as neonatal sclerosing cholangitis. Case 2 presented with renal failure at age 6 years. Renal ultrasound showed markedly dysplastic kidneys requiring transplantation. In addition to characteristic findings of Kabuki syndrome, she had coronal synostosis and was shown to have immune deficiency and an autoimmune disorder manifesting as Hashimoto thyroiditis and vitiligo.
Kawame et al. (1999) analyzed the clinical findings of Kabuki syndrome in 18 North American children. Most had postnatal growth retardation, and all had developmental delay and hypotonia. Feeding difficulties, with or without cleft palate, were common; 5 patients required gastrostomy tube placement. In all but 2 patients, developmental quotients/IQs were 60 or less. Seizures were seen in less than half of the patients, but ophthalmologic and otologic problems were common, particularly recurrent otitis media. Congenital heart defects were present in 7 (39%); 3 patients underwent repair of coarctation of the aorta. Other features included urinary tract anomalies, malabsorption, joint hypermobility and dislocation, congenital hypothyroidism, idiopathic thrombocytopenic purpura, and, in 1 patient, autoimmune hemolytic anemia and hypogammaglobulinemia. All patients had negative family histories for Kabuki syndrome.
McGaughran et al. (2000) described 2 females with typical Kabuki syndrome who presented in the first year of life with extrahepatic biliary atresia, a previously undescribed complication of the syndrome. Selicorni et al. (2001) described a similar case of atresia of the extrahepatic bile ducts and common bile duct identified in a 44-day-old infant. A Kasai procedure was performed at that time with complete disappearance of jaundice by the age of 5 months. However, recurrence of symptoms required liver transplantation which was successfully performed at the age of 20 years; she was in good condition 5 years thereafter.
Donadio et al. (2000) reported an Italian girl with Kabuki syndrome and diaphragmatic hernia. Donadio et al. (2000) reviewed 3 other cases of Kabuki syndrome with diaphragmatic defects, all of non-Asian origin.
Van Haelst et al. (2000) reported 2 patients with Kabuki syndrome and stenosis of the central airways (one with local stenosis of the right upper lobe bronchus, and the other with severe bronchomalacia and an abnormal right bronchial tree), a complication not previously reported in patients with Kabuki syndrome. One of the patients also had extrahepatic biliary atresia, and the other had congenital diaphragmatic hernia.
Kokitsu-Nakata et al. (1999) reported the case of a Brazilian girl with Kabuki syndrome associated with lower lip pits and anorectal anomalies. They found reports of at least 4 patients with Kabuki syndrome and anorectal anomalies (Matsumura et al., 1992). They found reports of lower lip pits only in a Kabuki syndrome patient reported by Franceschini et al., 1993. However, Makita et al. (1999) reported a 5-year-old Japanese girl with clinical manifestations of both Kabuki syndrome and the van der Woude lip-pit syndrome (VWS; 119300). Assuming that the association of the 2 syndromes was caused by a microdeletion involving putative genes for the 2 disorders, Makita et al. (1999) carried out fluorescence in situ hybridization and microsatellite analyses using PAC clones and dinucleotide repeat markers spanning the VWS1 critical region at 1q32-q41. No deletion was detected.
Igawa et al. (2000) studied 3 patients with Kabuki syndrome for middle and inner ear abnormalities by using CT of the petrous bones. No middle ear abnormalities were identified, but all 3 patients had bilateral dysplasia of the inner ear (hypodysplasia of the cochlea, vestibule, and semicircular canals). Audiometry on 2 of the patients showed a sharp decrease in hearing of the high tone range, bilateral in one and unilateral in the other. The authors concluded that CT of the petrous bones and audiometry should be performed in early infancy on all patients with Kabuki syndrome.
Matsune et al. (2001) described oral manifestations in 6 patients with Kabuki syndrome. These included a high-arched palate, malocclusion, microdontia, a small dental arch, hypodontia, severe maxillary recession, and midfacial hypoplasia.
McGaughran et al. (2001) described 9 patients with Kabuki syndrome from New Zealand, all having the characteristic facial dysmorphism and many of the well-described associated anomalies. Some had unusual abnormalities, including diaphragmatic eventration, severe congenital mitral stenosis, idiopathic thrombocytopenic purpura, and vitiligo. They also reported Arnold Chiari type 1 malformation and epibulbar dermoids, neither of which had been previously reported in this syndrome.
Digilio et al. (2001) presented the results of cardiac evaluations of 60 patients diagnosed with Kabuki syndrome at their institution. Cardiac evaluation included chest radiograph, electrocardiogram, and 2-dimensional and color Doppler echocardiography. Thirty-five of the patients (58%) had congenital heart defects. The most commonly observed defects were coarctation of the aorta (23%), atrial septal defect (20%), and ventricular septal defect (17%).
Kurosawa et al. (2002) reported 4 patients with Kabuki syndrome and patellar dislocation and reviewed 6 previously reported patients with this combination. In their 4 patients, the age at diagnosis of the patellar dislocation ranged from 11 to 23 years. Of the patients in whom gender was known, 7 were female and 2 were male. The authors concluded that patellar dislocation may be frequent among older children and young adults with Kabuki syndrome, especially among obese female patients with lax knee joints.
Fryns and Devriendt (1998) described an 8-year-old girl with signs and symptoms thought to be consistent with Kabuki syndrome. She also had bilateral defective, bipartite clavicles. Hinrichs et al. (2002) described 2 unrelated patients with this type of clavicular defect in association with Kabuki syndrome.
Mihci et al. (2002) described a 7-year-old boy with Kabuki syndrome whose head MRI showed migration defects, including periventricular nodular heterotopia present along the walls of both lateral ventricles and an underdeveloped corpus callosum.
Ming et al. (2003) reported 3 children with Kabuki syndrome who also had retinal coloboma. A diagnosis of CHARGE association (214800) was initially suggested in 2 of the patients before the typical facial features of Kabuki syndrome emerged. A review of reported cases showed that the incidence of coloboma is greatly increased in Kabuki syndrome.
White et al. (2004) documented the phenotype of 27 children and adults with Kabuki syndrome from Australia and New Zealand. Parents reported a behavior phenotype characterized by the avoidance of eye contact, a love of music, and an excellent long-term memory. There was no correlation between head circumference and severity of intellectual disability. Six of their patients showed a characteristic growth profile, with failure to thrive in infancy progressing to obesity or overweight in middle childhood or adolescence.
Wessels et al. (2002) reviewed the characteristics of Kabuki syndrome in 300 patients. Typical findings included mild to moderate mental retardation, fetal pads, cleft palate, and characteristic facies with long palpebral fissures, everted lower lateral eyelids, and arched eyebrows. Postnatal growth retardation and skeletal and visceral anomalies were present in a large percentage of the patients.
Genevieve et al. (2004) described 8 patients from a series of 20 who had atypical findings in Kabuki syndrome. Rare or atypical features included the following: chronic and/or severe diarrhea (4/20) including celiac disease, diaphragmatic defects (3/20), pseudarthrosis of the clavicles (2/20), vitiligo (2/20), and persistent hypoglycemia (2/20). Other occasional findings were severe autoimmune thrombopenia, cerebellar vermis atrophy, and myopathic features. One patient presented with a clinical overlap with CHARGE syndrome (214800).
Adam and Hudgins (2005) provided a detailed review of the clinical features, diagnostic criteria, and cytogenic abnormalities reported in Kabuki syndrome.
Turner et al. (2005) reported 7 patients with Kabuki syndrome. Three patients had previously undetected ocular abnormalities, including myopia, ptosis, strabismus, and tilted discs. Four patients had nocturnal lagophthalmos (sleeping with the eyes open). There was no evidence of an 8p duplication in any of the patients.
Hoffman et al. (2005) performed immunologic evaluation of 19 consecutive individuals with Kabuki syndrome and found decreased IgA levels in 15 of 19 patients (79%), 2 of whom had undetectable levels. Eight patients (42%) also had low total IgG levels, and specific IgG subclass abnormalities were found in 6 of 13 patients evaluated; IgM levels were less frequently decreased. One patient failed to generate anti-tetanus antibodies despite immunization. Hoffman et al. (2005) suggested that hypogammaglobulinemia is a frequent finding in Kabuki syndrome and noted that the pattern of antibody abnormalities resembles common variable immune deficiency (CVID; 240500).
Diagnosis
Adam et al. (2019) reported consensus diagnostic criteria for Kabuki syndrome that were developed by an international group of experts after a systematic review of the literature. The authors proposed that a definitive diagnosis could be made in a patient at any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features at some point of life. Typical dysmorphic features included long palpebral fissures with eversion of the lateral third of the lower eyelid and 2 or more the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent, or cupped ears; and (4) persistent fingertip pads. Criteria for probable and possible diagnoses were also included.
Population Genetics
Kabuki syndrome is estimated to occur in at least 1 per 32,000 Japanese individuals (Niikawa et al., 1988).
Cytogenetics
Li et al. (1996) excluded microdeletion within 22q11.2 as a causative factor of the syndrome in 5 patients (3 Japanese children, a German girl, and a Colombian boy). The region was chosen for study because of the presence of congenital heart defects in patients with Kabuki syndrome and speculation that the condition might have a common molecular cause with the 22q11.2 deletion syndromes, DiGeorge syndrome (188400) and velocardiofacial syndrome (192430).
Lo et al. (1998) found an interstitial duplication of the short arm of chromosome 1 with breakpoints involving 1p13.1 and 1p22.1 in a patient with some features suggesting Kabuki syndrome, i.e., mental retardation, small head, eversion of the lateral part of the lower eyelids, epicanthic folds, lateral flare of the eyebrows, short columella, and persistent fetal finger pads. Other chromosome abnormalities described in this disorder, usually as isolated cases, were reviewed.
Using comparative genomic hybridization (CGH), Milunsky and Huang (2003) found an 8p23.1-p22 duplication in 6 unrelated patients with Kabuki syndrome. They delimited the duplicated region in all cases to approximately 3.5 Mb by BAC-FISH analysis. No duplication of this region was found in 2 parents or 20 controls by either CGH or BAC-FISH. Because the 6 patients with Kabuki syndrome represented different races, the authors suggested that the duplication may represent a common etiologic basis for the disorder.
By FISH using 15 BAC clones covering 8p23.1-p22, Miyake et al. (2004) did not detect any duplication in 26 Japanese and 2 Thai patients with Kabuki syndrome. Based on examination of the facial photographs of cases 1 and 2 in the report by Milunsky and Huang (2003), Miyake et al. (2004) suggested that the patient populations studied may differ clinically, with the earlier reported patients having an 'atypical Kabuki syndrome.'
Using array-based comparative genomic hybridization and FISH, Hoffman et al. (2005) failed to detect a duplication of 8p23.1-p22 in 15 patients with Kabuki syndrome and suggested that the 8p duplication may not be a common mechanism for Kabuki syndrome.
Molecular Genetics
Ng et al. (2010) performed the exome sequencing of 10 unrelated patients with Kabuki syndrome, 7 of European ancestry, 2 of Hispanic ancestry and 1 of mixed European and Haitian ancestry, and identified nonsense or frameshift mutations in the MLL2 gene in 7 patients. Follow-up Sanger sequencing detected MLL2 mutations in 2 of the 3 remaining individuals with Kabuki syndrome and in 26 of 43 additional cases. In all, they identified 33 distinct MLL2 mutations in 35 of 53 families (66%) with Kabuki syndrome (see, e.g., 602113.0001-602113.0004). In each of 12 cases for which DNA from both parents was available, the MLL2 variant was found to have occurred de novo. MLL2 mutations were also identified in each of 2 families in which Kabuki syndrome was transmitted from parent to child. None of the additional MLL2 mutations was found in 190 control chromosomes from individuals of matched geographic ancestry. Ng et al. (2010) suggested that mutations in MLL2 are a major cause of Kabuki syndrome.
Hannibal et al. (2011) identified 70 mutations in the MLL2 gene in 81 (74%) of 110 kindreds with Kabuki syndrome. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, whereas a transmitted mutation was found in 2 of 3 familial cases. Most of the variants were nonsense or frameshift mutations predicted to result in haploinsufficiency. Mutations occurred throughout the gene, but were particularly common in exons 39 and 48. The clinical features of those with or without mutations were similar, except for renal anomalies, which occurred in 47% of mutation carriers compared to 14% of those who did not have a mutation.
Li et al. (2011) sequenced all 54 coding exons of the MLL2 gene in 34 patients with Kabuki syndrome and identified 18 distinct mutations in 19 patients, 11 of 12 tested de novo. Mutations were located throughout the gene and included 3 nonsense mutations, 2 splice site mutations, 6 small deletions or insertions, and 7 missense mutations. Li et al. (2011) compared frequencies of clinical symptoms in MLL2 mutation carriers versus noncarriers. MLL2 mutation carriers more often presented with short stature and renal anomalies (p = 0.026 and 0.031, respectively), and in addition, MLL2 showed a more typical facial gestalt (17 of 19) compared with noncarriers (9 of 15), although this result was not statistically significant (p = 0.1).
Miyake et al. (2013) identified MLL2 mutations in 50 (61.7%) of 81 patients with Kabuki syndrome. Most (70%) of the MLL2 mutations were predicted to be protein-truncating. The truncating mutations were distributed throughout the coding region, whereas the nontruncating mutations were most often within or adjacent to functional domains.
Using direct sequencing, MLPA, and quantitative PCR, Micale et al. (2014) screened 303 patients with Kabuki syndrome and identified 133 KMT2D mutations, 62 of which were novel. Micale et al. (2014) found that a number of KMT2D truncating mutations result in mRNA degradation through nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. The authors also demonstrated that the reduction of KMT2D protein levels in patients' lymphoblastoid and skin fibroblast cell lines carrying these mutations affects the expression levels of known KMT2D target genes.
Van Laarhoven et al. (2015) identified KMT2D mutations in 12 (32%) of 40 patients clinically diagnosed with Kabuki syndrome.
### Genotype-Phenotype Correlations
Banka et al. (2012) analyzed the MLL2 gene in a cohort of 116 patients with Kabuki syndrome, including 18 patients previously reported by Hannibal et al. (2011), and identified MLL2 variants in 74 (63.8%). Systematic Kabuki syndrome facial morphology study suggested that nearly all patients with typical Kabuki syndrome facial features have pathogenic MLL2 mutations, although the disorder can be phenotypically variable. In addition, Banka et al. (2012) showed that KABUK1 patients were more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations, and palatal malformations in comparison with MLL2 mutation-negative patients. Banka et al. (2012) concluded that the genetic heterogeneity of Kabuki syndrome is not as extensive as previously suggested; however, given the phenotypic variability of the disorder, MLL2 testing should be considered even in atypical patients.
Miyake et al. (2013) screened 81 patients with Kabuki syndrome for mutations in the MLL2 and KDM6A genes and identified MLL2 mutations in 50 (61.7%) and KDM6A mutations in 5 (6.2%). Patients with MLL2 truncating mutations (70%) had facies that were more typical of those seen in the patients originally reported with Kabuki syndrome. High-arched eyebrows, short fifth fingers, and infantile hypotonia were more commonly seen in patients with MLL2 mutations than in those with KDM6A mutations. Only half of the patients with MLL2 mutations had short stature and postnatal growth retardation, compared to all of the patients with KDM6A mutations.
### Exclusion Studies
Bottani et al. (2006) screened the TGFBR1 (190181) and TGFBR1 (190182) genes in 14 typical Kabuki patients and found no mutations.
In a girl with Kabuki syndrome, Maas et al. (2007) identified a heterozygous de novo 250-kb deletion in the MACROD2 gene (611567) at chromosome 20p12.1. No deletions or pathogenic mutations in the MACROD2 or FLRT3 (604808) genes were identified in 19 additional patients with Kabuki syndrome.
Among 43 Japanese patients with Kabuki syndrome, Kuniba et al. (2008) did not find mutations or deletions in the MACROD2 or FLRT3 genes.
Of 34 patients with Kabuki syndrome, Li et al. (2011) failed to find mutations in the MLL2 gene in 15. Mutation-negative patients were subsequently tested for mutations in 10 functional candidate genes, but no convincing causative mutations could be identified. Li et al. (2011) concluded that MLL2 is the major gene for Kabuki syndrome with a wide spectrum of de novo mutations but that there is further genetic heterogeneity accounting for MLL2 mutation-negative patients.
Nomenclature
Several authors, including Hughes and Davies (1994) and Burke and Jones (1995), have recommended that the term 'make-up' be removed from the designation of this syndrome because some families consider the term objectionable.
INHERITANCE \- Autosomal dominant GROWTH Other \- Postnatal growth retardation HEAD & NECK Head \- Microcephaly Face \- Trapezoid philtrum Ears \- Large prominent ears \- Recurrent otitis media in infancy \- Posteriorly rotated ears \- Hearing loss \- Preauricular pit Eyes \- Long palpebral fissures \- Eversion of lateral third of lower eyelids \- Thick eyelashes \- Ptosis \- Blue sclerae \- Broad, arched eyebrows \- Sparse eyebrows Nose \- Depressed nasal tip \- Short nasal columella Mouth \- Cleft palate \- High-arched palate CARDIOVASCULAR Heart \- Congenital heart defect \- Ventricular septal defect \- Atrial septal defect Vascular \- Coarctation of aorta RESPIRATORY Lung \- Aspiration pneumonia ABDOMEN Gastrointestinal \- Feeding difficulties \- Malabsorption \- Intestinal malrotation \- Anal stenosis \- Imperforate anus \- Anoperineal fistula GENITOURINARY External Genitalia (Male) \- Small penis Internal Genitalia (Male) \- Cryptorchidism Kidneys \- Crossed fused renal ectopia \- Single fused kidneys Ureters \- Ureteropelvic junction obstruction SKELETAL Spine \- Scoliosis \- Vertebral anomalies Pelvis \- Congenital hip dislocations Limbs \- Joint hyperextensibility Hands \- Short fifth finger \- Increased digital ulnar loop and hypothenar loop patterns \- Absent digital triradius c and/or d \- Persistence of fingerpads SKIN, NAILS, & HAIR Skin \- Cafe au lait spots Hair \- Hirsutism NEUROLOGIC Central Nervous System \- Mental retardation \- Seizures \- Developmental delay \- Hypotonia ENDOCRINE FEATURES \- Congenital hypothyroidism \- Premature thelarche HEMATOLOGY \- Idiopathic thrombocytopenic purpura \- Hemolytic anemia MISCELLANEOUS \- Increased susceptibility to infections \- Majority of cases are sporadic MOLECULAR BASIS \- Caused by mutation in the myeloid/lymphoid or mixed lineage leukemia 2 gene (MLL2, 602113.0001 ) ▲ 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
| KABUKI SYNDROME 1 | c0796004 | 2,642 | omim | https://www.omim.org/entry/147920 | 2019-09-22T16:39:21 | {"doid": ["0060473"], "mesh": ["C537705"], "omim": ["147920"], "orphanet": ["2322"], "synonyms": ["Alternative titles", "KABUKI SYNDROME", "KABUKI MAKE-UP SYNDROME", "NIIKAWA-KUROKI SYNDROME"], "genereviews": ["NBK62111"]} |
Lettuce big-vein disease
Causal agentslettuce big-vein associated virus (LBVaV)
HostsLettuce
VectorsOlpidium brassicae
TreatmentSee text
Lettuce big-vein disease causes leaf distortion and ruffling in affected lettuce plants.
This disease was first associated in 1983 with a rod-shaped virus named lettuce big-vein associated virus (LBVaV), which is transmitted by the obligately parasitic soil-inhabiting fungus, Olpidium brassicae.[1] However, in 2000, a second virus, Mirafiori lettuce virus, was found in lettuce showing big-vein symptoms. Furthermore, since the lettuce infected with this virus alone developed big-vein symptoms, it is considered to be a main agent of the big-vein disease.
## Symptoms[edit]
Affected plants have veins that become large and clear, causing the rest of the leaf to become ruffled. Severely infected plants may fail to form a lettuce head.[1]
## Control[edit]
* Grow disease-resistant cultivars.
* Use disease-free healthy seeds.
* Treat with methyl bromide, chloropicrin, or dazomet solution.
## References[edit]
1. ^ a b "Big Vein". University of California Integrated Pest Management Program. Retrieved 24 June 2019.
This plant virus article is a stub. You can help Wikipedia by expanding it.
* v
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* e
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*[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
| Lettuce big-vein disease | None | 2,643 | wikipedia | https://en.wikipedia.org/wiki/Lettuce_big-vein_disease | 2021-01-18T18:54:40 | {"wikidata": ["Q6533866"]} |
Apudoma
SpecialtyOncology
In pathology, an apudoma is an endocrine tumour that arises from an APUD cell[1][2] from structures such as the ampulla of Vater.[3] They were historically thought to be derived from neural crest cells,[4] but this has since been shown to be untrue (see neuroendocrine tumor).
The term dates back to at least 1975.[5] Because the label "Apudoma" is very general, it is preferred to use a more specific term when possible.[citation needed]
## See also[edit]
* VIPoma
* Carcinoid tumor
## References[edit]
1. ^ Welbourn RB (1977). "Current status of the apudomas". Ann. Surg. 185 (1): 1–12. doi:10.1097/00000658-197701000-00001. PMC 1396259. PMID 12724. Full Free Text
2. ^ Fukunaga Y, Hirata S, Tanimura S, et al. (2000). "Superficial undifferentiated small cell carcinoma of the esophagus showing an interesting growing pattern in histology". Hepatogastroenterology. 47 (32): 429–32. PMID 10791205.
3. ^ Galati G, Fiori E, Tiziano G, et al. (2002). "[Apudoma of Vater's ampulla: case report and review of the literature]". Il Giornale di Chirurgia (in Italian). 23 (3): 97–100. PMID 12109233.
4. ^ "eMedicine - VIPoma : Article by Robert J Ferry, Jr, MD". Archived from the original on 16 August 2007. Retrieved 2007-09-22.
5. ^ Spence RW, Burns-Cox CJ (1975). "ACTH-secreting 'apudoma' of gallbladder". Gut. 16 (6): 473–6. doi:10.1136/gut.16.6.473. PMC 1411036. PMID 168130.
## External links[edit]
Classification
D
* ICD-O: M8248/1
* MeSH: D001079
* v
* t
* e
Glandular and epithelial cancer
Epithelium
Papilloma/carcinoma
* Small-cell carcinoma
* Combined small-cell carcinoma
* Verrucous carcinoma
* Squamous cell carcinoma
* Basal-cell carcinoma
* Transitional cell carcinoma
* Inverted papilloma
Complex epithelial
* Warthin's tumor
* Thymoma
* Bartholin gland carcinoma
Glands
Adenomas/
adenocarcinomas
Gastrointestinal
* tract: Linitis plastica
* Familial adenomatous polyposis
* pancreas
* Insulinoma
* Glucagonoma
* Gastrinoma
* VIPoma
* Somatostatinoma
* Cholangiocarcinoma
* Klatskin tumor
* Hepatocellular adenoma/Hepatocellular carcinoma
Urogenital
* Renal cell carcinoma
* Endometrioid tumor
* Renal oncocytoma
Endocrine
* Prolactinoma
* Multiple endocrine neoplasia
* Adrenocortical adenoma/Adrenocortical carcinoma
* Hürthle cell
Other/multiple
* Neuroendocrine tumor
* Carcinoid
* Adenoid cystic carcinoma
* Oncocytoma
* Clear-cell adenocarcinoma
* Apudoma
* Cylindroma
* Papillary hidradenoma
Adnexal and
skin appendage
* sweat gland
* Hidrocystoma
* Syringoma
* Syringocystadenoma papilliferum
Cystic, mucinous,
and serous
Cystic general
* Cystadenoma/Cystadenocarcinoma
Mucinous
* Signet ring cell carcinoma
* Krukenberg tumor
* Mucinous cystadenoma / Mucinous cystadenocarcinoma
* Pseudomyxoma peritonei
* Mucoepidermoid carcinoma
Serous
* Ovarian serous cystadenoma / Pancreatic serous cystadenoma / Serous cystadenocarcinoma / Papillary serous cystadenocarcinoma
Ductal, lobular,
and medullary
Ductal carcinoma
* Mammary ductal carcinoma
* Pancreatic ductal carcinoma
* Comedocarcinoma
* Paget's disease of the breast / Extramammary Paget's disease
Lobular carcinoma
* Lobular carcinoma in situ
* Invasive lobular carcinoma
Medullary carcinoma
* Medullary carcinoma of the breast
* Medullary thyroid cancer
Acinar cell
* Acinic cell carcinoma
This oncology article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[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
| Apudoma | c0003650 | 2,644 | wikipedia | https://en.wikipedia.org/wiki/Apudoma | 2021-01-18T19:05:44 | {"mesh": ["D001079"], "umls": ["C0003650"], "wikidata": ["Q3621073"]} |
A number sign (#) is used with this entry because of evidence that Usher syndrome type IV (USH4) is caused by homozygous mutation in the ARSG gene (610008) on chromosome 17q24.
Description
An atypical form of Usher syndrome, here designated type IV, is an autosomal recessive disorder characterized by late onset of retinitis pigmentosa and usually late-onset of progressive sensorineural hearing loss without vestibular involvement (summary by Khateb et al., 2018).
For a discussion of genetic heterogeneity of Usher syndrome, see 276900.
Clinical Features
Khateb et al. (2018) described 5 patients from 3 Yemenite Jewish families (MOL0120, MOL0737, and TB55) with an atypical form of Usher syndrome. All affected individuals presented with a distinctive late-onset retinal phenotype, including ring-shaped retinal atrophy delimiting the vascular arcades temporally and extending beyond the optic nerve nasally, with relative preservation of the mid- and far-periphery. Over time, pigment migration occurred within the atrophic areas, forming bone-spicule-like pigmentary changes as well as pigment clumps, and the central macula also became involved. Electroretinographic testing showed severely decreased rod and mixed cone-rod responses. Electrooculography testing, which was performed on 3 patients, showed that the Arden ratio was reduced, suggesting injury to the retinal pigment epithelium, either as a primary event or secondary to photoreceptor degeneration. None of the patients reported significant abnormalities of the vestibular system. Affected sibs from 2 families presented with progressive moderate to severe sensorineural hearing loss at a relatively late age, usually after age 40; hearing loss in the single patient from the third family began in childhood and deteriorated around the age of 18.
Mapping
By homozygosity mapping followed by whole-genome and whole-exome sequencing in 3 Yemenite Jewish families segregating an atypical form of Usher syndrome, Khateb et al. (2018) identified a single shared homozygous 66- to 69.4-Mb region on chromosome 17.
Molecular Genetics
In 5 affected members of 3 consanguineous Yemenite Jewish families with an atypical form of Usher syndrome (618144), Khateb et al. (2018) identified homozygosity for a missense mutation in the ARSG gene (D45Y; 610008.0001). The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the families. All haplotypes surrounding the variant were identical, indicating that it is a founder mutation. The mutation was found in heterozygous state in 1 of 101 Yemenite Jewish controls, corresponding to a minor allele frequency of 0.005, and was not found in the gnomAD database.
INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Hearing loss, sensorineural, progressive (moderate to severe, late onset) \- No vestibular abnormalities Eyes \- Retinitis pigmentosa, late onset \- Retinal atrophy, ring-shaped \- Bone-spicule-like pigmentary changes \- Pigment clumps \- Decreased rod and mixed cone-rod responses seen on electroretinography \- Reduced Arden ratio MISCELLANEOUS \- Onset of vision and hearing loss occurs around 40 years of age \- Based on a report of 3 Yemenite Jewish families (last curated September 2018) MOLECULAR BASIS \- Caused by mutation in the arylsulfatase G gene (ARSG, 610008.0001 ) ▲ 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
| USHER SYNDROME, TYPE IV | None | 2,645 | omim | https://www.omim.org/entry/618144 | 2019-09-22T15:43:33 | {"omim": ["618144"]} |
Not to be confused with Harlequin type ichthyosis.
Harlequin syndrome
Other namesProgressive isolated segmental anhidrosis
A person exhibiting the asymmetric symptoms of Harlequin syndrome. One half of the forehead is red, and the other half is paler.
Harlequin syndrome is a condition characterized by asymmetric sweating and flushing on the upper thoracic region of the chest, neck and face. Harlequin syndrome is considered an injury to the autonomic nervous system (ANS). The ANS controls some of the body's natural processes such as sweating, skin flushing and pupil response to stimuli.[1] Such individuals with this syndrome have an absence of sweat skin flushing unilaterally; usually on the one side of the face, arms and chest. It is an autonomic disorder that may occur at any age.[2] Harlequin syndrome affects fewer than 200,000 people in the United States.
Symptoms associated with Harlequin syndrome are more likely to appear when a person has been in the following conditions: exercising, warm environment and intense emotional situation. Since one side of the body sweats and flushes appropriately to the condition, the other side of the body will have an absence of such symptoms.[3] This syndrome has also been called the "Harlequin sign" and thought to be one of the spectrum of diseases that may cause Harlequin syndrome.
It can also be the outcome of a one sided endoscopic thoracic sympathectomy (ETS) or endoscopic sympathetic blockade (ESB) surgery.[2][4]
Harlequin syndrome can also be seen as a complication of VA (veno-arterial) extracorporeal membrane oxygenation (ECMO). This involves differential hypoxemia (low oxygen levels in the blood) of the upper body in comparison to the lower body.[5]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Mechanism
* 4 Diagnosis
* 5 Treatment and prognosis
* 6 Research
* 7 Eponym
* 8 See also
* 9 References
* 10 External links
## Signs and symptoms[edit]
The "Harlequin sign" is unilateral flushing and sweating of the face, neck, and upper chest usually after exposure to heat or strenuous exertion.[6] Horner syndrome, another problem associated with the sympathetic nervous system, is often seen in conjunction with harlequin syndrome.
Since Harlequin syndrome is associated with a dysfunction in the autonomic nervous system, main symptoms of this dysfunction are in the following: Absence of sweat(anhidrosis) and flushing on one side of the face, neck, or upper thoracic area. In addition, other symptoms include cluster headaches, tearing of the eyes, nasal discharge, abnormal contraction of the pupils, weakness in neck muscles, and drooping of one side of the upper eyelid.[3]
## Causes[edit]
One possible cause of Harlequin syndrome is a lesion to the preganglionic or postganglionic cervical sympathetic fibers and parasympathetic neurons of the ciliary ganglion.[7] It is also believed that torsion (twisting) of the thoracic spine can cause blockage of the anterior radicular artery leading to Harlequin syndrome.[8] The sympathetic deficit on the denervated side causes the flushing of the opposite side to appear more pronounced. It is unclear whether or not the response of the undamaged side was normal or excessive, but it is believed that it could be a result of the body attempting to compensate for the damaged side and maintain homeostasis.[8]
Since the cause and mechanism of Harlequin syndrome is still unknown, there is no way to prevent this syndrome.
## Mechanism[edit]
Although the exact mechanism for Harlequin syndrome is still unclear, understanding what is affected with this syndrome is important. Majority of cases are thought to occur when nerve bundles in the head and neck are injured. Such bundles are able to send an action potential from the autonomic nervous system to the rest of the body. However, action potentials in this system are not being received by the second or third thoracic vertebrae which innervates the face, neck, and upper chest.[3] Damage or lesions near T2 or T3 could be between the stellate ganglion and superior cervical ganglion. This is where we would observe absence of sweat and skin flushing on one side of the face, neck, and upper chest.[citation needed]
## Diagnosis[edit]
Diagnosis of Harlequin syndrome is made when the individual has consistent signs and symptoms of the condition, therefore, it is made by clinical observation. In addition, a neurologist or primary care physician may require an MRI test to rule out similar disorders such as Horner's syndrome, Adie's syndrome, and Ross' syndrome.[3] In an MRI, a radiologist may observe areas near brain or spinal cord for lesions, or any damage to the nerve endings. It is also important that the clinician rules out traumatic causes by performing autonomic function tests.[9] Such tests includes the following: tilt table test, orthostatic blood pressure measurement, head-up test, valsalva maneuver, thermoregulatory sweat test, tendon reflex test, and electrocardiography (ECG). CT scan of the heart and lungs may also be performed to rule out a structural underlying lesion.[10] The medical history of the individual should be carefully noted.
## Treatment and prognosis[edit]
Harlequin syndrome is not debilitating so treatment is not normally necessary.[6] In cases where the individual may feel socially embarrassed, contralateral sympathectomy may be considered, although compensatory flushing and sweating of other parts of the body may occur.[10] In contralateral sympathectomy, the nerve bundles that cause the flushing in the face are interrupted. This procedure causes both sides of the face to no longer flush or sweat. Since symptoms of Harlequin syndrome do not typically impair a person’s daily life, this treatment is only recommended if a person is very uncomfortable with the flushing and sweating associated with the syndrome.[3]
## Research[edit]
In August 2016, researchers at the Instituto de Assistência dos Servidores do Estado do Rio de Janeiro used botulinum toxin as a method to block the acetylcholine release from the presynaptic neurons. Although they have seen a reduction in one sided flushing, sweating still occurs.[11]
There have been case studies of individuals who have experienced this syndrome after an operation. Two female patients suffering from metastatic cancer, ages 37-years-old and 58-years-old, were scheduled for placement of an intrathecal pump drug delivery system. After the intrathecal pump was placed, certain medications were given to the patients. Once the medications were administered, both patients had one sided facial flushes, closely resembling Harlequin Syndrome.[12] Patients were given neurological exams to confirm that their nerves were still intact. An MRI was performed and showed no significant evidence of bleeding or nerve compression. After close observation for 16 hours, symptoms of the Harlequin syndrome was diminished and both patients did not have another episode.
Another case study was based on a 6-year-old male visiting an outpatient setting for one sided flushes during or after physical activity or exposed to heat.[9] Vitals, laboratory tests, and CT scans were normal. Along with the flushes, the right pupil was 1.5 mm in size, while the left pupil was 2.5 mm in size; however, no ptosis, miosis, or enophthalmos was noted.[9] The patient also had an MRI scan to rule out any lesion near the brain or spinal cord. No abnormalities were noted and the patient did not receive any treatments. The patient was diagnosed with idiopathic Harlequin syndrome.
Although the mechanism is still unclear, the pathophysiology of this condition, close monitoring, and reassurance are vital factors for successful management.
## Eponym[edit]
The name for the syndrome is credited to Lance and Drummond who were inspired by resemblance patient’s half-flushed faces bore to colorful Harlequin masks.[2]
## See also[edit]
* Horner's syndrome
## References[edit]
1. ^ NIH - National Cancer Institute. "Autonomic Nervous System". PubMed Health.
2. ^ a b c Lance, J. W. (2005). "Harlequin syndrome". Practical Neurology. 5 (3): 176–177. doi:10.1111/j.1474-7766.2005.00306.x.
3. ^ a b c d e "Harlequin syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2017-11-07.
4. ^ Wasner, G.; Maag, R.; Ludwig, J.; Binder, A.; Schattschneider, J.; Stingele, R.; Baron, R. (2005). "Harlequin syndrome - one face of many etiologies". Nature Clinical Practice Neurology. 1 (1): 54–59. doi:10.1038/ncpneuro0040. PMID 16932492. S2CID 5324849.
5. ^ Al Hanshi, Said Ali Masoud; Othmani, Farhana Al (2017). "A case study of Harlequin syndrome in VA-ECMO". Qatar Medical Journal. 2017 (1): 39. doi:10.5339/qmj.2017.swacelso.39. PMC 5474607.
6. ^ a b National Institutes of Health: Office of Rare Diseases Research. (2009) "Harlequin syndrome." Genetic and Rare Diseases Information Center (GARD). http://rarediseases.info.nih.gov/GARD/Condition/8610/QnA/22289/Harlequin_syndrome.aspx. December 9, 2011.
7. ^ Corbett M., Abernethy D.A.; Abernethy (1999). "Harlequin syndrome". J Neurol Neurosurg Psychiatry. 66 (4): 544. doi:10.1136/jnnp.66.4.544. PMC 1736279. PMID 10201435.
8. ^ a b Lance, J. W.; Drummond, P. D.; Gandevia, S. C.; Morris, J. G. L. (1988) "Harlequin syndrome: the sudden onset of unilateral flushing and sweating." Journal of Nerology, Nerosurgery, and Psychiatry (51): 635-642.
9. ^ a b c Kim, Ju Young; Lee, Moon Souk; Kim, Seung Yeon; Kim, Hyun Jung; Lee, Soo Jin; You, Chur Woo; Kim, Jon Soo; Kang, Ju Hyung (November 2016). "A pediatric case of idiopathic Harlequin syndrome". Korean Journal of Pediatrics. 59 (Suppl 1): S125–S128. doi:10.3345/kjp.2016.59.11.S125. ISSN 1738-1061. PMC 5177694. PMID 28018464.
10. ^ a b Willaert, W. I. M.; Scheltinga, M. R. M.; Steenhuisen, S. F.; Hiel, J. a. P. (September 2009). "Harlequin syndrome: two new cases and a management proposal". Acta Neurologica Belgica. 109 (3): 214–220. ISSN 0300-9009. PMID 19902816.
11. ^ Manhães, Roberta K.J.V.; Spitz, Mariana; Vasconcellos, Luiz Felipe (2016). "Botulinum toxin for treatment of Harlequin syndrome". Parkinsonism & Related Disorders. 23: 112–113. doi:10.1016/j.parkreldis.2015.11.030. PMID 26750113.
12. ^ Zinboonyahgoon, Nantthasorn (June 2015). "Harlequin Syndrome Following Implantation of Intrathecal Pumps: A Case Series". Neuromodulation. 18 (8): 772–5. doi:10.1111/ner.12343. PMID 26399375.
## External links[edit]
Classification
D
* ICD-10: G90.8
* MeSH: C535634
External resources
* Orphanet: 199282
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Harlequin syndrome | c2029348 | 2,646 | wikipedia | https://en.wikipedia.org/wiki/Harlequin_syndrome | 2021-01-18T18:42:12 | {"gard": ["8610"], "mesh": ["C535634"], "umls": ["C2029348"], "orphanet": ["199282"], "wikidata": ["Q5658687"]} |
Kantaputra et al. (2003) described a 12-year-old Thai girl with what they proposed represents a 'new' syndrome of proximal and distal symphalangism, postaxial polydactyly, hypodontia, and multiple and hyperplastic frenula. Blepharoptosis and dysplastic ears were also described. The fingernails were not dysplastic. The patient was of short stature. In the feet there was absence of the distal phalanges of toes II-V and postaxial polydactyly of the left foot. Mutation analyses of NOG (602991) and GDF5 (601146), the genes responsible for symphalangism-related syndromes, were negative.
INHERITANCE \- Isolated cases GROWTH Height \- Short stature HEAD & NECK Head \- Dolichocephaly Ears \- Hypoplastic lobules \- Hypoplastic helices Eyes \- Blepharoptosis Nose \- Prominent, broad nasal bridge \- Broad philtrum Mouth \- Multiple hyperplastic frenula \- High-arched palate Teeth \- Hypodontia SKELETAL Hands \- Postaxial polydactyly \- Symphalangism, proximal and distal \- Brachydactyly Feet \- Postaxial polydactyly \- Brachydactyly \- Congenital absence of distal phalanges (toes 2-5) ▲ Close
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*[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
| THAI SYMPHALANGISM SYNDROME | c1842679 | 2,647 | omim | https://www.omim.org/entry/608028 | 2019-09-22T16:08:27 | {"mesh": ["C564303"], "omim": ["608028"]} |
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: "Olecranon fracture" – news · newspapers · books · scholar · JSTOR (December 2014) (Learn how and when to remove this template message)
Olecranon fracture
Fracture of the olecranon
SpecialtyOrthopedic
Olecranon fracture is a fracture of the bony portion of the elbow. The injury is fairly common and often occurs following a fall or direct trauma to the elbow. The olecranon is the proximal extremity of the ulna which is articulated with the humerus bone and constitutes a part of the elbow articulation. Its location makes it vulnerable to direct trauma.
## Contents
* 1 Signs and symptoms
* 2 Mechanism
* 3 Diagnosis
* 3.1 Classifications
* 3.1.1 Mayo classification
* 3.1.2 AO classification
* 3.1.3 Colton Classification
* 3.1.4 Schatzker Classification
* 4 Treatment
* 4.1 Nondisplaced fractures
* 4.2 Displaced fractures
* 4.2.1 Tension band fixation
* 4.2.2 Intramedullary fixation and plates
* 4.2.3 Excision and triceps advancement
* 5 Epidemiology
* 6 References
* 7 Further reading
* 8 External links
## Signs and symptoms[edit]
People with olecranon fractures present with intense elbow pain after a direct blow or fall.[1] Swelling over the bone site is seen and an inability to straighten the elbow is common. Due to the proximity of the olecranon to the ulnar nerve, the injury and swelling may cause numbness and tingling at the fourth and fifth fingers.[1] Examination can bring out a palpable defect at the site of the fracture.[2]
## Mechanism[edit]
Olecranon fractures are common. Typically they are caused by direct blows to the elbow (e.g. motor vehicle accidents), and due to falls when the triceps are contracted.[1][3] "Side-swipe" injury when driving a motor vehicle with an elbow projecting outside the vehicle resting on an open window's edge is an example.[4]
Direct trauma: This can happen in a fall with landing on the elbow or by being hit by a solid object. Trauma to the elbow often results in comminuted fractures of the olecranon.
Indirect trauma: by falling and landing with an outstretched arm.
Powerful pull of the triceps muscle can also cause avulsion fractures.
## Diagnosis[edit]
Olecranon fracture
To assess an olecranon fracture, a careful skin exam is performed to ensure there is no open fracture. Then a complete neurological exam of the upper limb should be documented.[5][2] Frontal and lateral X-ray views of the elbow are typically done to investigate the possibility of an olecranon fracture.[1] A true lateral x-ray is essential to determine the fracture pattern, degree of displacement, comminution, and the degree of articular involvement.
### Classifications[edit]
There are several classifications that describe different forms of olecranon fractures, yet none of them have gained widespread acceptance:[5]
#### Mayo classification[edit]
Based on the stability, the displacement and the comminution of the fracture. It is composed of three types, and each type is divided in two subtypes: subtype A (non-comminuted) and subtype B (comminuted).
* Type I: Non-displaced fracture – It can be either non-comminuted ones (Type IA) or comminuted (Type IB).
* Type II: Displaced, stable fractures – In this pattern, the proximal fracture fragment is displaced more than 3 mm, but the collateral ligaments are intact. That is why there is no elbow instability. It can be either non-comminuted ones (Type IIA) or comminuted (Type IIB).
* Type III: Displaced unstable fracture – In this case, the fracture fragments are displaced and the forearm is unstable in relation to the humerus. It is a fracture -dislocation. It also may be either non-comminuted (Type IIIA) or comminuted (Type IIIB).
#### AO classification[edit]
This classification incorporates all fractures of the proximal ulna and radius into one group, subdivided into three patterns:
* Type A: Extra-articular fractures of the metadiaphysis of either the radius or the ulna
* Type B: Intra-articular fractures of either the radius or ulna
* Type C: Complex fractures of both the proximal radius and ulna
#### Colton Classification[edit]
* Type I \- Nondisplaced - Displacement does not increase with elbow flexion
* Type II \- Avulsion (displaced)
* Type III \- Oblique and Transverse (displaced)
* Type IV \- Comminuted (displaced)
* Type V \- Fracture dislocation
#### Schatzker Classification[edit]
* Type A \- Simple transverse fracture
* Type B \- Transverse impacted fracture
* Type C \- Oblique fracture
* Type D \- Communuted fracture
* Type E \- More distal fracture, extra-articular
* Type F \- Fracture-dislocation
## Treatment[edit]
Fracture (left) and repair (right) with three pins, wires, and incision closure with staples
### Nondisplaced fractures[edit]
In fractures with little or no displacement, immobilization with a posterior splint may be sufficient.[1] Elbows may be immobilized at 45°–90° of flexion for 3 weeks, followed by limited (90°) flexion exercises.
### Displaced fractures[edit]
Most olecranon fractures are displaced and are best treated surgically:[1]
#### Tension band fixation[edit]
Tension band fixation is the most common form of internal fixation used for non-comminuted olecranon fractures.[5] It is typically reserved for noncomminuted fractures that are proximal to the coronoid.[2] This procedure is performed using Kirschner wire (K-wires) which converts tensile forces into compressive force.[2]
#### Intramedullary fixation and plates[edit]
Single intramedullary screws can be used to treat simple transverse or oblique fractures.[5] Plates can be used for all proximal ulna fracture types including Monteggia fractures, and comminuted fractures.[2]
#### Excision and triceps advancement[edit]
This method is indicated for cases when open reduction and internal fixation is unlikely to be successful. For example: extensive comminutions, elderly patients with osteoporotic bone, and small or non-union fractures.[5][2]
## Epidemiology[edit]
Olecranon fractures are rare in children, constituting only 5 to 7% of all elbow fractures. This is because in early life, olecranon is thick, short and much stronger than the lower extremity of the humerus.[5]
However, olecranon fractures are a common injury in adults. This is partly due to its exposed position on the point of the elbow.
## References[edit]
1. ^ a b c d e f Essentials of musculoskeletal care. Sarwark, John F. Rosemont, Ill.: American Academy of Orthopaedic Surgeons. 2010. ISBN 9780892035793. OCLC 706805938.CS1 maint: others (link)
2. ^ a b c d e f 1967-, Egol, Kenneth A. (2015). Handbook of fractures. Koval, Kenneth J., Zuckerman, Joseph D. (Joseph David), 1952-, Ovid Technologies, Inc. (5th ed.). Philadelphia: Wolters Kluwer Health. ISBN 9781451193626. OCLC 960851324.CS1 maint: numeric names: authors list (link)
3. ^ Current diagnosis & treatment emergency medicine. Stone, C. Keith., Humphries, Roger L. (7th ed.). New York: McGraw-Hill Medical. 2011. ISBN 9780071701075. OCLC 711520941.CS1 maint: others (link)
4. ^ Knapp, Kerry (2006). "The Elbow". In Hannon, Patrick; Knapp, Kerry (eds.). Forensic Biomechanics. Lawyers & Judges. pp. 243–8. ISBN 978-1-930056-27-5.
5. ^ a b c d e f Newman, S. D. S.; Mauffrey, C.; Krikler, S. (2009-06-01). "Olecranon fractures". Injury. 40 (6): 575–581. doi:10.1016/j.injury.2008.12.013. PMID 19394931.
## Further reading[edit]
* Carson, Sarah; Woolridge, Dale P.; Colletti, Jim; Kilgore, Kevin (2006). "Pediatric Upper Extremity Injuries". Pediatric Clinics of North America. 53 (1): 41–67, v. doi:10.1016/j.pcl.2005.10.003. PMID 16487784.
* Newman, S.D.S.; Mauffrey, C.; Krikler, S. (2009). "Olecranon fractures". Injury. 40 (6): 575–81. doi:10.1016/j.injury.2008.12.013. PMID 19394931.
* Veillette, Christian J.H.; Steinmann, Scott P. (2008). "Olecranon Fractures". Orthopedic Clinics of North America. 39 (2): 229–36, vii. doi:10.1016/j.ocl.2008.01.002. PMID 18374813.
* Olecranon Fractures at eMedicine
## External links[edit]
Classification
D
* ICD-10: Xxx.x
* ICD-9-CM: xxx
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*[AA]: Adrenergic agonist
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*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Olecranon fracture | c0555335 | 2,648 | wikipedia | https://en.wikipedia.org/wiki/Olecranon_fracture | 2021-01-18T18:30:37 | {"wikidata": ["Q2019348"]} |
Porcine stress syndrome, also known as malignant hyperthermia or PSS, is a condition in pigs. It is characterised by hyperthermia triggered by stress, anaesthesia with halothane or intense exercise. PSS may appear as sudden death in pigs, often after transport. It is an inherited, autosomal recessive disorder due to a defective ryanodine receptor leading to huge calcium influx, muscle contracture and increase in metabolism.
PSS can manifest itself in the abattoir as the production of Pale, Soft and Exudative meat due to a rapid fall in muscle pH and degradation of muscle proteins and structure. This meat is usually rejected after inspection.
This disorder is most common in Landrace, Piétrain and crossbreeds of these breeds of pig. The genes may have been favoured in the past due to a larger muscle bulk in these breeds. However this is not standard protocol in developed countries these days.
Common Industry Breeding Practice
## Clinical signs and diagnosis[edit]
Truckloads or railcar loads of PSS-susceptible pigs may be found with a higher-than-average percentage dead on arrival after stressful events such as transport.
Initial signs of the onset of PSS are pyrexia, panting, sweating, tachycardia and arrhythmias. Chronic cases may show muscle atrophy.
Under halothane anaesthesia, pigs will suddenly become rigid and pyrexic.
The halothane challenge was the historical method of diagnosis.
Genetic testing via a PCR enables affected and carrier animals to be found.
Psychologist Melanie Joy has likened PSS to post-traumatic stress disorder in humans.[1]
## Treatment and control[edit]
Removing the pig from the stressful situation can prevent the episode.[2]
Sedation and glucocorticoids may be beneficial.
Under anaesthesia, dantrolene sodium is a very effective treatment.
Genetic testing enables animals to be removed from the herd if they are positive for the gene. This means that the disorder is rare in the developed world these days.[2]
Stress at slaughter should be minimised in all cases.
## References[edit]
1. ^ Joy, Melanie (2011). Why We Love Dogs, Eat Pigs, and Wear Cows. Conari Press. pp. 42–43.
2. ^ a b Porcine Stress Syndrome expert reviewed and published by Wikivet accessed 09/10/2011.
This veterinary medicine–related article is a stub. You can help Wikipedia by expanding it.
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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
| Porcine stress syndrome | c0270589 | 2,649 | wikipedia | https://en.wikipedia.org/wiki/Porcine_stress_syndrome | 2021-01-18T18:48:21 | {"wikidata": ["Q7230002"]} |
A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-50 (MRD50) is caused by heterozygous mutation in the NAA15 gene (608000) on chromosome 4q31.
Clinical Features
Stessman et al. (2017) reported 13 unrelated patients with a variety of cognitive neurodevelopmental disorders associated with heterozygous variants in the NAA15 gene. Clinical details were limited since the patients were ascertained from large cohorts of DNA samples, but 10 of 11 (91%) had developmental delay/intellectual disability (DD/ID) that varied from mild to severe, 5 of 6 (83%) had delayed speech and language, and 5 of 8 (63%) had a formal diagnosis of autism spectrum disorder (ASD), although several other patients had autistic features. One of the patients was a 15-year-old boy diagnosed with Asperger syndrome. Two of 4 patients were noted to have motor delay. Other variable features included behavior problems, such as selective mutism or aggressive behavior, poor growth, and nonspecific dysmorphic features. None had seizures, and brain imaging, when performed, was normal. Three patients reportedly had a mother with mild intellectual disability.
Cheng et al. (2018) reported 39 individuals from 34 unrelated families with intellectual disability, autism spectrum disorder, and variable extraneurologic congenital anomalies associated with heterozygous likely gene disrupting (LGD) variants in the NAA15 gene (see MOLECULAR GENETICS). The cohort included the patients previously reported by Stessman et al. (2017). The phenotype was variable, but all patients had some degree of neurodevelopmental disability, including impaired motor abilities with mildly delayed walking, mild to moderate intellectual disability, impaired language development, and behavioral abnormalities, such as autism spectrum disorder, poor attention, and hyperactivity. Many had dysmorphic facial features, but there was no consistent pattern. Some patients had poor overall growth and some had short stature. Motor features included fine motor problems (12%) and hypotonia (14%). Other features included seizures (23%) and feeding difficulties (57%). Four patients had cardiac anomalies, one of whom had a complex heterotaxy syndrome. The patients were ascertained through international collaboration of research and clinical groups who shared whole-genome, whole-exome, or candidate gene sequencing results of patients with variable intellectual disability.
Inheritance
The transmission pattern MRD50 in 3 families reported by Cheng et al. (2018) was consistent with autosomal dominant inheritance. However, the majority of affected individuals carried a de novo heterozygous mutation in the NAA15 gene.
Molecular Genetics
In 13 unrelated patients with MRD50, Stessman et al. (2017) identified 13 different heterozygous variants in the NAA15 gene (see, e.g., 608000.0001-608000.0003). Ten of the variants were categorized as 'likely gene disruptive' (LGD) events, such as nonsense or frameshift variants, and 3 were missense variants predicted to be deleterious. Four of the variants, all of which were LGD, were demonstrated to occur de novo. One missense variant was paternally inherited without clinical information on the father, and parental DNA was not available for the other 8 patients to determine segregation. Ten of the variants were private, only identified in the affected patient (family), and 3 were classified as 'ultra-rare.' Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a large cohort of over 11,730 patients with autism spectrum disorder, intellectual disability, and/or developmental delay involving 15 centers across 7 countries and 4 continents. The authors used single-molecule molecular inversion probes (smMIPs) to sequence 208 candidate genes in these patient samples and confirmed the findings by Sanger sequencing. The findings of de novo LGD mutations in the NAA15 gene was statistically significant. Using statistical analysis, Stessman et al. (2017) stated that given the incidence of developmental delay in the general population (5.12%), the penetrance of LGD NAA15 mutations was estimated to be 35.3%.
In 39 patients from 34 unrelated families with MRD50, including the patients previously reported by Stessman et al. (2017), Cheng et al. (2018) identified 25 heterozygous variants in the NAA15 gene (see, e.g., 608000.0004-608000.0007). Most of the mutations occurred de novo, although 3 families showed autosomal dominant inheritance of the mutations. All of the mutations were classified as LGD mutations, including nonsense, frameshift, and splice site mutations. The mutations occurred throughout the gene and were predicted or demonstrated to result in nonsense-mediated mRNA decay and a loss of protein function in cells derived from some of the patients. Expression of several of the mutations in NatA-null yeast failed to rescue growth defects, indicating that they caused a loss of function. Cheng et al. (2018) concluded that haploinsufficiency of NAA15 was the most likely mechanism for this variable neurodevelopmental disorder, although the possibility of a dominant-negative or gain-of-function mechanism could not be excluded. A few patients had previously been reported in other large cohort studies (Zaidi et al., 2013, Longoni et al., 2017).
INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Dysmorphic features, nonspecific, variable (in some patients) NEUROLOGIC Central Nervous System \- Delayed development \- Intellectual disability, variable \- Motor delay \- Speech delay Behavioral Psychiatric Manifestations \- Autism spectrum disorder \- Autistic features \- Behavioral problems MISCELLANEOUS \- Highly variable phenotype \- De novo mutation (in most patients) MOLECULAR BASIS \- Caused by mutation in the N-alpha-acetyltransferase 15, NatA auxiliary subunit gene (NAA15, 608000.0001 ) ▲ 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
| MENTAL RETARDATION, AUTOSOMAL DOMINANT 50 | c4540470 | 2,650 | omim | https://www.omim.org/entry/617787 | 2019-09-22T15:44:45 | {"omim": ["617787"]} |
A number sign (#) is used with this entry because of evidence that Stankiewicz-Isidor syndrome (STISS) is caused by heterozygous mutation in the PSMD12 gene (604450) on chromosome 17q24.
Description
Stankiewicz-Isidor syndrome (STISS) is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, behavioral disorders, mild craniofacial anomalies, and variable congenital defects of the cardiac and/or urogenital systems (summary by Kury et al., 2017).
Clinical Features
Kury et al. (2017) reported 4 unrelated boys, ranging in age from 8 to 14 years, with a neurodevelopmental disorder. The patients had developmental delay with intellectual disability and abnormal behavior, including autism. Two patients had motor delay and 3 had speech delay. Other features were more variable, and included hypotonia, deafness, feeding difficulties, and thumb agenesis or hypoplasia. Three patients had variable cardiac abnormalities, including septal defects and patent ductus arteriosus, 2 had renal anomalies, such as fusion kidneys and duplicated ureters, and all had some kind of genital anomaly, such as hypospadias, micropenis, and cryptorchidism. Three patients were noted to have dysmorphic craniofacial features, 3 had low-set ears, 1 had retrognathia, and another had asymmetric facies with hypertelorism and large nose. One had eye tracking problems, another had cortical visual impairment with abnormal optic nerve heads, and a third had strabismus and horizontal nystagmus. Brain imaging in 1 patient showed a pineal cyst.
Cytogenetics
Kury et al. (2017) reported 6 unrelated children with a neurodevelopmental disorder associated with de novo heterozygous deletions of chromosome 17q24. The breakpoints of the deletions were different in each case, and the size of the deletions ranged from 0.62 to 4 Mb. All patients had delayed development with intellectual disability, and most also had delayed motor development and hypotonia with speech delay. One patient had seizures and another had deafness. Other features were highly variable, but included congenital cardiac (2 patients) and renal (4 patients) defects. Three had feeding difficulties. One boy had hypospadias and 1 girl had precocious puberty. All had dysmorphic craniofacial features, such as micro/retrognathia, hypertelorism, strabismus, low-set ears, short or long philtrum, high or prominent forehead, thin upper lip, and downturned corners of the mouth. Three patients had 2-3 toe syndactyly. Brain imaging was performed in 4 patients: 3 had normal imaging and 1 had cerebral atrophy with periventricular hypomyelination and a pineal cyst.
Molecular Genetics
In 4 unrelated patients with Stankiewicz-Isidor syndrome, Kury et al. (2017) identified de novo heterozygous truncating or splice site mutations in the PSMD12 gene (604450.0001-604450.0004). The mutations in 3 patients were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing; the mutation in the fourth patient was found by exome sequencing. Studies of 1 patient's cells showed decreased amounts of full-length PSMD12, consistent with haploinsufficiency. Cells transfected with the mutation (604450.0001) showed presence of the mutant transcript, but absence of the predicted truncated protein, suggesting translation inefficiency or increased degradation of the mutant protein. Transfected cells also showed abnormal accumulation of high-molecular-weight ubiquitin-modified proteins, although proteasome catalytic activity was not impaired. The findings supported the biologic importance of PSMD12 as a scaffolding subunit in proteasome function during development, with a particular role in neurogenesis.
Animal Model
Kury et al. (2017) found that CRISPR/Cas9-mediated disruption of the psmd12 ortholog in zebrafish embryos resulted in smaller optic tecta, suggestive of microcephaly, renal tubule defects, and craniofacial abnormalities.
INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Asymmetric facies \- Retrognathia \- Micrognathia Ears \- Low-set ears \- Deafness Eyes \- Nystagmus \- Strabismus \- Cortical visual impairment \- Abnormal optic nerve heads \- Eye tracking problems \- Hypertelorism Nose \- Large nose CARDIOVASCULAR Heart \- Congenital heart defects \- Septal defects \- Patent ductus arteriosus \- Truncus arteriosus Vascular \- Aortic hypoplasia ABDOMEN Gastrointestinal \- Feeding difficulties GENITOURINARY External Genitalia (Male) \- Hypospadias \- Micropenis \- Shawl scrotum Internal Genitalia (Male) \- Cryptorchidism Kidneys \- Renal abnormalities \- Fusion kidneys Ureters \- Duplicate ureters SKELETAL Hands \- Thumb hypoplasia \- Absent thumb Feet \- Toe syndactyly MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed development \- Intellectual disability \- Speech delay \- Seizures (in some patients) \- Pineal cyst Behavioral Psychiatric Manifestations \- Abnormal behavior \- Autistic features MISCELLANEOUS \- Highly variable phenotype \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the proteasome 26S subunit, non-ATPase, 12 gene (PSMD12, 604450.0001 ) ▲ 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
| STANKIEWICZ-ISIDOR SYNDROME | c4479599 | 2,651 | omim | https://www.omim.org/entry/617516 | 2019-09-22T15:45:39 | {"omim": ["617516"]} |
A primary early-onset glaucoma that is characterized by early onset, severe elevation of intra ocular pressure of rapid progression, leading to optic nerve excavation and, when untreated, substantial visual impairment.
## Epidemiology
The disorder is estimated to occur in 0,32/100 000 individuals before the age of 20 years.
## Clinical description
Juvenile glaucoma (JG) typically presents between the ages of 5 to 18 years, but it can appear later. Patients are initially asymptomatic and are often discovered incidentally on a routine examination. JG is generally bilateral; there can be a marked asymmetry between the two eyes. The intraocular pressure increases progressively leading to optic nerve excavation and eventually, substantial visual impairment and field loss.
## Etiology
JG is caused by impaired outflow of aqueous humor through the trabecular meshwork and into the Schlemm canal. Mutation in MYOC (1q23-q24) genes have been found in patients with JG. MYOC gene codes for the glycoprotein myocilin that is found in the trabecular meshwork and ocular tissue and mutations are disease-causing.
## Diagnostic methods
The diagnosis is suspected with the presence of clinical features such as increased intraocular pressure and optic nerve excavation. On gonioscopy the angle appears normal. Typical features of primary congenital glaucoma such as corneal edema and Haab's striae are not present. The refraction test reveals myopia. Typical glaucomatous field defects can be documented. Optic nerve head shows glaucomatous optic neuropathy.
## Differential diagnosis
Differential diagnoses include other forms of open angle glaucoma that can occur at any age, late recognized congenital glaucoma, steroid induced glaucoma, traumatic glaucoma and inflammatory glaucoma.
## Genetic counseling
Transmission is autosomal dominant with high penetrance. Genetic testing can be used to identify family members at risk of developing JG. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
## Management and treatment
Medical therapy (carbonic anhydrase inhibitors, beta blockers, prostaglandin analogues) is often useful in the treatment of JG. When the condition becomes unresponsive to medications, angle surgery (goniotomy, trabeculotomy), filtration surgery (trabeculectomy), LASER treatment (angle laser surgery or cyclodiode laser therapy) and/or aqueous shunt devices can be considered.
## Prognosis
Prognosis is good in patients diagnosed and treated early. Without treatment, the evolution towards blindness is possible.
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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
| Juvenile glaucoma | c2981140 | 2,652 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98977 | 2021-01-23T18:22:44 | {"omim": ["137750", "231300", "608695", "608696", "610535", "611274"], "umls": ["C2981140"]} |
A number sign (#) is used with this entry because susceptibility to hypertriglyceridemia has been associated with mutation in the apolipoprotein A5 gene (APOA5; 606368).
Description
Most individuals with familial hypertriglyceridemia have a hyperlipoproteinemia IV (144600) phenotype. Relatives of affected persons (ascertained in a study of survivors of coronary occlusion) were found to have normal cholesterol distribution and bimodal triglyceride distribution (Goldstein et al., 1973). Hypertriglyceridemia is not completely expressed in affected children.
Clinical Features
Namboodiri et al. (1977) studied a large kindred with a high frequency of cardiac illness and with hyperlipidemia. Triglycerides showed 75% of the 'variance accountable by genetic transmission' and cholesterol 52%. Whether the disorder in this kindred should be called hypertriglyceridemia or combined hyperlipidemia (144250) is not clear. The authors chose to call it hypertriglyceridemia. Hypertriglyceridemia gave a good fit to autosomal dominant inheritance, the minimal probability of misclassification being 9.3%. Linkage analysis with 27 markers showed a positive score only with pepsinogen (169700): lod of 0.73 at recombination fraction of 0.1.
In a 59-year-old man with severe hypertriglyceridemia, Breckenridge et al. (1978) found deficiency of apolipoprotein C-II (APOC2; 207750), which is an activator for lipoprotein lipase (LPL; 609708). After transfusion of 1 unit of plasma the patient's triglycerides fell, within 1 day, from 1000 to 250 mg per deciliter and remained below preinfusion concentration for 6 days.
Austin et al. (2000) provided 20-year follow-up on 101 families with combined hyperlipidemia (see 144250) or hypertriglyceridemia, ascertained in 2 studies conducted in the early 1970s. Compared with spouse controls, 20-year mortality risk from cardiovascular disease (CVD) was significantly increased among sibs and offspring in familial combined hyperlipidemia (relative risk, 1.7) but not in hypertriglyceridemia families. However, baseline triglyceride was associated with increased CVD mortality risk independent of total cholesterol among relatives in hypertriglyceridemia families (relative risk, 2.7), but not in combined hyperlipidemia families.
Mapping
Duggirala et al. (2000) conducted a genomewide scan for susceptibility genes influencing plasma triglyceride (TG) levels in a Mexican American population. They used both phenotypic and genotypic data from 418 individuals distributed across 27 low-income, extended Mexican American families. For the analyses, TG values were log transformed (ln TG). After accounting for the effects of sex and sex-specific age terms, they found significant evidence for linkage (lod = 3.88) of ln TG levels to a genetic location between the markers GABRB3 (137192) located at 15q11.2 and D15S165 located at 15q12-q13.1. This putative locus explains 39.7 +/- 7% (p = 0.000012) of total phenotypic variation in ln TG levels. Some evidence for linkage to 2 different locations on chromosome 7 was found.
Molecular Genetics
### APOA5
The apolipoprotein A5 gene (APOA5; 606368) plays an important role in determining plasma triglyceride concentrations in humans. Kao et al. (2003) described a novel variant in APOA5, G553T (606368.0001), that is associated with hypertriglyceridemia. The variant results in substitution of cysteine for glycine-185. The minor allele frequencies were 0.042 and 0.27 (P less than 0.001) for Chinese control and hypertriglyceridemic patients, respectively. The serum triglyceride level was significantly different among the genotypic groups (G/G 92.5 +/- 37.8 mg/dl, G/T 106.6 +/- 34.8 mg/dl, T/T 183.0 mg/dl, p = 0.014) in control subjects. Multiple logistic regression revealed that individuals carrying the minor allele had age, gender, and BMI (body mass index)-adjusted odds ratio of 11.73 (95% confidence interval of 6.617-20.793; P less than 0.0001) for developing hypertriglyceridemia in comparison to individuals without that allele.
The APOA5*2 haplotype includes the rare C allele of the SNP c.*158C-T (rs2266788; 606368.0004), located in the 3-prime untranslated region (UTR), in strong linkage disequilibrium with 3 other SNPs. Individuals with APOA5*2 display reduced APOA5 expression at the posttranscriptional level. Caussy et al. (2014) hypothesized that the hypertriglyceridemic effects of APOA5*2 could involve miRNA regulation in the APOA5 3-prime UTR. Bioinformatic studies identified the creation of a potential miRNA binding site for liver-expressed MIR485 (615385)-5p in the mutant APOA5 3-prime UTR with the c.*158C allele. In HEK293T cells cotransfected with an APOA5 3-prime UTR luciferase reporter vector and a MIR485-5p precursor, c.*158C allele expression was significantly decreased. Moreover, in Huh-7 cells endogenously expressing MIR485-5p, Caussy et al. (2014) observed that luciferase activity was significantly lower in the presence of the c.*158C allele than in the presence of the c.*158T allele, which was completely reversed by a MIR485-5p inhibitor. Caussy et al. (2014) suggested that the well-documented hypertriglyceridemic effect of APOA5*2 involves an APOA5 posttranscriptional downregulation mediated by MIR485-5p.
Do et al. (2015) found that a burden of rare alleles in APOA5 and LDLR contributes to risk for myocardial infarction, with APOA5 mutation carriers having higher plasma triglycerides and LDLR mutation carriers having higher plasma LDL cholesterol (see Other Associations).
### Other Associations
In a study of a total of 555 individuals with hypertriglyceridemia, diagnosed with Fredrickson hyperlipoproteinemia phenotypes 2B (144250), 3 (107741), 4 (144600), or 5 (144650), and 1,319 controls, Johansen et al. (2010) first performed a genomewide association study and identified common variants in the APOA5, GCKR (600842), LPL, and APOB (107730) genes that were associated with hypertriglyceridemia. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with hypertriglyceridemia compared to 53 variants in 327 controls (p = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% in affected individuals and 15.3% in controls (p = 2.6 x 10(-5)). Johansen et al. (2010) concluded that an accumulation of rare variants contributes to the heritability of complex traits among individuals at the extreme of a lipid phenotype.
In a 5-generation family of European American descent previously ascertained as part of a cohort for a study of familial combined hyperlipidemia (Austin et al., 2000), Rosenthal et al. (2013) performed Bayesian Markov chain Monte Carlo joint oligogenic linkage and association analysis combined with whole-exome sequencing data and detected shared, highly conserved, private missense variants in both SLC25A40 (610821) on chromosome 7 and PLD2 (602384) on chromosome 17. Jointly, these variants explained 49% of the genetic variance in triglyceridemia; however, only the SLC25A40 variant was significantly associated with triglyceride levels (p = 0.0001). The c.374A-G transition in exon 7 of the SLC25A40 gene results in a highly disruptive tyr125-to-cys (Y125C) substitution at a highly conserved residue just outside the second helical transmembrane region of the inner mitochondrial membrane transport protein. Rosenthal et al. (2013) noted that it is possible that the Y125C variant is not pathogenic but is in linkage disequilibrium with a causal variant. Whole-genome testing using Exome Sequencing Project data confirmed the association between 5 rare missense variants in SLC25A40 and triglyceride levels.
Do et al. (2015) sequenced the protein-coding regions of 9,793 genomes from patients with myocardial infarction (MI) at an early age (50 years or younger in males and 60 years or younger in females) along with MI-free controls. They identified 2 genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exomewide significance: LDLR (606945) and APOA5 (606368). Carriers of rare nonsynonymous mutations in LDLR were at 4.2-fold increased risk for MI, while carriers of null alleles in LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbor a rare, damaging mutation in LDLR; this estimate is similar to one made by Goldstein et al. (1973) using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol greater than 190 mg/dl. Carriers of rare nonsynonymous mutations in APOA5 were at 2.2-fold increased risk for MI. When compared with noncarriers, LDLR mutation carriers had higher plasma LDL cholesterol (see 143890), whereas APOA5 mutation carriers had higher plasma triglycerides. Evidence has connected MI risk with coding-sequence mutations at 2 genes functionally related to APOA5, namely lipoprotein lipase (LPL; 609708) and apolipoprotein C-III (APOC3; 107720). Do et al. (2015) concluded that LDL cholesterol as well as disordered metabolism of triglyceride-rich lipoproteins contributes to myocardial infarction risk.
### History
In DNA studies that showed that the APOA1 gene (107680) and the APOC3 gene (107720) are in close physical linkage, Karathanasis et al. (1983) also showed that the 2 genes are 'convergently transcribed' and that the polymorphism reported by Rees et al. (1983) to be associated with hypertriglyceridemia may be due to a single-basepair substitution in the 3-prime-noncoding region of apoC-III mRNA.
Inheritance \- Autosomal dominant Metabolic \- Abnormal glucose tolerance Misc \- Phenotype environmentally influenced, esp. by carbohydrate and ethanol consumption, uremia, hypopituitarism, contraceptive steroids, and glycogen storage disease I Lab \- Hypertriglyceridemia \- Increased plasma VLDL \- Plasma cholesterol and phospholipids usually normal \- Apolipoprotein C-II deficiency Skin \- Atheroeruptive xanthoma Vascular \- Precocious atherosclerosis ▲ Close
*[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
| HYPERTRIGLYCERIDEMIA, FAMILIAL | c0020480 | 2,653 | omim | https://www.omim.org/entry/145750 | 2019-09-22T16:39:46 | {"doid": ["1172"], "mesh": ["D006953"], "omim": ["145750"], "icd-9": ["272.1"], "icd-10": ["E78.1"]} |
A number sign (#) is used with this entry because dentatorubral-pallidoluysian atrophy (DRPLA) is caused by a heterozygous expanded trinucleotide repeat in the ATN1 gene (607462) on chromosome 12p13.
Clinical Features
In 5 families, Naito and Oyanagi (1982) reported a syndrome of myoclonic epilepsy, dementia, ataxia, and choreoathetosis. At autopsy, major neuropathologic changes consisted of combined degeneration of the dentatorubral and pallidoluysian systems. Inheritance was autosomal dominant. Onset was usually in the twenties and death in the forties. Although this condition was perhaps first described by Smith et al. (1958) and several sporadic cases have been reported from Western countries, this disorder seems to be very rare except in Japan where other hereditary cases have been described (Iizuka et al., 1984; Iwabuchi et al., 1985; Takahashi et al., 1988). Hirayama et al. (1981) classified 3 clinical forms of DRPLA: the ataxo-choreoathetoid form, the pseudo-Huntington form, and the myoclonic epilepsy form.
Tomoda et al. (1991) described a Japanese family with 12 affected individuals in 3 generations. They emphasized that patients with onset in childhood usually have the progressive myoclonic epilepsy (PME) syndrome (254800).
Warner et al. (1994) described 1 family in the United Kingdom in which the DRPLA repeat expansion was demonstrated in 3 affected sibs. In the course of studying Huntington disease (HD; 143100) in Wessex in the U.K., Connarty et al. (1996) found a second family with DRPLA. A father and daughter were affected.
In a single Japanese family, Saitoh et al. (1998) observed 5 different clinical types of DRPLA. Two sibs and their paternal uncle manifested the juvenile type, the father of the sibs had the late-adult type, and another paternal uncle had the early-adult type. Gene analysis confirmed the diagnosis for the proband and her sib. By following the clinical courses and electroencephalographic changes, they found that the types of epileptic seizures and the EEGs of the juvenile DRPLA patients changed as the course progressed. The sibs exhibited different levels of clinical severity despite the similar DNA expansion detected in their lymphocytes (see GENOTYPE/PHENOTYPE CORRELATIONS).
Shimojo et al. (2001) reported 2 unrelated patients with infantile DRPLA. Both patients developed normally until about 6 months of age, when motor signs, such as difficulty controlling the head, choreoathetosis, hyperkinetic movements, involuntary movements, and seizures developed. MRI of both patients showed cerebral atrophy and delayed myelination. CAG repeat sizes were 93 and 90, representing extreme repeat expansion. Although the parents refused DNA analysis, Shimojo et al. (2001) suggested that the early onset and severe clinical courses were related to the long repeats.
### Haw River Syndrome
Farmer et al. (1989) described a family, with ancestors born in Haw River, North Carolina, that contained members in 5 generations with an autosomal dominant neurologic disorder. It was characterized by the development between 15 and 30 years of age of ataxia, seizures, choreiform movements, progressive dementia, and death after 15 to 25 years of illness. Neuropathologic findings in 2 deceased family members demonstrated remarkably similar findings, including marked neuronal loss of the dentate nucleus, microcalcification of the globus pallidus, neuroaxonal dystrophy of the nucleus gracilis, and demyelination of the centrum semiovale. The clinical and pathologic findings were closely correlated: ataxia and chorea were related to severe neuronal loss in the dentate nucleus with calcification in the globus pallidus. Dementia occurred from progressive demyelination of the centrum semiovale, and loss of posterior column function occurred from neuroaxonal dystrophy of the nucleus gracilis and nucleus cuneatus.
Burke et al. (1994) noted that the phenotypic differences between Haw River syndrome and DRPLA include the absence of myoclonic seizures in HRS as well as the presence of extensive demyelinization of the subcortical white matter, basal ganglia calcifications, and neuroaxonal dystrophy which are not seen in DRPLA.
Mapping
Kondo et al. (1990) demonstrated that the mutant gene in this disorder is not an allele of the Huntington disease locus (143100), even though there is sufficient phenotypic overlap to lead to confusion of diagnosis; they found that in 4 families there were negative lod scores for DRPLA and D4S10, the locus first linked to HD.
Nagafuchi et al. (1994) cited linkage analyses using polymorphic markers in DRPLA families that localized the responsible gene locus to chromosome 12p. The DRPLA locus segregated with CD4 (186940), with maximum lod = 3.61 at theta = 0.00, and also with VWF (613160), with maximum lod = 3.32 at theta = 0.06. Both CD4 and VWF are located on chromosome 12pter-p12. To define the precise location of the DRPLA gene, Kuwano et al. (1996) studied genotypes of 4 patients, each with a different deletion of 12p. The gene for DRPLA was assigned to 12p13.1-p12.3.
Burke et al. (1994) found that HRS locus is tightly linked to the region of DRPLA on 12p.
Cancel et al. (1994) studied a large French kindred in which the disorder in 11 affected individuals was considered consistent with DRPLA. A suggestion of linkage was found, however, to the region of chromosome 14 (q24.3-qter) where the gene for spinocerebellar ataxia-3 (SCA3)/Machado-Joseph disease (607047) has been mapped.
Molecular Genetics
DRPLA is one of several examples of disorders related to expansion of a trinucleotide repeat. Koide et al. (1994) searched a catalog of genes identified by Li et al. (1993) that contained trinucleotide repeats expressed in human brain. One of these cDNAs, B37 (ATN1), known to map to chromosome 12, was examined and found to show CAG repeat expansion (607462.0001) in 22 individuals with DRPLA. Fragile X syndrome (300624), myotonic dystrophy (see 160900), Kennedy disease (313200), Huntington disease, spinocerebellar ataxia-1 (SCA1; 164400), and fragile XE mental retardation (see 309548) were the previously identified disorders due to expanded trinucleotide repeats.
Burke et al. (1994, 1994) demonstrated that despite their distinct cultural origins and clinical and pathologic differences, Haw River syndrome and DRPLA are is caused by the same expanded CAG repeat in the ATN1 gene (607462.0001).
Genotype/Phenotype Correlations
Burke et al. (1994) suggested that the difference in racial frequency of DRPLA is probably due to differences in the repeat size. The frequency of the repeat allele of intermediate size was very low in Europeans, somewhat higher in African Americans, and relatively high (5-10%) in Japanese. This is a situation comparable to the virtual absence of myotonic dystrophy (DM; 160900) in South African blacks, in whom the frequency of large-length CTG repeats is much lower than in white and Japanese populations (Goldman et al., 1994). See the graphs of the distribution of CAG trinucleotide repeat frequencies in 3 populations presented by Burke et al. (1994), including Japanese colleagues.
### Genetic Anticipation
Koide et al. (1994) found a good correlation between the size of the (CAG)n repeat expansion and the age of onset. Patients with earlier onset tended to have a phenotype of progressive myoclonic epilepsy and larger expansions. They proposed that the wide variety of clinical manifestations of DRPLA can be explained by the variable unstable expansion of the CAG repeat. Although only 5 cases of paternal transmission and 2 cases of maternal transmission were analyzed, the length of the repeat unit was altered in all cases: the average change in repeat length for paternal transmission was an increase of 4.2 repeats, while that of maternal transmission was a decrease of 1.0 repeat.
Nagafuchi et al. (1994) found that the repeat size varied from 7 to 23 in normal individuals. In patients, one allele was expanded to between 49 and 75 repeats or occasionally even more. Expansion was usually associated with paternal transmission. Like Koide et al. (1994), they found that repeat size correlated closely with age of onset of symptoms and with disease severity. Komure et al. (1995) analyzed CAG trinucleotide repeats in 71 individuals from 12 Japanese DRPLA pedigrees that included 38 affected individuals. Normal alleles varied from 7 to 23 repeats, whereas affected individuals had from 53 to 88 repeats. Like Koide et al. (1994) and Nagafuchi et al. (1994), they found a significant negative correlation between CAG repeat length and age of onset. In 80% of the paternal transmissions, there was an increase of more than 5 repeats, whereas all the maternal transmissions showed either a decrease or an increase of fewer than 5 repeats.
Aoki et al. (1994) demonstrated that anticipation with expansion of the CAG repeat can occur through mothers as well as through fathers. They investigated 2 families in which offspring showed progressive myoclonic epilepsy with onset in childhood. In 1 family, patients of the first generation showed mild cerebellar ataxia with onset at 52 to 60 years. A patient of the second generation, the mother, showed severe ataxia with onset in the early thirties. The offspring in the third generation showed mental retardation, convulsions and myoclonus beginning at age 8. Sano et al. (1994) studied 4 families and also demonstrated anticipation. Older-onset patients suffered from cerebellar ataxia with or without dementia, whereas younger-onset patients presented as progressive myoclonus epilepsy syndrome, consisting of mental retardation, dementia, and cerebellar ataxia as well as epilepsy and myoclonus. Anticipation with paternal transmission was significantly greater than with maternal transmission.
Sato et al. (1995) reported homozygosity for a modest (57-repeat) triplet repeat in a man with early onset of DRPLA at age 17. His parents were first cousins and were neurologically normal at ages 73 and 71, in spite of having 57 CAG repeats in heterozygous state. Four of the proband's sibs died at age 12 with the phenotype of progressive myoclonic epilepsy. These findings supported the hypothesis that the clinical features of DRPLA, like those of Machado-Joseph disease, are influenced by the dosage of expansion of triplet repeats, unlike Huntington disease, in which the homozygous state does not appear to be different clinically from the heterozygous state.
Norremolle et al. (1995) described a Danish family in which affected persons in at least 3 generations had been thought to be suffering from Huntington disease. Because analysis of the huntingtin gene revealed normal alleles and because some of the patients had seizures, they analyzed the B37 gene and found significantly elongated CAG repeats, as had been reported in cases of DRPLA. Norremolle et al. (1995) reported that affected persons with almost identical repeat lengths presented very different symptoms. Both expansion and contraction in paternal transmission was observed.
Ikeuchi et al. (1996) analyzed the segregation patterns of 411 transmissions of 24 DRPLA pedigrees and 80 transmissions in 7 Machado-Joseph disease (MJD; 109150) pedigrees, with the diagnoses confirmed by molecular testing. Significant distortions in favor of transmission of the mutant alleles were found in male meiosis, where the mutant alleles were transmitted to 62% of all offspring in DRPLA (P less than 0.01) and 73% in MJD (P less than 0.01). The results were considered consistent with meiotic drive in both disorders. The authors commented that since more prominent meiotic instability of the length of the CAG trinucleotide repeats is observed in male meiosis than in female meiosis and since meiotic drive is observed only in male meiosis, these results raised the possibility that a common molecular mechanism underlies the meiotic drive and the meiotic instability in male meiosis.
On the basis of studies in an extensively affected Tennessee family, Potter (1996) emphasized the intrafamilial variability and lack of close correlation between age of onset and (CAG)n repeat number in this disease. The studies were done on DNA derived from leukocytes; tissue-specific instability (somatic mosaicism) has been reported in DRPLA.
Takiyama et al. (1999) determined the CAG repeat size in 427 single sperm from 2 men with DRPLA. The mean variance of the change in the CAG repeat size in sperm from the DRPLA patients (288.0) was larger than any variances of the CAG repeat size in sperm from patients with Machado-Joseph disease (38.5), Huntington disease (69.0), and spinal and bulbar muscular atrophy (16.3; 313200), which is consistent with the clinical observation that the genetic anticipation on the paternal transmission of DRPLA is the most prominent among CAG repeat diseases. The variance was different in the 2 patients (51.0 vs 524.9, P greater than 0.0001). The segregation ratio of normal to expanded allele sperm was 1:1.
Vinton et al. (2005) reported a 3-generation Caucasian family of Macedonian origin with DRPLA, manifesting as very mild elderly onset, severe young-adult onset, and severe childhood onset presentations in the 3 generations, respectively. Atrophin-1 expansion sizes of 52, 57, and 66 repeats were demonstrated in the 3 patients, respectively. Vinton et al. (2005) stated that the grandparental trinucleotide expansion size of 52 repeats was the smallest overtly pathogenic mutation yet reported.
Pathogenesis
Studying the CAG expansion in brain and other tissues from 6 unrelated DRPLA patients, Ueno et al. (1995) showed that the sizes of the CAG expansion in various regions of the brain, except the cerebellum, were generally larger by several repeats than in other peripheral tissues. Brain samples showed greater variation of the expansion compared with other tissues, but neither the size of the CAG expansion nor the degree of CAG repeat variation paralleled the detailed findings of neuropathologic involvement. They concluded that somatic instability of the CAG repeat causes tissue variability, but that other regional or cell type-specific factors must explain the selectivity of cell damage in DRPLA.
Burke et al. (1996) demonstrated that synthetic polyglutamine peptides, DRPLA protein and huntingtin (613004) from unaffected individuals with normal-sized polyglutamine tracts bind to glyceraldehyde-3-phosphate dehydrogenase (GAPD; 138400). The authors postulated that diseases characterized by the presence of an expanded CAG repeat may share a common metabolic pathogenesis involving GAPD as a functional component. Roses (1996) and Barinaga (1996) reviewed the findings.
Hayashi et al. (1998) used an antibody against ubiquitin to examine the brains and spinal cords of 7 patients with DRPLA. They found small, round immunoreactive intranuclear inclusions in both neurons and glial cells in various brain regions. Electron microscopy showed that such inclusions are composed of granular and filamentous structures. The findings strongly suggested that, in DRPLA, the occurrence of neuronal and glial inclusions is directly related to the causative expanded CAG repeat, that neurons are affected much more widely than previously recognized, and that glial cells are also involved in the disease process.
Sisodia (1998) reviewed the significance of nuclear inclusions in glutamine repeat disorders. For a comprehensive review of DRPLA, including the Japanese literature, see Kanazawa (1998).
Yamada et al. (2002) noted that some patients with DRPLA have white matter lesions characterized neuropathologically by diffuse myelin pallor. The number of lesions correlates with increasing age, being milder in degree in juveniles and more severe in older adults. In immunohistochemical studies of brains of 12 affected patients and transgenic mice with expanded (CAG)n repeats, Yamada et al. (2002) found immunoreactivity for polyQ in some glial nuclei that was increased with larger expansions of (CAG)n repeats. The authors concluded that oligodendrocytes are a target for the polyQ pathogenesis in DRPLA and may lead to white matter degeneration.
Population Genetics
Since DRPLA occurs almost only in Japanese, Koide et al. (1994) suggested that there may exist a founder effect. In a nationwide survey of Japanese patients, Hirayama et al. (1994) estimated the prevalence of all forms of spinocerebellar degeneration to be 4.53 per 100,000, of which 2.5% were estimated to have DRPLA. Watanabe et al. (1998) investigated 101 kindreds with spinocerebellar ataxias from the central Honshu island of Japan, using a molecular diagnostic approach with amplification of the CAG trinucleotide repeat of the causative genes. DRPLA ranked second in prevalence, accounting for 19.8% of the cases.
DRPLA has been considered to be rare in Europe. Dubourg et al. (1995) failed to find a single case in a survey of 117 French patients with cerebellar ataxia from 94 families, concluding that DRPLA is rare in the French population.
Among 202 Japanese and 177 Caucasian families with autosomal dominant SCA, Takano et al. (1998) found that the prevalence of DRPLA was significantly higher in the Japanese population (20%) compared to Caucasian population (0%). This corresponded to higher frequencies of large normal ATN1 CAG alleles (greater than 17 repeats) in Japanese controls compared to Caucasian controls. The findings suggested that large normal alleles contribute to the generation of expanded alleles that lead to dominant SCA.
Shimizu et al. (2004) estimated the prevalence of autosomal dominant cerebellar ataxia (ADCA) in the Nagano prefecture of Japan to be at least 22 per 100,000. Thirty-one of 86 families (36%) were positive for SCA disease-causing repeat expansions: SCA6 (183086) was the most common form (19%), followed by DRPLA (10%), SCA3 (109150) (3%), SCA1 (2%), and SCA2 (183090) (1%). The authors noted that the prevalence of SCA3 was lower compared to other regions in Japan, and that the number of genetically undetermined SCA families in Nagano was much higher than in other regions. Nagano is the central district of the main island of Japan, located in a mountainous area surrounded by the Japanese Alps. The restricted geography suggested that founder effects may have contributed to the high frequency of genetically undetermined ADCA families.
History
DRPLA appears to have first been described by Smith et al. (1958). Smith (1975) wrote about the disorder under the designation dentatorubropallidoluysian atrophy.
INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Cerebellar ataxia \- Myoclonus \- Seizures \- Choreoathetosis \- Dementia \- Degeneration of the dentatorubral and pallidoluysian systems MISCELLANEOUS \- Mean age of onset 30 years (range first to seventh decade) \- Genetic anticipation \- Phenotypic heterogeneity MOLECULAR BASIS \- Caused by trinucleotide repeat expansion (CAG)n in the DRPLA gene (DRPLA, 607462.0001 ) ▲ Close
*[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
| DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY | c0751781 | 2,654 | omim | https://www.omim.org/entry/125370 | 2019-09-22T16:42:32 | {"doid": ["0060162"], "mesh": ["D020191"], "omim": ["125370"], "orphanet": ["101"], "synonyms": ["Alternative titles", "MYOCLONIC EPILEPSY WITH CHOREOATHETOSIS", "NAITO-OYANAGI DISEASE", "HAW RIVER SYNDROME", "ATAXIA, CHOREA, SEIZURES, AND DEMENTIA"], "genereviews": ["NBK1491"]} |
## Summary
### Clinical characteristics.
Hyperkalemic periodic paralysis (hyperPP) is characterized by attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, and trunk), hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness and/or provoking/worsening of an attack by oral potassium intake, normal serum potassium between attacks, and onset before age 20 years. Although the absence of paramyotonia (muscle stiffness aggravated by cold and exercise) was originally postulated as a means of distinguishing hyperPP from paramyotonia congenita (PMC), approximately 45% of individuals with hyperPP have paramyotonia. In approximately half of affected individuals, attacks of flaccid muscle weakness begin in the first decade of life, with 25% reporting their first attack at age ten years or older. Initially infrequent, the attacks then increase in frequency and severity over time until approximately age 50 years, after which the frequency of attacks declines considerably. Potassium-rich food or rest after exercise may precipitate an attack. A cold environment and emotional stress provoke or worsen the attacks. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to one hour, and then disappears. Cardiac arrhythmia or respiratory insufficiency usually does not occur during attacks. Between attacks, approximately half of individuals with hyperPP have mild myotonia (muscle stiffness) that does not impede voluntary movements. More than 80% of individuals with hyperPP older than 40 years report permanent muscle weakness and about one third develop a chronic progressive myopathy.
### Diagnosis/testing.
Diagnosis is based on clinical findings and/or the identification of a heterozygous pathogenic variant in SNC4A. In case of diagnostic uncertainty, one of three provocative tests can be employed.
### Management.
Treatment of manifestations: At the onset of weakness, attacks may be prevented or aborted with mild exercise and/or oral ingestion of carbohydrates, inhalation of salbutamol, or intravenous calcium gluconate.
Prevention of primary manifestations: Hyperkalemic attacks of weakness can be prevented by frequent meals rich in carbohydrates, continuous use of a thiazide diuretic or a carbonic anhydrase inhibitor, and avoidance of potassium-rich medications and foods, fasting, strenuous work, and exposure to cold.
Prevention of secondary complications: During surgery, avoid use of depolarizing anesthetic agents (including potassium, suxamethonium, and anticholinesterases) that aggravate myotonia and can result in masseter spasm and stiffness of respiratory and other skeletal muscles, interfering with intubation and mechanical ventilation.
Surveillance: Periodic assessment of neurologic status; in those with permanent muscle weakness, continuous medication (ie thiazide diuretic) and MRI of proximal leg muscles every one to three years; during prophylactic treatment, determination of serum potassium concentration twice per year to avoid severe diuretic-induced hypokalemia; annual monitoring of thyroid function.
Agents/circumstances to avoid: Potassium-rich medications and foods, fasting, strenuous work, exposure to cold, and use of depolarizing anesthetic agents during general anesthesia.
Evaluation of relatives at risk: It is appropriate to test asymptomatic at-risk family members for the pathogenic variant identified in an affected relative in order to institute preventive measures prior to surgery.
### Genetic counseling.
HyperPP is inherited in an autosomal dominant manner. Most individuals with hyperPP have an affected parent; the proportion of cases caused by a de novo pathogenic variant is unknown. Each child of an individual with hyperPP has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family has been identified.
## Diagnosis
### Suggestive Findings
Hyperkalemic periodic paralysis (hyperPP) should be suspected in individuals with the following clinical, family history, electromyogram (EMG), and suggestive laboratory findings:
Clinical findings
* History of at least two attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, breathing muscles and trunk)
* Onset or worsening of an attack as a result of oral potassium intake
* Disease manifestations before age 20 years
* Absence of cardiac arrhythmia between attacks
* Normal psychomotor development
Family history
* Typically, at least one affected first-degree relative
Note: Absence of a family history suggestive of hyperPP does not preclude the diagnosis.
Electromyogram (EMG)
* During the attack, EMG demonstrates a reduced number of motor units or may be silent (no insertional or voluntary activity).
* In the intervals between attacks, EMG may reveal myotonic activity (bursts of muscle fiber action potentials with amplitude and frequency modulation), even though myotonic stiffness may not be clinically present.
* In some individuals, especially in those with permanent weakness, a myopathic pattern may be visible.
Note: Approximately 50% of affected individuals have no detectable electrical myotonia.
Suggestive laboratory findings during attacks
* Hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L
Note: Serum potassium concentration seldom reaches cardiotoxic levels, but changes in the ECG (increased amplitude of T waves) may occur.
* Elevated serum creatine kinase (CK) concentration (sometimes 5-10x the normal range)
Suggestive laboratory findings between attacks
* Normal serum potassium concentration and muscle strength between attacks
Note: At the end of an attack of weakness, elimination of potassium via the kidney and reuptake of potassium by the muscle can cause transient hypokalemia that may lead to the misdiagnosis of hypokalemic periodic paralysis.
* Elevated serum CK concentration with normal serum sodium concentration
### Establishing the Diagnosis
The diagnosis of hyperkalemic periodic paralysis (hyperPP) is established in a proband with the above suggestive findings in whom other hereditary forms of hyperkalemia (see Differential Diagnosis) and acquired forms of hyperkalemia (drug abuse; renal and adrenal dysfunction) have been excluded and/or by the identification of a heterozygous pathogenic variant in SCN4A by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
* Single-gene testing. Sequence analysis of SCN4A is performed first and followed by sequencing of KCNJ2 and CACNA1S if no pathogenic variant is identified (see Differential Diagnosis).
* A multigene panel that includes SCN4A and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multigene panels vary by laboratory and over time.
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, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that contains SCN4A) fails to confirm a diagnosis in an individual with features of hyperPP.
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 Hyperkalemic Periodic Paralysis
View in own window
Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
SCN4ASequence analysis 3, 480% 5
Unknown 6NA
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\.
Ten common pathogenic variants are listed in Table 3; p.Thr704Met alone accounts for 69% of pathogenic variants [Jurkat-Rott & Lehmann-Horn 2007].
5\.
Authors, personal observation
6\.
At least one other locus, Xp27.3, has been mapped but the relevant gene has not yet been identified [Ryan et al 1999].
Provocative tests. In case of diagnostic uncertainty (i.e., in the absence of a measurement of ictal (during an attack) serum potassium concentration and normal molecular genetic studies), provocative tests may be employed to ensure the diagnosis. Systemic provocative tests carry the risk of inducing a severe attack; therefore, they must be performed by an experienced physician and a stand-by anesthetist, with close monitoring of the ECG and serum concentration of potassium:
* The classic provocative test consists of the administration of 2-10 g potassium under clinical surveillance with serum potassium concentration and strength measured at 20-minute intervals. Usually, an attack is induced within an hour and lasts approximately 30 to 60 minutes, accompanied by an increase in serum potassium concentration, similar to spontaneously occurring attacks of weakness. The test is contraindicated in individuals who already have hyperkalemia and in those individuals who do not have adequate renal or adrenal function.
* An alternative provocative test is exercise on a bicycle ergometer for 30 minutes to increase the heart rate to 120-160 beats/min, followed by absolute rest in bed. An affected individual's serum potassium concentration should rise during exercise, decline after exercise, and rise a second time 20 minutes after the conclusion of exercise.
* A local provocative test is measurement of evoked compound muscle action potentials (CMAP). They should have a greater-than-normal increase during two to five minutes of exercise followed by a progressive decline in amplitude that is greater than in normal controls and most rapid during the first 20 minutes after exercise. The decline is the more important parameter [Melamed-Frank & Marom 1999, Fournier et al 2004]. In the authors' experience, the CMAP results are not specific for hyperPP or a given pathogenic variant.
Muscle biopsy. Because no specific findings are observed on muscle biopsy and because the results do not influence therapeutic strategies or prognosis, a muscle biopsy is generally not recommended in individuals suspected of having hyperPP.
## Clinical Characteristics
### Clinical Description
The attacks of flaccid muscle weakness associated with hyperkalemic periodic paralysis (hyperPP) usually begin in the first decade of life and increase in frequency and severity over time, with 25% experiencing their sentinel attack in the second decade of life. Triggers include cold environment, rest after exercise, stress or fatigue, alcohol, hunger, changes in activity level, potassium in food, specific foods or beverages, changes in humidity, extra sleep, pregnancy, illness of any type, menstruation, medication, and potassium supplements [Charles et al 2013].
A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to an hour, and then passes. In about 20% of affected individuals the attacks last considerably longer, from more than two days to over one week. In some individuals, paresthesias, probably induced by the hyperkalemia, herald the weakness. During an attack of weakness, the muscle stretch reflexes are abnormally diminished or absent.
Sustained mild exercise after a period of strenuous exercise may postpone or prevent the weakness in the muscle groups being exercised and improve the recovery of muscle force, while the resting muscles become weak.
Usually, cardiac arrhythmia or respiratory insufficiency does not occur during the attacks. After an attack, affected individuals report clumsiness, weakness, and irritability, and in 62% muscle pain secondary to the attack. Between attacks, the majority report no or mild symptoms. However, 12% report severe symptoms between attacks that impair activities of daily living.
In more than 50% of individuals with hyperPP, mild myotonia (muscle stiffness) that does not impede voluntary movements is present between attacks. Myotonia is most readily observed in the facial, lingual, thenar, and finger extensor muscles; if present, it supports the diagnosis of hyperPP as opposed to other forms of familial periodic paralysis. Paramyotonia (muscle stiffness aggravated by cold and exercise) is present in about 45% of affected individuals.
Initially infrequent, the attacks increase in frequency and severity over time until approximately age 50 years, after which the frequency declines considerably. However, more than 80% of the affected individuals older than 40 years report permanent muscle weakness and approximately one third of older affected individuals develop a chronic progressive myopathy [Bradley et al 1990]. The myopathy mainly affects the pelvic girdle and proximal and distal lower-limb muscles.
As shown by a recent observational study, individuals with hyperPP appear to be at higher risk for thyroid dysfunction (relative risk of 3.6) than those in the general population [Charles et al 2013].
### Genotype-Phenotype Correlations
Given the clinical variability within a single family (i.e., among individuals with the same pathogenic variant), differences between pathogenic variants can be interpreted as causing a tendency to develop a feature, rather than actually causing a discrete feature (see Table 2).
The most notable tendency is that individuals without interictal myotonia are much more prone to develop progressive myopathy and permanent weakness than individuals with myotonia. This becomes especially obvious in individuals with the pathogenic p.Thr704Met variant, who usually do not have myotonia but in whom permanent myopathy commonly develops (~50% of individuals). Some individuals with "normokalemic periodic paralysis" have also had this common pathogenic variant [Lehmann-Horn et al 1993].
### Table 2.
Genotype-Phenotype Correlations in HyperPP
View in own window
SCN4A Pathogenic VariantSpecial FeaturesFirst Report
p.Asn440LysBoth hyperPP and paramyotonia and potassium aggravated myotoniaLehmann-Horn et al [2011]
p.Arg675GlnBoth hyperPP and normoPP and paramyotoniaLiu et al [2015], Vicart et al [2004]
p.Leu689IlePain resulting from muscle crampingBendahhou et al [2002]
p.Ile693ThrCold-induced weaknessPlassart et al [1996]
p.Thr704MetPermanent weakness, myopathyPtácek et al [1991]
p.Ala1156ThrReduced penetranceMcClatchey et al [1992]
p.Met1360ValReduced penetranceWagner et al [1997]
p.Met1370ValParamyotonia in one family, hyperPP in othersOkuda et al [2001]
p.Ile1495PheCramping pain, muscle atrophyBendahhou et al [1999b]
p.Met1592ValClassic clinical features with EMG myotoniaRojas et al [1991]
p.[Phe1490Leu; Met1493Ile]Malignant hyperthermia susceptibility 2Bendahhou et al [2000]
1\.
The anesthesia-related events could have been exaggerated myotonic reactions as in several other individuals with gain-of-function sodium channel variants [Klingler et al 2005].
### Penetrance
Usually, the penetrance is high (>90%). A few individuals with rare heterozygous pathogenic variants do not present with clinically detectable symptoms but have signs of myotonia detectable by EMG only [McClatchey et al 1992, Wagner et al 1997].
### Nomenclature
Hyperkalemic periodic paralysis was first described in the 1950s. Originally, it was known as "adynamia episodica hereditaria" or Gamstorp disease. Because potassium can provoke an attack of weakness and because a spontaneous attack is usually associated with an increase in serum potassium concentration, the term hyperkalemic periodic paralysis (hyperPP) is recommended [Lehmann-Horn et al 1993].
It has been suggested that the term normokalemic periodic paralysis should be abandoned. The term was originally applied to findings in two reports [Poskanzer & Kerr 1961, Meyers et al 1972]. Normokalemic periodic paralysis resembles hyperPP in many aspects; the only real differences are the lack of serum potassium concentration increase, even during serious attacks, and the lack of a beneficial effect of glucose administration. The existence of normokalemic PP as a nosologic entity has been questioned because of the potassium sensitivity and the identification of SCN4A pathogenic variants in families with normokalemic PP, including the original family described by Poskanzer and Kerr [Lehmann-Horn et al 1993, Chinnery et al 2002].
The name normokalemic periodic paralysis was used to describe a potassium-sensitive type of periodic paralysis with normokalemia and episodes of weakness reminiscent of both hyperPP and hypoPP (also known as HOKPP) caused by heterozygous pathogenic variants in SCN4A at codon 675 [Vicart et al 2004] (see Genetically Related Disorders). However, it has become clear that SCN4A pathogenic variants p.Arg675Gly, p.Arg675Gln, and p.Arg675Trp cause normokalemic PP (see Genetically Related Disorders).
### Prevalence
The prevalence of hyperPP is approximately 0.17/100,000 (95% CI 0.13-0.20) [Horga et al 2013].
## Differential Diagnosis
In addition to the allelic disorders described in Genetically Related Disorders, hereditary disorders with periodic paralysis or with hyperkalemia to consider when making the diagnosis of hyperkalemic periodic paralysis (hyperPP) are discussed below. Adult onset of clinical manifestations points to other diagnoses such as the Andersen-Tawil syndrome or secondary acquired forms of hyperPP.
Andersen-Tawil syndrome (potassium-sensitive cardiodysrhythmic type of periodic paralysis). Andersen-Tawil syndrome is characterized by the triad of: episodic flaccid muscle weakness (i.e., periodic paralysis); ventricular arrhythmias and prolonged QT interval; and common anomalies such as low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. In the first or second decade, affected individuals present with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or rest after exertion. Heterozygous pathogenic variants in the potassium channel gene KCNJ2 are causative [Plaster et al 2001]. Inheritance is autosomal dominant.
Molecular genetic testing, electrocardiogram, and Holter recording obtained between attacks of weakness are very important for distinguishing between hyperPP and Andersen-Tawil syndrome. In the experience of the author, the cardiologic manifestations precede the neuromuscular ones.
Hyperkalemic periodic paralysis with multiple sleep-onset REM periods. An individual with sporadic hyperPP and excessive daytime sleepiness with multiple sleep-onset REM periods has been reported. Symptoms were improved by a diuretic that decreased serum potassium concentration [Iranzo & Santamaria 1999]. Genetic analysis has not been performed.
Hereditary disorders characterized by hyperkalemia
* Adrenal insufficiency is characterized by hyperkalemia, hyponatremia, and hypoglycemia. Adrenal insufficiency in infancy may be caused by congenital adrenal hyperplasia (most commonly caused by 21-hydroxylase deficiency) and congenital adrenal hypoplasia including X-linked adrenal hypoplasia congenita. Adrenal cortical hypofunction (Addison disease) can be an autoimmune disorder with familial aggregation or combined with other endocrinopathies, particularly hypoparathyroidism. Addison disease also occurs in X-linked adrenoleukodystrophy.
* Recessive infantile hypoaldosteronism, another hyperkalemic disorder, leads to a rare form of salt wasting that may be life threatening during the first years of life. Recurrent dehydration and severe failure to thrive, associated with mild hyponatremia and hyperkalemia, are typical features. Laboratory tests reveal elevated plasma renin-to-serum aldosterone ratios and serum 18-hydroxycorticosterone to aldosterone ratios [Picco et al 1992].
* Pseudohypoaldosteronism type I is characterized by neonatal salt-wasting resistant to mineralocorticoids. The autosomal recessive form (OMIM 264350) with symptoms persisting into adulthood is caused by pathogenic loss-of-function variants in one of the three homologous subunits forming the amiloride-sensitive epithelial sodium channel, ENaC [Chang et al 1996]. The channel is rate limiting for electrogenic sodium reabsorption, particularly in the distal part of the renal tubule. The autosomal dominant or sporadic form (OMIM 177735) shows milder symptoms that remit with age. Truncation of the mineralocorticoid receptor has been identified in one family [Viemann et al 2001].
* Pseudohypoaldosteronism type II (PHAII), also known as Gordon's syndrome or familial hyperkalemia and hypertension, is characterized by hypertension, increased renal salt reabsorption, and impaired potassium and hydrogen excretion resulting in hyperkalemia that may be improved by thiazide diuretics. The genes in which mutation is known to cause PHAII are: WNK4 (PHAIIB), WNK1 (PHAIIC), KLHL3 (PHAIID), and CUL3 (PHAIIE) All types of PHAII are inherited in an autosomal dominant manner; PHAIID may also be inherited in an autosomal recessive manner.
Periodic paralysis secondary to acquired sustained hyperkalemia. This type of periodic paralysis can occur in any individual when the serum potassium concentration exceeds 7 mmol/L. Weakness can be accompanied by glove-and-stocking paresthesias. Hyperkalemia can cause cardiac arrhythmia, usually tachycardia, and typical ECG abnormalities (i.e., T-wave elevation, disappearance of P waves). Rest after exercise provokes weakness as in hyperPP. The diagnosis is suggested by very high serum potassium concentration during the attack, persistent hyperkalemia between attacks, and the underlying disorder. Serum potassium concentrations are far higher than those in hyperPP. The usual cause is chronic use of medications such as spironolactone, ACE inhibitors, trimethoprim, nonsteroidal anti-inflammatory drugs, and heparin. Myopathies associated with paroxysmal myoglobinuria (e.g., McArdle disease, carnitine palmitoyltransferase II deficiency) can damage the kidneys and thus also lead to potassium retention. Therapy of acquired sustained hyperkalemia involves restriction of dietary potassium intake and treating the underlying cause of the hyperkalemia.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with hyperkalemic periodic paralysis (hyperPP), the following evaluations are recommended:
* Determine neurologic status
* Perform 1H MRI (STIR) of proximal leg muscles to identify muscular water accumulation and fatty muscle degeneration [Weber et al 2006]. Edema should be extruded with long-term diuretics; evaluate by muscle strength measurement and MRI four weeks after start of treatment.
* Consult with a clinical geneticist and/or genetic counselor
### Treatment of Manifestations
Treatment for hyperPP is symptomatic and not curative.
* Attacks can often be prevented or aborted by continuing mild exercise and/or oral ingestion of carbohydrates at the onset of weakness (e.g., 2 g glucose per kg body weight).
* Attacks occur more frequently on holidays and weekends when people rest in bed longer than usual
* Individuals are advised to rise early and have a full breakfast.
* In some individuals attacks can be aborted or attenuated by intravenously injected glucocorticoids or the inhalation of two puffs of 0.1 mg salbutamol.
* Both mild exercise and treatment with β2-stimulating agents appear to work by stimulating the Na+K+-pumps [Clausen et al 2011].
* Calcium gluconate (0.5-2 g taken intravenously) may terminate attacks in some individuals [Lehmann-Horn et al 2004].
### Prevention of Primary Manifestations
Diet/environment. Preventive therapy for individuals with hyperPP consists of frequent meals rich in carbohydrates and avoidance of the following:
* Potassium-rich medications and foods (e.g., fruits, fruit juices)
* Fasting
* Strenuous work
* Exposure to cold
Diuretics. It is often advisable to prevent hyperkalemic attacks of weakness by the continuous use of a thiazide diuretic or a carbonic anhydrase inhibitor, such as acetazolamide or the recently approved medication dichlorphenamide. Diuretics are used in modest dosages at intervals from twice daily to twice weekly.
* Thiazide diuretics are preferable because they have fewer side effects than either acetazolamide or dichlorphenamide therapy.
* The dosage should be kept as low as possible (e.g., 25 mg hydrochlorothiazide daily or every other day). In severe cases, 50 mg or 75 mg of hydrochlorothiazide should be taken daily very early in the morning.
* Individuals should be monitored so that the serum potassium concentration does not fall below 3.3 mmol/L or the serum sodium concentration below 135 mmol/L [Lehmann-Horn et al 2004].
### Prevention of Secondary Complications
General anesthesia. Opioids or depolarizing agents such as potassium, anticholinesterases, and succinylcholine can aggravate a myotonic reaction and induce masseter spasms and stiffness of respiratory muscles. Intubation and mechanical ventilation may be impaired. Also, alterations of serum osmolarity, pH, and hypothermia-induced muscle shivering and mechanical stimuli can exacerbate the myotonic reaction.
An induction sequence incorporating inhalation of oxygen, cricoid pressure, thiamyal or thiopental, and two times the ED95 dose of an intermediate or short-action non-depolarizing muscle relaxant, followed by intubation, is a reasonable approach to securing the airway in persons with myotonia. Alternatively, inhalational induction may be a possibility for hyperkalemic paralysis and is well tolerated in those undergoing elective surgery.
Following administration of general anesthesia, the affected individual may develop respiratory distress in the recovery room resulting from weakness of respiratory muscles in addition to generalized weakness lasting for hours. The weakness is aggravated by drugs that depress respiration and by the hypothermia induced by anesthesia.
To prevent such attacks, glucose should be infused, a normal body temperature maintained, and serum potassium kept at low level [Klingler et al 2005, Mackenzie et al 2006, Jurkat-Rott & Lehmann-Horn 2007, Barker 2010].
Note: Because the generalized muscle spasms associated with such attacks may lead to an increase in body temperature, individuals with hyperPP have been considered to be susceptible to malignant hyperthermia. Most likely, anesthesia-related complications suggestive of a malignant hyperthermia crisis result from severe myotonic reactions [Lehmann-Horn et al 2004, Klingler et al 2005].
### Surveillance
The frequency of consultations needs to be adapted to the individual's clinical features and the response to preventive treatment.
During prophylactic treatment, measure serum potassium concentration twice per year to avoid severe diuretic-induced hypokalemia.
Neurologic examination with attention to muscle strength in the legs should be performed, in order to detect permanent weakness.
Permanent weakness requires continuous medication, e.g., with a thiazide diuretic, and MRI of the leg muscles once every one to three years. During treatment, serum potassium concentration should be measured twice per year to avoid severe diuretic-induced hypokalemia. The value should be between 3.0 and 3.5 mmol/L.
Annual monitoring of thyroid function is appropriate.
### Agents/Circumstances to Avoid
See Prevention of Primary Manifestations and Prevention of Secondary Complications.
### Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of preventive measures, particularly those that would decrease the risk of unexpected acute paralysis or anesthetic events.
* Molecular genetic testing can be pursued if the pathogenic variant in the family is known.
* When the results of genetic testing or presymptomatic testing are not known, the related family members must be considered at risk for complications and precautions are indicated, particularly during anesthesia.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Pregnancy Management
More than 90% of affected women report an increase in attack frequency during pregnancy. While approximately 80% reported improved muscle weakness during attacks, 75% also reported worse muscle stiffness during attacks [Charles et al 2013].
Women who are chronically treated with a diuretic may continue treatment in pregnancy. Human data on prenatal exposure to acetazolamide have not demonstrated an increased risk of fetal malformations. Human data on the use of oral dichlorphenamide therapy during pregnancy – and whether it leads to an increased risk of malformations in exposed fetuses – are limited.
### Therapies Under Investigation
A study that compared treatment with dichlorphenamide to treatment with placebo for prevention of episodes and for improvement of strength in individuals with hyperPP and hypoPP has recently been completed; for results, see ClinicalTrials.gov.
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.
### Other
Whether the spontaneous attacks of weakness usually associated with hyperPP are influenced by mexiletine (the drug of choice for several allelic disorders) is unknown.
No data concerning the influence of therapeutic drugs on the development of the myopathy are available.
Cation exchangers are less beneficial than diuretics in treating hyperPP because they result in more severe side effects.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Hyperkalemic Periodic Paralysis | c0238357 | 2,655 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1496/ | 2021-01-18T21:19:17 | {"mesh": ["D020513"], "synonyms": ["HyperPP"]} |
Transient tyrosinemia of the newborn is a benign disorder of tyrosine metabolism detected upon newborn screening and often observed in premature infants. It shows no clinical symptoms. It is characterized by tyrosinemia, moderate hyperphenylalaninemia, and tyrosiluria that usually resolve after 2 months of age.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Transient tyrosinemia of the newborn | None | 2,656 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3402 | 2021-01-23T17:25:00 | {"gard": ["5388"], "icd-10": ["P74.5"], "synonyms": ["Transient tyrosinemia of the neonate"]} |
Neurogenic Claudication
Other namesPseudoclaudication
CT scan of spinal stenosis and thickened ligamentum flavum, causing neurogenic claudication
SpecialtyOrthopedics, Neurology, Neurosurgery
SymptomsPain, tingling, tiredness, weakness, numbness or heaviness in the legs, hips, glutes and lower back.
ComplicationsPersistent pain in the lower body, difficulties standing, walking, exercising or performing general tasks, discomfort during sleep, bowel or bladder dysfunction
CausesLumbar spinal stenosis, osteoarthritis, spondylosis, rheumatoid arthritis, Paget's disease, spinal tumor, herniated or ruptured disks, scoliosis, trauma, achondroplasia
Risk factorsAge, obesity, previous spinal deformities or problems.
Diagnostic methodPhysical examination, medical imaging (CT and X-Rays).
Differential diagnosisVascular claudication, trochanteric bursitis, piriformis syndrome, muscle pain, vertebral compression fracture, compartment sydnrome, peripheral neuropathy, Lumbar radicular syndrome (lumbar radiculopathy) and pain in other spinal structures: hip, myofascia, sacroiliac joint
TreatmentPhysical therapy, medications, surgery
MedicationNon-steroidal anti-inflammatory drugs, prostaglandin-based drugs, gabapentin, methylcobalamin, epidural injections, lidocaine and steroids
Neurogenic claudication (NC), also known as pseudoclaudication, is the most common symptom of lumbar spinal stenosis (LSS) and describes intermittent leg pain from impingement of the nerves emanating from the spinal cord.[1][2] Neurogenic means that the problem originates within the nervous system. Claudication, from the Latin word for to limp, refers to painful cramping or weakness in the legs.[3] NC should therefore be distinguished from vascular claudication, which stems from a circulatory problem rather than a neural one.
The term neurogenic claudication is sometimes used interchangeably with spinal stenosis. However, the former is a clinical term, while the latter more specifically describes the condition of spinal narrowing.[4] NC is a medical condition most commonly caused by damage and compression to the lower spinal nerve roots.[5] It is a neurological and orthopedic condition that affects the motor nervous system of the body, specifically, the lower back, legs, hips and glutes.[5][6] NC does not occur by itself, but rather, is associated with other underlying spinal or neurological conditions such as spinal stenosis or abnormalities and degenerative changes in the spine. The International Association for the Study of Pain defines neurogenic claudication as, "pain from intermittent compression and/or ischemia of a single or multiple nerve roots within an intervertebral foramen or the central spinal canal.[4] This definition reflects the current hypotheses for the pathophysiology of NC, which is thought to be related to the compression of lumbosacral nerve roots by surrounding structures, such as hypertrophied facet joints or ligamentum flavum, bone spurs, scar tissue, and bulging or herniated discs.[7]
The predominant symptoms of NC involve one or both legs and usually presents as some combination of tingling, cramping discomfort, pain, numbness, or weakness in the lower back, calves, glutes, and/or thighs and is precipitated by walking and prolonged standing. However, the symptoms vary depending on the severity and cause of the condition. Lighter symptoms include pain or heaviness in the legs, hips, glutes and lower back, post-exercise.[6][8] Mild to severe symptoms include prolonged constant pain, tiredness and discomfort in the lower half of the body.[6][8] In severe cases, impaired motor function and ability in the lower body can be observed, and bowel or bladder dysfunction may be present.[6][8] Classically, the symptoms and pain of NC are relieved by a change in position or flexion of the waist.[9] Therefore, patients with NC have less disability in climbing steps, pushing carts, and cycling.[1]
Treatment options for NC depends on the severity and cause of the condition, and may be nonsurgical or surgical. Nonsurgical interventions include drugs, physical therapy, and spinal injections.[10] Spinal decompression is the main surgical intervention and is the most common back surgery in patients over 65.[1] Other forms of surgical procedures include: laminectomy, microdiscectomy and laminoplasty.[8][11] Patients with minor symptoms are usually advised to undergo physical therapy, such as stretching and strengthening exercises. In patients with more severe symptoms, medications such as pain relievers and steroids are prescribed in conjunction with physical therapy. Surgical treatments are predominantly used to relieve pressure on the spinal nerve roots and are used when nonsurgical interventions are ineffective or show no effective progress.[1][11]
Diagnosis of neurogenic claudication is based on typical clinical features, the physical exam, and findings of spinal stenosis on Computer Tomography (CT) or X-Ray imaging.[1] In addition to vascular claudication, diseases affecting the spine and musculoskeletal system should be considered in the differential diagnosis.[9]
## Contents
* 1 Signs and Symptoms
* 2 Causes
* 3 Diagnosis and Evaluation
* 3.1 Differential diagnosis
* 3.2 Neurogenic vs vascular claudication
* 4 Pathophysiology
* 5 Treatment
* 5.1 Physical Therapy
* 5.1.1 Stretching Exercises
* 5.1.2 Strengthening Exercises
* 5.2 Medications
* 5.3 Surgical Interventions
* 6 Prognosis
* 7 Epidemiology
* 8 Current research
* 8.1 Physical Therapy
* 8.2 Medications
* 8.3 Surgical Procedures
* 9 See also
* 10 References
## Signs and Symptoms[edit]
Neurogenic claudication commonly describes pain, weakness, fatigue, tingling, weakness, heaviness and/or paresthesias that extend into the lower extremities.[9] These symptoms may involve only one leg, but they usually involve both. Leg pain is usually more significant than back pain in individuals who have both.[12] NC is classically distinguished by symptoms improving or worsening with certain activities and manoeuvres. Pain may occur with walking, standing, and/or back extension. Sitting and bending or leaning forward tend to provide relief. Patients may also report that pain is worse while walking down stairs and improved while walking up stairs or using a bicycle or shopping cart.[1] A positive "shopping cart sign" refers to the worsening of pain with spinal extension and improvement with spinal flexion.[10]
Whilst these common symptoms are usually present in many patients with NC, rarer and more serious symptoms can occur in severe cases of NC. In extreme cases of NC constant discomfort, pain or numbness is experienced. This results in patients to have decreased mobility and function as excessive or constant movements cause pain. Exercise and prolonged walking often become difficult and are triggers of pain, tiredness, numbness and heaviness in the legs, lower back and hips.[13] Common tasks such as standing upright for an extended duration or picking up heavy objects may become increasingly difficult to perform.[6][13] In addition, patients with severe NC may experience difficulties sleeping as lying down on their back causes discomfort and pain.[8][13] In very extreme cases, bowel or bladder dysfunction can occur. However, this is a consequence of the underlying cause of NC rather than the condition itself. As most causes of NC involve increased pressure or damage to the nerves in the lower spine, damage and pressure on the nerves that extend to the bowel or bladder may occur, leading to bowel or bladder dysfunction.[14]
On physical examination, patients with NC have normal peripheral pulses.[1] The neurologic exam, straight leg raise, and femoral nerve stretch are typically normal. Abnormal signs may be revealed if the patient is observed walking until they exhibit NC. For example, a positive "stoop test" is observed if bending forward or stooping while walking relieves symptoms.[2] Occasionally, patients may have other signs such as sensory loss or gait changes.[9]
## Causes[edit]
Neurogenic claudication is the fundamental clinical feature of LSS, which may be congenital or acquired. As a result of LSS, the spinal canal in the lumbar spine narrows, causing damage and arthritic changes in the spine.[1] These changes, such as bulging disks, thickening of ligaments and overgrowth of bone spurs, lead to pressure and potentially damage to the spinal nerve roots.[2] The compression of the spinal nerve roots that control movements and sensations in the lower body subsequently causes the symptoms of NC.[5] The causes of LSS are most commonly acquired and include degenerative changes such as degenerative disc disease and spinal osteoarthritis. LSS may also be acquired from changes due to spinal surgery such as excess scar tissue or bone formation.[7] Other secondary causes include space-occupying lesions, ankylosing spondylitis, rheumatoid arthritis, and Paget's disease. Less commonly, the cause of spinal stenosis may be present at birth as seen in achondroplasia, spina bifida, and certain mucopolysaccharidoses.[15] In addition to spinal stenosis, other lower back conditions such as spondylosis, tumors, infections and herniated or ruptured discs can cause NC. These conditions contribute to the potential narrowing of the spinal cord, increasing pressure and inducing damage on the spinal nerve roots, thus, causing paing, tingling or weakness in the lower body.[5]
Risk factors for LSS include:[16][15]
* Age
* Degenerative changes of the spine
* Obesity
* Family history of spinal stenosis
* Tobacco use
* Occupation involving repetitive mechanical stress on the spine
* Past deformities or injuries to the spine
## Diagnosis and Evaluation[edit]
MRI of the lumbar spine showing spinal stenosis
Neurogenic claudication is one subtype of the clinical syndrome of lumbar spinal stenosis (LSS).[9] No gold standard diagnostic criteria currently exist, but evaluation and diagnosis is generally based on the patient history, physical exam, and medical imaging.[1] The accuracy of a diagnosis of NC increases with each additional suggestive clinical finding. Therefore, a combination of signs and symptoms may be more helpful in diagnosing NC than any single feature of the history or physical exam. These signs and symptoms include pain triggered by standing, pain relieved by sitting, symptoms above the knees, and a positive "shopping cart sign".[4]
Specific questions that may aid diagnosis include:[10]
* "Does the patient have leg or buttock pain while walking?"
* "Does the patient flex forward to relieve symptoms?"
* "Does patient feel relief when using a shopping cart or bicycle?"
* "Does the patient have motor or sensory disturbance while walking?"
* "Are the pulses in the foot present and symmetric?"
* "Does the patient have lower extremity weakness?"
* "Does the patient have low back pain?"
The physical exam may include observation, evaluation of pulses in the foot, lumbar spine range of motion, and components of a neurological exam.[1]
Helpful imaging may include x-rays, CT, CT myelogram, and magnetic resonance imaging (MRI), but MRI is preferred.[1] Abnormal MRI findings may be present in two-thirds of asymptomatic individuals, and imaging findings of spinal stenosis do not correlate well with symptom severity. Therefore, imaging findings must be considered in the context of a patient's history and physical exam when seeking a diagnosis.[2] The evidence for using objective imaging findings to define NC has been conflicting.[12]
### Differential diagnosis[edit]
Neurogenic claudication must be differentiated from other causes of leg pain, which may be present in a number of conditions involving the spine and musculoskeletal system. The differential diagnosis for NC includes:[9]
* Vascular claudication
* Lumbosacral radicular pain secondary to lumbar disc herniation
* Referred pain from spinal structures, hip or sacroiliac joint, myofascia, or viscera
* Trochanteric bursitis
* Piriformis syndrome
* Muscle pain
* Vertebral compression fracture
* Compartment syndrome
* Peripheral neuropathy
### Neurogenic vs vascular claudication[edit]
Neurogenic vs Vascular Claudication[2][10][4] Clinical feature Neurogenic Vascular
Pain worse with Standing, walking Walking
Pain relieved by Spinal flexion, sitting Standing
Timing of relief Within minutes Immediately
Location Above the knees Below the knees
Radiation of pain Extends down legs Extends up legs
Quality of pain Sharp Cramping, dull
Back pain Common Sometimes
Peripheral pulses Present May be absent
Both neurogenic claudication and vascular claudication manifest as leg pain with walking, but several key features help distinguish between these conditions.[7] In contrast to NC, vascular claudication does not vary with changes in posture.[9] Patients with vascular claudication may experience relief with standing, which may provoke symptoms in NC. The walking distance necessary to produce pain in vascular claudication is more consistent than in neurogenic claudication.[12]
## Pathophysiology[edit]
Degenerative changes cause compression of the spinal cord
Degenerative disc disease (DDD) may trigger the pathogenesis of neurogenic claudication. When intervertebral discs degenerate and change shape in DDD, the normal movements of the spine are interrupted. This results in spinal instability and more degenerative changes in spinal structures including facet joints, ligamentum flavum, and intervertebral discs. These pathologic changes result in narrowing of the vertebral canal and neurovascular compression at the lumbosacral nerve roots.[1][17] The compression of these spinal nerve roots that control sensation and movement in the lower body results in the tingling, pain and weakness NC patients often experience. However, because the severity of symptoms does not correlate well with the degree of stenosis and nerve root compression, a clear understanding of the specific pathogenesis remains challenging.[7]
It is currently unknown which exact cellular mechanisms within the body causes the pain of NC as a response to the compression of spinal nerves. The two main proposed mechanisms agree that neurovascular compression plays a role. The ischemic theory proposes that poor blood supply to the spinal nerve roots results in NC. In contrast, the venous stasis theory proposes that a combination of low oxygen levels and metabolite buildup are responsible due to venous backup at the cauda equina.[7] Pain with walking may be partially explained by the corresponding increase in nerve root oxygen requirements.[15]
These changes in blood flow may occur during back extension when shifts in vertebral structures and ligaments narrow the spinal canal and compress the neurovasculature.[15] Compared to a neutral position, extended spines exhibit 15% less cross-sectional area of the intervertebral foramina, and nerve root compression is present one-third of the time.[10] These dynamic changes in the shape of the spinal canal are more pronounced in individuals with spinal stenosis. The amount of narrowing may be 67% in LSS compared to 9% in healthy spines.[1]
## Treatment[edit]
See also: Lumbar spinal stenosis § Management
Spinal injection into the epidural space
Treatment options for NC aim to cure the underlying cause of the condition, such as lumbar spinal stenosis (LSS) or other degenerative spinal diseases. Decreased walking and lower body motor ability due to NC is the primary disabling feature of LSS.[17] Constant discomfort and pain in the lower extremities and an inability to sleep lying down are also disabling features of NC that affect a patient's quality of life. Therefore the target of most treatments is to solve these complications.[17] Currently, several treatment options are available to patients, and they can be grouped broadly into nonsurgical and surgical options.[17][7] Nonsurgical treatments include medications, physical therapy, and spinal injections. Medication options for neurogenic claudication have included non-steroidal anti-inflammatory drugs (NSAIDs), prostaglandin-based drugs, gabapentin, and methylcobalamin. However, the quality of evidence supporting their use is not high enough for specific recommendations. Physical therapy is commonly prescribed to patients, but the quality of evidence supporting its use for neurogenic claudication is also low.[10] One quarter of all epidural injections are administered to treat symptoms of LSS.[17] Preparations may contain lidocaine and/or steroids. They may be considered for short-term pain relief or to delay surgery, but their benefit is considered small.[1]
### Physical Therapy[edit]
Patients that experience light to mild symptoms are commonly treated through physical therapy, which involves stretching and strengthening the lower back, abdominal (core) and leg muscles.[18] Common stretches used include the knee to chest stretch, posterior pelvic tilt, neural stretching of the legs, hip-flexor stretch and lower trunk rotation.[18][19] In conjunction with these stretches, various strengthening exercises are often implemented, targeting the core, lower back and hip muscles. Common exercises include bridges, bird to dog, tabletop leg press, clamshell and knees to chest.[19][20] Depending on the age, mobility and physical health of patients, a combination of easier and more difficult exercises should be prescribed to suit the patient's needs. More difficult exercises may include the incorporation of resistance training (weights), gym equipment and more explosive movements. Other exercises such as cycling (stationary), swimming and water-based activities have also been found to strengthen and improve overall stability and strength in the core, lower back and hips.[19] Ultimately, the aim of physical therapy is to loosen and relax the tight muscles and ligaments that contribute to the symptoms, and to strengthen those muscles to prevent further reocurrences of the condition. However, studies have found conflicting conclusions in regards to the effectiveness of physical therapy as a treatment option for NC patients.[10][21] Thus, the low quality of evidence supporting its use has prompted further research into physical therapy as a treatment option for NC to be necessary.[10][21][22][23]
#### Stretching Exercises[edit]
Common stretching exercises used to relieve pain and treat NC include:[20]
* Knee to chest stretch - Laying down on the back, bring one leg up and pull it towards the chest and hold for 30–45 seconds.
* Posterior pelvic tilt (bridges) - Laying on the back, bend both legs and place your feet on the floor. Raise stomach from the ground, lifting the back and pelvis, until the back is straight. Hold for 5–10 seconds and relax.
* Neural Stretching of the legs - Laying on the back, bring one leg up with a stretching band until a stretch is felt in the legs. Ensure your legs are straight. Once the stretch is felt, hold for 30–45 seconds and relax.
* Hip-flexor stretch - To stretch the right hip-flexor, bring the left leg forward, and kneel on the right knee. Push the pelvis forward (lean forward), whilst keeping the upper body straight. Hold the position for 30–45 seconds and relax. To stretch the left hip-flexor, bring swap the positions of the legs.
* Lower trunk rotation - Laying down on the back, bring both knees towards your chest whilst keeping the back flat on the floor. Rotate the bent legs from the left to right side and vice versa whilst keeping back flat on the ground.
#### Strengthening Exercises[edit]
Common strengthening exercises used to treat and prevent future reocurrences of NC include:[19][20]
* Posterior pelvic tilt (bridges) - Laying on the back, bend both legs and place your feet on the floor. Raise stomach from the ground, lifting the back and pelvis, until the back is straight. Hold for 5–10 seconds and relax.
* Quadruped opposite arm/leg (bird to dog) - On all fours (knees on ground and arms against floor supporting upper body) straighten one knee whilst straightening the opposite side arm and hold for 3 seconds and repeat for the other arm/leg pair.
* Tabletop leg press press - Laying on the back, bring both knees towards the chest and then straighten both legs (such that legs are hanging in the air), whilst keeping the back flat on the ground.
* Clamshell - Whilst laying on the side with knees bent inwards, bring the top knee up (whilst keeping leg bent) and hold for 3 seconds. To exercise the opposite leg, lay on the opposite side and repeat.
* Abdominal draw-in (knee to chest ) - Laying flat on the back, bend both legs and bring knees towards the chest without lifting the back from the ground and then straighten legs again. For a more difficult version of the exercise, keep one leg bent and feet on the ground and bring the other leg towards the chest.
### Medications[edit]
Medications such as NSAIDs, prostaglandin-based drugs, gabapentin, methylcobalamin and epidural steroid injections are often used in conjunction with physical therapy to treat patients with mild or moderate symptoms of NC.[15] The main goal of these medications is to reduce pain and provide temporary relief for NC patients. NSAIDs and prostaglandin-based medications control inflammation at sites of nerve damage or pressure by inhibiting cyclooxygenase activity, and reducing the production of prostaglandins, a key contributor of inflammation.[24][25] By reducing inflammation, less pressure is put on the nerve roots, decreasing pain, and providing relief for NC patients.[26] Gabapentin aims to reduce pain and provide relief by altering the normal functioning of neurotransmitters that induce a sensation of pain and discomfort.[27] However, the exact mechanism of Gabapentin’s functioning in the body is not completely understood and current knowledge is based on experimental studies that target the nervous system.[28] Methylcobalamin is another medication that targets the nervous system to reduce pain and provide NC patients with temporary pain-relief. The drug produces myelin to cover and protect nerves from damage, preventing pain induced from damaged nerve roots, as described in some cases of NC.[29] Epidural steroid injections are the main epidural injections prescribed to treat NC. They inhibit the inflammatory cascade signalling to reduce inflammation at sites of spinal nerve damage or pressure. Consequently, they reduce pain and provide relief to individuals with NC.[30][31] Whilst the use of medications is common among NC patients that experience frequent or constant pain, their effectiveness has yielded mixed results in studies.[27][32] Further research into their viability as a medication for NC is necessary to allow doctors to provide better care and treatment options for NC patients.[33]
### Surgical Interventions[edit]
Depending on the cause and severity of the condition, surgical options for NC vary. Symptoms of LSS, including NC, are the most common reason patients 65 and older undergo spinal surgery. Surgery is generally reserved for patients whose symptoms do not improve with nonsurgical treatments, and the main objective of surgery is to relieve pressure on the spinal nerve roots and recover normal mobility and quality of life.[10] Lower Spinal Decompression is considered the mainstay of surgical treatment.[2] In this procedure, the ligamentum flavum is first removed, followed by the removal of the superior facet osteophyte in the spinal canal, and then the decompression of the spinal nerve root.[5][11] Another surgical method of decompression is the Fenestration method, which involves creating a small window in the spinal canal and then decompressing the nerves.[8] Alternative surgical options include the use of interspinous process spacers, minimally invasive lumbar decompression (MILD) procedure, laminectomy, microdiscectomy and placement of a spinal cord stimulator. The MILD procedure aims to relieve spinal cord compression by percutaneous removal of portions of the ligamentum flavum and lamina.[10] Laminectomy also involves partial or complete removal and sacrifice of the lamina, but in addition, facets in one or more segments of the spinal cord are usually sacrificed as well.[8][11] Microdiscectomy is another surgical alternative which uses small incisions, and a miniature camera for viewing, to enter the spinal cord and release pressure on the nerve roots.[5][8] Laminoplasty and spinal fusion surgeries are other alternative surgical procedures that can be performed. However, they are relatively new methods which still require more research and advancements in order for it to be safely performed with minimal risks.[11][34]
The use of interspinous spacers is associated with increased costs and rates of reoperation, while evidence comparing effectiveness of the MILD procedure to spinal decompression is insufficient.[7] The effectiveness of laminectomy, microdiscectomy, laminoplasty and spinal fusion surgeries as an alternative to spinal decompression has also been heavily debated, with studies showing conflicting results.[35][36] While studies show that surgery improves walking ability, minimizes constant pain and improves quality of life, comparisons between the efficacy of surgical and nonsurgical treatment of LSS have yielded mixed results.[17][7]
## Prognosis[edit]
Individuals with LSS may be asymptomatic for many years before developing symptoms such as NC.[1] However, most LSS patients that present with NC often seek medical help and treatment due to the condition causing pain and affecting their quality of life.[13] Consequently, the prognosis of untreated LSS and NC has not been well reported and is unknown. Based on the physiological cause of NC, it is projected that the symptoms of NC can worsen over time, with roughly one-third of patients showing signs of improvement with time.[7]
For NC patients that develop worse symptoms over time, severe consequences can occur. Over time, untreated NC and LSS can lead to chronic pain and muscle weakness.[13] In severe cases, caudea equina syndrome can develop, disrupting sensory and motor function in the lower body and bladder.[15] Consequently, disability in the lower extremities may develop over time in individuals with untreated NC and LSS.[15] Whilst some patients may recover and improve their NC condition over time, without the help of medical treatment or interventions, this is only prevalent in individuals with light or very mild symptoms of NC. In most scenarios, the prognosis of NC can lead to potential disability, muscle weakness or constant pain in the lower body.[13][15]
## Epidemiology[edit]
NC is a noncommunicable condition and thus, does not pose any community risks in terms of infectiousness. Rather, NC is associated with increasing age and mostly affects individuals over the age of 60. Age is a major contributing factor to the onset of NC due to spinal degenerative changes that are brought by aging and the weakening of bones and ligaments in the lumbar area.[6] NC is also more likely present in individuals with other spinal comorbidities.[1] A history of spinal injuries or deformities is also a contributing factor to the increased likelihood of the onset of NC.[37] Other factors such as exercise and bone density have also been found to be associated with NC. Increased exercise activity in the form of strength training has also been found to increase bone density, muscle strength and thus, decrease the likelihood of NC as aging occurs.[38]
One of the main causes of NC is the onset of LSS in elderly patients. Relative to their respective age groups, 16% of individuals aged less than 40 experience LSS whilst 38.8% of individuals aged over 60 experience LSS.[39][40] Between the ages of 60 and 69, the prevalence of LSS relative to this population group is 47.2%.[39] Data obtained from medical practitioners suggest that the incidence of LSS is 5 cases per 100 000.[40] This increased prevalence of LSS as a consequence of aging, heavily contributes to the epidemiology and acquiring of NC. Among individuals with spinal stenosis, NC is present in greater than 90% of patients and present in almost half of patients that present with low back pain, with over 200,000 people being affected in the United States.[2][1][7] The prevalence of NC and spinal stenosis in elderly men is also evident, with studies finding that roughly 1 in 10 elderly men experience leg pain in combination with low back pain (symptoms of NC) and this incidence rate is also doubled in retirement communities.[9] As the global life expectancy increases, the impact of spinal disease symptoms such as NC is likely to increase.[15]
## Current research[edit]
Current treatment options for NC are not diverse and lack extensive and detailed research to support their effectiveness, resulting in patients having to choose from a small pool of treatment options, some of which may not be effective.[10] This lack of evidence to support the effectiveness of treatment options for NC is especially prevalent in nonsurgical treatments, such as physical therapy and medications.[21][32] Among surgical interventions for NC, current research into improving methods of surgery to minimize post-surgery complication and to improve quality of life have also been of concern.[41][42]
### Physical Therapy[edit]
Studies have found that physical therapies such as stretches and strengthening exercises have yielded mixed results in terms of its effectiveness in treating NC. Reports have shown that physical therapy does aid in treating NC in patients with light to mild symptoms,[21][43] whilst others have shown the contrary.[10][22] It has also been found that patients with more severe symptoms of NC find less long-term success in treating the condition through physical therapy. Thus, doctors have concluded that further research into the effectiveness of physical therapy as a treatment option for NC is necessary. With more detailed research, doctors will then be able to suggest the best treatment options for their patients, to help them recover from the condition.[21][22][23]
### Medications[edit]
Medications commonly prescribed to NC patients are generally steroids, pain relievers or anti-inflammatories that aim to reduce pain and provide pain-relief. However, studies have found that these medications only provide temporary relief for patients, and do not provide a permanent solution, with symptoms often reoccurring several months following the disuse of medications.[18][44] Hence, doctors have reported that it is important to research possible medications that can provide long term relief or a permanent solution for patients.[19][44] Currently, Tanezumab, a monoclonal antibody that suppresses nerve activity, has been in development for use in patents with back pain, such as NC.[45] The drug functions by selectively targeting and inhibiting Nerve Growth Factors (NGF) in the body. By blocking NGF in the body, Tanezumab aims to prevent pain signals produced in the body from reaching the brain, thus, reducing pain and providing relief for patients.[46] Whilst positive results have been shown in several studies, further research is still necessary for its safe and effective use.[45][47]
### Surgical Procedures[edit]
Whilst surgical procedures exist to treat NC, current methods involve partial or complete removal of the lamina and segments of the spinal cord, leading to poor stability.[15] Hence, orthopedic surgeons and neurosurgeons have been developing and researching other surgical techniques that reduce this side effect. Haruo Tsuji, in 1990, introduced a procedure known as Laminoplastie En-block expansive Laminoplasty as an alternative to laminectomy and since then, variations and further developments have been made on that procedure, with developments still being currently.[48] This procedure involves a reconstruction of the vertebral lamina such that it creates a hinge on one side, allowing for decreased pressure on spinal nerve roots.[49] Advances in this procedure involve finding ways to access the spinal cord with minimal incisions and to more effectively create hinges that replicate normal functioning of the spine.[50][51] In addition to Laminoplasty, spinal fusion surgeries have also been of growing interest to orthopedic surgeons and neurosurgeons.[52] This process involves connecting two vertebrae of the bones together to reduce pain or correct any spinal deformities.[53] As such this form of surgery has the potential to treat the underlying cause of NC. However, these types of surgeries are difficult and dangerous to perform due to the sensitive nature of the spinal area. Additionally, these techniques are relatively new and thus, more research and advances in its methodology is still required for it to be considered a reliable and viable option to treat NC patients.[54][55]
## See also[edit]
* Lumbar spinal stenosis
* Spondylosis
* Spinal disease
* Lumbar disc disease
* Claudication
* Orthopedic surgery
* Neurosurgery
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44. ^ a b Haddadi K, Asadian L, Isazade A (2016-01-01). "Effects of Nasal Calcitonin vs. Oral Gabapentin on Pain and Symptoms of Lumbar Spinal Stenosis: A Clinical Trial Study". Clinical Medicine Insights. Arthritis and Musculoskeletal Disorders. 9: 133–8. doi:10.4137/CMAMD.S39938. PMC 4934406. PMID 27398032.
45. ^ a b Webb MP, Helander EM, Menard BL, Urman RD, Kaye AD (2018-02-21). "Tanezumab: a selective humanized mAb for chronic lower back pain". Therapeutics and Clinical Risk Management. 14: 361–367. doi:10.2147/TCRM.S144125. PMC 5825994. PMID 29503555.
46. ^ Nair AS (2018). "Tanezumab: Finally a Monoclonal Antibody for Pain Relief". Indian Journal of Palliative Care. 24 (3): 384–385. doi:10.4103/IJPC.IJPC_208_17 (inactive 2020-12-27). PMC 6069623. PMID 30111960.CS1 maint: DOI inactive as of December 2020 (link)
47. ^ Patel MK, Kaye AD, Urman RD (2018-01-01). "Tanezumab: Therapy targeting nerve growth factor in pain pathogenesis". Journal of Anaesthesiology Clinical Pharmacology. 34 (1): 111–116. doi:10.4103/joacp.JOACP_389_15 (inactive 2020-12-27). PMC 5885425. PMID 29643634.CS1 maint: DOI inactive as of December 2020 (link)
48. ^ Tsuji H, Itoh T, Sekido H, Yamada H, Katoh Y, Makiyama N, Yamagami T (1990). "Expansive laminoplasty for lumbar spinal stenosis". International Orthopaedics. 14 (3): 309–14. doi:10.1007/BF00178765. PMID 2279841. S2CID 39499491.
49. ^ Yang YM, Yoo WK, Bashir S, Oh JK, Kwak YH, Kim SW (2018). "Spinal Cord Changes After Laminoplasty in Cervical Compressive Myelopathy: A Diffusion Tensor Imaging Study". Frontiers in Neurology. 9: 696. doi:10.3389/fneur.2018.00696. PMC 6124480. PMID 30210428.
50. ^ Fehlings MG, Ahuja CS, Mroz T, Hsu W, Harrop J (March 2017). "Future Advances in Spine Surgery: The AOSpine North America Perspective". Neurosurgery. 80 (3S): S1–S8. doi:10.1093/neuros/nyw112. PMID 28350952. S2CID 25153345.
51. ^ Hirano Y, Ohara Y, Mizuno J, Itoh Y (January 2018). "History and Evolution of Laminoplasty". Neurosurgery Clinics of North America. 29 (1): 107–113. doi:10.1016/j.nec.2017.09.019. PMID 29173422.
52. ^ Proietti L, Scaramuzzo L, Schiro' GR, Sessa S, Logroscino CA (July 2013). "Complications in lumbar spine surgery: A retrospective analysis". Indian Journal of Orthopaedics. 47 (4): 340–5. doi:10.4103/0019-5413.114909. PMC 3745686. PMID 23960276.
53. ^ Daniels CJ, Wakefield PJ, Bub GA, Toombs JD (December 2016). "A Narrative Review of Lumbar Fusion Surgery With Relevance to Chiropractic Practice". Journal of Chiropractic Medicine. 15 (4): 259–271. doi:10.1016/j.jcm.2016.08.007. PMC 5106443. PMID 27857634.
54. ^ Harris IA, Traeger A, Stanford R, Maher CG, Buchbinder R (December 2018). "Lumbar spine fusion: what is the evidence?". Internal Medicine Journal. 48 (12): 1430–1434. doi:10.1111/imj.14120. PMID 30517997. S2CID 54524476.
55. ^ Dhillon KS (March 2016). "Spinal Fusion for Chronic Low Back Pain: A 'Magic Bullet' or Wishful Thinking?". Malaysian Orthopaedic Journal. 10 (1): 61–68. PMC 5333707. PMID 28435551.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Neurogenic claudication | c0580173 | 2,657 | wikipedia | https://en.wikipedia.org/wiki/Neurogenic_claudication | 2021-01-18T18:51:35 | {"umls": ["C0580173"], "wikidata": ["Q1097931"]} |
A number sign (#) is used with this entry because of evidence that osteoporosis and susceptibility to fracture can be caused by homozygous or heterozygous mutation in the MIR2861 gene (613405) on chromosome 9q34.
For a discussion of genetic heterogeneity of bone mineral density, see BMND1 (601884).
Clinical Features
Li et al. (2009) studied a 15-year-old boy with a history of peripheral fractures, in whom x-rays confirmed metaphyseal and compression fractures, all of which resulted from low-impact trauma. He had a normal 25-hydroxyl vitamin D serum concentration. His 17-year-old sister also had a history of repeated fracture, including metaphyseal and compression fractures; her bone mineral density (BMND) Z score was -4.5, and she fulfilled the criteria for primary osteoporosis in adolescents. Examination of family members revealed that the parents, a paternal aunt, and both grandfathers had osteoporosis, with BMND T scores of less than -2.5; the remainder of the family members, including an older brother who had no history of fracture, had BMND T or Z scores ranging from -0.3 to 1.6. By Northern blot analysis, Li et al. (2009) demonstrated that bone MIR2861 expression was undetectable in the proband and his sister.
Molecular Genetics
Li et al. (2009) analyzed the MIR2861 gene in a brother and sister with a history of peripheral and compression fractures and identified homozygosity for a C-to-G substitution in pre-MIR2861 (613405.0001). The parents, a paternal aunt, and both grandfathers, all of whom had osteoporosis, were heterozygous for the mutation, which was not found in unaffected family members or in 357 normal children, 396 healthy adults, or 369 adult patients with osteoporosis. Li et al. (2009) concluded that the mutation represents a rare variant of MIR2861, which plays a role in osteoblast differentiation and contributes to the development of osteoporosis when mutated.
INHERITANCE \- Autosomal dominant \- Autosomal recessive SKELETAL \- Osteoporosis \- Compression fractures (in homozygotes) \- Metaphyseal fractures (in homozygotes) MOLECULAR BASIS \- Caused by mutation in the micro RNA 2861 gene (MIR2861, 613405.0001 ) ▲ 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
| BONE MINERAL DENSITY QUANTITATIVE TRAIT LOCUS 15 | c3150680 | 2,658 | omim | https://www.omim.org/entry/613418 | 2019-09-22T15:58:45 | {"omim": ["613418"], "synonyms": ["Alternative titles", "OSTEOPOROSIS, SUSCEPTIBILITY TO", "METAPHYSEAL FRACTURE, SUSCEPTIBILITY TO", "COMPRESSION FRACTURE, SUSCEPTIBILITY TO"]} |
Progressive nodular histiocytosis is a rare, normolipemic, non-Langerhans cell histiocytosis characterized by progressive growth of multiple to disseminated, asymptomatic skin lesions that range in appearance from yellow plaques to coalescence-prone red-brown papules, nodules and pedunculated tumors up to 5 cm in size, located typically on the face, trunk and extremities (and rarely on conjuctiva and mucous membranes). Characteristic microscopic findings include a storiform spindle cell infiltrate in the deep dermis with xanthomatized macrophages and some Touton cells in the upper dermis. It is usually not associated with systemic 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
| Progressive nodular histiocytosis | c4707331 | 2,659 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=158022 | 2021-01-23T16:55:35 | {"icd-10": ["D76.3"]} |
X-linked Charcot-Marie-Tooth disease type 6 is a rare, genetic, principally axonal, peripheral sensorimotor neuropathy characterized by an X-linked dominant inheritance pattern and the childhood-onset of slowly progressive, moderate to severe, distal muscle weakness and atrophy of the lower extremities, as well as distal, panmodal sensory abnormalities, bilateral foot deformities (pes cavus, clawed toes), absent ankle reflexes and gait abnormalities (steppage gait). Females are usually asymptomatic or only present mild manifestations (mild postural hand tremor, mild wasting of hand intrinsic muscles).
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| X-linked Charcot-Marie-Tooth disease type 6 | c3806702 | 2,660 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=352675 | 2021-01-23T17:26:10 | {"gard": ["12445"], "omim": ["300905"], "icd-10": ["G60.0"], "synonyms": ["CMT6X", "CMTX6"]} |
Aspirin exacerbated respiratory disease
Other namesAspirin-induced asthma, Samter's triad, Samter's syndrome, nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD)[1]
Aspirin in coated tablets
SpecialtyPulmonology
Aspirin exacerbated respiratory disease (AERD), also termed aspirin-induced asthma,[1] is a medical condition initially defined as consisting of three key features: asthma, respiratory symptoms exacerbated by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and nasal polyps.[2][3][4] The symptoms of respiratory reactions in this syndrome are hypersensitivity reactions to NSAIDs rather than the typically described true allergic reactions that trigger other common allergen-induced asthma, rhinitis, or hives. The NSAID-induced reactions do not appear to involve the common mediators of true allergic reactions, immunoglobulin E or T cells.[4] Rather, AERD is a type of NSAID-induced hypersensitivity syndrome. EAACI/WHO classifies the syndrome as one of five types of NSAID hypersensitivity or NSAID hypersensitivity reactions.
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Treatment
* 3.1 Medication
* 3.2 Surgery
* 3.3 Diet
* 4 Alternate and related names
* 5 History
* 6 See also
* 7 References
* 8 External links
## Signs and symptoms[edit]
The various non-allergic NSAID hypersensitivity syndromes affect 0.5–1.9% of the general population, with AERD affecting about 7% of all asthmatics and about 14% of adults with severe asthma.[5] AERD, which is slightly more prevalent in women, usually begins in young adulthood (twenties and thirties are the most common onset times, although children are afflicted with it and present a diagnostic problem in pediatrics)[6][7] and may not include any other allergies. Most commonly the first symptom is rhinitis (inflammation or irritation of the nasal mucosa), which may manifest as sneezing, runny nose, or congestion. The disorder typically progresses to asthma, then nasal polyposis, with aspirin sensitivity coming last. Anosmia (lack of smell) also is common, as inflammation within the nose and sinuses likely reaches the olfactory receptors.[8]
The respiratory reactions to NSAIDs vary in severity, ranging from mild nasal congestion and eye watering to lower respiratory symptoms including wheezing, coughing, an asthma attack, and in rare cases, anaphylaxis. In addition to the typical respiratory reactions, about 10% of patients with AERD manifest skin symptoms such as urticaria and/or gastrointestinal symptoms such as abdominal pain or vomiting during their reactions to aspirin.[2]
In addition to aspirin, patients also react to other NSAIDs such as ibuprofen, and to any medication that inhibits the cyclooxygenase-1 (COX-1) enzyme, although paracetamol (acetaminophen) in low doses [9] is generally considered safe. NSAIDs that are highly selective in blocking COX-2 and do not block its closely related paralog, COX-1, such as the COX-2 inhibitors celecoxib and rofecoxib, also are regarded as safe.[10] Nonetheless, recent studies do find that these types of drugs, e.g. acetaminophen and celecoxib, may trigger adverse reactions in these patients; caution is recommended in using any COX inhibitors.[11] In addition to aspirin and NSAIDs, consumption of even small amounts of alcohol also produces uncomfortable respiratory reactions in many patients.[12]
## Cause[edit]
The disorder is thought to be caused by an anomaly in the arachidonic acid metabolizing cascade that leads to increased production of pro-inflammatory cysteinyl leukotrienes, a series of chemicals involved in the body's inflammatory response. When medications such as NSAIDs or aspirin block the COX-1 enzyme, production of thromboxane and some anti-inflammatory prostaglandins is decreased, and in patients with aspirin-induced asthma, this results in the overproduction of pro-inflammatory leukotrienes, which can cause severe exacerbations of asthma and allergy-like symptoms.[13][14][15][4][16][17] The underlying cause of the disorder is not fully understood, but there have been several important findings:
* Abnormally low levels of prostaglandin E2 (PGE2), which is protective for the lungs, has been found in patients with aspirin-induced asthma and may worsen their lung inflammation.[18]
* In addition to the overproduction of cystinyl leukotrienes, overproduction of 15-lipoxygenase-derived arachidonic acid metabolites viz., 15-hydroxyicosatetraenoic acid and eoxins by the eosinophils isolated from the blood of individuals with AERD; certain of these products may help promote the inflammatory response.[19]
* Overexpression of both the cysteinyl leukotriene receptor 1[20] and the leukotriene C4 synthase[21] enzyme has been shown in respiratory tissue from patients with aspirin-induced asthma, which likely relates to the increased response to leukotrienes and increased production of leukotrienes seen in the disorder.
* The attachment of platelets to certain leukocytes in the blood of patients with aspirin-sensitive asthma also has been shown to contribute to the overproduction of leukotrienes.[22]
* There may be a relationship between aspirin-induced asthma and TBX21, PTGER2, and LTC4S.[23]
* Eosinophils isolated from the blood of aspirin-induced asthma subjects (as well as severe asthmatic patients) greatly overproduce 15-hydroxyicosatetraenoic acid and eoxin C4 when challenged with arachidonic acid or calcium ionophore A23187, compared to the eosinophils taken from normal or mildly asthmatic subjects; aspirin treatment of eosinophils from aspirin intolerant subjects causes the cells to mount a further increase in eoxin production.[19] These results suggest that 15-lipoxygenase and certain of its metabolites, perhaps eoxin C4, is contributing to aspirin-induced asthma in a fashion similar to 5-lipoxygenase and its leukotriene metabolites.
## Treatment[edit]
### Medication[edit]
Avoidance of NSAID medications will not stop the progression of the disease. The preferred treatment for many patients is desensitization to aspirin, undertaken at a clinic or hospital specializing in such treatment.[24] Patients who are desensitized then take a maintenance dose of aspirin daily to maintain their desensitization. The recommended maintenance dose for symptom control is 650mg to 1300mg aspirin daily.[25] While on daily aspirin, most patients have reduced need for supporting medications, fewer asthma and sinusitis symptoms than previously, and an improved sense of smell. Desensitization to aspirin reduces the chance of nasal polyp recurrence and may slow the regrowth of nasal polyps.[26] Once desensitized to aspirin, most patients can safely take other NSAID medications again.[27]
Even patients desensitized to aspirin may continue to need other medications including nasal steroids, inhaled steroids, and leukotriene antagonists. Leukotriene antagonists and inhibitors (montelukast, zafirlukast, and zileuton) often are helpful in treating the symptoms of AERD. In a large survey of AERD patients, it was reported that Zyflo (zileuton) was significantly more effective at controlling the symptoms of the disease than Singulair (montelukast).[28]
Biologic medications such as mepolizumab (Nucala) may also be of benefit.[29]
Despite optimal medical management, many patients continue to require oral steroid medications to alleviate asthma and chronic nasal congestion.[30]
### Surgery[edit]
Often surgery is required to remove nasal polyps,[31] although they typically recur, particularly if aspirin desensitization is not undertaken. 90% of patients have been shown to have recurrence of nasal polyps within five years after surgery, with 47% requiring revision surgery in the same time period.[32] A complete endoscopic sinus surgery followed by aspirin desensitization has been shown to reduce the need for revision surgeries.[33]
### Diet[edit]
This section needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed.
Find sources: "Aspirin exacerbated respiratory disease" – news · newspapers · books · scholar · JSTOR (March 2019)
The majority of those with aspirin exacerbated respiratory disease experience respiratory reactions to alcohol. One study found that 83% reported such reactions. Of those who had reactions, 75% had a sinus reaction (runny nose, nasal congestion) and 51% had a lower respiratory reaction (wheezing, shortness of breath).[12] The current theory on the cause of these reactions is that they may be related to polyphenols found in alcoholic beverages.[34] A 2017 study found that alcohol sensitive patients reacted to catechins in red wine, but not to resveratrol.[35] It has been suggested that steel fermented white wines and clear liquors may cause less of a reaction than other alcoholic beverages.[36] Desensitization to aspirin has been found to reduce reactions to alcohol.[37]
Some people have reported relief of symptoms by following a low-salicylate diet such as the Feingold diet. Aspirin is quickly converted in the body to salicylic acid, also known as 2-Hydroxybenzoic acid. A prospective randomized trial with 30 patients following a low-salicylate diet for six weeks demonstrated a clinically significant decrease in both subjective and objective scoring of severity of disease, but made note of the challenge for patients in following what is a fairly stringent diet.[38] Despite these findings, experts on the disease do not believe that dietary salicylates contribute to AERD symptoms.[39] Dietary salicylates do not significantly inhibit the COX-1 enzyme, which is the cause of AERD reactions. One confounding factor in the study that showed a benefit from avoidance of dietary salicylates is that a low salicylate diet involves eliminating wine and beer. The majority of AERD patients react to wine and beer for reasons that do not involve their salicylate content.[12] There is also a strong placebo effect involved with any dietary intervention. In contrast to aspirin, dietary salicylates are not acetylated and therefore do not block cyclooxygenases and hence, there is no rationale why a low salicylate diet would be beneficial for AERD patients.[40][unreliable medical source]
A diet low in omega-6 oils (precursors of arachidonic acid), and high in omega-3 oils may also be of benefit. In a small study, aspirin-sensitive asthma patients taking 10 grams of fish oil daily reported relief of most symptoms after six weeks, however, symptoms returned if the supplement was stopped.[41] In another study, a diet low in omega 6 fatty acids and high in omega 3 fatty acids significantly reduced sinus symptoms in AERD patients.[42]
## Alternate and related names[edit]
* Aspirin-induced asthma
* Leukotriene associated hypersensitivity [43]
* Samter's triad
* Acetylsalicylic acid triad [44]
* Widal's triad
* Francis' triad
* Aspirin triad
* Aspirin-exacerbated respiratory disease (AERD).[45]
* NSAID-exacerbated respiratory disease (NERD)
* Aspirin-induced asthma and rhinitis (AIAR) [46]
A person who has not yet experienced asthma or aspirin sensitivity might be diagnosed as having:
* Non-allergic rhinitis
* Non-allergic rhinitis with eosinophilia syndrome (NARES)
## History[edit]
The syndrome is named for Max Samter.[47]
Initial reports on a linkage among asthma, aspirin, and nasal polyposis were made by Widal in 1922.[48] Further studies were conducted by Samter and Beers in reports published in 1968.[49]
## See also[edit]
* Salicylate sensitivity
* Drug intolerance
* Alcohol-induced respiratory reactions
## References[edit]
1. ^ a b Kowalski ML, Asero R, Bavbek S, Blanca M, Blanca-Lopez N, Bochenek G, et al. (October 2013). "Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs". Allergy. 68 (10): 1219–32. doi:10.1111/all.12260. PMID 24117484. S2CID 32169451.
2. ^ a b Zeitz HJ (December 1988). "Bronchial asthma, nasal polyps, and aspirin sensitivity: Samter's syndrome". Clinics in Chest Medicine. 9 (4): 567–76. PMID 3069289.
3. ^ Kim JE, Kountakis SE (July 2007). "The prevalence of Samter's triad in patients undergoing functional endoscopic sinus surgery". Ear, Nose, & Throat Journal. 86 (7): 396–9. doi:10.1177/014556130708600715. PMID 17702319.
4. ^ a b c Kowalski ML, Makowska JS, Blanca M, Bavbek S, Bochenek G, Bousquet J, et al. (July 2011). "Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) - classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA*". Allergy. 66 (7): 818–29. doi:10.1111/j.1398-9995.2011.02557.x. PMID 21631520. S2CID 11807449.
5. ^ Rajan JP, Wineinger NE, Stevenson DD, White AA (March 2015). "Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature". The Journal of Allergy and Clinical Immunology. 135 (3): 676–81.e1. doi:10.1016/j.jaci.2014.08.020. PMID 25282015.
6. ^ Welch KC. "Aspirin Desensitization". American Rhinologic Society.
7. ^ Chen BS, Virant FS, Parikh SR, Manning SC (February 2013). "Aspirin sensitivity syndrome (Samter's Triad): an unrecognized disorder in children with nasal polyposis". International Journal of Pediatric Otorhinolaryngology. 77 (2): 281–3. doi:10.1016/j.ijporl.2012.10.017. PMID 23149179.
8. ^ Fahrenholz JM (April 2003). "Natural history and clinical features of aspirin-exacerbated respiratory disease". Clinical Reviews in Allergy & Immunology. 24 (2): 113–24. doi:10.1385/CRIAI:24:2:113. PMID 12668892. S2CID 22318636.
9. ^ Settipane RA, Schrank PJ, Simon RA, Mathison DA, Christiansen SC, Stevenson DD (October 1995). "Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects". The Journal of Allergy and Clinical Immunology. 96 (4): 480–5. doi:10.1016/S0091-6749(95)70290-3. PMID 7560658.
10. ^ Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, Luchsinger JA, Ogunniyi A, Perry EK, Potocnik F, Prince M, Stewart R, Wimo A, Zhang ZX, Antuono P (September 2008). "Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors". The Lancet. Neurology. 7 (9): 812–26. doi:10.1016/S1474-4422(08)70169-8. PMC 2860610. PMID 18667359.
11. ^ Kim YJ, Lim KH, Kim MY, Jo EJ, Lee SY, Lee SE, et al. (March 2014). "Cross-reactivity to Acetaminophen and Celecoxib According to the Type of Nonsteroidal Anti-inflammatory Drug Hypersensitivity". Allergy, Asthma & Immunology Research. 6 (2): 156–62. doi:10.4168/aair.2014.6.2.156. PMC 3936045. PMID 24587953.
12. ^ a b c Cardet JC, White AA, Barrett NA, Feldweg AM, Wickner PG, Savage J, Bhattacharyya N, Laidlaw TM (2014). "Alcohol-induced respiratory symptoms are common in patients with aspirin exacerbated respiratory disease". The Journal of Allergy and Clinical Immunology. In Practice. 2 (2): 208–13. doi:10.1016/j.jaip.2013.12.003. PMC 4018190. PMID 24607050.
13. ^ Narayanankutty A, Reséndiz-Hernández JM, Falfán-Valencia R, Teran LM (May 2013). "Biochemical pathogenesis of aspirin exacerbated respiratory disease (AERD)". Clinical Biochemistry. 46 (7–8): 566–78. doi:10.1016/j.clinbiochem.2012.12.005. PMID 23246457.
14. ^ Claesson HE (September 2009). "On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma". Prostaglandins & Other Lipid Mediators. 89 (3–4): 120–5. doi:10.1016/j.prostaglandins.2008.12.003. PMID 19130894.
15. ^ Kupczyk M, Kurmanowska Z, Kupryś-Lipińska I, Bocheńska-Marciniak M, Kuna P (October 2010). "Mediators of inflammation in nasal lavage from aspirin intolerant patients after aspirin challenge". Respiratory Medicine. 104 (10): 1404–9. doi:10.1016/j.rmed.2010.04.017. PMID 20452758.
16. ^ Ledford DK, Wenzel SE, Lockey RF (2014). "Aspirin or other nonsteroidal inflammatory agent exacerbated asthma". The Journal of Allergy and Clinical Immunology. In Practice. 2 (6): 653–7. doi:10.1016/j.jaip.2014.09.009. PMID 25439353.
17. ^ Choi JH, Kim MA, Park HS (February 2014). "An update on the pathogenesis of the upper airways in aspirin-exacerbated respiratory disease". Current Opinion in Allergy and Clinical Immunology. 14 (1): 1–6. doi:10.1097/ACI.0000000000000021. PMID 24300420. S2CID 205433452.
18. ^ Picado C (2002). "Aspirin-intolerant asthma: role of cyclo-oxygenase enzymes". Allergy. 57 Suppl 72: 58–60. doi:10.1034/j.1398-9995.57.s72.14.x. PMID 12144557. S2CID 34704099.
19. ^ a b Neighbour H (2014). "Mechanisms of aspirin-intolerant asthma: identifying inflammatory pathways in the pathogenesis of asthma". International Archives of Allergy and Immunology. 163 (1): 1–2. doi:10.1159/000355949. PMID 24247362.
20. ^ Sousa AR, Parikh A, Scadding G, Corrigan CJ, Lee TH (November 2002). "Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis". The New England Journal of Medicine. 347 (19): 1493–9. doi:10.1056/NEJMoa013508. PMID 12421891.
21. ^ Cowburn AS, Sladek K, Soja J, Adamek L, Nizankowska E, Szczeklik A, Lam BK, Penrose JF, Austen FK, Holgate ST, Sampson AP (February 1998). "Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma". The Journal of Clinical Investigation. 101 (4): 834–46. doi:10.1172/JCI620. PMC 508632. PMID 9466979.
22. ^ Laidlaw TM, Kidder MS, Bhattacharyya N, Xing W, Shen S, Milne GL, Castells MC, Chhay H, Boyce JA (April 2012). "Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes". Blood. 119 (16): 3790–8. doi:10.1182/blood-2011-10-384826. PMC 3335383. PMID 22262771.
23. ^ Online Mendelian Inheritance in Man (OMIM): Asthma, Nasal Polyps, and Aspirin Intolerance - 208550
24. ^ Waldram JD, Simon RA (November 2016). "Performing Aspirin Desensitization in Aspirin-Exacerbated Respiratory Disease". Immunology and Allergy Clinics of North America. 36 (4): 693–703. doi:10.1016/j.iac.2016.06.006. PMID 27712764.
25. ^ Lee JY, Simon RA, Stevenson DD (January 2007). "Selection of Aspirin dosages for aspirin desensitization treatment in patients with aspirin-exacerbated respiratory disease". Journal of Allergy and Clinical Immunology. 119 (1): 157–164. doi:10.1016/j.jaci.2006.09.011. PMID 17208597.
26. ^ Berges Gimeno MP, Simon RA, Stevenson DD (January 2003). "Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease". Journal of Allergy and Clinical Immunology. 111 (1): 180–186. doi:10.1067/mai.2003.7. PMID 12532116.
27. ^ Pleskow WW, Stevenson DD, Mathison DA, Simon RA, Schatz M, Zeiger RS (January 1982). "Aspirin desensitization in aspirin-sensitive asthmatic patients: clinical manifestations and characterization of the refractory period". The Journal of Allergy and Clinical Immunology. 69 (1 Pt 1): 11–9. doi:10.1016/0091-6749(82)90081-1. PMID 7054250.
28. ^ Ta V, White AA (September 2015). "Survey-Defined Patient Experiences With Aspirin-Exacerbated Respiratory Disease". Journal of Allergy and Clinical Immunology: In Practice. 3 (5): 711–718. doi:10.1016/j.jaip.2015.03.001. PMID 25858054.
29. ^ Tuttle KL, Buchheit KM, Schneider T, Hsu Blatman KS, Barrett NA, Laidlaw TM, Cahill KN (February 2018). "A pragmatic analysis of mepolizumab in patients with aspirin-exacerbated respiratory disease". Journal of Allergy and Clinical Immunology. 141 (2): AB168. doi:10.1016/j.jaci.2017.12.537.
30. ^ Szczeklik, A; Nizankowska, E; Duplaga, M (2000). "Natural history of aspirin-induced asthma. AIANE Investigators. European Network on Aspirin-Induced Asthma". The European Respiratory Journal. 16 (3): 432–6. doi:10.1034/j.1399-3003.2000.016003432.x. PMID 11028656.
31. ^ McMains KC, Kountakis SE (2006). "Medical and surgical considerations in patients with Samter's triad". American Journal of Rhinology. 20 (6): 573–6. doi:10.2500/ajr.2006.20.2913. PMID 17181095. S2CID 33480314.
32. ^ Mendelsohn D, Jeremic G, Wright ED, Rotenberg BW (March 2011). "Revision rates after endoscopic sinus surgery: a recurrence analysis". The Annals of Otology, Rhinology, and Laryngology. 120 (3): 162–6. doi:10.1177/000348941112000304. PMID 21510141. S2CID 26696888.
33. ^ Adappa ND, Ranasinghe VJ, Trope M, Brooks SG, Glicksman JT, Parasher AK, Palmer JN, Bosso JV (January 2018). "Outcomes after complete endoscopic sinus surgery and aspirin desensitization in aspirin exacerbated respiratory disease". International Forum of Allergy & Rhinology. 8 (1): 49–53. doi:10.1002/alr.22036. PMID 29105347. S2CID 5811563.
34. ^ Payne SC (September 2014). "RE: Alcohol-induced respiratory symptoms are common in patients with aspirin exacerbated respiratory disease". The Journal of Allergy and Clinical Immunology: In Practice. 2 (5): 644. doi:10.1016/j.jaip.2014.05.003. PMID 25213072.
35. ^ Payne SC, Peters RD, Negri JA, Steinke JW, Borish L (February 2017). "Activation of Basophils and Eosinophils by EtOH in Alcohol Sensitive Patients with CRS and Asthma". Journal of Allergy and Clinical Immunology. 139 (2): AB90. doi:10.1016/j.jaci.2016.12.246.
36. ^ "Wine and Beer May Make Your Lungs and Sinuses Worse". www.aaaai.org. American Academy of Allergy Asthma & Immunology. August 3, 2018.
37. ^ Glicksman JT, Parasher AK, Doghramji L, Brauer D, Waldram J, Waters K, Bulva J, Palmer JN, Addapa ND, White AA, Bosso JV (July 2018). "Alcohol-induced respiratory symptoms improve after aspirin desensitization in patients with aspirin-exacerbated respiratory disease". International Forum of Allergy & Rhinology. 3 (5): 711–718. doi:10.1016/j.jaip.2015.03.001. PMID 25858054.
38. ^ Sommer DD, Rotenberg BW, Sowerby LJ, Lee JM, Janjua A, Witterick IJ, et al. (April 2016). "A novel treatment adjunct for aspirin exacerbated respiratory disease: the low-salicylate diet: a multicenter randomized control crossover trial". International Forum of Allergy & Rhinology. 6 (4): 385–91. doi:10.1002/alr.21678. PMID 26751262. S2CID 205339377.
39. ^ Modena BD, White AA (2018). "Can Diet Modification Be an Effective Treatment in Aspirin-Exacerbated Respiratory Disease?". The Journal of Allergy and Clinical Immunology. In Practice. 6 (3): 832–833. doi:10.1016/j.jaip.2017.11.043. PMC 6455762. PMID 29747986.
40. ^ "A Low Salicylate Diet for AERD (Samter's Triad)". The Samter's Society.
41. ^ Healy E, Newell L, Howarth P, Friedmann PS (December 2008). "Control of salicylate intolerance with fish oils". The British Journal of Dermatology. 159 (6): 1368–9. doi:10.1111/j.1365-2133.2008.08830.x. PMID 18795922. S2CID 25041594.
42. ^ Schneider TR, Johns CB, Palumbo ML, Murphy KC, Cahill KN, Laidlaw TM (2018). "Dietary Fatty Acid Modification for the Treatment of Aspirin-Exacerbated Respiratory Disease: A Prospective Pilot Trial". The Journal of Allergy and Clinical Immunology. In Practice. 6 (3): 825–831. doi:10.1016/j.jaip.2017.10.011. PMC 5945343. PMID 29133219.
43. ^ Lewis C (2017). "Leukotriene Associated Hypersensitivity". Enteroimmunology: A Guide to the Prevention and Treatment of Chronic Inflammatory Disease. Carrabelle Florida: Psy Press. pp. 148–58. ISBN 978-1-938318-06-1.
44. ^ Amar YG, Frenkiel S, Sobol SE (February 2000). "Outcome analysis of endoscopic sinus surgery for chronic sinusitis in patients having Samter's triad". The Journal of Otolaryngology. 29 (1): 7–12. PMID 10709165.
45. ^ Williams AN, Woessner KM (May 2008). "The clinical effectiveness of aspirin desensitization in chronic rhinosinusitis". Current Allergy and Asthma Reports. 8 (3): 245–52. doi:10.1007/s11882-008-0041-7. PMID 18589844. S2CID 12166132.
46. ^ Bochenek G, Bánska K, Szabó Z, Nizankowska E, Szczeklik A (March 2002). "Diagnosis, prevention and treatment of aspirin-induced asthma and rhinitis". Current Drug Targets. Inflammation and Allergy. 1 (1): 1–11. doi:10.2174/1568010023345011. PMID 14561202.
47. ^ Samter's syndrome at Who Named It?
48. ^ Widal F, Abrami P, Lermoyez J (1922). "Anaphylaxie et idiosyncraise" [Anaphylaxis and idiosyncrasy]. La Presse Médicale (in French). 30 (18): 189–93.
49. ^ Samter M, Beers RF (May 1968). "Intolerance to aspirin. Clinical studies and consideration of its pathogenesis". Annals of Internal Medicine. 68 (5): 975–83. doi:10.7326/0003-4819-68-5-975. PMID 5646829.
## External links[edit]
Classification
D
* ICD-10: J45.1, J45.8
* ICD-9-CM: 493.1
* OMIM: 208550
* MeSH: D055963
* 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
* 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
* t
* e
Cell surface receptor deficiencies
G protein-coupled receptor
(including hormone)
Class A
* TSHR (Congenital hypothyroidism 1)
* LHCGR (Luteinizing hormone insensitivity, Leydig cell hypoplasia, Male-limited precocious puberty)
* FSHR (Follicle-stimulating hormone insensitivity, XX gonadal dysgenesis)
* GnRHR (Gonadotropin-releasing hormone insensitivity)
* EDNRB (ABCD syndrome, Waardenburg syndrome 4a, Hirschsprung's disease 2)
* AVPR2 (Nephrogenic diabetes insipidus 1)
* PTGER2 (Aspirin-induced asthma)
Class B
* PTH1R (Jansen's metaphyseal chondrodysplasia)
Class C
* CASR (Familial hypocalciuric hypercalcemia)
Class F
* FZD4 (Familial exudative vitreoretinopathy 1)
Enzyme-linked receptor
(including
growth factor)
RTK
* ROR2 (Robinow syndrome)
* FGFR1 (Pfeiffer syndrome, KAL2 Kallmann syndrome)
* FGFR2 (Apert syndrome, Antley–Bixler syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson–Weiss syndrome)
* FGFR3 (Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome)
* INSR (Donohue syndrome
* Rabson–Mendenhall syndrome)
* NTRK1 (Congenital insensitivity to pain with anhidrosis)
* KIT (KIT Piebaldism, Gastrointestinal stromal tumor)
STPK
* AMHR2 (Persistent Müllerian duct syndrome II)
* TGF beta receptors: Endoglin/Alk-1/SMAD4 (Hereditary hemorrhagic telangiectasia)
* TGFBR1/TGFBR2 (Loeys–Dietz syndrome)
GC
* GUCY2D (Leber's congenital amaurosis 1)
JAK-STAT
* Type I cytokine receptor: GH (Laron syndrome)
* CSF2RA (Surfactant metabolism dysfunction 4)
* MPL (Congenital amegakaryocytic thrombocytopenia)
TNF receptor
* TNFRSF1A (TNF receptor associated periodic syndrome)
* TNFRSF13B (Selective immunoglobulin A deficiency 2)
* TNFRSF5 (Hyper-IgM syndrome type 3)
* TNFRSF13C (CVID4)
* TNFRSF13B (CVID2)
* TNFRSF6 (Autoimmune lymphoproliferative syndrome 1A)
Lipid receptor
* LRP: LRP2 (Donnai–Barrow syndrome)
* LRP4 (Cenani–Lenz syndactylism)
* LRP5 (Worth syndrome, Familial exudative vitreoretinopathy 4, Osteopetrosis 1)
* LDLR (LDLR Familial hypercholesterolemia)
Other/ungrouped
* Immunoglobulin superfamily: AGM3, 6
* Integrin: LAD1
* Glanzmann's thrombasthenia
* Junctional epidermolysis bullosa with pyloric atresia
EDAR (EDAR hypohidrotic ectodermal dysplasia)
* PTCH1 (Nevoid basal-cell carcinoma syndrome)
* BMPR1A (BMPR1A juvenile polyposis syndrome)
* IL2RG (X-linked severe combined immunodeficiency)
See also
cell surface receptors
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Aspirin exacerbated respiratory disease | c1859648 | 2,661 | wikipedia | https://en.wikipedia.org/wiki/Aspirin_exacerbated_respiratory_disease | 2021-01-18T18:42:34 | {"mesh": ["C565935", "D055963"], "umls": ["C1859648"], "icd-9": ["493.1"], "icd-10": ["J45.1", "J45.8"], "wikidata": ["Q2039267"]} |
A number sign (#) is used with this entry because of evidence that bone marrow failure syndrome-5 (BMFS5) is caused by heterozygous mutation in the TP53 gene (191170) on chromosome 17p13.
Description
Bone marrow failure syndrome-5 (BMFS5) is a hematologic disorder characterized by infantile onset of severe red cell anemia requiring transfusion. Additional features include hypogammaglobulinemia, poor growth with microcephaly, developmental delay, and seizures (summary by Toki et al., 2018)
For a discussion of genetic heterogeneity of BMFS, see BMFS1 (614675).
Clinical Features
Toki et al. (2018) reported 2 unrelated patients who presented in the first days or months of life with anemia and hypogammaglobulinemia. Both patients required blood transfusions and IgG replacement. Other blood parameters were normal. Bone marrow examination showed selective erythroid hypoplasia. Both patients had additional syndromic features. Patient 1 was a 20-year-old man who developed seizures at age 3 months, had poor growth with severe microcephaly (-6 SD), and global developmental delay with impaired cognition. He also had reticular skin pigmentation, tooth anomalies, hypogonadism, and delayed bone age. At age 13, his anemia showed spontaneous remission, suggesting a clonal genetic reversion event. However, his platelet counts gradually decreased, and bone marrow showed mild trilineage hypoplasia. The second patient was a 5-year-old boy who had an afebrile seizure at age 9 months. He also had severe growth retardation, microcephaly (-4.9 SD), and overall developmental delay. He died at age 5 after a bone marrow transplant. Telomere length in both patients was normal, neither patient developed cancer, and neither had recurrent infections.
Molecular Genetics
In 2 unrelated patients with BMFS5, Toki et al. (2018) identified de novo heterozygous mutations in the TP53 gene (191170.0043 and 191170.0044) that resulted in the same truncation of the protein with a loss of 32 residues from the C-terminal end (Ser362AlafsTer8). The mutations were found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that both TP53 mutants had increased transcriptional activity compared to controls. Human induced pluripotent stem cells expressing a CRISPR/Cas9-derived C-terminal truncated TP53 showed significantly elevated expression of downstream TP53 targets, as well as impaired erythroid differentiation. Toki et al. (2018) postulated that the deletion may compromise binding of negative transcriptional regulators. The findings indicated that augmented p53 function, not loss of function, was responsible for the phenotype. Toki et al. (2018) noted that mouse models with animals lacking the C-terminal end of Tp53 show similar abnormalities (Simeonova et al., 2013, Hamard et al., 2013).
Animal Model
Toki et al. (2018) found that expression of a C-terminal truncated tp53 in zebrafish resulted in developmental defects with severe morphologic abnormalities, reduced erythrocyte production, and increased lethality.
INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature Other \- Poor overall growth HEAD & NECK Head \- Microcephaly (up to -6 SD) Teeth \- Tooth anomalies (patient A) GENITOURINARY External Genitalia (Male) \- Testicular atrophy (patient A) SKELETAL \- Delayed bone age (patient A) SKIN, NAILS, & HAIR Skin \- Reticular pigmentation (patient A) NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Impaired intellectual development \- Seizures ENDOCRINE FEATURES \- Hypogonadism (patient A) HEMATOLOGY \- Anemia \- Red cell aplasia \- Bone marrow shows selective erythroid hypoplasia IMMUNOLOGY \- Hypogammaglobulinemia MISCELLANEOUS \- Onset in early infancy \- De novo mutation \- Two unrelated patients have been reported (last curated October 2018) MOLECULAR BASIS \- Caused by mutation in the tumor protein p53 gene (TP53, 191170.0043 ) ▲ 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
| BONE MARROW FAILURE SYNDROME 5 | None | 2,662 | omim | https://www.omim.org/entry/618165 | 2019-09-22T15:43:18 | {"omim": ["618165"]} |
## Summary
### Clinical characteristics.
Untreated complete plasminogen activator inhibitor 1 (PAI-1) deficiency is characterized by mild-to-moderate bleeding, although in some instances bleeding can be life threatening. Most commonly, delayed bleeding is associated with injury, trauma, or surgery; spontaneous bleeding does not occur. While males and females with complete PAI-1 deficiency are affected equally, females may present more frequently with clinical manifestations or earlier in life than males due to menorrhagia and postpartum hemorrhage. Fewer than ten families with complete PAI-1 deficiency have been reported to date. The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant. In one family from this Old Order Amish population, seven individuals had cardiac fibrosis ranging from minimal-to-moderate (6 individuals) to severe (1).
### Diagnosis/testing.
The diagnosis of complete PAI-1 deficiency is established in a proband when PAI-1 antigen is undetectable and PAI-1 activity is lower than 1 IU/mL-1 and/or biallelic SERPINE1 pathogenic variants are identified on molecular genetic testing. Note that because the normal range of functional PAI-1 activity assay starts at zero in most laboratories, the ability to discriminate between normal and abnormal levels of activity is limited.
### Management.
Treatment of manifestations: Management of the bleeding disorder by a team of experts in the treatment of individuals with bleeding disorders is highly recommended. Intravenous antifibrinolytics (e.g., epsilon-aminocaproic acid [EACA] and tranexamic acid) can be used for severe bleeding manifestations, including intracranial hemorrhage (with or without hematoma evacuation). Infusion of fresh-frozen plasma can be used as needed to increase PAI-1 activity prior to achieving therapeutic steady state levels of antifibrinolytics. Heavy menstrual bleeding can often be managed with antifibrinolytics or hormonal suppression therapy. Treatment of cardiac fibrosis is symptomatic.
Prevention of primary manifestations: Antifibrinolytics should be used to prevent bleeding for surgical and dental procedures, childbirth, and other invasive procedures.
Surveillance: Regular follow up with a team of experts in the treatment of individuals with bleeding disorders is recommended. For all individuals with complete PAI-1 deficiency, screening echocardiogram for evidence of cardiac fibrosis is recommended beginning at age 15 years with follow up for those with positive findings as indicated by a cardiologist and every two years for those with no cardiac findings at the time of the last screening.
Agents/circumstances to avoid: Medications that affect coagulation including aspirin, ibuprofen, and some herbal remedies; high-risk activities such as contact sports.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with complete PAI-1 deficiency in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.
Pregnancy management: Recommendations based on published findings during pregnancies in two women with complete PAI-1 deficiency are oral administration of either tranexamic acid or EACA for intermittent bleeding in the first and second trimester, from 26 weeks’ gestation through delivery, and for at least two weeks post partum. Note: Evidence that these recommendations would be effective in all pregnancies of women with complete PAI-1 deficiency is lacking; the teratogenicity of EACA and tranexamic acid is unknown and information regarding their safety during pregnancy and lactation is limited.
### Genetic counseling.
Complete PAI-1 deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency. 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 SERPINE1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk for complete PAI-1 deficiency, and preimplantation genetic testing are possible.
## Diagnosis
No formal diagnostic criteria for establishing a diagnosis of complete plasminogen activator inhibitor 1 (PAI-1) deficiency have been published.
### Suggestive Findings
Complete PAI-1 deficiency should be suspected in individuals with the following medical history and laboratory findings.
#### Medical History
Bleeding disorder that typically presents as:
* Delayed bleeding following injury, trauma, or surgery
* In females, menorrhagia and abnormal bleeding with pregnancy
Absence of other known bleeding disorders including:
* von Willebrand disease
* Factor V deficiency
* Factor X deficiency
* Factor II deficiency
* Alpha 2 antiplasmin deficiency
* Factor XIII deficiency
* Platelet function disorders (including Scott syndrome and Quebec platelet disorder)
#### Laboratory Findings
Normal: common tests of coagulation including prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin clotting time (TCT)
Abnormal tests indicative of a hyperfibrinolytic state; these may include the following:
* Decreased plasma plasminogen
* Decreased plasma α-2-antiplasmin
* Decreased plasma total and free levels of tissue-type plasminogen activator antigen (t-PA)
* Shortened euglobin lysis time (ECLT) in plasma. Note: While ECLT is shortened due to excessive fibrinolysis in persons with complete PAI-1 deficiency, and ECLT and whole blood clotting assays (e.g., the thromboelastogram) can be helpful in diagnosis of hyperfibrinolytic states, these tests are insufficient to confirm or exclude the diagnosis of complete PAI-1 deficiency.
PAI-1 specific assays:
* PAI-1 antigen assay (to determine the level of PAI-1 antigen) can be helpful in identifying complete PAI-1 deficiency if no PAI-1 is produced, but is not helpful if dysfunctional protein is produced [Gupta et al 2014].
* PAI-1 activity assay can be used to exclude a diagnosis of complete PAI-1 deficiency when PAI-1 activity levels are clearly within the normal range. Because the normal range of the functional PAI-1 activity assay starts at zero in most laboratories, the ability to discriminate between normal and abnormal levels of activity is limited [Fay et al 1997, Mehta & Shapiro 2008].
Note: If the PAI-1 antigen level is normal and PAI-1 activity is decreased, the phenotype is referred to as "qualitative PAI-1deficiency," the clinical significance of which is unknown [Fay et al 1997, Mehta & Shapiro 2008].
### Establishing the Diagnosis
The diagnosis of complete PAI-1 deficiency is established in a proband when [Fay et al 1997, Iwaki et al 2011]:
* PAI-1 antigen is undetectable and PAI-1 activity is lower than 1 IU/mL
Note: (1) Because the majority of PAI-1 activity assays are used to detect increased PAI-1 activity rather than decreased PAI-1 activity, they lack the sensitivity to differentiate between low normal activity and complete deficiency. Thus, a PAI-1 activity level of zero is often reported to be within the normal limits. (2) PAI-1 activity also demonstrates diurnal variation: because higher levels are observed in the morning and lower levels in the afternoon, the activity should be assayed in a sample drawn in the morning.
AND/OR
* Biallelic SERPINE1 pathogenic variants are identified on molecular genetic testing (see Table 1). See also Molecular Genetics.
Molecular genetic testing approaches can include single-gene testing and use of a multigene panel.
Single-gene testing
* Sequence analysis of SERPINE1 is performed first. If only one or no SERPINE1 pathogenic variant is identified, gene-targeted deletion/duplication analysis can be considered; however, to date no SERPINE1 exon or whole-gene deletions/duplications have been reported.
* Targeted analysis for the c.699_700dupTA pathogenic variant can be performed first in individuals from the Old Order Amish community of eastern and southern Indiana. Note: This variant has not been identified in other Old Order Amish populations.
A multigene panel that includes SERPINE1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
### Table 1.
Molecular Genetic Testing Used in Plasminogen Activator Inhibitor 1 (PAI-1) Deficiency
View in own window
Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
SERPINE1Sequence analysis 3Unknown
Gene-targeted deletion/duplication analysis 4None reported 5
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\.
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.
5\.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
### Clinical Description
Untreated complete plasminogen activator inhibitor 1 (PAI-1) deficiency is characterized by mild-to-moderate bleeding, although in some instances bleeding can be life-threatening. Most commonly, delayed bleeding is associated with injury, trauma, or surgery; spontaneous bleeding episodes such as those observed in classic hemophilia A and hemophilia B do not occur.
While males and females with complete PAI-1 deficiency are affected equally, females may present more frequently with clinical manifestations or earlier in life than males, due to menorrhagia and postpartum hemorrhage. In addition, females experience bleeding with pregnancy and have difficulty carrying a pregnancy to term.
Bleeding disorder. Mucocutaneous bleeding, a hallmark of complete PAI-1 deficiency, includes oral bleeding, epistaxis and – in females – menorrhagia and postpartum bleeding.
Post-traumatic bleeding can include joint bleeds and hematomas [Schleef et al 1989, Diéval et al 1991, Minowa et al 1999]. Affected members of the kindred from the Old Order Amish community of eastern and southern Indiana developed knee and elbow hemarthroses after minor trauma, extensive subperiosteal bleeding after minor jaw trauma, and epidural hematoma (in an infant) after a head injury [Fay et al 1997].
The male reported by Zhang et al [2005] experienced soft tissue hematomas of the leg and hip following minor leg trauma that required treatment; he subsequently manifested muscle atrophy.
Post-surgical bleeding has been reported in individuals with a molecularly confirmed diagnosis of complete PAI-1 deficiency:
* A child age five years experienced postoperative bleeding following surgical repair of a ventricular septal defect [Iwaki et al 2011].
* A member of the Old Order Amish community had delayed bleeding after surgical repair of an inguinal hernia [Fay et al 1997].
* Delayed bleeding was reported after total hip arthroplasty [Hirose et al 2016].
Prolonged bleeding after dental extraction has been reported in individuals with a molecularly confirmed diagnosis of complete PAI-1 deficiency [Fay et al 1997, Iwaki et al 2011].
A palatal hemorrhage complicated a dental abscess, requiring hospitalization and transfusion [Fay et al 1992].
Prolonged wound healing occurred in one individual [Iwaki et al 2011].
Menorrhagia is a consistent characteristic of complete PAI-1 deficiency [Minowa et al 1999, Mehta & Shapiro 2008, Iwaki et al 2011]. In some instances treatment with transfusion of packed red blood cells [Mehta & Shapiro 2008] or whole blood is required [Iwaki et al 2011].
In one woman rupture of an ovarian follicle resulted in hemoperitoneum requiring hospitalization, treatment with antifibrinolytics, and red cell transfusion.
Pregnancy can be complicated by sporadic antenatal bleeding, preterm labor, postpartum bleeding, and miscarriage. Gupta et al [2014] (full text) followed two women with PAI-1 deficiency through a total of seven pregnancies: six live born premature infants and one miscarriage. Bleeding, which began between eight and 19 weeks’ gestation and recurred prior to delivery, was treated with epsilon-aminocaproic acid (EACA). Postpartum bleeding was treated with EACA for up to six weeks (see Pregnancy Management).
Iwaki et al [2012] also reported on three pregnancies in a woman with complete PAI-1 deficiency in which antenatal bleeding, preterm labor, and miscarriage were complications.
Cardiac fibrosis. Cardiac fibrosis has only been reported in an Old Order Amish kindred with complete PAI-1 deficiency, which is – to the authors' knowledge – the largest number of affected individuals with this finding reported to date [Flevaris et al 2017; Author, personal observation]. Of the seven individuals with cardiac fibrosis, one had severe involvement and six had minimal-to-moderate cardiac fibrosis between ages 15 and 35 years. Thus, to date, information about cardiac fibrosis in complete PAI-1 deficiency is limited.
### Genotype-Phenotype Correlations
Because data on the phenotype associated with biallelic SERPINE1 pathogenic variants are limited, no genotype-phenotype correlations can be made at this time.
### Nomenclature
Complete plasminogen activator inhibitor 1 (PAI-1) deficiency, the topic of this GeneReview, is defined as undetectable PAI-1 antigen levels and undetectable PAI-1 activity. Complete PAI-1 deficiency may also be referred to as "quantitative PAI-1 deficiency" or "homozygous PAI-1 deficiency."
Qualitative PAI-1 deficiency, not addressed in this GeneReview, refers to normal PAI-1 antigen levels and decreased PAI-1 activity and is thought to be associated with either a heterozygous SERPINE1 pathogenic variant (i.e., the carrier state for an autosomal recessive disorder) or compound heterozygosity for variants that produce a reduced amount of protein that is nonetheless sufficient to avoid complete deficiency. The clinical significance of qualitative PAI-1 deficiency is unknown. See also Molecular Genetics.
### Prevalence
The prevalence of complete PAI-1 deficiency is unknown, in large part because of the inability of the majority of tests of PAI-1 activity to differentiate between low normal activity and complete deficiency (see Establishing the Diagnosis).
Fewer than ten families with complete PAI-1 deficiency have been reported to date.
Complete PAI-1 deficiency has no known racial or ethnic predominance. It has been reported in North America, Europe, and Asia.
Of note, the incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant (see Molecular Genetics). To date, this pathogenic variant has not been found in other Old Order Amish communities.
## Differential Diagnosis
### Table 2.
Disorders Associated with Mild-to-Moderate Bleeding (often Associated with Injury, Surgery, or Dental Procedures) to Consider in the Differential Diagnosis of Complete PAI-1 Deficiency
View in own window
DiffDx Disorder 1Gene(s)MOIClinical Feature Unique to DiffDx DisorderRelated GeneReview / OMIM Entry
Alpha-2 antiplasmin deficiencySERPINF2ARAbnormal PLI assay 2262850
Factor XIII deficiencyF13A1, F13BARLow factor XIII level613225
Factor II deficiencyF2ARLow factor II level613679
Factor V deficiencyF5ARLow factor V level227400
Factor X deficiencyF10ARLow factor X level227600
Platelet function defectsGP1BAADAbnormal platelet studies177820
GP1BBAR231200
GP9AR
ANO6AR262890
ITGA2BAD187800
ITGB3
von Willebrand disease (VWD)VWFAD, ARAbnormal VWD lab evalvon Willebrand Disease
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; PLI = plasmin inhibitor
1\.
Disorders are listed alphabetically.
2\.
Alpha-2 antiplasmin deficiency. Moderate bleeding seen in alpha-2 antiplasmin deficiency is not characteristically associated with injury, surgery, or dental procedures.
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with complete plasminogen activator inhibitor 1 (PAI-1) deficiency, the following evaluations are recommended:
* Questions to elicit a patient's history of:
* Epistaxis
* Poor wound healing
* Bleeding in association with injury or trauma
* Bleeding with dental extractions
* Additional oral bleeding
* Post-surgical bleeding
* In females:
* Heavy menstrual bleeding
* Postpartum bleeding
* Bleeding during pregnancy
* Preterm delivery
* Bleeding in association with ovulation
* History of therapies tried in the past and the response to each specific therapy
Note that response to antifibrinolytic therapy supports the diagnosis of complete PAI-1 deficiency (see Treatment of Manifestations).
* Evaluation by a hematologist with training in hemostasis
* Consultation with a clinical geneticist and/or genetic counselor
### Treatment of Manifestations
Bleeding disorder. Management by a team of experts in the treatment of individuals with bleeding disorders is highly recommended. In the US, such teams are often identified through the federally funded hemophilia treatment center network.
Severe bleeding manifestations, including intracranial hemorrhage (with or without hematoma evacuation) have been successfully managed with intravenous antifibrinolytics. Response to both epsilon-aminocaproic acid and tranexamic acid have been documented.
If PAI-1 activity needs to be increased prior to achieving the therapeutic steady state level of antifibrinolytics, infusion of fresh-frozen plasma (FFP) (10-15 mL/kg) can be used. Duration of use of FFP is individualized based on clinical course and response to therapy. Note: The use of FFP does not appear to be effective in pregnancy for the prevention of bleeding in women with complete PAI-1 deficiency [Iwaki et al 2012]. Fresh-frozen plasma to replace PAI-1 during pregnancy may be difficult due to the PAI-1 level achieved with plasma, the volume required, and the need for repeated infusion, all of which may be associated with risk of volume overload and/or infusion reactions [Gupta et al 2014].
Heavy menstrual bleeding can often be effectively managed with antifibrinolytics or hormonal suppression therapy (oral contraceptives).
Occasionally, patients with complete PAI-1 deficiency experience excessive menstrual bleeding or bleeding following a procedure or trauma that requires infusion of packed red blood cells to manage the acute blood loss.
Education regarding bleeding manifestations and when to seek treatment includes the following:
* For females, anticipatory counseling regarding onset of menses and potential complications
* Prompt reporting of injuries and planned procedures to allow early initiation of treatment to prevent significant bleeding
Cardiac fibrosis. There is currently no specific treatment for cardiac fibrosis associated with complete PAI-1 deficiency; treatment is symptomatic.
### Prevention of Primary Manifestations
Antifibrinolytics should be used to prevent bleeding for surgical and dental procedures, childbirth, and other invasive procedures. Antifibrinolytics can be administered IV, PO, or topically, the latter especially during dental procedures.
Women who have heavy menstrual bleeding often benefit from continuous or intermittent prophylactic use of the antifibrinolytics tranexamic acid and epsilon-aminocaproic acid.
### Surveillance
Bleeding disorder. Regular follow up with a team of experts in the treatment of individuals with bleeding disorders is recommended. Such teams are often identified through the federal hemophilia treatment center network in the US.
For menstruating females:
* Regular monitoring: hemoglobin and/or hematocrit and iron studies including ferritin for possible iron deficiency and/or anemia
* Assessment of the effectiveness of therapeutic interventions such as antifibrinolytics or hormonal suppressive agents (oral contraceptives)
Cardiac fibrosis. Because of clinical experience (albeit limited to date) with cardiac fibrosis in persons with complete PAI-1 deficiency [Flevaris et al 2017; Author, personal observation], screening echocardiogram can be considered beginning at age 15 years. In those with no cardiac findings, follow-up screening in two years is indicated; and in those with cardiac findings, follow up yearly or more frequently if indicated by a cardiologist [Ghosh et al 2010; Ghosh et al 2013; Author, personal observation].
### Agents/Circumstances to Avoid
The following should be avoided:
* Medications that affect coagulation including aspirin, ibuprofen, and some herbal remedies
* High-risk activities such as contact sports
### Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with complete PAI-1 deficiency in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:
* Molecular genetic testing if the SERPINE1 pathogenic variants in the family are known;
* Measurement of PAI-1 antigen levels and PAI-1 activity if the SERPINE1 pathogenic variants in the family are not known.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Pregnancy Management
Recommendations based on published findings during pregnancies in two women with complete PAI-1 deficiency are administration of either tranexamic acid (25 mg kg-1 per dose, maximum 1300 milligrams, orally 3-4x/day) or epsilon-aminocaproic acid (EACA) (100 mg kg-1 per dose, maximum 3 g, orally 4x/day) for intermittent bleeding in the first and second trimester, from 26 weeks’ gestation through delivery, and for at least two weeks post partum [Heiman et al 2014]. Note that evidence that these recommendations would be effective in all pregnancies of women with complete PAI-1 deficiency is lacking.
A woman with complete PAI-1 deficiency was treated with FFP during three pregnancies at eight to 11 weeks' gestation two to three times per week; treatment was increased to daily at 20-28 weeks' gestation. The first pregnancy ended in miscarriage at 19 weeks. The second and third pregnancies were delivered at 32 and 27 weeks’ gestation, respectively, as a result of uncontrollable contractions and placental abruption [Iwaki et al 2012].
Of note, the teratogenicity of EACA and tranexamic acid is unknown and information regarding their safety during pregnancy and lactation is limited. There is a need to establish dosing guidelines for the use of antifibrinolytics during pregnancy and the postpartum period.
See www.mothertobaby.org for further information on medication use 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.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Complete Plasminogen Activator Inhibitor 1 Deficiency | None | 2,663 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK447152/ | 2021-01-18T21:33:46 | {"synonyms": ["Complete PAI-1 Deficiency", "Homozygous PAI-1 Deficiency"]} |
Effect of long-term ergot poisoning
Ergotism
Other namesSaint Anthony's Fire, ergotoxicosis
Advanced ergotism with gangrene
SpecialtyEmergency medicine
Symptoms
* Convulsive ergotism: spasms, diarrhea, paresthesias, mania, psychosis, headaches, nausea, vomiting
* Gangrenous ergotism: desquamation, weak peripheral pulses, loss of peripheral sensation, edema
TypesConvulsive, gangrenous
CausesLong-term ergot poisoning
Ergotism (pron. /ˈɜːrɡətˌɪzəm/ UR-gət-iz-əm) is the effect of long-term ergot poisoning, traditionally due to the ingestion of the alkaloids produced by the Claviceps purpurea fungus—from the Latin noun clava meaning club, and the suffix -ceps meaning head, i.e. the purple club-headed fungus—that infects rye and other cereals, and more recently by the action of a number of ergoline-based drugs. It is also known as ergotoxicosis, ergot poisoning, and Saint Anthony's Fire.
## Contents
* 1 Signs and symptoms
* 1.1 Convulsive
* 1.2 Gangrenous
* 2 Causes
* 2.1 Identification of agent
* 3 Prevention
* 4 History
* 4.1 Salem witchcraft accusations
* 5 See also
* 6 References
* 7 External links
## Signs and symptoms[edit]
The symptoms can be roughly divided into convulsive symptoms and gangrenous symptoms.
### Convulsive[edit]
Convulsive symptoms of ergotism
Convulsive symptoms include painful seizures and spasms, diarrhea, paresthesias, itching, mental effects including mania or psychosis, headaches, nausea and vomiting. Usually the gastrointestinal effects precede central nervous system effects.
### Gangrenous[edit]
The dry gangrene is a result of vasoconstriction induced by the ergotamine-ergocristine alkaloids of the fungus. It affects the more poorly vascularized distal structures, such as the fingers and toes. Symptoms include desquamation or peeling, weak peripheral pulses, loss of peripheral sensation, edema and ultimately the death and loss of affected tissues. Vasoconstriction is treated with vasodilators.[1]
## Causes[edit]
Claviceps purpurea fungal sclerotia growing on barley
Historically, eating grain products, particularly rye, contaminated with the fungus Claviceps purpurea was the cause of ergotism.
The toxic ergoline derivatives are found in ergot-based drugs (such as methylergometrine, ergotamine or, previously, ergotoxine). The deleterious side-effects occur either under high dose or when moderate doses interact with potentiators such as erythromycin.
The alkaloids can pass through lactation from mother to child, causing ergotism in infants.
### Identification of agent[edit]
Ergot in barley
Dark-purple or black grain kernels, known as ergot bodies, can be identifiable in the heads of cereal or grass just before harvest. In most plants the ergot bodies are larger than normal grain kernels, but can be smaller if the grain is a type of wheat. A larger separation between the bodies and the grain kernels show the removal of ergot bodies during grain cleaning.
## Prevention[edit]
Removal of ergot bodies is done by placing the yield in a brine solution; the ergot bodies float while the healthy grains sink.[2] Infested fields need to be deep plowed; ergot cannot germinate if buried more than one inch in soil and therefore will not release its spores into the air. Rotating crops using non-susceptible plants helps reduce infestations since ergot spores only live one year. Crop rotation and deep tillage, such as deep mold-board ploughing, are important components in managing ergot, as many cereal crops in the 21st century are sown with a "no-till" practice (new crops are sown directly into the stubble from the previous crop to reduce soil erosion).[3] Wild and escaped grasses and pastures can be mown before they flower to help limit the spread of ergot.
Chemical controls can also be used but are not considered economical, especially in commercial operations, and germination of ergot spores can still occur under favorable conditions even with the use of such controls.
## History[edit]
Detail from the painting Temptation of St Anthony by Matthias Grünewald, showing a patient suffering advanced ergotism.
Epidemics of the disease were identified throughout history, though the references in classical writings are inconclusive. Rye, the main vector (route) for transmitting ergotism, was not grown much around the Mediterranean. When Fuchs separated references to ergotism from erysipelas and other afflictions in 1834 he found the earliest reference to ergotism in the Annales Xantenses for the year 857: "a great plague of swollen blisters consumed the people by a loathsome rot, so that their limbs were loosened and fell off before death."
In the Middle Ages the gangrenous poisoning was known as "holy fire" or "Saint Anthony's fire", named after monks of the Order of St. Anthony who were particularly successful at treating this ailment. According to Snorri Sturluson, in his Heimskringla, King Magnus II of Norway, son of King Harald Sigurtharson, who was the half-brother of Saint King Olaf Haraldsson, died from ergotism shortly after the Battle of Hastings. The 12th-century chronicler Geoffroy du Breuil of Vigeois recorded the mysterious outbreaks in the Limousin region of France, where the gangrenous form of ergotism was associated with the local Saint Martial. Likewise, an outbreak in Paris c. 1129 was reported to be cured by the relics of Saint Genevieve, a miracle commemorated in the 26 November "Feast of the Burning Ones".[4]
The blight, named cockspur[5] owing to the appearance of infected grains, was identified and named by Denis Dodart, who reported the relation between ergotized rye and bread poisoning in a letter to the French Royal Academy of Sciences in 1676 (John Ray mentioned ergot for the first time in English the next year). "Ergotism", in this modern sense, was first recorded in 1853.
Notable epidemics of ergotism occurred into the 19th century. Fewer outbreaks have occurred since then owing to rye being carefully monitored in developed countries. However a severe outbreak of something akin to ergot poisoning occurred in the French village of Pont-Saint-Esprit in 1951, resulting in five deaths.[6] The outbreak and the diagnostic confusion surrounding it are vividly described in John Grant Fuller's book The Day of St Anthony's Fire.[7]
There is evidence[8] of ergot poisoning serving a ritual purpose in the ritual killing of certain bog bodies.[9]
When milled, the ergot is reduced to a red powder,[10] obvious in lighter grasses but easy to miss in dark rye flour. In less wealthy countries, ergotism still occurs; an outbreak in Ethiopia occurred in mid-2001 from contaminated barley. Whenever there is a combination of moist weather, cool temperatures, delayed harvest in lowland crops and rye consumption, an outbreak is possible.
Poisonings due to consumption of seeds treated with mercury compounds are sometimes misidentified as ergotism.[11][12] Simon Cotton of the Chemistry Department of Uppingham School, UK said that there have been numerous cases of mass-poisoning due to consumption of mercury-treated seeds.[13]
### Salem witchcraft accusations[edit]
The convulsive symptoms from ergot-tainted rye may have been the source of accusations of bewitchment that spurred the Salem witch trials. This medical explanation for the theory of "bewitchment" was first propounded by Linnda R. Caporael in 1976 in an article in Science. In her article, Caporael argues that the convulsive symptoms, such as crawling sensations in the skin, tingling in the fingers, vertigo, tinnitus aurium, headaches, disturbances in sensation, hallucination, painful muscular contractions, vomiting, and diarrhea, as well as psychological symptoms, such as mania, melancholia, psychosis, and delirium, were all symptoms reported in the Salem witchcraft records. Caporael also states there was an abundance of rye in the region as well as climate conditions that could support the tainting of rye.[14] In 1982, historian Mary Matossian raised Caporael’s theory in an article in American Scientist in which she argued that symptoms of "bewitchment" resemble the ones exhibited in those afflicted with ergot poisoning.[15]
The hypothesis that ergotism could explain cases of bewitchment has been subject to debate and has been criticized by several scholars. Within a year of Caporael's article, historians Spanos and Gottlieb argued against the idea in the same journal. In Spanos and Gottlieb's rebuttal to Caporael's article, they concluded that there are several flaws in the explanation. For example, they argued that, if the food supply were contaminated, the symptoms would have occurred by household, not individual. However, historian Leon Harrier said that even if supplies were properly cooked, residents suffering stomach ulcers had a risk of absorbing the toxin through the stomach lining, offering a direct route to the bloodstream. Being similar to Lysergic acid diethylamide (L.S.D.), ergot would not survive in the acidic environment of a typical human's stomach, especially in properly cooked food. But if some but not all residents were malnourished and suffering bleeding stomach ulcers, only they could be affected by ingesting contaminated grains, leaving the majority unaffected, explaining why ergotism was not previously recognized. Harrier argued that the numbers could have been larger, possibly including the entire town, but due to the trials on bewitchment and heresy, and the fear of being accused and subsequently executed, few could come forward while suffering legitimate medical conditions.
Spanos and Gottlieb also state that ergot poisoning has additional symptoms not associated with the events in Salem, and that the proportion of children afflicted was less than in a typical ergotism epidemic.[16] Anthropologist H. Sidky noted that ergotism had been known for centuries before the Salem witch trials, and argued that its symptoms would have been recognizable during the time of the Salem witch trials.[17]
In 2003 it was pointed out that ergots produced by different strains of Claviceps purpurea, and those growing in different soils, may produce different ergot alkaloid compositions. This may explain the different manifestations of ergotism in different outbreaks. For example, an alkaloid present in high concentrations in ergots from Europe east of the Rhine may have caused convulsive ergotism, while ergot from the west caused epidemics of gangrenous ergotism.[18]
## See also[edit]
* Dancing plague of 1518
## References[edit]
1. ^ Piquemal R, Emmerich J, Guilmot JL, Fiessinger JN (June 1998). "Successful treatment of ergotism with Iloprost—a case report". Angiology. 49 (6): 493–97. doi:10.1177/000331979804900612. PMID 9631897. S2CID 6348648.
2. ^ Wegulo, Stephen N; Carlson, Michael P (2011). "Ergot of Small Grain Cereals and Grasses and Its Health Effects on Humans and Livestock" (PDF). University of Nebraska–Lincoln Extension.
3. ^ "American Phytopathological Society". American Phytopathological Society.
4. ^ Missale Parisiense (Paris: Jean Dupré, 1481), fol. 241r, accessed via Gallica, [1].
5. ^ "cockspur". Oxford English Dictionary (Online ed.). Oxford University Press. (Subscription or participating institution membership required.)
6. ^ Richards, Ira S (2008). Principles and Practice of Toxicology in Public Health. Sudbury, MA: Jones & Bartlett. p. 64. ISBN 978-0-7637-3823-5.
7. ^ Fuller, John (1969). The Day of St Anthony's Fire. London: Hutchinson. ISBN 0-09-095460-2.
8. ^ Taylor, Timothy (2003), The Buried Soul: How Humans Invented Death, Fourth Estate.[page needed]
9. ^ Stødkilde-Jørgensen, Hans; Jacobsen, Niels Otto; Warncke, Esbern; Heinemeier, Jan (March 2008). "The intestines of a more than 2000 years old peat-bog man: microscopy, magnetic resonance imaging and 14C-dating". Journal of Archaeological Science. 35 (3): 530–4. doi:10.1016/j.jas.2007.05.010.
10. ^ Cadwick, Ian. "Scripturient: Blog & Commentary." Scripturient Blog Commentary. 9 Nov. 2013. Web. 30 Nov. 2014. <http://ianchadwick.com/blog/bread-madness-and-christianity/>.
11. ^ Ott, Jonathan (1993), Pharmacotheon: Entheogenic Drugs, their Plant Sources and History, Kennewick, WA: Natural Products, p. 145.
12. ^ Hofmann, Albert (1980), "1: How LSD Originated", LSD: My Problem Child, New York, NY: McGraw-Hill, p. 6, archived from the original on 2016-05-22.
13. ^ Cotton, Simon (October 2003), "Dimethylmercury and Mercury Poisoning", Molecule of the Month, UK: School of Chemistry, University of Bristol, "More horrifying than this were epidemics of poisoning, caused by people eating treated seed grains. There was a serious epidemic in Iraq in 1956 and again in 1960, whilst use of seed wheat (which had been treated with a mixture of C2H5HgCl and C6H5HgOCOCH3) for food, caused the poisoning of about 100 people in West Pakistan in 1961. Another outbreak happened in Guatemala in 1965. Most serious was the disaster in Iraq in 1971–2, when according to official figures 459 died. Grain had been treated with methyl mercury compounds as a fungicide and should have been planted. Instead it was sold for milling and made into bread. It had been dyed red as a warning and also had warning labels in English and Spanish that no one could understand.".
14. ^ Caporael, Linnda R (April 1976). "Ergotism: The Satan Loose in Salem". Science. 192 (4234): 21–6. Bibcode:1976Sci...192...21C. doi:10.1126/science.769159. PMID 769159.
15. ^ Matossian, Mary (July–August 1982). "Ergot and the Salem Witchcraft Affair". American Scientist. 70 (4): 355–7. Bibcode:1982AmSci..70..355M. PMID 6756230.
16. ^ Spanos, Nicholas; Gottlieb, John ‘Jack’ (December 1976). "Ergotism and the Salem Village Witch Trials". Science. 194 (4272): 1390–4. Bibcode:1976Sci...194.1390S. doi:10.1126/science.795029. PMID 795029. S2CID 41615273.
17. ^ Sidky, H (1997). Witchcraft, Lycanthropy, Drugs and Disease: An Anthropological Study of the European Witch Hunts. Peter Lang. ISBN 0-8204-3354-3.[page needed]
18. ^ Eadie MJ (July 2003). "Convulsive ergotism: epidemics of the serotonin syndrome?". Lancet Neurology. 2 (7): 429–34. doi:10.1016/S1474-4422(03)00439-3. PMID 12849122. S2CID 12158282.
## External links[edit]
* Media related to Ergotism at Wikimedia Commons
Classification
D
* ICD-10: T62.2
* ICD-9-CM: 988.2
* MeSH: D004881
* DiseasesDB: 30715
* v
* t
* e
* Poisoning
* Toxicity
* Overdose
History of poison
Inorganic
Metals
Toxic metals
* Beryllium
* Cadmium
* Lead
* Mercury
* Nickel
* Silver
* Thallium
* Tin
Dietary minerals
* Chromium
* Cobalt
* Copper
* Iron
* Manganese
* Zinc
Metalloids
* Arsenic
Nonmetals
* Sulfuric acid
* Selenium
* Chlorine
* Fluoride
Organic
Phosphorus
* Pesticides
* Aluminium phosphide
* Organophosphates
Nitrogen
* Cyanide
* Nicotine
* Nitrogen dioxide poisoning
CHO
* alcohol
* Ethanol
* Ethylene glycol
* Methanol
* Carbon monoxide
* Oxygen
* Toluene
Pharmaceutical
Drug overdoses
Nervous
* Anticholinesterase
* Aspirin
* Barbiturates
* Benzodiazepines
* Cocaine
* Lithium
* Opioids
* Paracetamol
* Tricyclic antidepressants
Cardiovascular
* Digoxin
* Dipyridamole
Vitamin poisoning
* Vitamin A
* Vitamin D
* Vitamin E
* Megavitamin-B6 syndrome
Biological1
Fish / seafood
* Ciguatera
* Haff disease
* Ichthyoallyeinotoxism
* Scombroid
* Shellfish poisoning
* Amnesic
* Diarrhetic
* Neurotoxic
* Paralytic
Other vertebrates
* amphibian venom
* Batrachotoxin
* Bombesin
* Bufotenin
* Physalaemin
* birds / quail
* Coturnism
* snake venom
* Alpha-Bungarotoxin
* Ancrod
* Batroxobin
Arthropods
* Arthropod bites and stings
* bee sting / bee venom
* Apamin
* Melittin
* scorpion venom
* Charybdotoxin
* spider venom
* Latrotoxin / Latrodectism
* Loxoscelism
* tick paralysis
Plants / fungi
* Cinchonism
* Ergotism
* Lathyrism
* Locoism
* Mushrooms
* Strychnine
1 including venoms, toxins, foodborne illnesses.
* Category
* Commons
* WikiProject
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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
| Ergotism | c0014714 | 2,664 | wikipedia | https://en.wikipedia.org/wiki/Ergotism | 2021-01-18T18:49:49 | {"mesh": ["D004881"], "icd-9": ["988.2"], "icd-10": ["T62.2"], "wikidata": ["Q955948"]} |
Familial progressive hyperpigmentation
Other namesMelanosis universalis hereditaria[1]
This condition in inherited in an autosomal dominant manner
Familial progressive hyperpigmentation is characterized by patches of hyperpigmentation, present at birth, which increase in size and number with age. This is a genetic disease, however the gene that accounts for this spotty darkening of the skin has yet to be discovered. Although rare, the congenital disease is most prevalent among populations originating from China.[2]:858
## See also[edit]
* Skin lesion
## References[edit]
1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Familial progressive hyperpigmentation". www.orpha.net. Retrieved 20 April 2019.
2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
The American Journal of Human Genetics 84, 672–677, May 15, 2009
## External links[edit]
Classification
D
* ICD-10: L81.4
* OMIM: 145250
External resources
* Orphanet: 79146
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
| Familial progressive hyperpigmentation | c2681535 | 2,665 | wikipedia | https://en.wikipedia.org/wiki/Familial_progressive_hyperpigmentation | 2021-01-18T19:01:43 | {"umls": ["C2681535", "C1835039", "C1840392"], "icd-10": ["L81.4"], "orphanet": ["79146"], "wikidata": ["Q5432946"]} |
A number sign (#) is used with this entry because of evidence that maturity-onset diabetes of the young type 6 (MODY6) is caused by heterozygous mutation in the NEUROD1 gene (601724) on chromosome 2q31.
For a general phenotypic description and a discussion of genetic heterogeneity of MODY, see 606391.
Molecular Genetics
In a family reported by Malecki et al. (1999), members with mutations in the NEUROD1 gene met the diagnostic criteria for MODY including an autosomal pattern of inheritance, onset of diabetes before 25 years of age in 3 carriers, and a requirement for insulin treatment in 5 carriers; see 601724.0002.
Pathogenesis
In a review of the various forms of MODY, Fajans et al. (2001) suggested that the molecular basis of MODY6 is abnormal transcription/regulation of beta cell development and function.
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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
| MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 6 | c0342276 | 2,666 | omim | https://www.omim.org/entry/606394 | 2019-09-22T16:10:32 | {"doid": ["0111104"], "mesh": ["C562772"], "omim": ["606394"], "orphanet": ["552"], "synonyms": ["Alternative titles", "MODY, TYPE 6"], "genereviews": ["NBK500456"]} |
Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection is a rare primary immunodeficiency due to a defect in innate immunity disorder characterized by selective susceptibility to viral infections, particularly after systemic challenge with live viral vaccines, such as the measles, mumps and rubella (MMR) vaccine. Patients present severe, potentially fatal, manifestations to viral illness, including encephalitis, hepatitis and pneumonitis.
*[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
| Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection | c4225260 | 2,667 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=431166 | 2021-01-23T16:57:40 | {"omim": ["616636", "616669"], "icd-10": ["D84.8"], "synonyms": ["Primary immunodeficiency with post-MMR vaccine viral infection"]} |
A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with mental retardation (type B14; MDDGB14) is caused by homozygous or compound heterozygous mutation in the gene encoding the beta subunit of GDP-mannose pyrophosphorylase (GMPPB; 615320) on chromosome 3p21.
Mutation in the GMPPB gene can also cause a more severe congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A14; MDDGA14; 615350) and a less severe limb-girdle muscular dystrophy-dystroglycanopathy (type C14; MDDGC14; 615352).
Description
MDDGB14 is an autosomal recessive congenital muscular dystrophy characterized by severe muscle weakness apparent in infancy and mental retardation. Some patients may have additional features, such as microcephaly, cardiac dysfunction, seizures, or cerebellar hypoplasia. It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Carss et al., 2013).
For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Clinical Features
Carss et al. (2013) reported 4 unrelated patients, 2 of Mexican descent and 2 girls of southern Italian descent, with congenital muscular dystrophy (CMD) with mental retardation. The patients presented between birth and 4 months of age with severe hypotonia. Three had shown decreased fetal movements in utero. There was some variation in additional features. The 2 Mexican patients had mild mental retardation, delayed walking at about 3 years, cataracts, strabismus, ptosis, and cardiac anomalies. One had long QT syndrome (see LQT1, 192500) and the other had left ventricular dilatation. One also had microcephaly, ileal atresia, and torticollis. Brain MRI in both patients was normal. The 2 Italian patients, previously reported by Messina et al. (2009), had severe hypotonia, microcephaly, generalized muscle weakness, feeding difficulties, drug-resistant epilepsy, and severe mental retardation. One was unable to sit, and 1 could sit at age 2 years. Brain MRI of both girls showed cerebellar hypoplasia. One died at age 14 years and the other was bedridden and unable to speak at age 10 years. All patients had increased serum creatine kinase and muscle biopsies consistent with muscular dystrophy showing hypoglycosylation of DAG1. Isoelectric focusing of serum transferrin was normal.
Inheritance
The transmission pattern of MDDGB14 in the families reported by Carss et al. (2013) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 2 Mexican patients with MDDGB14, Carss et al. (2013) identified a homozygous mutation in the GMPPB gene (615320.0004). Two unrelated Italian girls with the disorder were compound heterozygous for mutations in the GMPPB gene (615320.0005 and 615320.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder.
INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly \- Poor head control Face \- Myopathic face Eyes \- Cataracts (in some patients) \- Strabismus (in some patients) \- Ptosis (in some patients) \- Nystagmus (in some patients) CARDIOVASCULAR Heart \- Long QT syndrome (1 patient) \- Left ventricular dilatation (1 patient) ABDOMEN Gastrointestinal \- Feeding difficulties SKELETAL \- Contractures (in some patients) MUSCLE, SOFT TISSUES \- Muscular dystrophy \- Hypotonia \- Muscle weakness, severe \- Generalized muscle wasting \- Increased muscle tone (early in life) \- Dystrophic features seen on muscle biopsy \- Hypoglycosylation of alpha-dystroglycan seen on muscle biopsy NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation, mild to severe \- Absent speech \- Delayed or absent independent walking \- Seizures (in some patients) \- Cerebellar hypoplasia (in some patients) PRENATAL MANIFESTATIONS Movement \- Decreased fetal movements LABORATORY ABNORMALITIES \- Increased serum creatine kinase MISCELLANEOUS \- Onset at birth or in early infancy \- Variable severity MOLECULAR BASIS \- Caused by mutation in the GDP-mannose pyrophosphorylase B gene (GMPPB, 615320.0004 ) ▲ 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
| MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 14 | c3809221 | 2,668 | omim | https://www.omim.org/entry/615351 | 2019-09-22T15:52:28 | {"doid": ["0050588"], "omim": ["615351"], "orphanet": ["370959", "370968"], "synonyms": ["CMD with cerebellar involvement", "CMD-CRB", "Alternative titles", "MUSCULAR DYSTROPHY, CONGENITAL, GMPPB-RELATED", "CMD with intellectual disability", "CMD-MR"]} |
A number sign (#) is used with this entry because of evidence that susceptibility to age-related macular degeneration-5 (ARMD5) is conferred by heterozygous mutation in the ERCC6 gene (609413) on chromosome 10q11.
For a phenotypic description and a discussion of genetic heterogeneity of age-related macular degeneration, see 603075.
Molecular Genetics
In a cohort of 460 advanced cases of age-related macular degeneration and 269 age-matched controls and 57 archived ARMD cases and 18 age-matched non-ARMD controls, Tuo et al. (2006) found that a -6530C-G SNP (609413.0010; rs3793784) in the ERCC6 gene was associated with ARMD susceptibility, both independently and through interaction with an intronic SNP in the CFH gene (see 134370.0008; rs380390) previously reported to be highly associated with ARMD.
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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
| MACULAR DEGENERATION, AGE-RELATED, 5 | c3151063 | 2,669 | omim | https://www.omim.org/entry/613761 | 2019-09-22T15:57:35 | {"omim": ["613761"]} |
Legius syndrome, also known as NF1-like syndrome, is a rare, genetic skin pigmentation disorder characterized by multiple café-au-lait macules with or without axillary or inguinal freckling.
## Epidemiology
The prevalence of Legius syndrome is not known. Fewer than 200 cases have been reported to date. Prevalence may be higher than expected due to misdiagnosis of cases as neurofibromatosis type 1 (NF1, see this term). The incidence of NF1 is reported to be 1/3000, and about 2% of patients fulfilling diagnostic criteria for NF1 are found to have the genetic mutation underlying Legius syndrome (SPRED1).
## Clinical description
The clinical presentation of Legius syndrome is very similar to that of NF1. Patients typically present with multiple café-au-lait spots sometimes associated with intertriginous freckling, but lack Lisch nodules, optic pathway gliomas, bone abnormalities, neurofibromas or other tumor manifestations. The number of café-au-lait macules tends to increase with age during childhood. Other less common manifestations include short stature, macrocephaly, Noonan-like facies, pectus excavatum/carinatum, lipomas, hypopigmented macules, vascular lesions, learning disabilities, attention deficit/hyperactivity disorder (ADHD), and developmental delay.
## Etiology
Legius syndrome is caused by heterozygous inactivating mutations in the SPRED1 gene (15q14), involved in regulation of the RAS-MAPK signal transduction pathway. Nearly 100 different mutations in this gene have been identified. The proportion of cases related to de novo mutations is not yet known. No genotype-phenotype correlations have been found.
## Diagnostic methods
About 50% of patients with Legius syndrome fulfill the diagnostic criteria for NF1, but they have a far milder phenotype compared to NF1 patients. Diagnosis based solely on the presence of clinical features is difficult, given the overlap with other disorders characterized by multiple café-au-lait spots. The presence of characteristic clinical signs in parents of affected individuals is supportive of diagnosis. However, molecular genetic testing is required to confirm the diagnosis and testing is available on a clinical basis.
## Differential diagnosis
Legius syndrome is differentiated from NF1 by the absence of the non-pigmentary clinical manifestations seen in this disorder (i.e. Lisch nodules, neurofibromas, optic glioma, bone abnormalities). Correct diagnosis is essential because of the differences in prognosis and long-term monitoring between Legius syndrome and NF1. Other disorders to consider include Noonan syndrome, Noonan syndrome with lentigines (LEOPARD syndrome), and McCune-Albright syndrome (see these terms).
## Antenatal diagnosis
Prenatal diagnosis is possible and requires prior identification of the disease-causing mutation in the family.
## Genetic counseling
Legius syndrome follows an autosomal dominant pattern of inheritance. Genetic counseling should be provided to affected families.
## Management and treatment
Drug therapy should be considered for the behavioral manifestations of the disorder (ADHD). Physical, speech, and occupational therapy is recommended for those with developmental delay and educational support for those with learning difficulties.
## Prognosis
Given the current knowledge of disease manifestations and complications, the prognosis for patients with Legius syndrome is considered to be very good.
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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
| Legius syndrome | c1969623 | 2,670 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=137605 | 2021-01-23T18:08:57 | {"gard": ["10714"], "mesh": ["C548032"], "omim": ["611431"], "umls": ["C1969623"], "icd-10": ["Q85.0"], "synonyms": ["NF1-like syndrome", "Neurofibromatosis 1-like syndrome"]} |
Spinocerebellar ataxia type 42 is a rare, autosomal dominant cerebellar ataxia characterized by pure and slowly progressive cerebellar signs combining gait instability, dysarthria, nystagmus, saccadic eye movements and diplopia. Less frequent clinical signs and symptoms include spasticity, hyperreflexia, decreased distal vibration sense, urinary urgency or incontinence and postural tremor.
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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
| Spinocerebellar ataxia type 42 | c4225205 | 2,671 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=458803 | 2021-01-23T17:28:52 | {"omim": ["616795"], "icd-10": ["G11.8"], "synonyms": ["SCA42"]} |
Human parainfluenza viruses
Transmission electron micrograph of a parainfluenza virus. Two intact particles and free filamentous nucleocapsid
Scientific classification
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Negarnaviricota
Class: Monjiviricetes
Order: Mononegavirales
Family: Paramyxoviridae
Groups included
* Respirovirus (part)
* Human respirovirus 1 (formerly Human parainfluenza virus 1)
* Human respirovirus 3 (formerly Human parainfluenza virus 3)
* Rubulavirus (part)
* Human rubulavirus 2 (formerly Human parainfluenza virus 2)
* Human rubulavirus 4 (formerly Human parainfluenza virus 4)[1]
Cladistically included but traditionally excluded taxa
* Aquaparamyxovirus
* Avulavirus
* Ferlavirus
* Henipavirus
* Morbillivirus
* Respirovirus (part)
* Bovine respirovirus 3
* Murine respirovirus
* Porcine respirovirus 1
* Rubulavirus (part)
* Achimota rubulavirus 1
* Achimota rubulavirus 2
* Bat mumps rubulavirus
* Mammalian rubulavirus 5
* Mapuera rubulavirus
* Menangle rubulavirus
* Mumps rubulavirus
* Porcine rubulavirus
* Simian rubulavirus
* Sosuga rubulavirus
* Teviot rubulavirus
* Tioman rubulavirus
* Tuhoko rubulavirus 1
* Tuhoko rubulavirus 2
* Tuhoko rubulavirus 3
* Pneumoviridae
* Rhabdoviridae
* Sunviridae
* Xinmoviridae
Human parainfluenza viruses (HPIVs) are the viruses that cause human parainfluenza. HPIVs are a paraphyletic group of four distinct single-stranded RNA viruses belonging to the Paramyxoviridae family. These viruses are closely associated with both human and veterinary disease.[2] Virions are approximately 150–250 nm in size and contain negative sense RNA with a genome encompassing about 15,000 nucleotides.[3]
Fusion glycoprotein trimer, Human parainfluenza virus 3 (hPIV3).
The viruses can be detected via cell culture, immunofluorescent microscopy, and PCR.[4] HPIVs remain the second main cause of hospitalisation in children under 5 years of age suffering from a respiratory illness (only Human orthopneumovirus (Respiratory syncytial virus (RSV)) causes more respiratory hospitalisations for this age group).[5]
## Contents
* 1 Classification
* 1.1 Viral structure and organisation
* 1.2 Viral entry and replication
* 1.3 Host range
* 2 Clinical significance
* 2.1 Airway inflammation
* 2.2 Immunology
* 3 Diagnosis
* 4 Morbidity and mortality
* 4.1 Risk factors
* 5 Prevention
* 6 Medication
* 7 Interactions with the environment
* 8 Economic burden
* 9 References
* 10 Further reading
* 11 External links
## Classification[edit]
The first HPIV was discovered in the late 1950s. The taxonomic division is broadly based on antigenic and genetic characteristics, forming four major serotypes or clades, which today are considered distinct viruses.[6] These include:
Virus GenBank acronym NCBI taxonomy Notes
Human parainfluenza virus type 1 HPIV-1 12730 Most common cause of croup
Human parainfluenza virus type 2 HPIV-2 11212 Causes croup and other upper and lower respiratory tract illnesses
Human parainfluenza virus type 3 HPIV-3 11216 Associated with bronchiolitis and pneumonia
Human parainfluenza virus type 4 HPIV-4 11203 Includes subtypes 4a and 4b
HPIVs belong to two genera: Respirovirus (HPIV-1 & HPIV-3) and Rubulavirus (HPIV-2 & HPIV-4).[3]
### Viral structure and organisation[edit]
hPIVs are characterised by producing enveloped virions and containing single stranded negative sense RNA.[3] Non-infectious virions have also been reported to contain RNA with positive polarity.[3] HPIV genomes are about 15,000 nucleotides in length and encode six key structural proteins.[3]
The structural gene sequence of HPIVs is as follows: 3′-NP-P-M-F-HN-L-5′ (the protein prefixes and further details are outlined in the table below).[7]
Structural protein Location Function
Hemagglutinin-neuraminidase (HN) Envelope Attachment and cell entry
Fusion Protein (F) Envelope Fusion and cell entry
Matrix Protein (M) Within the envelope Assembly
Nucleoprotein (NP) Nucleocapsid Forms a complex with the RNA genome
Phosphoprotein (P) Nucleocapsid Forms as part of RNA polymerase complex
Large Protein (L) Nucleocapsid Forms as part of RNA polymerase complex
With the advent of reverse genetics, it has been found that the most efficient human parainfluenza viruses (in terms of replication and transcription) have a genome nucleotide total that is divisible by the number 6. This has led to the "rule of six" being coined. Exceptions to this rule have been found and its exact advantages are not fully understood.[8]
Electrophoresis has shown that the molecular weight (MW) of the proteins for the four HPIVs are similar (with the exception of the phosphoprotein, which shows significant variation).[3][9]
### Viral entry and replication[edit]
Viral replication is initiated only after successful entry into a cell by attachment and fusion between the virus and the host cell lipid membrane. Viral RNA (vRNA) is initially associated with nucleoprotein (NP), phosphoprotein (P) and the large protein (L). The hemagglutinin–neuraminidase (HN) is involved with viral attachment and thus hemadsorption and hemagglutination. Furthermore, the fusion (F) protein is important in aiding the fusion of the host and viral cellular membranes, eventually forming syncytia.[10]
Initially the F protein is in an inactive form (F0) but can be cleaved by proteolysis to form its active form, F1 and F2, linked by di-sulphide bonds. Once complete, this is followed by the HPIV nucleocapsid entering the cytoplasm of the cell. Subsequently, genomic transcription occurs using the viruses own 'viral RNA-dependent RNA polymerase' (L protein). The cell's own ribosomes are then tasked with translation, forming the viral proteins from the viral mRNA.[10]
Towards the end of the process, (after the formation of the viral proteins) the replication of the viral genome occurs. Initially, this occurs with the formation of a positive-sense RNA (intermediate step, necessary for producing progeny), and finally, negative-sense RNA is formed which is then associated with the nucleoprotein. This may then be either packaged and released from the cell by budding or used for subsequent rounds of transcription and replication.[11]
The observable and morphological changes that can be seen in infected cells include the enlargement of the cytoplasm, decreased mitotic activity and 'focal rounding', with the potential formation of multi-nucleate cells (syncytia).[12]
The pathogenicity of HPIVs is mutually dependent on the viruses having the correct accessory proteins that are able to elicit anti-interferon properties. This is a major factor in the clinical significance of disease.[11]
### Host range[edit]
The main host remains the human. However, infections have been induced in other animals (both under natural and experimental situations), although these were always asymptomatic.[13]
## Clinical significance[edit]
It is estimated that there are 5 million children with lower respiratory infections (LRI) each year in the United States alone.[14] HPIV-1, HPIV-2 and HPIV-3 have been linked with up to a third of these infections.[15] Upper respiratory infections (URI) are also important in the context of HPIV, however, they are caused to a lesser extent by the virus.[16] The highest rates of serious HPIV illnesses occur among young children, and surveys have shown that about 75% of children aged 5 or older have antibodies to HPIV-1.
For infants and young children, it has been estimated that about 25% will develop "clinically significant disease".[17]
Repeated infection throughout the life of the host is not uncommon and symptoms of later breakouts include upper respiratory tract illness, such as cold and a sore throat.[3] The incubation period for all four serotypes is 1 to 7 days.[18] In immunosuppressed people, parainfluenza virus infections can cause severe pneumonia, which can be fatal.[19]
HPIV-1 and HPIV-2 have been demonstrated to be the principal causative agent behind croup (laryngotracheobronchitis), which is a viral disease of the upper airway and is mainly problematic in children aged 6–48 months of age.[20][21] Biennial epidemics starting in Autumn are associated with both HPIV-1 and 2; however, HPIV-2 can also have yearly outbreaks.[14] Additionally, HPIV-1 tends to cause biennial outbreaks of croup in the Fall. In the United States, large peaks have presently been occurring during odd-numbered years.
HPIV-3 has been closely associated with bronchiolitis and pneumonia and principally targets those aged <1 year.[22]
HPIV-4 remains infrequently detected. However, it is now believed to be more common than previously thought, but is less likely to cause severe disease. By the age of 10, the majority of children are sero-positive for HPIV-4 infection which may be indicative of a large proportion of asymptomatic or mild infections.[3]
Important epidemiological factors that are associated with a higher risk of infection and mortality are those who are immuno-compromised and may be taken ill with more extreme forms of LRI.[13] Associations between HPIVs and neurologic disease are known; for example, hospitalisation with certain HPIVs has a strong association with febrile seizures.[23] HPIV-4B has the strongest association (up to 62%) followed by hPIV-3 and -1.[3]
HPIVs have also been linked with rare cases of virally caused meningitis[24] and Guillain–Barré syndrome.[12]
HPIVs are spread from person to person ('horizontal transmission') by contact with infected secretions through respiratory droplets or contaminated surfaces or objects. Infection can occur when infectious material contacts mucous membranes of the eyes, mouth, or nose, and possibly through the inhalation of droplets generated by a sneeze or cough. HPIVs can remain infectious in airborne droplets for over an hour.
Overall, HPIVs remain best known for its effects on the respiratory system and this appears to be where the majority of the focus has been upon.
### Airway inflammation[edit]
The inflammation of the airway is a common attribute of HPIV infection. It is believed to occur due to the large scale up-regulation of inflammatory cytokines. Common cytokines, expected to be up-regulated, include IFN–α, various other interleukins (IL–2, IL-6) and TNF–α. Various chemokines and inflammatory proteins are also believed to be associated with the common symptoms of HPIV infection.[12]
Recent evidence seems to suggest that virus-specific antibodies (IgE) may be responsible for mediating large-scale releases of histamine in the trachea, which are believed to cause croup.[12] More detail on the pathways and interactions can be found here.
### Immunology[edit]
The body's primary defense against HPIV infection remains humoral immunity. This is mainly directed against surface proteins which can be found on the virus. In particular the proteins HN and F prove to be most immunogenic in terms of stimulating the immune system.[12]
Recently the importance of the 'cell mediated immune system' has been scrutinized. Reports have shown that those with defective adaptive immune responses are at a higher risk of severe infection.[12]
## Diagnosis[edit]
Diagnosis can be made in several ways, encompassing a range of multi-faceted techniques:[4]
* Isolation and detection of the virus in cell culture.
* Detection of viral antigens directly within bodily respiratory tract secretions using immunofluorescence, enzyme immunoassays or fluoroimmunoassays.
* Polymerase chain reaction (PCR).
* Analysis of specific IgG antibodies showing a subsequent rise in titre following infection (using paired serum specimens).
Because of the similarity in terms of the antigenic profile between the viruses, hemagglutination assay (HA) or hemadsorption inhibition (HAdI) processes are often used. Both complement fixation, neutralisation and enzyme linked immunosorbent assays – ELISA, can also be used to aid in the process of distinguishing between viral serotypes.[3]
## Morbidity and mortality[edit]
Mortality caused by HPIVs in developed regions of the world remains rare. Where mortality has occurred, it is principally in the three core risk groups (very young, elderly and immuno-compromised). Long term changes can however be associated with airway remodelling and are believed to be a significant cause of morbidity.[25] The exact associations between HPIVs and diseases such as chronic obstructive pulmonary disease (COPD) are still being investigated.[26]
In developing regions of the world, preschool children remain the highest mortality risk group. Mortality may be a consequence of primary viral infection or secondary problems such as bacterial infection. Predispositions, such as malnutrition and other deficiencies may further elevate the chances of mortality associated with infection.[12]
Overall, LRI's cause approximately 25–30% of total deaths in preschool children in the developing world. HPIVs is believed to be associated with 10% of all LRI cases, thus remaining a significant cause of mortality.[12]
### Risk factors[edit]
Numerous factors have been suggested and linked to a higher risk of acquiring the infection, inclusive of malnutrition, vitamin A deficiency, absence of breastfeeding during the early stages of life, environmental pollution and overcrowding.[27]
## Prevention[edit]
Despite decades of research, no vaccines currently exist.[28]
Recombinant technology has however been used to target the formation of vaccines for HPIV-1, -2 and -3 and has taken the form of several live-attenuated intranasal vaccines. Two vaccines in particular were found to be immunogenic and well tolerated against HPIV-3 in phase I trials. HPIV-1 and -2 vaccine candidates remain less advanced.[17]
Vaccine techniques which have been used against HPIVs are not limited to intranasal forms, but also viruses attenuated by cold passage, host range attenuation, chimeric construct vaccines and also introducing mutations with the help of reverse genetics to achieve attenuation.[29]
Maternal antibodies may offer some degree of protection against HPIVs during the early stages of life via the colostrum in breast milk.[30]
## Medication[edit]
Ribavirin is one medication which has shown good potential for the treatment of HPIV-3 given recent in-vitro tests (in-vivo tests show mixed results).[12] Ribavirin is a broad-spectrum antiviral, and is currently being administered to those who are severely immuno-compromised, despite the lack of conclusive evidence for its benefit.[12] Protein inhibitors and novel forms of medication have also been proposed to relieve the symptoms of infection.[13]
Furthermore, antibiotics may be used if a secondary bacterial infection develops. Corticosteroid treatment and nebulizers are also a first line choice against croup if breathing difficulties ensue.[12]
## Interactions with the environment[edit]
Parainfluenza viruses last only a few hours in the environment and are inactivated by soap and water. Furthermore, the virus can also be easily destroyed using common hygiene techniques and detergents, disinfectants and antiseptics.[4]
Environmental factors which are important for HPIV survival are pH, humidity, temperature and the medium within which the virus is found. The optimal pH is around the physiologic pH values (7.4 to 8.0), whilst at high temperatures (above 37 °C) and low humidity, infectivity reduces.[31]
The majority of transmission has been linked to close contact, especially in nosocomial infections. Chronic care facilities and doctors' surgeries are also known to be transmission 'hotspots' with transmission occurring via aerosols, large droplets and also fomites (contaminated surfaces).[32]
The exact infectious dose remains unknown.[13]
## Economic burden[edit]
In the poorest regions of the world, HPIV infection can be measured in terms of mortality. In the developed world where mortality remains rare, the economic costs of the infection can be estimated. Estimates from the US are suggestive of a cost (based on extrapolation) in the region of $200 million per annum.[3]
## References[edit]
1. ^ "Virus Taxonomy: 2018 Release". International Committee on Taxonomy of Viruses (ICTV). October 2018. Retrieved 25 January 2019.
2. ^ Vainionpää R, Hyypiä T (April 1994). "Biology of parainfluenza viruses". Clin. Microbiol. Rev. 7 (2): 265–275. doi:10.1128/CMR.7.2.265. PMC 358320. PMID 8055470.
3. ^ a b c d e f g h i j k Henrickson, KJ (April 2003). "Parainfluenza viruses". Clinical Microbiology Reviews. 16 (2): 242–264. doi:10.1128/CMR.16.2.242-264.2003. PMC 153148. PMID 12692097.
4. ^ a b c "Human Parainfluenza Viruses". Centers for Disease Control and Prevention (2011). Archived from the original on 20 March 2012. Retrieved 21 March 2012.
5. ^ Schmidt, Alexander; Anne Schaap-Nutt; Emmalene J Bartlett; Henrick Schomacker; Jim Boonyaratanakornkit; Ruth A Karron; Peter L Collins (1 February 2011). "Progress in the development of human parainfluenza virus vaccines". Expert Review of Respiratory Medicine. 5 (4): 515–526. doi:10.1586/ers.11.32. PMC 3503243. PMID 21859271.
6. ^ "Paramyxoviruses". Parainfluenza Viruses. University of Texas Medical Branch at Galveston. 1996. ISBN 9780963117212. Retrieved 2009-03-15.
7. ^ Hunt, Dr. Margaret. "PARAINFLUENZA, RESPIRATORY SYNCYTIAL AND ADENO VIRUSES". Reference.MD. Retrieved 21 March 2012.
8. ^ Vulliémoz, D; Roux, L (May 2001). "'Rule of six': how does the Sendai virus RNA polymerase keep count?". Journal of Virology. 75 (10): 4506–4518. doi:10.1128/JVI.75.10.4506-4518.2001. PMC 114204. PMID 11312321.
9. ^ Henrickson, K. J (2003). "Parainfluenza Viruses". Clinical Microbiology Reviews. 16 (2): 242–264. doi:10.1128/CMR.16.2.242-264.2003. PMC 153148. PMID 12692097.
10. ^ a b Moscona, A (July 2005). "Entry of parainfluenza virus into cells as a target for interrupting childhood respiratory disease". The Journal of Clinical Investigation. 115 (7): 1688–1698. doi:10.1172/JCI25669. PMC 1159152. PMID 16007245.
11. ^ a b Chambers R, Takimoto T (2011). Parainfluenza Viruses. eLS. Wiley. doi:10.1002/9780470015902.a0001078.pub3. ISBN 978-0470016176.
12. ^ a b c d e f g h i j k "Parainfluenza Virus: Epidemiology". eMedicine. Retrieved 21 March 2012.
13. ^ a b c d "HUMAN PARAINFLUENZA VIRUS". Public Health Agency of Canada. 2011-04-19. Retrieved 21 March 2012.
14. ^ a b Henrickson, KJ; Kuhn, SM; Savatski, LL (May 1994). "Epidemiology and cost of infection with human parainfluenza virus types 1 and 2 in young children". Clinical Infectious Diseases. 18 (5): 770–9. doi:10.1093/clinids/18.5.770. PMID 8075269.
15. ^ Denny, FW; Clyde WA, Jr (May 1986). "Acute lower respiratory tract infections in nonhospitalized children". The Journal of Pediatrics. 108 (5 Pt 1): 635–46. doi:10.1016/S0022-3476(86)81034-4. PMID 3009769.
16. ^ "Acute Respiratory Infections". WHO. Retrieved 21 March 2012.
17. ^ a b Durbin, AP; Karron, RA (December 15, 2003). "Progress in the development of respiratory syncytial virus and parainfluenza virus vaccines". Clinical Infectious Diseases. 37 (12): 1668–1677. doi:10.1086/379775. PMID 14689350.
18. ^ "General information: human parainfluenza viruses". Health Protection Agency. Retrieved 21 March 2012.
19. ^ Sable CA, Hayden FG (December 1995). "Orthomyxoviral and paramyxoviral infections in transplant patients". Infect. Dis. Clin. North Am. 9 (4): 987–1003. PMID 8747776.
20. ^ "CDC - Human Parainfluenza Viruses: Common cold and croup". Archived from the original on 2009-03-03. Retrieved 2009-03-15.
21. ^ "Croup Background". Medscape Reference. Retrieved 21 March 2012.
22. ^ "Parainfluenza Virus Review". Medscape. Retrieved 21 March 2012.
23. ^ Stephen B Greenberg; Robert L Atmar. "Parainfluenza Viruses—New Epidemiology and Vaccine Developments". Touch Infectious Disease. Retrieved 21 March 2012.
24. ^ Arguedas, A; Stutman, HR; Blanding, JG (March 1990). "Parainfluenza type 3 meningitis. Report of two cases and review of the literature". Clinical Pediatrics. 29 (3): 175–178. doi:10.1177/000992289002900307. PMID 2155085. S2CID 25043753.
25. ^ Dimopoulos, G; Lerikou, M; Tsiodras, S; Chranioti, A; Perros, E; Anagnostopoulou, U; Armaganidis, A; Karakitsos, P (February 2012). "Viral epidemiology of acute exacerbations of chronic obstructive pulmonary disease". Pulmonary Pharmacology & Therapeutics. 25 (1): 12–8. doi:10.1016/j.pupt.2011.08.004. PMC 7110842. PMID 21983132.
26. ^ Beckham, JD; Cadena, A; Lin, J; Piedra, PA; Glezen, WP; Greenberg, SB; Atmar, RL (May 2005). "Respiratory viral infections in patients with chronic, obstructive pulmonary disease". The Journal of Infection. 50 (4): 322–30. doi:10.1016/j.jinf.2004.07.011. PMC 7132437. PMID 15845430.
27. ^ Berman, S (May–Jun 1991). "Epidemiology of acute respiratory infections in children of developing countries". Reviews of Infectious Diseases. 13 Suppl 6: S454–62. doi:10.1093/clinids/13.supplement_6.s454. PMID 1862276.
28. ^ Sato M, Wright PF (October 2008). "Current status of vaccines for parainfluenza virus infections". Pediatr. Infect. Dis. J. 27 (10 Suppl): S123–5. doi:10.1097/INF.0b013e318168b76f. PMID 18820572.
29. ^ "Parainfluenza Viruses". eLS. Retrieved 21 March 2012.
30. ^ "Definition of Human parainfluenza virus". MedicineNet. Retrieved 21 March 2012.
31. ^ HAMBLING, MH (December 1964). "Survival of the Respiratory Syncytial Virus During Storage Under Various Conditions". British Journal of Experimental Pathology. 45 (6): 647–55. PMC 2093680. PMID 14245166.
32. ^ "Common Cold, Croup and Human Parainfluenza Viruses: Symptoms and Prevention". NewsFlu. Retrieved 21 March 2012.
## Further reading[edit]
* Henrickson KJ (2003). "Parainfluenza viruses". Clin. Microbiol. Rev. 16 (2): 242–64. doi:10.1128/cmr.16.2.242-264.2003. PMC 153148. PMID 12692097.
* Human Parainfluenza Viruses (HPIVs)
## External links[edit]
* Human Parainfluenza Viruses – information provided by the CDC
Classification
D
* ICD-10: B34.8, J12.2, J20.4
* ICD-9-CM: 480.2
* MeSH: D018184
* DiseasesDB: 30631
External resources
* MedlinePlus: 001370
* v
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*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Human parainfluenza viruses | c0030389 | 2,672 | wikipedia | https://en.wikipedia.org/wiki/Human_parainfluenza_viruses | 2021-01-18T19:02:22 | {"mesh": ["D018184"], "umls": ["C0030389", "C0302507"], "icd-9": ["480.2"], "icd-10": ["B34.8", "J20.4", "J12.2"], "wikidata": ["Q2051533"]} |
Leslie and Pyke (1978) observed CPAF in a mother and her 2 daughters with diabetes mellitus. They were prompted thereby to study the response to chlorpropamide and alcohol (in the form of sherry) in noninsulin-dependent diabetics (sometimes known as maturity-onset or type 2), in insulin-dependent diabetics (sometimes known as juvenile-onset or type 1), and in normals. CPAF was common in the first group and rare in the other two. Twin and family studies supported autosomal dominant inheritance. In a second study, Pyke and Leslie (1978) concluded that the CPAF test detects noninsulin-dependent diabetes before the onset of glucose intolerance. About one-fifth of all cases of noninsulin-dependent diabetes showed CPAF. Thus, a special subclass was identified. They called this the Mason type after the first family they observed (see 125850). They observed CPAF-positive families in which onset of diabetes was late (after 30) and concluded that they represent the same disorder. Known by the trade name Diabinase, chlorpropamide is an oral hypoglycemic. The sulfonylurea oral hypoglycemic agents other than chlorpropamide do not have a flushing effect when taken with alcohol. Retinopathy (see 603933) is less prevalent and less severe in patients with the flushing reaction (Leslie et al., 1979). The flush can be reproduced in susceptible persons by infusion of a met-enkephalin analog and blocked by naloxone (Leslie et al., 1979). Facial temperature before the flush is lower in flushers than in nonflushers (Leslie et al., 1979). Nondiabetic relatives of diabetic flushers may show the same phenomenon. Aspirin suppresses the flush (Strakosch et al., 1980). A prostaglandin-dependent step in the mechanism of the flush was postulated.
Inheritance \- Autosomal dominant Misc \- Occurs in about one-fifth of noninsulin-dependent diabetics \- Diabetic retinopathy less prevalent and less severe Skin \- Alcohol induced flushing \- Chlorpropamide induced flushing ▲ 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
| CHLORPROPAMIDE-ALCOHOL FLUSHING | c1861630 | 2,673 | omim | https://www.omim.org/entry/118430 | 2019-09-22T16:43:22 | {"mesh": ["C566132"], "omim": ["118430"]} |
Lowry (1972) described brothers with this combination. The parents were related. Lowry (1993) provided a follow-up of one of the brothers at the age of 25 years. He was of average intelligence and had completed 2 years of college. He showed markedly hypoplastic calves.
INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Craniosynostosis SKELETAL Limbs \- Fibular aplasia ▲ 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
| CRANIOSYNOSTOSIS WITH FIBULAR APLASIA | c1857492 | 2,674 | omim | https://www.omim.org/entry/218550 | 2019-09-22T16:29:14 | {"mesh": ["C565665"], "omim": ["218550"], "orphanet": ["1533"]} |
A number sign (#) is used with this entry because this form of Zellweger syndrome (PBD5A) is caused by homozygous mutation in the PEX2 gene (170993) on chromosome 8q21.
Description
The peroxisomal biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006).
For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100.
Individuals with PBDs of complementation group 5 (CG5, equivalent to CG10 and CGF) have mutations in the PEX2 gene. For information on the history of PBD complementation groups, see 214100.
Clinical Features
Shimozawa et al. (1992) studied a Japanese girl (M.M.), aged 8 months, with typical clinical findings of Zellweger syndrome as well as accumulation of very long chain fatty acids in serum, absence of liver homogenates in all 3 peroxisomal beta-oxidation enzymes, absent peroxisomes in skin fibroblasts, and, at autopsy, macrogyria and polymicrogyria in the brain, hepatosplenomegaly, and many small cysts in the renal cortices bilaterally.
Molecular Genetics
In a Japanese patient (M.M.) with Zellweger syndrome, Shimozawa et al. (1992) identified a homozygous nonsense mutation in the PEX2 gene (170993.0001). Shimozawa et al. (1993) identified this mutation in a Dutch patient with Zellweger syndrome.
In 3 patients with Zellweger syndrome, Gootjes et al. (2004) identified homozygous mutations in the PEX2 gene (170993.0001-170993.0003).
INHERITANCE \- Autosomal recessive GROWTH Other \- Prenatal growth failure \- Failure to thrive HEAD & NECK Head \- High forehead \- Dolichoturricephaly Face \- Micrognathia \- Flat face \- Round face Ears \- Low set ears \- Helix abnormal Eyes \- Puffy lids \- Hypertelorism \- Epicanthic folds \- Brushfield spots \- Cloudy cornea \- Cataracts \- Pigmentary retinopathy \- Optic nerve dysplasia Mouth \- Cleft palate CARDIOVASCULAR Heart \- Congenital heart defect ABDOMEN Liver \- Intrahepatic biliary dysgenesis \- Hepatomegaly Spleen \- Splenomegaly Gastrointestinal \- Poor suck GENITOURINARY External Genitalia (Female) \- Clitoromegaly Internal Genitalia (Male) \- Cryptorchidism Kidneys \- Multiple small renal cortical cysts SKELETAL \- Stippled chondral calcification \- Chondrodysplasia punctata Skull \- Large fontanels Limbs \- Cubitus valgus Hands \- Camptodactyly \- Transverse palmar crease Feet \- Metatarsus adductus \- Talipes equinovarus SKIN, NAILS, & HAIR Skin \- Jaundice NEUROLOGIC Central Nervous System \- Macrogyria \- Polymicrogyria \- Mental retardation \- Seizures \- Absent Moro response \- Hypotonia \- Areflexia LABORATORY ABNORMALITIES \- Accumulation of very-long-chain fatty acids in serum \- Absent peroxisomes in skin fibroblasts MISCELLANEOUS \- Death in infancy or early childhood MOLECULAR BASIS \- Caused by mutation in the peroxisome biogenesis factor 2 gene (PEX2, 170993.0001 ) ▲ Close
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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
| PEROXISOME BIOGENESIS DISORDER 5A (ZELLWEGER) | c0043459 | 2,675 | omim | https://www.omim.org/entry/614866 | 2019-09-22T15:53:57 | {"doid": ["0080480"], "mesh": ["D015211"], "omim": ["614866"], "orphanet": ["912"]} |
Grant syndrome is a rare osteogenesis imperfecta-like disorder, described in two patients to date, characterized clinically by persistent wormian bones, blue sclera, mandibular hypoplasia, shallow glenoid fossa, and campomelia. There have been no further descriptions in the literature since 1986.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Grant syndrome | c1841835 | 2,676 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2097 | 2021-01-23T18:00:34 | {"gard": ["2559"], "mesh": ["C537293"], "omim": ["138930"], "umls": ["C1841835"], "icd-10": ["Q87.5"]} |
Sickle cell retinopathy
SpecialtyOphthalmology
ComplicationsBlindness
CausesSickle cell disease
Risk factorsHeredity
Diagnostic methodEye examination
TreatmentMedical, laser and surgery
Sickle cell retinopathy is a major ocular complication of the sickle cell disease (SCD) which causes permanent loss of vision. Retinopathy can occur in sickling hemoglobinopathies like sickle cell disease, sickle cell C disease, and sickle cell thalassaemia disease.[1]
## Contents
* 1 Classification
* 1.1 Non-proliferative sickle cell retinopathy (NPSCR)
* 1.2 Proliferative sickle cell retinopathy (PSCR)
* 1.2.1 Goldberg classification[4]
* 2 Signs and symptoms
* 3 Cause
* 4 Diagnosis
* 4.1 Differential diagnosis
* 5 Prevention
* 6 Treatment
* 6.1 Medical
* 6.2 Laser
* 6.3 Surgery
* 7 References
## Classification[edit]
Sickle cell retinopathy can be classified as non-proliferative or proliferative forms.
### Non-proliferative sickle cell retinopathy (NPSCR)[edit]
The retinal changes in non-proliferative sickle cell retinopathy or background sickle cell retinopathy occur secondary to retinal ischemia due to vascular occlusion. Ocular manifestations NPSCR includes venous tortuosity, salmon-patches, schisis cavity, iridescent spots and the black sunburst spots.[2]
* Arteriovenous shunting from the retinal periphery may cause venous tortuosity.[3] Since the same occur in many other ocular diseases, it has no diagnostic value.[2]
* Salmon patches occur due to retinal hemorrhages, especially in mid-peripheral retina, adjacent to a retinal arteriole.[4] Since they are located in peripheral retina, there will not be any visual symptoms.
* The schisis cavity represents the space created by the reconstruction of the intra-retinal portion of the hemorrhage. The refractive bodies that glow in the schisis cavity are known as iridescent spots.
* Migration and proliferation of retinal pigment epithelium may cause black sunburst spots.[4] Since sunburst spots are also located in peripheral retina, these lesions usually do not produce any visual symptoms.[2]
* Angioid streaks: Angioid streaks may be seen in up to 6% of cases.[1]
### Proliferative sickle cell retinopathy (PSCR)[edit]
Proliferative sickle retinopathy is the most severe ocular complication of sickle cell disease. Even though PSCR begins in the first decade of life, the condition remains asymptomatic and unnoticed until visual symptoms occur due to vitreous hemorrhage or retinal detachment.[5]
#### Goldberg classification[4][edit]
Goldberg classified PSR into following 5 different self-explanatory stages:
1. Stage of peripheral arterial occlusion and ischemia: It is the earliest abnormality that can be visualized by fundus examination. The occluded arterioles can be seen as dark red lines. They eventually turn into white silver-wire vessels.[2]
2. Stage of peripheral arteriolar-venular anastomoses: Arteriolar-venular anastomoses develop as blood is diverted from blocked arteries to nearby venules.
3. Stage of neovascularization and fibrous proliferation: Neovascularization starts from the arteriolar-venular anastomoses, and grow into the ischemic retina. Characteristic fan-shaped appearance due to neovasularization is known as sea fan neovascularization.[2]
4. Stage of vitreous hemorrhage. Peripheral neovascular tufts bleed and cause vitreous hemorrhage.
5. Stage of vitreoretinal traction bands and tractional retinal detachment: Traction on the sea fan and adjacent retina causes traction retinal detachment.
## Signs and symptoms[edit]
* Comma sign: Comma shaped vessels in the bulbar conjunctiva is due to vascular occlusion of conjunctival vessels.[4]
* Vitreoretinal traction or retinal detachment cause flashes, floaters or dark shadows.[4]
* Sudden loss of vision may occur due to retinal artery occlusion, vitreous hemorrhage or retinal detachment.
* Intravascular occlusions may be seen in optic disc vessels.[2]
## Cause[edit]
Normal adult hemoglobin A molecule comprises two α and two β globin chains associated with a heme ring. Mutation at the 6th position of the beta chain is the cause of sickle cell disease.[4] Due to sickle cell disease, vascular occlusion may occur in the conjunctiva, iris, retina, or choroid. Retinal changes occur due to blockage of retinal blood vessels by abnormal RBCs.[6]
## Diagnosis[edit]
Diagnosisis usually done in a multidiciplinary manner. Patient may have history of sickle cell disease. External eye examination may show comma sign in the conjunctiva. Vascular changes in the retina and choroid can be diagnosed by ophthalmoscopy, fluorescein angiography or indocyanine green angiography. Combination of OCT and angiography is considered as a gold standard in detecting retinal ischemia in patients with sickle cell disease.[7]
### Differential diagnosis[edit]
Sickle cell retinopathy should be differentiated from other retinal conditions like:
* Diabetic retinopathy
* Retinal vascular occlusions like Central retinal vein occlusion (CRVO), Branch retinal vein occlusion (BRVO) etc.
* Retinopathy of prematurity (ROP)
* Eales disease
* Familial exudative vitreoretinopathy
* Chronic myelogenous leukemia
* Scleral buckle
## Prevention[edit]
To prevent blindness due to sickle cell retinopathy, complete ophthalmic examination twice a year is recommended for all sickle cell patients.[4] Since the use of carbonic anhydrase inhibitors increase the chance of sickling and vascular occlusions, its use is contraindicated in sickle cell patients.[1]
## Treatment[edit]
### Medical[edit]
Hydroxycarbamide may be used to prevent sickle cell retinopathy in children.[4] Intravitreal injection of anti-vascular endothelial growth factor may be used to treat neovascularization.[4]
### Laser[edit]
Laser photocoagulation is the most widely used treatment method in proliferative sickle cell retinopathy. Argon laser or xenon laser photocoagulation is used in sea fan treatment.[5]
### Surgery[edit]
Surgical procedures may be performed to treat complications like retinal detachments, nonclearing vitreous hemorrhage, and epiretinal membranes.[3] Pars plana vitrectomy may be advised in complications like vitreous hemorrhage and retinal detachment.[7]
## References[edit]
1. ^ a b c John F, Salmon (13 December 2019). "Retinal vascular disease". Kanski's clinical ophthalmology : a systematic approach (9th ed.). p. 533. ISBN 978-0-7020-7711-1.
2. ^ a b c d e f "Sickle-Cell Retinopathy". Albert & Jakobiec's principles and practice of ophthalmology (3rd ed.). Saunders Elsevier. ISBN 9781416000167.
3. ^ a b "Ophthalmologic Manifestations of Sickle Cell Disease (SCD)". 21 November 2019.
4. ^ a b c d e f g h i "Sickle Cell Retinopathy". eyewiki.aao.org.
5. ^ a b Bonanomi, Maria Teresa Brizzi Chizzotti; Lavezzo, Marcelo Mendes (October 2013). "Sickle cell retinopathy: diagnosis and treatment". Arquivos Brasileiros de Oftalmologia. 76 (5): 320–327. doi:10.1590/S0004-27492013000500016. PMID 24232951.
6. ^ Khurana, AK (2015). "Diseases of Retina". Comprehensive ophthalmology (6th ed.). Jaypee, The Health Sciences Publisher. ISBN 978-93-86056-59-7.
7. ^ a b Menaa, Farid; Khan, Barkat Ali; Uzair, Bushra; Menaa, Abder (30 August 2017). "Sickle cell retinopathy: improving care with a multidisciplinary approach". Journal of Multidisciplinary Healthcare. 10: 335–346. doi:10.2147/JMDH.S90630. ISSN 1178-2390. PMC 5587171. PMID 28919773.
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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
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*[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
| Sickle cell retinopathy | c0339491 | 2,677 | wikipedia | https://en.wikipedia.org/wiki/Sickle_cell_retinopathy | 2021-01-18T18:43:30 | {"umls": ["C0339491"], "wikidata": ["Q97403851"]} |
Extrapyramidal symptoms
Other namesExtrapyramidal side effects (EPSE)
SpecialtyNeurology
Extrapyramidal symptoms (EPS), also known as extrapyramidal side effects (EPSE) is drug-induced movement disorders, which include acute and long-term symptoms. These symptoms include dystonia (continuous spasms and muscle contractions), akathisia (may manifest as motor restlessness),[1] parkinsonism characteristic symptoms such as rigidity, bradykinesia (slowness of movement), tremor, and tardive dyskinesia (irregular, jerky movements).[2] Extrapyramidal symptoms are a reason why subjects drop out of clinical trials of antipsychotics; of the 213 (14.6%) subjects that dropped out of one of the largest clinical trials of antipsychotics (the CATIE trial(Clinical Antipsychotic trials for intervention Effectiveness), which included 1460 randomized subjects), 58 (27.2%) of those discontinuations were due to EPS.[3]
## Contents
* 1 Causes
* 1.1 Medications
* 1.2 Non-medication-related
* 2 Diagnosis
* 3 Classification
* 4 Treatment
* 4.1 Dystonia
* 4.2 Akathisia
* 4.3 Pseudoparkinsonism
* 4.4 Tardive dyskinesia
* 5 History
* 6 See also
* 7 References
* 8 External links
## Causes[edit]
### Medications[edit]
Extrapyramidal symptoms are most commonly caused by typical antipsychotic drugs that antagonize dopamine D2 receptors.[2] The most common typical antipsychotics associated with EPS are haloperidol and fluphenazine.[4] Atypical antipsychotics have lower D2 receptor affinity or higher serotonin 5-HT2A receptor affinity which lead to lower rates of EPS.[5]
Other anti-dopaminergic drugs, like the antiemetic metoclopramide, can also result in extrapyramidal side effects.[6] Short and long-term use of antidepressants such as selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), and norepinephrine-dopamine reuptake inhibitors (NDRI) have also resulted in EPS.[7] Specifically, duloxetine, sertraline, escitalopram, fluoxetine, and bupropion have been linked to the induction of EPS.[7]
### Non-medication-related[edit]
Other causes of extrapyramidal symptoms can include brain damage and meningitis.[8] However, the term "extrapyramidal symptoms" generally refers to medication-induced causes in the field of psychiatry.[9]
## Diagnosis[edit]
Since it is difficult to measure extrapyramidal symptoms, rating scales are commonly used to assess the severity of movement disorders. The Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), and Extrapyramidal Symptom Rating Scale (ESRS) are rating scales frequently used for such assessment and are not weighted for diagnostic purposes;[2] these scales can help clinicians weigh the benefit/expected benefit of a medication against the degree of distress which the side effects are causing the patient, aiding in the decision to maintain, reduce, or discontinue the causative medication(s).
## Classification[edit]
* Acute dystonic reactions: painful, muscular spasms of neck, jaw, back, extremities, eyes, throat, and tongue; highest risk in young men.[2][10]
* Oculogyric crisis is a kind of acute dystonic reaction that involves the prolonged involuntary upward deviation of the eyes.
* Akathisia: A feeling of internal motor restlessness that can present as tension, nervousness, or anxiety.[2] Clinical manifestations include pacing and an inability to sit still.[10]
* Pseudoparkinsonism: drug-induced parkinsonism (rigidity, bradykinesia, tremor, masked facies, shuffling gait, stooped posture, sialorrhoea, and seborrhoea; greater risk in the elderly).[2] Although Parkinson's disease is primarily a disease of the nigrostriatal pathway and not the extrapyramidal system, loss of dopaminergic neurons in the substantia nigra leads to dysregulation of the extrapyramidal system. Since this system regulates posture and skeletal muscle tone, a result is the characteristic bradykinesia of Parkinson's.
* Tardive dyskinesia: involuntary muscle movements in the lower face and distal extremities; this can be a chronic condition associated with long-term use of antipsychotics.[2]
## Treatment[edit]
Medications are used to reverse the symptoms of extrapyramidal side effects caused by antipsychotics or other drugs, either by directly or indirectly inhibiting dopaminergic neurotransmission. The treatment varies by the type of the EPS, but may involve anticholinergic agents such as procyclidine, benztropine, diphenhydramine, and trihexyphenidyl, and (rarely) dopamine agonists like pramipexole.
If the EPS are induced by an antipsychotic, EPS may be reduced by decreasing the dose of the antipsychotic or by switching from a typical antipsychotic to an (or to a different) atypical antipsychotic, such as aripiprazole, ziprasidone, quetiapine, olanzapine, risperidone, or clozapine. These medications possess an additional mode of action that is believed to mitigate their effect on the nigrostriatal pathway, which means they are associated with fewer extrapyramidal side-effects than "conventional" antipsychotics (chlorpromazine, haloperidol, etc.)[11]
### Dystonia[edit]
Anticholinergic medications are used to reverse acute dystonia. If the symptoms are particularly severe, the anticholinergic medication may be administered by injection into a muscle to rapidly reverse the dystonia.[9]
### Akathisia[edit]
Certain second-generation antipsychotics, such as lurasidone and the partial D2-agonist aripiprazole, are more likely to cause akathisia compared to other second-generation antipsychotics.[12] If akathisia occurs, switching to an antipsychotic with a lower risk of akathisia may improve symptoms.[13] Beta blockers (like propranolol) are frequently used to treat akathisia. Other medications that are sometimes used include clonidine, mirtazapine, or even benzodiazepines. Anticholinergic medications are not helpful for treating akathisia.[9]
### Pseudoparkinsonism[edit]
Medication interventions are generally reserved for cases in which withdrawing the medication that caused the pseudoparkinsonism is either ineffective or infeasible. Anticholinergic medications are sometimes used to treat pseudoparkinsonism, but they can be difficult to tolerate when given chronically. Amantadine is sometimes used as well. It is rare for dopamine agonists to be used for antipsychotic-induced EPS, as they may exacerbate psychosis.[9]
### Tardive dyskinesia[edit]
When other measures fail or are not feasible, medications are used to treat tardive dyskinesia. These include the vesicular monoamine transporter 2 inhibitors tetrabenazine and deutetrabenazine.[9]
## History[edit]
Extrapyramidal symptoms (also called extrapyramidal side effects) get their name because they are symptoms of disorders in the extrapyramidal system, which regulates posture and skeletal muscle tone. This is in contrast to symptoms originating from the pyramidal tracts.
## See also[edit]
* Neuroleptic malignant syndrome
* Rabbit syndrome
## References[edit]
1. ^ Akagi, Hiroko; Kumar, T Manoj (2002-06-22). "Akathisia: overlooked at a cost". BMJ : British Medical Journal. 324 (7352): 1506–1507. doi:10.1136/bmj.324.7352.1506. ISSN 0959-8138. PMC 1123446. PMID 12077042.
2. ^ a b c d e f g Pierre, JM (2005). "Extrapyramidal symptoms with atypical antipsychotics: incidence, prevention and management". Drug Safety. 28 (3): 191–208. doi:10.2165/00002018-200528030-00002. PMID 15733025. S2CID 41268164.
3. ^ Jeffrey A. Lieberman, M.D.; T. Scott Stroup, M.D., M.P.H.; Joseph P. McEvoy, M.D.; Marvin S. Swartz, M.D.; Robert A. Rosenheck, M.D.; Diana O. Perkins, M.D., M.P.H.; Richard S.E. Keefe, Ph.D.; Sonia M. Davis, Dr.P.H.; Clarence E. Davis, Ph.D.; Barry D. Lebowitz, Ph.D.; Joanne Severe, M.S.; John K. Hsiao, M.D. & for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators (September 22, 2005). "Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia". N Engl J Med. 353 (12): 1209–1223. doi:10.1056/NEJMoa051688. PMID 16172203.
4. ^ Nevena Divac; Milica Prostran; Igor Jakovcevski & Natasa Cerovac (2014). "Second-Generation Antipsychotics and Extrapyramidal Adverse Effects". BioMed Research International. 2014: 6 pages. doi:10.1155/2014/656370. PMC 4065707. PMID 24995318.
5. ^ Correll C (2014). "Mechanism of Action of Antipsychotic Medications". J Clin Psychiatry. 75 (9): e23. doi:10.4088/jcp.13078tx4c.
6. ^ Moos, DD.; Hansen, DJ. (October 2008). "Metoclopramide and Extrapyramidal Symptoms: A Case Report". Journal of PeriAnesthesia Nursing. 23 (5): 292–299. doi:10.1016/j.jopan.2008.07.006. PMID 18926476.
7. ^ a b Madhusoodanan S, Alexeenko L, Sanders R, Brenner R (2010). "Extrapyramidal symptoms associated with antidepressants—A review of the literature and an analysis of spontaneous reports" (PDF). Annals of Clinical Psychiatry. 22 (3): 148–156. PMID 20680187.
8. ^ Ori Scott; Simona Hasal & Helly R. Goez (November 2013) [September 10, 2012]. "Basal Ganglia Injury With Extrapyramidal Presentation: A Complication of Meningococcal Meningitis". J Child Neurol. 28 (11): 1489–1492. doi:10.1177/0883073812457463. PMID 22965562. S2CID 30536341.
9. ^ a b c d e "Involuntary Movement Disorders (Ch. 18)". Kaufman's Clinical Neurology for Psychiatrists (8th ed.). Elsevier Inc.
10. ^ a b "Be Drug Wise: Psychotherapeutic Meds". Educational Global Technologies, Inc. Retrieved 10 September 2020.
11. ^ Michael J. Peluso; Shôn W. Lewis; Thomas R. E. Barnes; Peter B. Jones (2012). "Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs". The British Journal of Psychiatry. 200 (5): 387–92. doi:10.1192/bjp.bp.111.101485. PMID 22442101.
12. ^ E. Thomas, Jennifer; Caballero, Joshua; A. Harrington, Catherine (13 October 2015). "The Incidence of Akathisia in the Treatment of Schizophrenia with Aripiprazole, Asenapine and Lurasidone: A Meta-Analysis". Current Neuropharmacology. 13 (5): 681–691. doi:10.2174/1570159X13666150115220221. PMC 4761637. PMID 26467415.
13. ^ Salem, Haitham; Nagpal, Caesa; Pigott, Teresa; Teixeira, Antonio Lucio (15 June 2017). "Revisiting Antipsychotic-induced Akathisia: Current Issues and Prospective Challenges". Current Neuropharmacology. 15 (5): 789–798. doi:10.2174/1570159X14666161208153644. PMC 5771055. PMID 27928948.
## External links[edit]
Classification
D
* ICD-9-CM: 333.90
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Extrapyramidal symptoms | c0234133 | 2,678 | wikipedia | https://en.wikipedia.org/wiki/Extrapyramidal_symptoms | 2021-01-18T19:02:29 | {"umls": ["C0234133"], "wikidata": ["Q1385411"]} |
Borna disease viruses 1 and 2
SpecialtyVeterinary medicine
Borna disease, also known as sad horse disease,[1] is an infectious neurological syndrome[2] of warm-blooded animals, caused by Borna disease viruses 1 and 2 (BoDV-1/2), both of which are members of the species Mammalian 1 orthobornavirus. BoDV-1 and 2 cause abnormal behaviour and fatality. Borna disease viruses 1 and 2 are neurotropic viruses and members of the Bornaviridae family within the Mononegavirales order.
Although Borna disease viruses 1 and 2 are mainly seen as the causative agent of Borna disease in horses and other animals, they are also controversially discussed as human infectious agents and therefore as potential zoonotic agents. The role of BoDV-1 and -2 in human illness is controversial and it is yet to be established whether BoDV-1 or -2 cause any overt disease in humans. However, correlative evidence exists linking BoDV-1/2 infection with neuropsychiatric disorders such as bipolar disorder.[3]
## Contents
* 1 Animals affected
* 2 Cause
* 2.1 Vectors
* 3 History
* 3.1 Psychiatric disease
* 4 References
* 5 External links
## Animals affected[edit]
Borna diseases viruses 1 and 2 appear to have wide host ranges, having been detected in horses, cattle, sheep, dogs and foxes. In 1995, BoDV-1 was isolated from cats suffering from a "staggering disease" in Sweden. Since that time, BoDV-1 has also been detected in cats in Japan and Britain.
Borna virus has been detected in humans, and researchers have presented evidence connecting these infections with psychiatric disorders.[4][5][6]
Experimental infection of rats has been demonstrated to lead to learning impairments and altered social behaviour. The virus appears to be distributed primarily in the limbic system of the brain, including the hippocampus and entorhinal cortex. These areas of the brain are considered to be of importance in emotion.
Originally identified in sheep and horses[7] in Europe, it has since been found to occur in a wide range of warm-blooded animals including birds, cattle, cats[8] and primates and has been found in animals in Europe, Asia, Africa and North America. The virus name is derived from the town of Borna in Saxony, Germany, which suffered an epidemic of the disease in horses in 1885.
Avian bornaviruses, a group of related viruses, have been reported, yet not proven, as the cause of proventricular dilatation disease (PDD), a disease of pet parrots. The use of a 'positive' brain cell culture containing ABV to inoculate another psittacine (parrot) bird resulted in the inoculated bird's death and subsequent histopathological diagnosis of PDD (mononuclear infiltrative ganglioneuritis). Earlier research with purified avian bornavirus inoculant (while did result in the death of parrots) did not reproduce histopathological changes associated with PDD.[citation needed]
Borna disease in sheep and horses arises after a four-week incubation period followed by the development of immune-mediated meningitis and encephalomyelitis. Clinical manifestations vary but may include excited or depressed behaviour, ataxia, ocular disorders and abnormal posture and movement. Mortality rates are 80-100% in horses and greater than 50% in sheep.
Borna disease in the horse gives rise to signs like:
* Unusual posture, gait and ear positions
* Movement Disturbances (principally ataxia or excess movement)
## Cause[edit]
Orthobornavirus
Virus classification
Group:
Group V ((−)ssRNA)
Order:
Mononegavirales
Family:
Bornaviridae
Genus:
Orthobornavirus
Species
Mammalian 1 orthobornavirus
### Vectors[edit]
The mode of transmission of BoDV-1/2 is unclear but probably occurs through intranasal exposure to contaminated saliva or nasal secretions. Following infection, individuals may develop Borna disease, or may remain subclinical, possibly acting as a carrier of the virus.
## History[edit]
The first antibodies to BoDV-1 in humans were discovered in the mid-1980s. Since then, there have been conflicting results from various studies in regards to whether an association exists between the agent and clinical disease. Antibodies to BoDV-1, which indicate prior infection, and BoDV-1 antigen have also been detected in blood donors.
### Psychiatric disease[edit]
There is some evidence that there may be a relationship between BoDV-1 infection and psychiatric disease.[4][5]
In 1990, Janice E. Clements and colleagues reported in the journal Science that antibodies to a protein encoded by the BoDV-1 genome are found in the blood of patients with behavioral disorders.[6] In the early 1990s, researchers in Germany, America, and Japan conducted an investigation of 5000 patients with psychiatric disorders and 1000 controls, in which a significantly higher percentage of patients than controls were positive for BoDV-1 antibodies.[6] Subsequent studies have also presented evidence for an association between BoDV-1 and human psychiatric disorders.[9][10][11] However, not all researchers consider the link between BoDV-1 and human psychiatric disease to be conclusively proven. A study published in 2003 found no BoDV-1 antibodies in 62 patients with the deficit form of schizophrenia.[12]
Additional evidence for a role of BoDV-1 in psychiatric disorders comes from reports that the drug amantadine, which is used to treat influenza infections, has had some success in treating depression and clearing BoDV-1 infection.[13] Counter-claims state that Borna virus infections are not cleared by amantadine.[citation needed] The issue is further complicated by the fact that amantadine is also used in the treatment of Parkinson's disease and may have direct effects on the nervous system.
## References[edit]
1. ^ Colman, Andrew M. (2009-01-01), "Sad horse disease", A Dictionary of Psychology, Oxford University Press, doi:10.1093/acref/9780199534067.001.0001, ISBN 978-0-19-953406-7, retrieved 2020-01-16
2. ^ Ackermann A, Staeheli P, Schneider U (August 2007). "Adaptation of Borna disease virus to new host species attributed to altered regulation of viral polymerase activity". J. Virol. 81 (15): 7933–40. doi:10.1128/JVI.00334-07. PMC 1951315. PMID 17522214.
3. ^ (Quoted) Liv Bode - Robert Koch Institute, Ron Ferszt - Free University of Berlin (August 31, 1998). "Research suggests virus may play role in depression". CNN Health. Archived from the original on March 3, 2012.
4. ^ a b Bode L, Ludwig H (July 2003). "Borna disease virus infection, a human mental-health risk". Clin. Microbiol. Rev. 16 (3): 534–45. doi:10.1128/CMR.16.3.534-545.2003. PMC 164222. PMID 12857781.
5. ^ a b VandeWoude S, Richt JA, Zink MC, Rott R, Narayan O, Clements JE (November 1990). "A borna virus cDNA encoding a protein recognized by antibodies in humans with behavioral diseases". Science. 250 (4985): 1278–81. Bibcode:1990Sci...250.1278V. doi:10.1126/science.2244211. PMID 2244211.
6. ^ a b c Rott R, Herzog S, Bechter K, Frese K (1991). "Borna disease, a possible hazard for man?". Archives of Virology. 118 (3–4): 143–9. doi:10.1007/BF01314025. PMID 2069502.
7. ^ Dauphin G, Legay V, Pitel PH, Zientara S (2002). "Borna disease: current knowledge and virus detection in France". Vet. Res. 33 (2): 127–38. doi:10.1051/vetres:2002002. PMID 11944803.
8. ^ Kamhieh S, Flower RL (June 2006). "Borna disease virus (BDV) infection in cats. A concise review based on current knowledge". Vet Q. 28 (2): 66–73. doi:10.1080/01652176.2006.9695210. PMID 16841569.
9. ^ Miranda HC, Nunes SO, Calvo ES, Suzart S, Itano EN, Watanabe MA (January 2006). "Detection of Borna disease virus p24 RNA in peripheral blood cells from Brazilian mood and psychotic disorder patients". J Affect Disord. 90 (1): 43–7. doi:10.1016/j.jad.2005.10.008. PMID 16324750.
10. ^ Fukuda K, Takahashi K, Iwata Y, et al. (February 2001). "Immunological and PCR analyses for Borna disease virus in psychiatric patients and blood donors in Japan". J. Clin. Microbiol. 39 (2): 419–29. doi:10.1128/JCM.39.2.419-429.2001. PMC 87754. PMID 11158085.
11. ^ Waltrip RW, Buchanan RW, Carpenter WT, et al. (February 1997). "Borna disease virus antibodies and the deficit syndrome of schizophrenia". Schizophr. Res. 23 (3): 253–7. doi:10.1016/S0920-9964(96)00114-4. PMID 9075304.
12. ^ "Wiley InterScience :: JOURNALS :: Acta Neuropsychiatrica". Archived from the original on 2013-01-05. Retrieved 2009-01-20.
13. ^ Dietrich DE, Bode L, Spannhuth CW, et al. (March 2000). "Amantadine in depressive patients with Borna disease virus (BDV) infection: an open trial". Bipolar Disord. 2 (1): 65–70. doi:10.1034/j.1399-5618.2000.020110.x. PMID 11254023.
## External links[edit]
Classification
D
* ICD-9-CM: 062.9
* MeSH: D001890
* DiseasesDB: 1529
* v
* t
* e
Zoonotic viral diseases (A80–B34, 042–079)
Arthropod
-borne
Mosquito
-borne
Bunyavirales
* Arbovirus encephalitides: La Crosse encephalitis
* LACV
* Batai virus
* BATV
* Bwamba Fever
* BWAV
* California encephalitis
* CEV
* Jamestown Canyon encephalitis
* Tete virus
* Tahyna virus
* TAHV
* Viral hemorrhagic fevers: Rift Valley fever
* RVFV
* Bunyamwera fever
* BUNV
* Ngari virus
* NRIV
Flaviviridae
* Arbovirus encephalitides: Japanese encephalitis
* JEV
* Australian encephalitis
* MVEV
* KUNV
* Saint Louis encephalitis
* SLEV
* Usutu virus
* West Nile fever
* WNV
* Viral hemorrhagic fevers: Dengue fever
* DENV-1-4
* Yellow fever
* YFV
* Zika fever
* Zika virus
Togaviridae
* Arbovirus encephalitides: Eastern equine encephalomyelitis
* EEEV
* Western equine encephalomyelitis
* WEEV
* Venezuelan equine encephalomyelitis
* VEEV
* Chikungunya
* CHIKV
* O'nyong'nyong fever
* ONNV
* Pogosta disease
* Sindbis virus
* Ross River fever
* RRV
* Semliki Forest virus
Reoviridae
* Banna virus encephalitis
Tick
-borne
Bunyavirales
* Viral hemorrhagic fevers: Bhanja virus
* Crimean–Congo hemorrhagic fever (CCHFV)
* Heartland virus
* Severe fever with thrombocytopenia syndrome (Huaiyangshan banyangvirus)
* Tete virus
Flaviviridae
* Arbovirus encephalitides: Tick-borne encephalitis
* TBEV
* Powassan encephalitis
* POWV
* Viral hemorrhagic fevers: Omsk hemorrhagic fever
* OHFV
* Kyasanur Forest disease
* KFDV
* AHFV
* Langat virus
* LGTV
Orthomyxoviridae
* Bourbon virus
Reoviridae
* Colorado tick fever
* CTFV
* Kemerovo tickborne viral fever
Sandfly
-borne
Bunyavirales
* Adria virus (ADRV)
* Oropouche fever
* Oropouche virus
* Pappataci fever
* Toscana virus
* Sandfly fever Naples virus
Rhabdoviridae
* Chandipura virus
Mammal
-borne
Rodent
-borne
Arenaviridae
* Viral hemorrhagic fevers: Lassa fever
* LASV
* Venezuelan hemorrhagic fever
* GTOV
* Argentine hemorrhagic fever
* JUNV
* Brazilian hemorrhagic fever
* SABV
* Bolivian hemorrhagic fever
* MACV
* LUJV
* CHPV
Bunyavirales
* Hemorrhagic fever with renal syndrome
* DOBV
* HTNV
* PUUV
* SEOV
* AMRV
* THAIV
* Hantavirus pulmonary syndrome
* ANDV
* SNV
Herpesviridae
* Murid gammaherpesvirus 4
Bat
-borne
Filoviridae
* BDBV
* SUDV
* TAFV
* Marburg virus disease
* MARV
* RAVV
Rhabdoviridae
* Rabies
* ABLV
* MOKV
* DUVV
* LBV
* CHPV
Paramyxoviridae
* Henipavirus encephalitis
* HeV
* NiV
Coronaviridae
* SARS-related coronavirus
* SARS-CoV
* MERS-CoV
* SARS-CoV-2
Primate
-borne
Herpesviridae
* Macacine alphaherpesvirus 1
Retroviridae
* Simian foamy virus
* HTLV-1
* HTLV-2
Poxviridae
* Tanapox
* Yaba monkey tumor virus
Multiple
vectors
Rhabdoviridae
* Rabies
* RABV
* Mokola virus
Poxviridae
* Monkeypox
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Borna disease | c0006023 | 2,679 | wikipedia | https://en.wikipedia.org/wiki/Borna_disease | 2021-01-18T18:41:29 | {"mesh": ["D001890"], "umls": ["C0006023"], "icd-9": ["062.9"], "wikidata": ["Q9430213"]} |
A number sign (#) is used with this entry because of evidence that Alazami syndrome (ALAZS) is caused by homozygous or compound heterozygous mutation in the LARP7 gene (612026), a chaperone of 7SK noncoding RNA (616505), on chromosome 4q25.
Description
Alazami syndrome is an autosomal recessive disorder characterized by severe growth restriction present at birth, severely impaired intellectual development, and distinctive facial features. Some patients have been reported with skeletal and behavioral features (summary by Imbert-Bouteille et al., 2019).
Clinical Features
Alazami et al. (2012) described a large consanguineous family from the Southern Province in Saudi Arabia in which 10 children among 3 interrelated branches had facial dysmorphism, severely impaired intellectual development, and primordial dwarfism. All patients had growth parameters 3.5 SD below the mean. Some patients had nonspecific and inconsistent skeletal findings, for example, scoliosis and mild epiphyseal changes in the proximal phalanges, but no frank dysplasia and a bone age consistent with chronological age. Consistent dysmorphic features included malar hypoplasia, deep-set eyes, broad nose, short philtrum, and macrostomia. Laboratory investigation revealed normal plasma amino acids and acylcarnitines, urine organic acids, very long-chain fatty acids, CBC, renal profile, and bone profile. MRI, which was performed on 2 patients, was largely unremarkable in one and showed unilateral mild insular and anterior frontal gyrus cortical thickening in the other.
Ling and Sorrentino (2016) reported a 2-year-old Caucasian girl, born of unrelated parents, with Alazami syndrome. She had failure to thrive, poor overall growth, short stature (-4 SD), and developmental delay with involuntary hand movements and poor speech. Dysmorphic features included 'small-appearing' head, prominent forehead, deep-set eyes, low-set ears, flat and wide nasal bridge, triangular facies with malar hypoplasia, wide mouth, full lips, and widely spaced teeth. She also had poor balance with wide-based gait and hypersensitivity to touch and sound, and she reportedly showed anxiety. Brain imaging was normal.
Imbert-Bouteille et al. (2019) reported 2 sisters, born to consanguineous Algerian parents, with Alazami syndrome. The authors reviewed the clinical information on 15 previously reported patients in addition to their 2 newly reported patients and confirmed the key features of the syndrome: severe growth restriction, severely impaired intellectual development, and distinguishing facial features, including broad nose, malar hypoplasia, wide mouth, full lips, and widely spaced teeth. They also noted that most patients (11/14) had disproportionately mild microcephaly (with height more severely affected than head circumference) and that some patients had thickened skin over the hands and feet (11/14), stereotypic hand wringing (2/5), severe anxiety (2/5), and scoliosis (4/13).
Mapping
Alazami et al. (2012) performed genomewide linkage analysis on 6 affected sibs from a large consanguineous Saudi family segregating a syndrome of facial dysmorphism, intellectual disability, and primordial dwarfism, and identified a 26.5-Mb autozygous region between SNPs (rs13142562 and rs2391504) on chromosome 4q24-q28.2 (maximum multipoint lod score of 4.456).
Molecular Genetics
By sequencing the LARP7 gene within the critical region of 4q identified for a syndrome of facial dysmorphism, intellectual disability, and primordial dwarfism in a consanguineous Saudi family, Alazami et al. (2012) identified a homozygous 7-bp duplication in exon 8 (612026.0001), which fully segregated with the disorder. The mutation was not found in 188 unrelated Saudi controls, a local database of 194 exomes, or the 1000 Genomes Project database. Western blot analysis revealed complete lack of LARP7 on patient cell lysates, and real-time PCR demonstrated reduced LARP7 expression in patient cells, compared to those of healthy controls, in both lymphoblast and fibroblast tissues, suggesting that total loss of the protein was due to nonsense-mediated decay. Concurrent with this was a profound reduction of the 7SK ncRNA. By introducing a LARP7 expression vector, Alazami et al. (2012) rescued 7SK levels in patient fibroblasts. Conversely, siRNA-mediated knockdown using 2 different oligos directed at LARP7 mRNA resulted in ablation of 7SK levels in healthy fibroblast cells.
In 2 affected members of a consanguineous Iranian family segregating severe intellectual disability and microcephaly, Najmabadi et al. (2011) had identified an 'apparently disease-causing' homozygous mutation in the LARP7 gene (612026.0002). No other clinical information was provided.
In a 2-year-old Caucasian girl, born of unrelated parents, with Alazami syndrome, Ling and Sorrentino (2016) identified compound heterozygous frameshift mutations in the LARP7 gene (612026.0003 and 612026.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.
In 2 sisters, born to consanguineous Algerian parents, with Alazami syndrome, Imbert-Bouteille et al. (2019) identified a homozygous frameshift mutation in the LARP7 gene (612026.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the Exome Sequencing Project, 1000 Genomes Project, or gnomAD databases.
INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature (<3.5 SD below the mean) Weight \- Low weight (<3.5 SD below the mean) HEAD & NECK Head \- Microcephaly, disproportionately mild (<3.5 SD below the mean) Face \- Malar hypoplasia Ears \- Low-set ears Eyes \- Deep-set eyes Nose \- Broad nose \- Flat nasal bridge \- Wide nasal bridge Mouth \- Short philtrum \- Macrostomia \- Wide mouth \- Full lips SKELETAL Spine \- Scoliosis Hands \- Epiphyseal changes in the proximal phalanges, mild SKIN, NAILS, & HAIR Skin \- Thickened skin on hands and feet NEUROLOGIC Central Nervous System \- Intellectual disability \- Delayed psychomotor development \- Unstable gait Behavioral Psychiatric Manifestations \- Stereotypic hand-wringing (less common) \- Anxiety, severe (less common) MOLECULAR BASIS \- Caused by mutation in the La ribonucleoprotein domain family, member 7 gene (LARP7, 612026.0001 ) ▲ 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
| ALAZAMI SYNDROME | c3554439 | 2,680 | omim | https://www.omim.org/entry/615071 | 2019-09-22T15:53:16 | {"omim": ["615071"], "orphanet": ["319671"], "synonyms": ["Alazami syndrome", "Alternative titles", "FACIAL DYSMORPHISM, INTELLECTUAL DISABILITY, AND PRIMORDIAL DWARFISM"]} |
Squamous-cell thyroid carcinoma
Other namesSCTC
Micrograph of squamous-cell carcinoma (H&E stain)
SpecialtyOncology
Squamous-cell thyroid carcinoma is rare malignant neoplasm of thyroid gland which shows tumor cells with distinct squamous differentiation. The incidence of SCTC is less than 1% out of thyroid malignancies.[1]
## Contents
* 1 Pathophysiology
* 2 Diagnosis
* 2.1 FNAC
* 2.2 Radiological examination
* 2.3 Markers
* 3 Treatment
* 4 Prognosis
* 5 References
* 6 External links
## Pathophysiology[edit]
Squamous epithelial cells are not found in normal thyroid, thus the origin of SCTC is not clear. However, it might be a derived from the embryonic remnants such as thyroglossal duct or branchial clefts. Often SCTC is diagnosed in one of the thyroid lobes, but not in the pyramidal lobe. Another possible way of SCTC development can be through the squamous metaplasia of cells. However, that theory is also controversial, since the Hashimoto's thyroiditis and chronic lymphocytic thyroiditis (neoplasms to be showed[clarification needed] squamous metaplasia) are not associated with SCTC. Primary STCT is usually diagnosed in both lobes of thyroid gland. The histopathology of STCT shows a squamous differentiation of tumor cells.
## Diagnosis[edit]
The SCTC is biologically aggressive malignant neoplasm which is associated with rapid growth of neck mass followed by infiltration of thyroid-adjacent structures. Patients usually demonstrate the dysphagia, dyspnea, and voice changes, as well as local pain in the neck.
### FNAC[edit]
Ultrasound-guided FNAC should be performed for verification of SCTC.
### Radiological examination[edit]
There are no specific radiological tests for SCTC verification. However these tests might be useful for identification of tumor borders and in planning of surgery.
### Markers[edit]
Immunohistochemistry is performed as additional test. The strong positive expression of cytokeratin 19 was shown in primary SCTC, and negative in metastatic SCTC.
## Treatment[edit]
Thyroidectomy and neck dissection show good results in early stages of SCTC. However, due to highly aggressive phenotype, surgical treatment is not always possible. The SCTC is a radioiodine-refractory tumor. Radiotherapy might be effective in certain cases, resulting in relatively better survival rate and quality of life. Vincristine, Adriamycin, and bleomycin are used for adjuvant chemotherapy, but their effects are not good enough according to published series.
## Prognosis[edit]
SCTC exhibits a highly aggressive phenotype, thus prognosis of that malignancy is extremely poor. The overall survival is less than 1 year in most of cases.[2]
## References[edit]
1. ^ MI Syed; M Stewart; S Syed; S Dahill; C Adams; DR Mclellan; LJ Clark (2011). "Squamous cell carcinoma of the thyroid gland: primary or secondary disease?". The Journal of Laryngology & Otology. 125 (1): 3–9. doi:10.1017/S0022215110002070. PMID 20950510.
2. ^ Booya F, Sebo TJ, Kasperbauer JL, Fatourechi V (2006). "Primary squamous cell carcinoma of the thyroid: report of ten cases". Thyroid. 16 (1): 89–93. doi:10.1089/thy.2006.16.89. PMID 16487020.
## External links[edit]
Classification
D
* ICD-10: C73
* ICD-9-CM: 193
* MeSH: D002294
* 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
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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
| Squamous-cell thyroid carcinoma | c1710177 | 2,681 | wikipedia | https://en.wikipedia.org/wiki/Squamous-cell_thyroid_carcinoma | 2021-01-18T18:34:12 | {"umls": ["C1710177"], "icd-9": ["193"], "icd-10": ["C73"], "wikidata": ["Q5073466"]} |
Edmonds and Keeler (1940) described pits in the earlobes at the exact point where women (and men) puncture their ears for earrings. Irregular dominant inheritance was suggested. Ramirez and Cantu (1982) observed the trait in 9 persons in 3 generations with failure of expression in 1 female and many instances of male-to-male transmission.
Inheritance \- Autosomal dominant Ears \- Congenital earlobe sinuses ▲ Close
*[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
| EARRING HOLES, NATURAL | c1851895 | 2,682 | omim | https://www.omim.org/entry/129000 | 2019-09-22T16:41:56 | {"omim": ["129000"], "synonyms": ["Alternative titles", "EARLOBE SINUSES"]} |
A number sign (#) is used with this entry because of evidence that ventricular septal defect-2 (VSD2) can be caused by heterozygous mutation in the CITED2 gene (602937) on chromosome 6q24.
Description
Ventricular septal defect (VSD) is the most common form of congenital cardiovascular anomaly, occurring in nearly 50% of all infants with a congenital heart defect and accounting for 14% to 16% of cardiac defects that require invasive treatment within the first year of life. Congenital VSDs may occur alone or in combination with other cardiac malformations. Large VSDs that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger's syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death (summary by Wang et al. (2011, 2011)).
For a discussion of genetic heterogeneity of ventricular septal defect, see VSD1 (614429).
Molecular Genetics
Sperling et al. (2005) screened a cohort of 392 patients with congenital heart defects for mutations in the CITED2 gene (602937) and identified a 27-bp deletion in a patient with a perimembranous ventricular septal defect. The mutation, which was not found in 192 controls, resulted in significant loss of HIF1A (603348) transcriptional repressive capacity and significantly diminished TFAP2C (601602) coactivation.
INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Ventricular septal defect, perimembranous MOLECULAR BASIS \- Caused by mutation in the CBP/p300-interacting transactivator, with glu/asp-rich C-terminal domain, 2 gene (CITED2, 602937.0001 ) ▲ Close
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*[AD]: Acetaldehyde dehydrogenase
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*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| VENTRICULAR SEPTAL DEFECT 2 | c3280783 | 2,683 | omim | https://www.omim.org/entry/614431 | 2019-09-22T15:55:21 | {"omim": ["614431"]} |
Encircling double aortic arch is a very rare congenital anomaly of the great arteries characterized by the presence of two aortic arches (right and left) which encircle and compress the trachea and esophagus, resulting in various respiratory and gastrointestinal symptoms (e.g. harsh breathing, stridor, dyspnea, cyanotic and choking episodes, chronic cough, recurrent respiratory tract infections, dysphagia and reflux). Esophageal atresia and tracheoesophageal fistula have also been reported. It usually occurs isolated, but, on occasion, may be associated with other congenital heart anomalies and chromosomal aberations.
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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
| Encircling double aortic arch | c4706940 | 2,684 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99075 | 2021-01-23T18:50:46 | {"icd-10": ["Q25.4"]} |
The features are formation of bullae without evident trauma, absence of all hair, hyperpigmentation, depigmentation, acrocyanosis, dwarfism, microcephaly, mental inferiority, short tapering fingers, and sometimes anomalies of the nails. The disorder is lethal to affected males early in life; most patients die before attaining adulthood (van der Valk, 1922). This disorder was first described in a family living in the Netherlands by Mendes da Costa and van der Valk (1908), and studies by Carol and Kooij (1937) and Woerdeman (1958) provided follow-up information on the Dutch family. This disorder had been observed in only a single Dutch kindred (Hassing and Doeglas, 1980) until a second family with bullous dystrophy was described by Lungarotti et al. (1994). Carrier females showed none of the clinical features exhibited by affected males. Because some clinical features are similar to those observed in epidermolysis bullosa, Gedde-Dahl and Anton-Lamprecht (1990) classified this disorder as an X-linked form of epidermolysis bullosa. Haber et al. (1985) argued that bullous dystrophy should not be considered a type of epidermolysis bullosa, since blisters in EBM occur only spontaneously and cannot be provoked by trauma. Wijker et al. (1995) demonstrated by linkage analysis that the gene lies in the Xq27.3-qter region.
Hair \- Alopecia totalis Head \- Microcephaly Growth \- Dwarfism Neuro \- Mental retardation Skin \- Bullae without evident trauma \- Hyperpigmentation \- Depigmentation \- Acrocyanosis Nails \- Nail anomalies Inheritance \- X-linked Misc \- Early lethal Limbs \- Short tapering fingers ▲ 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
| BULLOUS DYSTROPHY, HEREDITARY MACULAR TYPE | c0795974 | 2,685 | omim | https://www.omim.org/entry/302000 | 2019-09-22T16:18:44 | {"mesh": ["C563065"], "omim": ["302000"], "orphanet": ["1867"], "synonyms": ["Alternative titles", "EPIDERMOLYSIS BULLOSA, MACULAR TYPE"]} |
Hydrocephalus due to congenital stenosis of aqueduct of sylvius (HSAS) is a form of L1 syndrome, which is an inherited disorder that primarily affects the nervous system. Males with HSAS are typically born with severe hydrocephalus and adducted thumbs (bent towards the palm). Other sign and symptoms of the condition include severe intellectual disability and spasticity. HSAS, like all forms of L1 syndrome, is caused by changes (mutations) in the L1CAM gene and is inherited in an X-linked 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
| Hydrocephalus due to congenital stenosis of aqueduct of sylvius | c0265216 | 2,686 | gard | https://rarediseases.info.nih.gov/diseases/434/hydrocephalus-due-to-congenital-stenosis-of-aqueduct-of-sylvius | 2021-01-18T17:59:57 | {"mesh": ["C536078"], "omim": ["307000"], "umls": ["C0265216"], "orphanet": ["2182"], "synonyms": ["Hydrocephalus, X-linked", "HSAS1", "Aqueductal stenosis, X-linked", "HSAS", "HYCX", "XLAS"]} |
Ischemic colitis
Ischemic colitis on the transverse colon of an 82 year old female
SpecialtyGastroenterology
Ischemic colitis (also spelled ischaemic colitis) is a medical condition in which inflammation and injury of the large intestine result from inadequate blood supply. Although uncommon in the general population, ischemic colitis occurs with greater frequency in the elderly, and is the most common form of bowel ischemia.[1][2][3] Causes of the reduced blood flow can include changes in the systemic circulation (e.g. low blood pressure) or local factors such as constriction of blood vessels or a blood clot. In most cases, no specific cause can be identified.[4]
Ischemic colitis is usually suspected on the basis of the clinical setting, physical examination, and laboratory test results; the diagnosis can be confirmed by endoscopy or by using sigmoid or endoscopic placement of a visible light spectroscopic catheter (see Diagnosis). Ischemic colitis can span a wide spectrum of severity; most patients are treated supportively and recover fully, while a minority with very severe ischemia may develop sepsis and become critically,[5] sometimes fatally, ill.[6]
Patients with mild to moderate ischemic colitis are usually treated with IV fluids, analgesia, and bowel rest (that is, no food or water by mouth) until the symptoms resolve. Those with severe ischemia who develop complications such as sepsis, intestinal gangrene, or bowel perforation may require more aggressive interventions such as surgery and intensive care. Most patients make a full recovery; occasionally, after severe ischemia, patients may develop long-term complications such as a stricture[7] or chronic colitis.[8]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 2.1 Non-occlusive ischemia
* 2.2 Occlusive ischemia
* 3 Pathophysiology
* 3.1 Colonic blood supply
* 3.2 Development of ischemia
* 3.3 Pathologic findings
* 4 Diagnosis
* 4.1 Diagnostic tests
* 5 Treatment
* 6 Prognosis
* 6.1 Long-term complications
* 7 Epidemiology
* 8 References
* 9 External links
## Signs and symptoms[edit]
Three progressive phases of ischemic colitis have been described:[9][10]
* A hyperactive phase occurs first, in which the primary symptoms are severe abdominal pain and the passage of bloody stools. Many patients get better and do not progress beyond this phase.
* A paralytic phase can follow if ischemia continues; in this phase, the abdominal pain becomes more widespread, the belly becomes more tender to the touch, and bowel motility decreases, resulting in abdominal bloating, no further bloody stools, and absent bowel sounds on exam.
* Finally, a shock phase can develop as fluids start to leak through the damaged colon lining. This can result in shock and metabolic acidosis with dehydration, low blood pressure, rapid heart rate, and confusion. Patients who progress to this phase are often critically ill and require intensive care.
Symptoms of ischemic colitis vary depending on the severity of the ischemia. The most common early signs of ischemic colitis include abdominal pain (often left-sided), with mild to moderate amounts of rectal bleeding.[11] The sensitivity of findings among 73 patients were:[12]
* abdominal pain (78%)
* lower digestive bleeding (62%)
* diarrhea (38%)
* Fever higher than 38 °C (100.4 °F) (34%)
Physical examination[12]
* abdominal pain (77%)
* abdominal tenderness (21%)
## Causes[edit]
Ischemic colitis is often classified according to the underlying cause. Non-occlusive ischemia develops because of low blood pressure or constriction of the vessels feeding the colon; occlusive ischemia indicates that a blood clot or other blockage has cut off blood flow to the colon.
### Non-occlusive ischemia[edit]
In hemodynamically unstable patients (i.e. shock) the mesenteric perfusion may be compromised. This condition is commonly asymptomatic, and usually only apparent through a systemic inflammatory response.
### Occlusive ischemia[edit]
Mostly the result of a thromboembolism. Commonly the embolism is caused by atrial fibrillation, valvular disease, myocardial infarction, or cardiomyopathy.
In addition, ischemic colitis is a well-recognized complication of abdominal aortic aneurysm repair, when the origin of the inferior mesenteric artery is covered by the aortic graft.[13][14] In a 1991 review concerning 2137 patients the accidental inferior mesenteric artery ligation was the most common cause (74%) of ischemic colitis.[15] Thus, patients without adequate collateralization are at risk for ischemia of the descending and sigmoid colon. Bloody diarrhea and leukocytosis in the postoperative period are essentially diagnostic of ischemic colitis. The complication can be prevented through careful selection of subjects that may require replanting inferior mesenteric artery (IMA) and completing the pre surgical procedure information with an instrumental evaluation during surgical treatment.[16]
## Pathophysiology[edit]
### Colonic blood supply[edit]
Colonic blood supply. Pink - supply from superior mesenteric artery (SMA) and its branches: middle colic, right colic, ileocolic arteries. Blue - supply from inferior mesenteric artery (IMA) and its branches: left colic, sigmoid, superior rectal artery. 7 is for so-called Cannon-Böhm point (the border between the areas of SMA and IMA supplies), which lies at the splenic flexure
The colon receives blood from both the superior and inferior mesenteric arteries. The blood supply from these two major arteries overlap, with abundant collateral circulation via the marginal artery of the colon. However, there are weak points, or "watershed" areas, at the borders of the territory supplied by each of these arteries, such as the splenic flexure and the rectosigmoid junction. These watershed areas are most vulnerable to ischemia when blood flow decreases, as they have the fewest vascular collaterals.
The rectum receives blood from both the inferior mesenteric artery and the internal iliac artery; the rectum is rarely involved by colonic ischemia due to this dual blood supply.
### Development of ischemia[edit]
Under ordinary conditions, the colon receives between 10% and 35% of the total cardiac output.[17][18] If blood flow to the colon drops by more than about 50%, ischemia will develop. The arteries feeding the colon are very sensitive to vasoconstrictors; presumably this is an evolutionary adaptation to shunt blood away from the bowel and to the heart and brain in times of stress.[19] As a result, during periods of low blood pressure, the arteries feeding the colon clamp down vigorously; a similar process can result from vasoconstricting drugs such as ergotamine, cocaine, or vasopressors. This vasoconstriction can result in non-occlusive ischemic colitis.
### Pathologic findings[edit]
A range of pathologic findings are seen in ischemic colitis, corresponding to the spectrum of clinical severity. In its mildest form, mucosal and submucosal hemorrhage and edema are seen, possibly with mild necrosis or ulceration.[4] With more severe ischemia, a pathologic picture resembling inflammatory bowel disease (i.e. chronic ulcerations, crypt abscesses and pseudopolyps) may be seen.[20] In the most severe cases, transmural infarction with resulting perforation may be seen; after recovery, the muscularis propria may be replaced by fibrous tissue, resulting in a stricture.[4] Following restoration of normal blood flow, reperfusion injury may also contribute to the damage to the colon.[21]
## Diagnosis[edit]
Ischemic colitis must be differentiated from the many other causes of abdominal pain and rectal bleeding (for example, infection, inflammatory bowel disease, diverticulosis, or colon cancer). It is also important to differentiate ischemic colitis, which often resolves on its own, from the more immediately life-threatening condition of acute mesenteric ischemia of the small bowel.
There are devices which test the sufficiency of oxygen delivery to the colon. The first device approved by the U.S. FDA in 2004 uses visible light spectroscopy to analyze capillary oxygen levels. Use during Aortic Aneurysm repair detected when colon oxygen levels fell below sustainable levels, allowing real-time repair. In several studies, Specificity has been 90% or higher for acute colonic ischemia, and 83% for chronic mesenteric ischemia, with a sensitivity of 71%-92%. This device must be placed using endoscopy, however.[22][23][24]
### Diagnostic tests[edit]
There is a recent optical test, but it requires endoscopy (see Diagnosis). There are no specific blood tests for ischemic colitis. The sensitivity of tests among 73 patients were:[12]
* The white blood cell count was more than 15,000/mm3 in 20 patients (27%)
* The serum bicarbonate level was less than 24 mmol/L in 26 patients (36%)
Plain X-rays are often normal or show non-specific findings.[25] In a series of 73 patients, plain abdominal radiography (56%) showing colic distension in 53% or a pneumoperitoneum in 3%.[12]
CT scans are often used in the evaluation of abdominal pain and rectal bleeding, and may suggest the diagnosis of ischemic colitis, pick up complications, or suggest an alternate diagnosis.[26][27][28]
Endoscopic evaluation, via colonoscopy or flexible sigmoidoscopy, is the procedure of choice if the diagnosis remains unclear. Ischemic colitis has a distinctive endoscopic appearance; endoscopy can also facilitate alternate diagnoses such as infection or inflammatory bowel disease. Biopsies can be taken via endoscopy to provide more information. Visible light spectroscopy, performed using catheters placed through the 5 mm channel of the endoscope, is diagnostic (see Diagnosis).
## Treatment[edit]
Except in the most severe cases, ischemic colitis is treated with supportive care. IV fluids are given to treat dehydration, and the patient is placed on bowel rest (meaning nothing to eat or drink) until the symptoms resolve. If possible, cardiac function and oxygenation should be optimized to improve oxygen delivery to the ischemic bowel. A nasogastric tube may be inserted if an ileus is present.
Antibiotics are sometimes given in moderate to severe cases; the data supporting this practice date to the 1950s,[29] although there is more recent animal data suggesting that antibiotics may increase survival and prevent bacteria from crossing the damaged lining of the colon into the bloodstream.[30][31][32] The use of prophylactic antibiotics in ischemic colitis has not been prospectively evaluated in humans, but many authorities recommend their use based on the animal data.[33]
Patients being treated supportively are carefully monitored. If they develop worsening symptoms and signs such as high white blood cell count, fever, worsened abdominal pain, or increased bleeding, then they may require surgical intervention; this usually consists of laparotomy and bowel resection.
## Prognosis[edit]
Most patients with ischemic colitis recover fully, although the prognosis depends on the severity of the ischemia. Patients with pre-existing peripheral vascular disease or ischemia of the ascending (right) colon may be at increased risk for complications or death.
Non-gangrenous ischemic colitis, which comprises the vast majority of cases, is associated with a mortality rate of approximately 6%.[34] However, the minority of patients who develop gangrene as a result of colonic ischemia have a mortality rate of 50–75% with surgical treatment; the mortality rate is almost 100% without surgical intervention.[35]
### Long-term complications[edit]
About 20% of patients with acute ischemic colitis may develop a long-term complication known as chronic ischemic colitis.[8] Symptoms can include recurrent infections, bloody diarrhea, weight loss, and chronic abdominal pain. Chronic ischemic colitis is often treated with surgical removal of the chronically diseased portion of the bowel.
A colonic stricture is a band of scar tissue which forms as a result of the ischemic injury and narrows the lumen of the colon. Strictures are often treated observantly; they may heal spontaneously over 12–24 months. If a bowel obstruction develops as a result of the stricture, surgical resection is the usual treatment,[36] although endoscopic dilatation and stenting have also been employed.[37][38]
## Epidemiology[edit]
The exact incidence of ischemic colitis is difficult to estimate, as many patients with mild ischemia may not seek medical attention. Ischemic colitis is responsible for about 1 in 2000 hospital admissions, and is seen on about 1 in 100 endoscopies.[4] Men and women are affected equally; ischemic colitis is a disease of the elderly, with more than 90% of cases occurring in people over the age of 60.[4]
## References[edit]
1. ^ Higgins P, Davis K, Laine L (2004). "Systematic review: the epidemiology of ischaemic colitis" (PDF). Aliment Pharmacol Ther. 19 (7): 729–38. doi:10.1111/j.1365-2036.2004.01903.x. hdl:2027.42/74164. PMID 15043513.
2. ^ Brandt LJ, Boley SJ (2000). "AGA technical review on intestinal ischemia. American Gastrointestinal Association". Gastroenterology. 118 (5): 954–68. doi:10.1016/S0016-5085(00)70183-1. PMID 10784596.
3. ^ American Gastroenterological Association (2000). "American Gastroenterological Association Medical Position Statement: guidelines on intestinal ischemia". Gastroenterology. 118 (5): 951–3. doi:10.1016/S0016-5085(00)70182-X. PMID 10784595. http://www.guideline.gov/summary/summary.aspx?ss=15&doc_id=3069&nbr=2295 Archived 2007-09-27 at the Wayback Machine
4. ^ a b c d e Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 7th ed., 2002 Saunders, p. 2332.
5. ^ Medina C, Vilaseca J, Videla S, Fabra R, Armengol-Miro J, Malagelada J (2004). "Outcome of patients with ischemic colitis: review of fifty-three cases". Dis Colon Rectum. 47 (2): 180–4. doi:10.1007/s10350-003-0033-6. PMID 15043287.
6. ^ "Brighton marathon runner died from bowel failure". The Guardian newspaper. Press Association. 28 August 2013. Retrieved 29 August 2013.
7. ^ Simi M, Pietroletti R, Navarra L, Leardi S (1995). "Bowel stricture due to ischemic colitis: report of three cases requiring surgEsophageal dilatationery". Hepatogastroenterology. 42 (3): 279–81. PMID 7590579.
8. ^ a b Cappell M (1998). "Intestinal (mesenteric) vasculopathy. II. Ischemic colitis and chronic mesenteric ischemia". Gastroenterol Clin North Am. 27 (4): 827–60, vi. doi:10.1016/S0889-8553(05)70034-0. PMID 9890115.
9. ^ Boley SJ, Brandt LJ, Veith FJ (April 1978). "Ischemic disorders of the intestines". Curr Probl Surg. 15 (4): 1–85. doi:10.1016/S0011-3840(78)80018-5. PMID 365467.
10. ^ Hunter G, Guernsey J (1988). "Mesenteric ischemia". Med Clin North Am. 72 (5): 1091–115. doi:10.1016/S0025-7125(16)30731-3. PMID 3045452.
11. ^ Greenwald D, Brandt L, Reinus J (2001). "Ischemic bowel disease in the elderly". Gastroenterol Clin North Am. 30 (2): 445–73. doi:10.1016/S0889-8553(05)70190-4. PMID 11432300.
12. ^ a b c d Huguier M, Barrier A, Boelle PY, Houry S, Lacaine F (2006). "Ischemic colitis". Am. J. Surg. 192 (5): 679–84. doi:10.1016/j.amjsurg.2005.09.018. PMID 17071206.
13. ^ Welling RE, Roedersheimer LR, Arbaugh JJ, Cranley JJ (December 1985). "Ischemic colitis following repair of ruptured abdominal aortic aneurysm". Archives of Surgery. 120 (12): 1368–70. doi:10.1001/archsurg.1985.01390360034008. PMID 4062543.
14. ^ Kaiser MM, Wenk H, Sassen R, Müller G, Bruch HP (April 1996). "[Ischemic colitis after vascular surgery reconstruction of an abdominal aortic aneurysm]". Der Chirurg (in German). 67 (4): 380–6. PMID 8646925.
15. ^ Brewster DC, Franklin DP, Cambria RP, Darling RC, Moncure AC, Lamuraglia GM, Stone WM, Abbott WM (April 1991). "Intestinal ischemia complicating abdominal aortic surgery". Surgery. 109 (4): 447–54. PMID 1844392.
16. ^ Panier Suffat L, Tridico F, Rebecchi F, Bianco A, Monticone C, Lanza S, Calello G, Contessa L, Giaccone C, Panier Suffat P (February 2003). "[Prevention of ischemic colitis following aortic reconstruction: personal experience of the role of transmural oximetry in the decision for inferior mesenteric artery reimplantation]". Minerva Chirurgica (in Italian). 58 (1): 71–6. PMID 12692499.
17. ^ Hasibeder, W. (Oct 2010). "Gastrointestinal microcirculation: still a mystery?". Br J Anaesth. 105 (4): 393–6. doi:10.1093/bja/aeq236. PMID 20837720.
18. ^ UpToDate, Colonic ischemia, accessed 2 September 2006.
19. ^ Rosenblum J, Boyle C, Schwartz L (1997). "The mesenteric circulation. Anatomy and physiology". Surg Clin North Am. 77 (2): 289–306. doi:10.1016/S0039-6109(05)70549-1. PMID 9146713.
20. ^ Brandt L, Boley S, Goldberg L, Mitsudo S, Berman A (September 1981). "Colitis in the elderly. A reappraisal". Am. J. Gastroenterol. 76 (3): 239–45. PMID 7315820.
21. ^ Granger D, Rutili G, McCord J (1981). "Superoxide radicals in feline intestinal ischemia". Gastroenterology. 81 (1): 22–9. doi:10.1016/0016-5085(81)90648-X. PMID 6263743.
22. ^ Lee ES, Bass A, Arko FR, et al. (2006). "Intraoperative colon mucosal oxygen saturation during aortic surgery". The Journal of Surgical Research. 136 (1): 19–24. doi:10.1016/j.jss.2006.05.014. PMID 16978651.
23. ^ Friedland S, Benaron D, Coogan S, et al. (2007). "Diagnosis of chronic mesenteric ischemia by visible light spectroscopy during endoscopy". Gastrointest Endosc. 65 (2): 294–300. doi:10.1016/j.gie.2006.05.007. PMID 17137857.
24. ^ Lee ES, Pevec WC, Link DP, et al. (2008). "Use of T-Stat to predict colonic ischemia during and after endovascular aneurysm repair". J Vasc Surg. 47 (3): 632–634. doi:10.1016/j.jvs.2007.09.037. PMC 2707776. PMID 18295116.
25. ^ Smerud M, Johnson C, Stephens D (1990). "Diagnosis of bowel infarction: a comparison of plain films and CT scans in 23 cases". AJR Am J Roentgenol. 154 (1): 99–103. doi:10.2214/ajr.154.1.2104734. PMID 2104734.
26. ^ Alpern M, Glazer G, Francis I (1988). "Ischemic or infarcted bowel: CT findings". Radiology. 166 (1 Pt 1): 149–52. doi:10.1148/radiology.166.1.3336673. PMID 3336673.
27. ^ Balthazar E, Yen B, Gordon R (1999). "Ischemic colitis: CT evaluation of 54 cases". Radiology. 211 (2): 381–8. doi:10.1148/radiology.211.2.r99ma28381. PMID 10228517.
28. ^ Taourel P, Deneuville M, Pradel J, Régent D, Bruel J (1996). "Acute mesenteric ischemia: diagnosis with contrast-enhanced CT". Radiology. 199 (3): 632–6. doi:10.1148/radiology.199.3.8637978. PMID 8637978.
29. ^ Path EJ, McClure JN (February 1950). "Intestinal obstruction; the protective action of sulfasuxidine and sulfathalidine to the ileum following vascular damage". Ann. Surg. 131 (2): 159–70, illust. doi:10.1097/00000658-195002000-00003. PMC 1616406. PMID 15402790.
30. ^ Plonka A, Schentag J, Messinger S, Adelman M, Francis K, Williams J (1989). "Effects of enteral and intravenous antimicrobial treatment on survival following intestinal ischemia in rats". J Surg Res. 46 (3): 216–20. doi:10.1016/0022-4804(89)90059-0. PMID 2921861.
31. ^ Bennion R, Wilson S, Williams R (1984). "Early portal anaerobic bacteremia in mesenteric ischemia". Arch Surg. 119 (2): 151–5. doi:10.1001/archsurg.1984.01390140017003. PMID 6696611.
32. ^ Redan J, Rush B, Lysz T, Smith S, Machiedo G (1990). "Organ distribution of gut-derived bacteria caused by bowel manipulation or ischemia". Am J Surg. 159 (1): 85–9, discussion 89–90. doi:10.1016/S0002-9610(05)80611-7. PMID 2403765.
33. ^ Feldman (2002). Sleisenger & Fordtran's Gastrointestinal and Liver Disease (7th ed.). Saunders. p. 2334.
34. ^ Longo W, Ballantyne G, Gusberg R (1992). "Ischemic colitis: patterns and prognosis". Dis Colon Rectum. 35 (8): 726–30. doi:10.1007/BF02050319. PMID 1643995.
35. ^ Parish K, Chapman W, Williams L (1991). "Ischemic colitis. An ever-changing spectrum?". Am Surg. 57 (2): 118–21. PMID 1992867.
36. ^ Simi M, Pietroletti R, Navarra L, Leardi S (1995). "Bowel stricture due to ischemic colitis: report of three cases requiring surgery". Hepatogastroenterology. 42 (3): 279–81. PMID 7590579.
37. ^ Oz M, Forde K (1990). "Endoscopic alternatives in the management of colonic strictures". Surgery. 108 (3): 513–9. PMID 2396196.
38. ^ Profili S, Bifulco V, Meloni G, Demelas L, Niolu P, Manzoni M (1996). "[A case of ischemic stenosis of the colon-sigmoid treated with self-expandable uncoated metallic prosthesis]". Radiol Med (Torino). 91 (5): 665–7. PMID 8693144.
## External links[edit]
Classification
D
* ICD-10: K55.9
* ICD-9-CM: 557.9
* MeSH: D017091
* DiseasesDB: 34162
External resources
* MedlinePlus: 000258
* eMedicine: radio/180
* v
* t
* e
Diseases of the digestive system
Upper GI tract
Esophagus
* Esophagitis
* Candidal
* Eosinophilic
* Herpetiform
* Rupture
* Boerhaave syndrome
* Mallory–Weiss syndrome
* UES
* Zenker's diverticulum
* LES
* Barrett's esophagus
* Esophageal motility disorder
* Nutcracker esophagus
* Achalasia
* Diffuse esophageal spasm
* Gastroesophageal reflux disease (GERD)
* Laryngopharyngeal reflux (LPR)
* Esophageal stricture
* Megaesophagus
* Esophageal intramural pseudodiverticulosis
Stomach
* Gastritis
* Atrophic
* Ménétrier's disease
* Gastroenteritis
* Peptic (gastric) ulcer
* Cushing ulcer
* Dieulafoy's lesion
* Dyspepsia
* Pyloric stenosis
* Achlorhydria
* Gastroparesis
* Gastroptosis
* Portal hypertensive gastropathy
* Gastric antral vascular ectasia
* Gastric dumping syndrome
* Gastric volvulus
* Buried bumper syndrome
* Gastrinoma
* Zollinger–Ellison syndrome
Lower GI tract
Enteropathy
Small intestine
(Duodenum/Jejunum/Ileum)
* Enteritis
* Duodenitis
* Jejunitis
* Ileitis
* Peptic (duodenal) ulcer
* Curling's ulcer
* Malabsorption: Coeliac
* Tropical sprue
* Blind loop syndrome
* Small bowel bacterial overgrowth syndrome
* Whipple's
* Short bowel syndrome
* Steatorrhea
* Milroy disease
* Bile acid malabsorption
Large intestine
(Appendix/Colon)
* Appendicitis
* Colitis
* Pseudomembranous
* Ulcerative
* Ischemic
* Microscopic
* Collagenous
* Lymphocytic
* Functional colonic disease
* IBS
* Intestinal pseudoobstruction / Ogilvie syndrome
* Megacolon / Toxic megacolon
* Diverticulitis/Diverticulosis/SCAD
Large and/or small
* Enterocolitis
* Necrotizing
* Gastroenterocolitis
* IBD
* Crohn's disease
* Vascular: Abdominal angina
* Mesenteric ischemia
* Angiodysplasia
* Bowel obstruction: Ileus
* Intussusception
* Volvulus
* Fecal impaction
* Constipation
* Diarrhea
* Infectious
* Intestinal adhesions
Rectum
* Proctitis
* Radiation proctitis
* Proctalgia fugax
* Rectal prolapse
* Anismus
Anal canal
* Anal fissure/Anal fistula
* Anal abscess
* Hemorrhoid
* Anal dysplasia
* Pruritus ani
GI bleeding
* Blood in stool
* Upper
* Hematemesis
* Melena
* Lower
* Hematochezia
Accessory
Liver
* Hepatitis
* Viral hepatitis
* Autoimmune hepatitis
* Alcoholic hepatitis
* Cirrhosis
* PBC
* Fatty liver
* NASH
* Vascular
* Budd–Chiari syndrome
* Hepatic veno-occlusive disease
* Portal hypertension
* Nutmeg liver
* Alcoholic liver disease
* Liver failure
* Hepatic encephalopathy
* Acute liver failure
* Liver abscess
* Pyogenic
* Amoebic
* Hepatorenal syndrome
* Peliosis hepatis
* Metabolic disorders
* Wilson's disease
* Hemochromatosis
Gallbladder
* Cholecystitis
* Gallstone / Cholelithiasis
* Cholesterolosis
* Adenomyomatosis
* Postcholecystectomy syndrome
* Porcelain gallbladder
Bile duct/
Other biliary tree
* Cholangitis
* Primary sclerosing cholangitis
* Secondary sclerosing cholangitis
* Ascending
* Cholestasis/Mirizzi's syndrome
* Biliary fistula
* Haemobilia
* Common bile duct
* Choledocholithiasis
* Biliary dyskinesia
* Sphincter of Oddi dysfunction
Pancreatic
* Pancreatitis
* Acute
* Chronic
* Hereditary
* Pancreatic abscess
* Pancreatic pseudocyst
* Exocrine pancreatic insufficiency
* Pancreatic fistula
Other
Hernia
* Diaphragmatic
* Congenital
* Hiatus
* Inguinal
* Indirect
* Direct
* Umbilical
* Femoral
* Obturator
* Spigelian
* Lumbar
* Petit's
* Grynfeltt-Lesshaft
* Undefined location
* Incisional
* Internal hernia
* Richter's
Peritoneal
* Peritonitis
* Spontaneous bacterial peritonitis
* Hemoperitoneum
* Pneumoperitoneum
* v
* t
* e
Ischaemia and infarction
Ischemia
* Location
* Brain ischemia
* Heart
* Large intestine
* Small intestine
Infarction
* Types
* Anemic
* Hemorrhagic
* Location
* Heart
* Brain
* Spleen
* Limb
* Gangrene
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Ischemic colitis | c0162529 | 2,687 | wikipedia | https://en.wikipedia.org/wiki/Ischemic_colitis | 2021-01-18T18:47:48 | {"mesh": ["D017091"], "umls": ["C0162529"], "wikidata": ["Q1532338"]} |
Thoracic dysplasia-hydrocephalus syndrome is an extremely rare primary bone dysplasia syndrome characterized by short ribs with a narrow chest and thoracic dysplasia, mild rhizomelic shortening of the limbs, communicating hydrocephalus, and developmental delay. There have been no further descriptions in the literature since 1987.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Thoracic dysplasia-hydrocephalus syndrome | c1848864 | 2,688 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1861 | 2021-01-23T17:38:06 | {"gard": ["5180"], "mesh": ["C564774"], "omim": ["273730"], "umls": ["C1848864"], "icd-10": ["Q87.8"]} |
Insulinoma is the most common type of functioning pancreatic neuroendocrine tumor (see this term) characterized most commonly by a solitary, small pancreatic lesion that causes hyperinsulinemic hypoglycemia.
## Epidemiology
The incidence in the general population is 1/1,000,000-1/250,000 (but higher in autopsy studies). There is a slight female predominance. It is the most common endogenous cause of hyperinsulinemic hypoglycemia. Malignant insulinoma has an incidence 0.01/100,000 in Europe.
## Clinical description
Insulinoma can present at any age but the median age of diagnosis is in the 5th decade of life. It manifests with various autonomic and neuroglycopenic symptoms such as tremor, palpitations, weakness, diaphoresis, hyperphagia, visual disturbances, confusion, behavioral and personality changes, seizures and coma. Symptoms occur more often during times of fasting, exercise or with a delay in meals. 20-40% of patients are overweight. Insulinomas are malignant in only 7-10% of cases and the most common sites of metastasis are the liver and lymph nodes. They can also be associated with multiple endocrine neoplasia type 1 (MEN1) (see this term). Extra-pancreatic insulinoma is most commonly found in the duodenal wall but is extremely rare. The tumor can also rarely be non-functioning.
## Etiology
The etiology is unknown. Insulinoma originates in the islet beta cells that are equally distributed thoughout the pancreas. When functioning, the tumor manifests with hypersecretion of insulin and consequently causes hypoglycemia.
## Diagnostic methods
Diagnosis is suspected on the presence of Whipple's triad (hypoglycemia with blood glucose levels of <50 mg/dL, neuroglycopenic symptoms, and immediate relief of symptoms following the administration of glucose) and confirmed by biological testing, including a 72 hour fasting test (measuring levels of insulin, C-peptide and proinsulin during hypoglycemia). The insulin/C-peptide ratio is >1.0 in patients with insulinoma. Localization of insulinoma can be achieved by imaging techniques such as transabdominal ultrasound, computed tomography and magnetic resonance imaging, as well as by endoscopic ultrasonography (EUS), angiography, and arterial stimulation venous sampling.
## Differential diagnosis
Differential diagnoses include other causes of hypoglycemia such as diffuse hepatic disease, Addison disease (see this term), and alcoholism, but insulin is not elevated in these conditions.
## Genetic counseling
Although the majority of insulinomas occur sporadically, about 5% to 10% may be associated with MEN1, which is inherited in an autosomal dominant manner. Genetic counseling should be offered to insulinoma patients with MEN1.
## Management and treatment
Surgical resection is the standard treatment for a benign insulinoma and is often curative. Enucleation, partial or middle pancreatomy, laparoscopic resection and radical resection are all options for benign insulinomas. Octreotide, a somatostatin analogue, can be given pre-operatively as it may be successful in controlling blood glucose levels (not necessary in most cases). Malignant insulinomas require aggressive surgical resection (extended pancreatic and liver resection) along with aggressive secondary treatments (i.e. chemoembolization, radiofrequency ablation (RFA)). In those with unresectable tumors, octreotide should be administered and glucose monitored regularly, and mammalian target of rapamycin (mTOR) inhibitors are particularly effective in controlling hypoglycemia. Sunitinib malate can be used for malignant insulinomas.
## Prognosis
In most cases, insulinomas are benign, and surgical resection is curative. The reported 10-year survival rate of those with a malignant insulinoma, however, is 29%.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Insulinoma | c0021670 | 2,689 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=97279 | 2021-01-23T17:42:01 | {"gard": ["3010"], "mesh": ["D007340"], "umls": ["C0021670"], "icd-10": ["E16.8"]} |
Patient-controlled analgesia
A patient-controlled analgesia infusion pump, configured for epidural administration of fentanyl and bupivacaine for postoperative analgesia
MeSHD016058
[edit on Wikidata]
Patient-controlled analgesia (PCA[1]) is any method of allowing a person in pain to administer their own pain relief.[2] The infusion is programmable by the prescriber. If it is programmed and functioning as intended, the machine is unlikely to deliver an overdose of medication.[3] Providers must always observe the first administration of any PCA medication which has not already been administered by the provider to respond to allergic reactions.
## Contents
* 1 Routes of administration
* 1.1 Oral
* 1.2 Intravenous
* 1.3 Epidural
* 1.4 Inhaled
* 1.5 Nasal
* 1.6 Transcutaneous
* 2 Advantages and disadvantages
* 3 History
* 4 References
* 5 Further reading
## Routes of administration[edit]
### Oral[edit]
The most common form of patient-controlled analgesia is self-administration of oral over-the-counter or prescription painkillers. For example, if a headache does not resolve with a small dose of an oral analgesic, more may be taken. As pain is a combination of tissue damage and emotional state, being in control means reducing the emotional component of pain.[citation needed]
### Intravenous[edit]
A patient-controlled analgesia infusion pump, configured for intravenous administration of morphine for postoperative analgesia
In a hospital setting, a PCA refers to an electronically controlled infusion pump that delivers an amount of intravenous analgesic when the patient presses a button.[4] PCA can be used for both acute and chronic pain patients. It is commonly used for post-operative pain management, and for end-stage cancer patients.[5]
Narcotics are the most common analgesics administered through PCAs.[6][7] It is important for caregivers to monitor patients for the first two to twenty-four hours to ensure they are using the device properly.[8]
With a PCA the patient is protected from overdose by the caregiver programming the PCA to deliver a dose at set intervals. If the patient presses the button sooner than the prescribed intake pressing the button does not operate the PCA. (The PCA can be set to emit a beep telling the patient a dose was NOT delivered). Dosage is also controlled when the patient is too sedated to press the button; preventing the patient from receiving needless doses and keeping the patient safe from overdosing.
### Epidural[edit]
Patient-controlled epidural analgesia (PCEA) is a related term describing the patient-controlled administration of analgesic medicine in the epidural space, by way of intermittent boluses or infusion pumps. This can be used by women in labour, terminally ill cancer patients or to manage post-operative pain.[5]
### Inhaled[edit]
In 1968, Robert Wexler of Abbott Laboratories developed the Analgizer, a disposable inhaler that allowed the self-administration of methoxyflurane vapor in air for analgesia.[9] The Analgizer consisted of a polyethylene cylinder 5 inches long and 1 inch in diameter with a 1 inch long mouthpiece. The device contained a rolled wick of polypropylene felt which held 15 milliliters of methoxyflurane. Because of the simplicity of the Analgizer and the pharmacological characteristics of methoxyflurane, it was easy for patients to self-administer the drug and rapidly achieve a level of conscious analgesia which could be maintained and adjusted as necessary over a period of time lasting from a few minutes to several hours. The 15 milliliter supply of methoxyflurane would typically last for two to three hours, during which time the user would often be partly amnesic to the sense of pain; the device could be refilled if necessary.[10] The Analgizer was found to be safe, effective, and simple to administer in obstetric patients during childbirth, as well as for patients with bone fractures and joint dislocations,[10] and for dressing changes on burn patients.[11] When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent adverse effect on Apgar scores.[10] All vital signs remain normal in obstetric patients, newborns, and injured patients.[10] The Analgizer was widely utilized for analgesia and sedation until the early 1970s, in a manner that foreshadowed the patient-controlled analgesia infusion pumps of today.[12][13][14][15] The Analgizer inhaler was withdrawn in 1974, but use of methoxyflurane as a sedative and analgesic continues in Australia and New Zealand in the form of the Penthrox inhaler.[16][17][18][19][20][21]
### Nasal[edit]
Patient Controlled Intranasal Analgesia (PCINA or Nasal PCA) refers to PCA devices in a Nasal spray form with inbuilt features to control the number of sprays that can be delivered in a fixed time period.[22]
### Transcutaneous[edit]
Transcutaneous delivery systems, including iontophoretic systems, are available. These are popular for administration of opioids such as fentanyl, or local anesthetics such as lidocaine. Iontocaine is one example of such a system.
## Advantages and disadvantages[edit]
Advantages of patient-controlled analgesia include self-delivery of pain medication, faster alleviation of pain because the patient can address pain with medication, and dosage monitoring by medical staff (dosage can be increased or decreased depending on need). With a PCA the patient spends less time in pain and as a corollary to this, patients tend to use less medication than in cases in which medication is given according to a set schedule or on a timer.[5]
Disadvantages include the possibility that a patient will use the pain medication non-medically, self-administering the narcotic for its euphoric properties even though the patient's pain is sufficiently controlled. If a PCA device is not programmed properly for the patient this can result in an under-dose or overdose in a medicine.[23] The system may also be inappropriate for certain individuals, for example patients with learning difficulties or confusion. Also, patients with poor manual dexterity may be unable to press the buttons as would those who are critically ill. PCA may not be appropriate for younger patients.
## History[edit]
The PCA pump was developed and introduced by Philip H. Sechzer in the late 1960s and described in 1971.[24]
## References[edit]
1. ^ Karanikolas M, Aretha D, Kiekkas P, Monantera G, Tsolakis I, Filos KS (October 2010). "Case report. Intravenous fentanyl patient-controlled analgesia for perioperative treatment of neuropathic/ischaemic pain in haemodialysis patients: a case series". J Clin Pharm Ther. 35 (5): 603–8. doi:10.1111/j.1365-2710.2009.01114.x. PMID 20831684. S2CID 205331535.
2. ^ Cathy S. Jewell; Chambers, James Q.; Chearney, Lee Ann; Romaine, Deborah S.; Candace B. Levy (2007). The Facts on File encyclopedia of health and medicine. New York: Facts on File. ISBN 978-0-8160-6063-4.
3. ^ Patient controlled analgesia for adults. Thomson Healthcare, Inc. 2010.
4. ^ Sarg, Michael; Altman, Roberta; Gross, Ann D (2007). The cancer dictionary. New York: Facts on File. ISBN 978-0-8160-6412-0.
5. ^ a b c Beers, Mark (2006). "Injuries". The Merck Manual of Diagnostics and Therapy (18th ed.). Merck Research Laboratories.
6. ^ Loeser, John David; Bonica, John J.; Butler, Stephen H.; Chapman, C. Richard (2001). Bonica's Management of Pain (3 ed.). Philadelphia, PA: Lippincott Williams & Wilkins. p. 772. ISBN 978-0-683-30462-6.
7. ^ Glanze, Walter D.; Anderson, Kenneth; Anderson, Lois E. (1998). Mosby's medical, nursing, & allied health dictionary. St. Louis: Mosby. ISBN 978-0-8151-4800-5.
8. ^ Taber, Clarence Wilbur; Venes, Donald (2009). Taber's encyclopedic medical dictionary. F a Davis Co. pp. 108–9. ISBN 978-0-8036-1559-5.
9. ^ Wexler RE (1968). "Analgizer: Inhaler for supervised self-administration of inhalation anesthesia". Abbott Park, Illinois: Abbott Laboratories. Retrieved 2010-11-21. Cite journal requires `|journal=` (help)
10. ^ a b c d Romagnoli A, Busque L, Power DJ (1970). "The "analgizer" in a general hospital: a preliminary report". Canadian Journal of Anesthesia. 17 (3): 275–8. doi:10.1007/BF03004607. PMID 5512851.
11. ^ Packer KJ, Titel JH (1969). "Methoxyflurane analgesia for burns dressings: experience with the Analgizer (subscription required)". British Journal of Anaesthesia. 41 (12): 1080–5. CiteSeerX 10.1.1.1028.6601. doi:10.1093/bja/41.12.1080. PMID 4903969.
12. ^ Major V, Rosen M, Mushin WW (1966). "Methoxyflurane as an obstetric analgesic: a comparison with trichloroethylene". BMJ. 2 (5529): 1554–61. doi:10.1136/bmj.2.5529.1554. PMC 1944957. PMID 5926260.
13. ^ Dragon A, Goldstein I (1967). "Methoxyflurane: preliminary report on analgesic and mood modifying properties in dentistry (subscription required)". Journal of the American Dental Association. 75 (5): 1176–81. doi:10.14219/jada.archive.1967.0358. PMID 5233333.
14. ^ Firn S (1972). "Methoxyflurane analgesia for burns dressings and other painful ward procedures in children (subscription required)". British Journal of Anaesthesia. 44 (5): 517–22. doi:10.1093/bja/44.5.517. PMID 5044082.
15. ^ Josephson CA, Schwartz W (1974). "The Cardiff Inhaler and Penthrane. A method of sedation analgesia in routine dentistry". Journal of the Dental Association of South Africa. 29 (2): 77–80. PMID 4534883.
16. ^ Babl F, Barnett P, Palmer G, Oakley E, Davidson A (2007). "A pilot study of inhaled methoxyflurane for procedural analgesia in children (subscription required)". Pediatric Anesthesia. 17 (2): 148–53. doi:10.1111/j.1460-9592.2006.02037.x. PMID 17238886. S2CID 30105092.
17. ^ Grindlay J, Babl FE (2009). "Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting". Emergency Medicine Australasia. 21 (1): 4–11. doi:10.1111/j.1742-6723.2009.01153.x. PMID 19254307. S2CID 40158248.
18. ^ Babl FE, Jamison SR, Spicer M, Bernard S (2006). "Inhaled methoxyflurane as a prehospital analgesic in children (subscription required)". Emergency Medicine Australasia. 18 (4): 404–10. doi:10.1111/j.1742-6723.2006.00874.x. PMID 16842312. S2CID 1619160.
19. ^ McLennan JV (2007). "Is methoxyflurane a suitable battlefield analgesic?" (PDF). Journal of the Royal Army Medical Corps. 153 (2): 111–3. doi:10.1136/jramc-153-02-08. PMID 17896540. S2CID 38517296. Archived from the original (PDF) on 2011-07-15. Retrieved 2010-11-21.
20. ^ Medical Developments International Pty. Ltd. (2009). "PENTHROX (methoxyflurane) Inhalation: Product Information" (PDF). Springvale, Victoria, Australia: Medical Developments International Limited. Retrieved 2010-11-21.
21. ^ National Prescribing Service (2010). "Methoxyflurane (Penthrox) for analgesia (doctor's bag listing)" (PDF). NPS RADAR. Canberra, Australia: National Prescribing Service, Department of Health and Ageing. Retrieved 2010-11-21.[permanent dead link]
22. ^ Miaskowski C (August 2005). "Patient-controlled modalities for acute postoperative pain management". J. Perianesth. Nurs. 20 (4): 255–67. doi:10.1016/j.jopan.2005.05.005. PMID 16102706.
23. ^ "Patient-controlled analgesia system (PCA)". Clinical Reference Systems. 10. McKesson Health Solutions. 2010.
24. ^ Pearce, Jeremy (2004-10-04). "Philip H. Sechzer, 90, Expert On Pain and How to Ease It". The New York Times. Retrieved 2010-11-22.
## Further reading[edit]
* Crombie, JM (1876). "On the self-administration of chloroform". The Practitioner. 16 (2): 97–101. ISSN 0032-6518. Retrieved 2010-11-23.
* Klieman RL, Lipman AG, Hare BD, MacDonald SD: A comparison of morphine administered by patient-controlled analgesia and regularly scheduled intramuscular injection in severe, postoperative pain. J Pain Sympt Manag 1988;3:15-22
* Sechzer, PH (1971). "Studies in pain with the analgesic-demand system". Anesthesia and Analgesia. 50 (1): 1–10. doi:10.1213/00000539-197101000-00001. ISSN 0003-2999. PMID 5100236. S2CID 39886476.
* Fast Fact and Concept #085: Epidural Analgesia, End of Life/Palliative Education Resource Center, Medical College of Wisconsin
* White PF: use of patient-controlled analgesia for the treatment of acute pain. JAMA 1988;259:242-247
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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
| Patient-controlled analgesia | None | 2,690 | wikipedia | https://en.wikipedia.org/wiki/Patient-controlled_analgesia | 2021-01-18T18:31:32 | {"wikidata": ["Q1382057"]} |
Chronic Hallucinatory Psychosis
SpecialtyPsychiatry
Chronic hallucinatory psychosis is a psychosis subtype, classified under "Other nonorganic psychosis" by the ICD-10 Chapter V: Mental and behavioural disorders. Other abnormal mental symptoms in the early stages are, as a rule, absent. The patient is most usually quiet and orderly, with a good memory.
It has often been a matter of the greatest difficulty to decide under which heading of the recognized classifications individual members of this group should be placed. As the hallucinations give rise to slight depression, some might possibly be included under melancholia. In others, paranoia may develop. Others, again, might be swept into the widespread net of dementia praecox. This state of affairs cannot be regarded as satisfactory, for they are not truly cases of melancholia, paranoia, dementia praecox or any other described affection.
This disease, as its name suggests, is a hallucinatory case, for it is its main feature. These may be of all senses, but auditory hallucinations are the most prominent. At the beginning, the patient may realize that the hallucination is a morbid phenomenon and unaccountable. They may claim to hear a "voice" speaking, though there is no one in the flesh actually doing so. Such a state of affairs may last for years and possibly, though rarely, for life, and the subject would not be deemed insane in the ordinary sense of the word.
It's probable, however, that this condition forms the first stage of the illness, which eventually develops on definite lines. What usually happens is the patient seeks an explanation for the hallucinations. As none is forthcoming he/she tries to account for their presence and the result is a delusion, and, most frequently, a delusion of persecution. Also, it needs to be noted that the delusion is a comparatively late arrival and is the logical result of the hallucinations.[1]
## References[edit]
1. ^ A paper read at the Quarterly Meeting of the Medico-Psychological Association on February 24th, 1920, written by Robert Hunter Steen, King's College Hospital, London
## External links[edit]
Classification
D
* ICD-10: F28
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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
| Chronic hallucinatory psychosis | c2874859 | 2,691 | wikipedia | https://en.wikipedia.org/wiki/Chronic_hallucinatory_psychosis | 2021-01-18T19:09:58 | {"umls": ["C2874859"], "icd-10": ["F28"], "wikidata": ["Q3410138"]} |
A rare multiple congenital anomalies/dysmorphic syndrome characterized by a large omphalocele containing liver and small intestine, diaphragmatic hernia, cardiovascular anomalies (e. g. aortic coarctation), variable limb malformations (including radioulnar synostosis, agenesis of the radius and/or thumb, generalized syndactyly, and numerical reduction of toes), and dysmorphic facial features. Additional reported manifestations are unilateral absence of umbilical artery, intestinal malrotation, hypoplastic ovaries, and unilateral renal agenesis, among others. The condition is mostly fatal in the neonatal period.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome | c1836007 | 2,692 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=496693 | 2021-01-23T18:41:42 | {"mesh": ["C563701"], "omim": ["609545"], "synonyms": ["Gershoni-Baruch syndrome"]} |
A number sign (#) is used with this entry because of evidence that gastrointestinal defects and immunodeficiency syndrome (GIDID) is caused by homozygous or compound heterozygous mutation in the TTC7A gene (609332) on chromosome 2p21.
Description
Gastrointestinal defects and immunodeficiency syndrome (GIDID) is characterized by multiple intestinal atresia, in which atresia occurs at various levels throughout the small and large intestines. Surgical outcomes are poor, and the condition is usually fatal within the first month of life. Some patients exhibit inflammatory bowel disease (IBD), with or without intestinal atresia, and in some cases, the intestinal features are associated with either mild or severe combined immunodeficiency (Samuels et al., 2013; Avitzur et al., 2014; Lemoine et al., 2014).
Clinical Features
Multiple intestinal atresia is likely separate from duodenal atresia (223400) and jejunal atresia (243600) because of the wide distribution of involvement, from stomach to anus (Guttman et al., 1973). Dallaire and Perreault (1974) reported 5 French Canadian patients with multiple intestinal atresia in 3 sibships with common ancestry. Two of the 3 sibships had demonstrably consanguineous parents. Intraluminal calcifications were demonstrable radiographically.
Blackburn et al. (1983) reported a male with multiple intestinal atresia whose older sib and a paternal uncle had died as neonates with similar anomalies.
Kao et al. (1983) reported 2 affected black sibs; Arnal-Monreal et al. (1983) reported 2 affected Spanish sibs; and Puri et al. (1985) reported 3 affected Irish sibs.
Shen-Schwarz and Fitko (1990) reviewed 18 cases from the literature and reported an isolated case in an infant with imperforate anus.
Moreno et al. (1990) reported a family in which 3 brothers had multiple intestinal atresia in combination with severe combined immunodeficiency (SCID; see 601457). All 3 died in the first months of life. Since both are known to be autosomal recessive disorders, it is possible that this represents an instance of genetic linkage of intestinal atresia with an autosomal recessive form of SCID. Deficiency of adenosine deaminase was excluded. Bigorgne et al. (2014) reported 6 patients from 6 unrelated pedigrees with multiple intestinal atresia with combined immunodeficiency, including the younger sister of the patients reported by Moreno et al. (1990). She was born with a prepyloric diaphragm defect, 'micro-small' intestine, microcolon, and colic atresia. At 7 months of age, she developed SCID. A thymus could not be visualized on chest x-ray at age 20 months. She died at age 2.5 years of sepsis. Bigorgne et al. (2014) also reported a male born in France, whose parents came from geographically close villages in Sri Lanka, who was diagnosed prenatally with intestinal atresia. He later displayed rapidly progressive, generalized, profound SCID. At age 4 years, he developed progressive skin abnormalities with mild pachyderma on both hands and feet. He was still alive at age 8.
Gungor et al. (1995) reported 2 affected children, the offspring of consanguineous Turkish parents. Most reported cases have been either prematurely born or small for gestational age. Polyhydramnios can be detected prenatally in some cases. Plain radiographs of the abdomen demonstrated calcified areas, which were found to be intraluminal during surgery. In some of the patients, the intraluminal material is described as a pasty milky substance. Calcification of intraluminal meconium is probably secondary to intestinal stasis. The calcific collections may permit prenatal detection of the disorder by ultrasonography (McHugh and Daneman, 1991). Low level of disaccharidase in the amniotic fluid at 15-19 weeks of gestation is another diagnostic test (Morin et al., 1980).
Bilodeau et al. (2004) reviewed 16 cases of multiple intestinal atresia, 11 female and 5 male, occurring over 30 years in the Quebec area, including 4 probands from Saguenay-Lac-St-Jean. Five patients presented with intrauterine growth retardation. Other associated anomalies included malrotation in 3 patients, common bile duct dilation in 2, and omphalocele, ventricular septal defect, and congenital cystic adenomatoid malformation in 1 patient each. Two patients had IgM immunodeficiency. Intestinal atresia was strongly suspected prenatally in 6 of 13 patients who had prenatal ultrasound scans, based on the presence of polyhydramnios, calcifications, and/or bowel distention. Laparotomy was performed on all patients, and all had multiple areas of type I and/or type II atresia from the foregut to the hindgut. Despite an attempt at curative surgery in 11 patients, none regained bowel function; all patients eventually died, with a mean survival time of 50 days. Pathologic examination of the resected bowel revealed sieve-like luminae in 10 of 15 patients. Other frequent findings included mucous membrane ulceration and granulation tissue, each noted in 3 cases.
Chen et al. (2013) studied 8 unrelated patients with multiple intestinal atresia from families of various ethnic origins, including Arabic, Serbian, Bosnian, French Canadian, mixed European, and Italian. Profound CD8+ T-cell lymphopenia was observed in all 7 patients tested. Severe hypogammaglobulinemia was a common feature, and all patients had recurrent and severe infections. Chen et al. (2013) noted that in contrast to typical SCID cases, these patients had fewer viral infections and a higher frequency of bloodstream infections caused by intestinal microbes, and suggested that this might reflect abnormalities of the gut barrier in patients with multiple congenital atresia. Postmortem analysis of the thymus from 1 patient showed severe lymphoid depletion and vague corticomedullary demarcation with preservation of Hassell corpuscles; severe lymphoid depletion affecting both T and B cells was also demonstrated in peripheral lymph nodes from 2 patients. Chen et al. (2013) designated the phenotype in these patients 'combined immunodeficiency with multiple intestinal atresias (CID-MIA).'
Avitzur et al. (2014) reported 5 infants from 3 families who had severe IBD, associated with immunodeficiency in 2 families and with jejunal atresia in 1 family. Three patients died in the first year of life and another at 19 months; 1 patient was alive and partially treated with total parenteral nutrition (TPN). Pathologic analysis of patient intestinal specimens from all 3 families showed similar features, including loss of intestinal architecture, focal scarring, and severe inflammation with increased enterocyte apoptosis as well as areas where surface epithelium was detached. Avitzur et al. (2014) designated the disorder in these families as a very early-onset inflammatory bowel disease (VEOIBD).
Lemoine et al. (2014) described 13 affected members of a large consanguineous kindred who had enteropathy associated with T-cell, B-cell, and natural killer cell combined immunodeficiency. All patients exhibited signs of IBD within the first days or months of life, with recurrent severe diarrhea that was sometimes bloody. The severity of gastrointestinal manifestations gradually decreased with age; the 9 patients who required parenteral nutrition were able to discontinue it by 5 years of age, although the enteropathy was fatal in 1 case. Endoscopy showed severe inflammation, with an erythematous stomach and multiple areas of ulcerative lesions in the sigmoid; immunohistopathologic analysis revealed major lesions in the antrum and colon in all patients, whereas the small intestine was relatively unaffected. The changes observed in the fundus and antrum were similar in all patients analyzed at different ages, and included disorganized epithelial architecture with tufting, loss of apical mucin, abnormal pseudostratified cell organization with glandular distortion, and epithelial apoptosis. Colon lesions were severe and widespread, with epithelial dedifferentiation and little remaining mucus-secreting tissue; glandular necrosis, cell apoptosis, and crypt abscesses in multiple sites were also observed. There was an inflammatory infiltrate of mononuclear cells and a high eosinophil count in the lamina propria of both the gastric and colonic areas. Five patients in this family also had with transient alopecia from the age of 2 to 4 years, and 4 had onychopathy; 4 patients developed signs of autoimmune disease in the second decade of life, including autoimmune hepatitis, hemolytic anemia, thyroiditis, psoriasis, and type I diabetes. Of 13 affected individuals, 8 were alive at the time of the report, with the 3 oldest being 14, 28, and 50 years of age. Lemoine et al. (2014) also studied a 2-year-old boy from an unrelated family who had a similar but milder phenotype, with protracted neonatal bloody diarrhea and recurrent anal abscesses. He received partial enteral nutrition for 10 months, and had recurrent respiratory tract infections associated with hypogammaglobulinemia. He also had sparse hair, including absent eyebrows. Lemoine et al. (2014) designated the condition in the 2 families 'enteropathy-lymphocytopenia-alopecia (ELA).'
Neves et al. (2018) reported a 5-year-old girl who presented with type 1 ileal atresia (ileocecal membrane) at 2 months of age. At 5 months she developed bloody diarrhea, and colon biospy showed inflammatory pseudopolyps, caliciform cell depletion, and glandular distortion/atrophy. Examination showed dysmorphic features including prominent forehead and hypertelorism as well as enamel dysplasia. At 20 months she developed self-limited but recurrent elevations of liver enzymes, and biopsy showed mild fibrosis and interface hepatitis. She also experienced episodes of leukocytosis and thrombocytosis unrelated to infections, and immunologic evaluation revealed severe symptomatic hypogammaglobulinemia, associated with recurrent respiratory infections and absent serologic response to vaccines. Subcutaneous immunoglobulin replacement resulted in dramatic improvement, with fewer infections, no more episodes of leukocytosis, and improvement in colonic inflammation. At age 5 years, she had been asymptomatic for 12 months and was at the 50th centile for height, weight, and head circumference, with normal neurologic development.
Inheritance
The transmission pattern of multiple intestinal atresia in several reported families (e.g., Dallaire and Perreault, 1974, Puri et al. (1985), and Gungor et al., 1995) was consistent with autosomal recessive inheritance.
Population Genetics
Shen-Schwarz and Fitko (1990) noted that the patients reported by Guttman et al. (1973), Dallaire and Perreault (1974), Martin et al. (1976), Daneman and Martin (1979), and Skoll et al. (1987) were all French Canadian, suggesting an increased frequency in this ethnic group.
Mapping
In a large consanguineous kindred with enteropathy and combined immunodeficiency, Lemoine et al. (2014) performed genomewide homozygosity mapping with a SNP array that revealed a common 4-Mb region on chromosome 2p21-p16.3.
Molecular Genetics
Samuels et al. (2013) sequenced the exomes of 3 French Canadian probands with multiple intestinal atresia and identified only 1 homozygous variant shared by all 3 patients, a 4-bp deletion in the TTC7A gene (609332.0001), which was confirmed by Sanger sequencing and segregated with disease in each family. Sanger sequencing in 4 more affected French Canadian families revealed homozygosity for the 4-bp deletion in 1 proband; in 2 families in which DNA was unavailable from the deceased affected individuals, the parents were heterozygous for the deletion. In another French Canadian family, 2 affected sibs, 1 of whom exhibited severe immunodeficiency characterized by recurrent infections associated with hypogammaglobulinemia and profound T-cell lymphopenia, were compound heterozygous for the 4-bp deletion and a missense mutation (L832P; 609332.0002) in the TTC7A gene. Samuels et al. (2013) concluded that TTC7A was the likely causal gene for multiple intestinal atresia.
In 8 unrelated patients of varying ethnic origins who had combined immunodeficiency and multiple intestinal atresia, Chen et al. (2013) identified homozygous or compound heterozygous mutations in the TTC7A gene (see, e.g., 609332.0001, 609332.0002, 609332.0008-609332.0010). All of the mutations were not found or were rare in the 1000 Genomes Project and Exome Sequencing Project (ESP65400) databases, and were located at highly conserved regions of the gene.
Bigorgne et al. (2014) reported 6 patients from 6 unrelated pedigrees with multiple intestinal atresia and combined immunodeficiency who had mutations in the TTC7A gene (see, e.g., 609332.0003-609332.0007). Using gut organoids from 2 of these patients, Bigorgne et al. (2014) found that a lack of TTC7A led to disorganized and pseudostratified cell structures, low numbers of villi, and high levels of apoptosis. The authors found that TTC7A plays a critical role in apicobasal polarization of epithelial cells by regulating the RhoA (165390) signaling pathway.
In 5 infants from 3 families with apoptotic enterocolitis, variably associated with immunodeficiency and/or intestinal atresia, Avitzur et al. (2014) identified homozygosity or compound heterozygosity for mutations in the TTC7A gene (609332.0011-609332.0015). The authors noted that all reported TTC7A-deficient patients either died in infancy due to progressive bowel disease or failed allogeneic hematopoietic stem cell transplantation, or survived with short gut and total parenteral nutrition.
In a large consanguineous kindred with enteropathy and combined immunodeficiency mapping to chromosome 2p21-p16.3, Lemoine et al. (2014) sequenced the candidate gene TTC7A and identified homozygosity for a previously reported missense mutation (E71K; 609332.0014), which segregated with disease in the family. In addition, an affected 2-year-old boy from an unrelated family was compound heterozygous for a 1-bp deletion and a missense mutation in TTC7A.
In a 5-year-old girl with enteropathy, hepatic abnormalities, and isolated hypogammaglobulinemia, who was negative for mutation in the TTC37 (614589) and SKIV2L (600478) genes, Neves et al. (2018) performed whole-exome sequencing and identified compound heterozygosity for missense mutations in the TTC7A gene (A863T, 609332.0016 and S539L, 609332.0017). Her unaffected parents were each heterozygous for 1 of the mutations, both of which were rare in the gnomAD database.
Genotype/Phenotype Correlations
Neves et al. (2018) stated that 52 patients with GIDID had been reported worldwide, and noted that there appeared to be a severe form, with multiple intestinal atresia and combined immunodeficiency, resulting in premature death, and a milder form, with predominant features of very early-onset IBD, less severe immunologic involvement, and hair abnormalities. The authors suggested that the milder phenotype was associated with missense mutations that were likely hypomorphic, whereas the severe phenotype was associated with null mutations.
History
Mishalany and Der Kaloustian (1971) described multiple-level intestinal atresia in 2 sons of distantly related parents.
INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth retardation HEAD & NECK Face \- Prominent forehead (rare) Eyes \- Hypertelorism (rare) Teeth \- Enamel dysplasia (rare) CARDIOVASCULAR Heart \- Ventricular septal defect (rare) RESPIRATORY Lung \- Cystic adenomatoid malformation, congenital (rare) ABDOMEN External Features \- Omphalocele (rare) Liver \- Autoimmune hepatitis (rare) \- Mild fibrosis (rare) \- Interface hepatitis (rare) Biliary Tract \- Common bile duct dilation (in some patients) Gastrointestinal \- Multiple areas of atresia along the small and large intestines \- Intestinal malrotation (in some patients) \- Intraluminal calcification on prenatal ultrasound or plain abdominal radiographs \- Bowel distention on prenatal ultrasound \- Multiple small luminae with a sieve-like appearance seen on microscopic examination \- Mucous membrane ulceration (in some patients) \- Granulation tissue (in some patients) \- Bloody diarrhea \- Apoptotic enteropathy \- Focal scarring \- Disorganized epithelial architecture \- Tufting \- Loss of apical mucin \- Glandular distortion and necrosis \- Crypt abscesses \- Inflammatory infiltrate in lamina propria SKIN, NAILS, & HAIR Skin \- Psoriasis (rare) Nails \- Onychopathy (rare) Hair \- Transient alopecia in early childhood (in some patients) ENDOCRINE FEATURES \- Autoimmune thyroiditis (rare) \- Diabetes, type 1 (rare) HEMATOLOGY \- Autoimmune hemolytic anemia (rare) IMMUNOLOGY \- IgM immunodeficiency (in some patients) \- Immunodeficiency, severe combined (in some patients) \- Autoimmunity (rare) \- Thymus hypoplasia (in some patients) \- Isolated hypogammaglobulinemia (rare) PRENATAL MANIFESTATIONS Amniotic Fluid \- Polyhydramnios MISCELLANEOUS \- Fatal in first few months of life in most cases MOLECULAR BASIS \- Caused by mutation in the tetratricopeptide repeat domain-containing protein-7A gene (TTC7A, 609332.0001 ) ▲ Close
*[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
| GASTROINTESTINAL DEFECTS AND IMMUNODEFICIENCY SYNDROME | c0220744 | 2,693 | omim | https://www.omim.org/entry/243150 | 2019-09-22T16:26:19 | {"doid": ["14671"], "mesh": ["C562441"], "omim": ["243150"], "orphanet": ["436252", "2300"], "synonyms": ["FAMILIAL INTESTINAL POLYATRESIA SYNDROME", "INTESTINAL ATRESIA, MULTIPLE", "INTESTINAL ATRESIA, MULTIPLE AND/OR INFLAMMATORY BOWEL DISEASE WITH OR WITHOUT IMMUNODEFICIENCY", "Alternative titles", "CID-MIA/early-onset IBD"]} |
Hereditary sensory and autonomic neuropathy type I
SpecialtyNeurology
Hereditary sensory and autonomic neuropathy type I (HSAN I) or hereditary sensory neuropathy type I (HSN I) is a group of autosomal dominant inherited neurological diseases that affect the peripheral nervous system particularly on the sensory and autonomic functions. The hallmark of the disease is the marked loss of pain and temperature sensation in the distal parts of the lower limbs. The autonomic disturbances, if present, manifest as sweating abnormalities.[1][2]
The beginning of the disease varies between adolescence and adulthood. Since affected individuals cannot feel pain, minor wounds or blisters in the painless area may not be immediately recognized and can develop into extensive and deep foot ulcerations. Once infection occurs, the complications such as inflammation and progressive destruction of the underlying bones may follow and may require amputation of the surrounding area.[1][2][3][4]
HSAN I is the most common type among the five types of HSAN. As a heterogeneous group of diseases, HSAN I can be divided into five subtypes HSAN IA-E. Most of the genes associated with the diseases have been identified. However, the molecular pathways leading to the manifestation of the diseases are not fully understood. Therefore, the potential targets for therapeutic interventions are not known. Moreover, gene-based therapies for patients with the diseases are not available to date, hence supportive care is the only treatment available for the patients.[2]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 2.1 HSAN IA
* 2.2 HSAN IB
* 2.3 HSAN IC
* 2.4 HSAN ID
* 2.5 HSAN IE
* 3 Diagnosis
* 3.1 Subtypes
* 4 Management
* 4.1 Genetic counseling
* 5 Prognosis
* 6 Epidemiology
* 7 History
* 8 See also
* 9 References
* 10 External links
## Signs and symptoms[edit]
At the beginning, affected individuals often notice the loss of pain and temperature sensation or all sensory modalities in their feet. As the disease progresses, the sensory abnormalities may extend up to the knees. However, they often do not notice sensory loss for a long time.[5] Many affected individuals only become aware of the disease when they notice painless injuries and burns or when they seek medical advice for slowly healing wounds or foot ulcers. Foot ulcerations may appear due to permanent pressure, such as long walks or badly fitting shoes. Minor wounds or blisters may then lead to deep foot ulcerations. Once infection occurs, complications such as inflammation and destruction of the underlying bones may follow.[1][2][3][6] Affected individuals who do not lose sensation may experience spontaneous pain.[3] In addition, many affected individuals exhibit, to a variable degree, symmetrical distal muscle weakness and wasting.[7][6]
HSAN I is characterized by marked sensory disturbances mainly as the loss of pain and temperature sensation in the distal parts of the lower limbs. The loss of sensation can also extend to the proximal parts of the lower limbs and the upper limbs as the disease progresses.[2] Some affected individuals do not lose sensation, but instead experience severe shooting, burning, and lancinating pains in the limbs or in the trunk. Autonomic disturbances, if present, manifest as decreased sweating.[3][8] The degree of motor disturbances is highly variable, even within families, ranging from absent to severe distal muscle weakness and wasting.[1]
The disease progresses slowly, but often disables the affected individuals severely after a long duration. The onset of the disease varies between the 2nd and 5th decade of life,[2] albeit congenital or childhood onset has occasionally been reported.[1][9] With the progression of the disease, the affected individuals lose the ability to feel pain in their feet and legs. Minor injuries in the painless area can result in slow-healing wounds which, if not immediately recognized, can develop into chronic ulcerations. Once infection occurs, these ulcerations can result in severe complications that lead to foot deformity, such as inflammation of the underlying bones, spontaneous bone fractures, and progressive degeneration of weight-bearing joints. Furthermore, foot deformity promotes skin changes such as hyperkeratosis at pressure points. These complications may necessitate amputation of the affected foot.[3][8]
Biopsies of severely affected sural nerve (short saphenous nerve) in patients with HSAN I showed evidence of neuronal degeneration. Only a very few myelinated fibers were observed some of which showed a sign of primary (segmental) demyelination. A reasonable number of unmyelinated axons remained, although the presence of stacks of flattened Schwann cell processes suggested unmyelinated axon loss.[1] Electrophysiological testing provides additional evidence that neuronal degeneration underlies the disease. Sensory potentials are usually absent in the lower limbs but are often recordable or even normal in the upper limbs of the patients.[1][3] In addition, motor conduction is slow, possibly implying a demyelinating process.[10][11]
## Cause[edit]
Advances in molecular genetics have enabled identification of most genes associated with HSAN I. However, the molecular mechanisms that underlie the disease are not fully understood and are under investigation. One of challenges in the investigation is to elucidate how faulty genes that are ubiquitously expressed and are involved in basic cellular functions, such as sphingolipid metabolism, maintenance of organellar integrity, membrane dynamics, and transcription regulation, affect specific populations of neurons.[8]
### HSAN IA[edit]
HSAN IA is associated with heterozygous missense mutations in the SPTLC1 gene.[9][12][13][14] The gene encodes SPTLC1 protein, which together with SPTLC2 protein, forms serine palmitoyltransferase (SPT) in humans. SPT is a pyridoxal-5'-phosphate-dependent enzyme that catalyzes the first and rate-limiting step in the de novo biosynthesis of sphingolipids.[15] Together with cholesterol, sphingolipids form the main component of lipid rafts, structures in the plasma membrane that facilitate efficient signal transduction.[16] Many intermediate sphingoid bases and their derivatives, as well as complex sphingolipids, are active as extracellular and intracellular regulators of growth, differentiation, migration, survival, and cellular responses to stress.[17]
Initially, mutations in the SPTLC1 gene were associated with increased activity of SPT.[12] Subsequent studies rather suggested that the mutations reduce the activity of the enzyme.[18][19] However, it cannot account for the aberrant sphingolipid-related cellular features in heterozygous patient-derived cells[20] or the HSAN IA clinical features in heterozygous mice.[21] These results suggest that the activity of non-mutant SPTLC1 protein may be sufficient for maintaining normal sphingolipid biosynthesis and cell viability. Therefore, the neuronal degeneration in HSAN IA is likely due to subtler and rather long-term effects of the mutations or perhaps accumulation of toxic lipids produced by mutant enzymes.[20]
Further studies supported the latter notion. The mutations have been shown in vitro to facilitate substrate promiscuity of SPT. Mutant SPT mediates the condensation not only of its normal substrate serine, but also of alanine or glycine, with palmitoyl-coenzyme A. The reactions lead to the formation of two aberrant sphingolipid metabolites 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine, respectively. As the metabolites lack a hydroxyl group that is required for their further conversion and degradation, they accumulate inside the cell.[22][23] The metabolites have been shown to be more toxic to sensory neurons than to motor neurons.[22] They accumulate in the peripheral nervous system where HSAN manifest, but not in the central nervous system in mice bearing a HSAN IA-associated mutation.[24] Furthermore, serine-enriched diet reduced the levels of the metabolites and improved sensory and motor performance of the mice. A small-scale clinical trial also showed similar results. These studies demonstrated that an altered substrate selectivity of the mutant SPT is the key to the pathophysiology of HSAN IA.[25]
### HSAN IB[edit]
HSAN IB is linked to a 3.42 cM interval on chromosome 3p22–p24.[26] This finding was confirmed in another family with similar clinical features. However, mutation analysis of genes in the candidate region has not revealed any disease-causing gene.[27] Since then, this rare form of HSAN I has not been reported in other families. The gene associated with the disease still remains to be identified.[citation needed]
### HSAN IC[edit]
HSAN IC is associated with heterozygous missense mutations in the SPTLC2 gene. The gene encodes SPTLC2 protein which is one of two subunits of SPT. As mutations in the gene affect the same enzyme as those in the SPTLC1 gene, the molecular basis of the disease is suggested to be the same as that of HSAN IA.[28]
### HSAN ID[edit]
HSAN ID is caused by heterozygous missense mutations in the ATL1 gene which encodes atlastin-1.[29] Atlastin-1 is a member of the dynamin/Mx/guanylate-binding protein superfamily of large GTPases. The enzyme contains an endoplasmic reticulum (ER) retention moiety, indicating that it functions predominantly in the organelle. It is highly expressed in the mammalian central nervous system and is enriched in the hippocampus and pyramidal neurons.[30] However, information on the expression of the gene in the peripheral nervous system is still lacking.[8]
In fruit fly (Drosophila melanogaster), atlastin-1 has been shown to induce tethering and fusion of membranes adjacent to the ER to help maintain the integrity of the ER.[31] The function of atlastin-1 is crucially dependent on its GTPase activity. In humans, a HSAN ID-associated mutation caused significant loss of the GTPase activity of the enzyme, leading to prominent disruption of ER network.[29] In addition to maintaining the integrity of the ER, atlastin-1 also has neuron-related functions. The enzyme is implicated in the trafficking and signaling of type I bone morphogenetic protein (BMP) receptors in zebra fish (Danio rerio). BMP signaling is involved in axon guidance and synapse formation, as well as axonal transport and the organization of the microtubule network in developing neurons. The signaling is disturbed in several neurodegenerative disorders.[32] It also regulates membrane dynamics in the neuronal growth cone in rat.[33]
Mutations in the ATL1 gene are also a common cause of early-onset hereditary spastic paraplegia (HSP) in humans.[34] The disease is characterized by progressive stiffness and contraction (spasticity) in the lower limbs due to damage to or dysfunction of the nerves. The vast majority of HSP-associated mutations are missense mutations that are scattered throughout the affected protein. Some of these mutations have been shown to reduce the GTPase activity of atlastin-1 in vitro.[33] However, the unique molecular signature of the mutations or the functional domains of the ATL1 gene that are affected in patients with HSAN ID and HSP that could explain the differences in clinical features between these two diseases are not clear. This finding indicates that additional genetic and/or environmental factors may modulate the clinical manifestation of the main causative mutation.[8]
### HSAN IE[edit]
HSAN IE is associated with heterozygous missense mutations in the DNMT1 gene which encodes DNA methyltransferase 1 (Dnmt1).[35] Dnmt1 belongs to a family of enzymes that catalyze the transfer of a methyl group from S-adenosyl methionine to DNA. Dnmt1 has a high preference for hemimethylated DNA, hence it is called maintenance methyltransferase. The protein also has de novo DNA methyltransferase activity which is responsible for establishing methylation patterns during embryonic development.[36] Dnmt1 is highly expressed in post-mitotic neurons in the adult central nervous system, with peak expression during the S-phase of the cell cycle.[37]
The mutations are located in the DNA-sequence-targeting domain of Dnmt1 which is responsible for chromatin binding during the late S-phase and for sustaining the association of Dnmt1 with DNA during the G2 and M-phases of the cell cycle. Mutant Dnmt1 is misfolded and unable to bind to heterochromatin after the S-phase. Therefore, the mutant proteins are quickly targeted for degradation. In patients with the mutations, global hypomethylation and local hypermethylation are observed in their genomic DNA. These observations establish a formal causal link between DNA methylation defects and a disease of the peripheral nervous system.[36]
## Diagnosis[edit]
The diagnosis of HSAN I is based on the observation of symptoms described above and is supported by a family history suggesting autosomal dominant inheritance. The diagnosis is also supported by additional tests, such as nerve conduction studies in the lower limbs to confirm a sensory and motor neuropathy. In sporadic cases, acquired neuropathies, such as the diabetic foot syndrome and alcoholic neuropathy, can be excluded by the use of magnetic resonance imaging and by interdisciplinary discussion between neurologists, dermatologists, and orthopedics.[1][2]
The diagnosis of the disease has been revolutionized by the identification of the causative genes. The diagnosis is now based on the detection of the mutations by direct sequencing of the genes. Nevertheless, the accurate phenotyping of patients remains crucial in the diagnosis.[4] For pregnant patients, termination of pregnancy is not recommended.[1][2]
HSAN I must be distinguished from hereditary motor and sensory neuropathy (HMSN) and other types of hereditary sensory and autonomic neuropathies (HSAN II-V). The prominent sensory abnormalities and foot ulcerations are the only signs to separate HSAN I from HMSN.[2][38][39] HSAN II can be differentiated from HSAN I as it is inherited as an autosomal recessive trait, it has earlier disease onset, the sensory loss is diffused to the whole body, and it has less or no motor symptoms. HSAN III-V can be easily distinguished from HSAN I because of congenital disease onset. Moreover, these types exhibit typical features, such as the predominant autonomic disturbances in HSAN III or congenital loss of pain and anhidrosis in HSAN IV.[1][2]
### Subtypes[edit]
In 1993, Peter James Dyck divided HSAN I further into five subtypes HSAN IA-E based on the presence of additional features. These features were thought to result from the genetic diversity of HSAN I (i.e. the expression of different genes, different alleles of a single gene, or modifying genes) or environmental factors.[40] Molecular genetic studies later confirmed the genetic diversity of the disease.[41]
Subtype Gene or locus Mutation (DNA/Amino acid)* Clinical features Age of onset OMIM*
IA SPTLC1 399T>G/C133W; 398G>A/C133Y;[12][13] 431T>A/V144D[12] Predominant loss of pain and temperature sensation; sometimes initial sign with long preservation of vibration sense; burning and lancinating pains; ulcerative mutilations; variable distal motor involvement Adolescence* 162400
IB 3p24-p22[26][27] unknown Predominant sensory neuropathy with cough and gastroesophageal reflux; foot ulcerations (rare) Adulthood 608088
IC SPTLC2[28] 1075G>A/V359M; 1145G>T/G382V; 1510A>T/I504F Loss of pain and temperature sensation; lancinating pain; ulcerative mutilations; variable distal motor involvement; acro-mutilating complications Adulthood*[42] 613640
ID ALT1[29] 196G>C/E66Q; 976delG/[V326WfsX8]* Severe distal sensory loss and amyotrophy in lower limbs; trophic skin and nail changes; ulcerative mutilations Adulthood 613708
IE DNMT1[35] 1484A>G/Y495C; 1470-1472TCC>ATA/D490E-P491Y* Loss of all somatosensory modalities; lancinating pain; ulcerative mutilations; sensorineuronal hearing loss, dementia Adulthood 614116
^DNA; A: adenine, T: thymine, G: guanine, C: cytosine. Amino acid; C: cysteine, W: tryptophan, Y: tyrosine, V: valine, D: aspartic acid, M: methionine, G: glycine, I: isoleucine, F: phenylalanine, E: glutamic acid, Q: glutamine, P: proline.
^The nucleotide deletion predicted to cause a large C-terminal protein truncation.
^A triple nucleotide change.
^Congenital onset in one patient with hypotonia, cataracts, microcephaly, and vocal cord paralysis.
^Childhood onset in one patient.
^OMIM: Online Mendelian Inheritance in Man.
## Management[edit]
Gene-based therapies for patients with HSAN I are not available to date, hence supportive care is the only treatment available for the patients. Ulcero-mutilating complications are the most serious, prominent, and leading diagnostic features in HSAN I. Since the complications mimic foot ulcers caused by diabetic neuropathy, the treatment for foot ulcers and infections can follow the guidelines given for diabetic foot care which starts with early and accurate counseling of patients about risk factors for developing foot ulcerations. Orthopedic care and the use of well fitting shoes without pressure points should also be included. Recently, the treatment of the foot complications has reached an efficient level allowing treatment on an outpatient basis. Early treatment of the foot complications often avoids hospitalization and, in particular, amputations. In sum, the principles of the treatment are removal of pressure to the ulcers, eradication of infection, and specific protective footwear afterwards.[1][2]
### Genetic counseling[edit]
Autosomal dominant mode of inheritance
Genetic counseling is an important tool for preventing new cases if this is wished by at-risk family members. Appropriate genetic counseling is based on an accurate diagnosis. Therefore, clinicians and genetic counselors should use ulcero-mutilating complications as the main diagnostic criteria.[43] Since the disease is inherited as an autosomal dominant trait, there is a Mendelian risk of 50% for subsequent generations regardless of their sex. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in the family. Predictive testing is useful for young people to avoid serious complications of the disease.[1][2]
## Prognosis[edit]
If patients with HSAN I receive appropriate treatment and counseling, the prognosis is good. Early treatment of foot infections may avoid serious complications. Nevertheless, the complications are manageable, thus allowing an acceptable quality of life. The disease progresses slowly and does not influence the life expectancy if signs and symptoms are properly treated.[1][2]
## Epidemiology[edit]
HSAN I constitutes a clinically and genetically heterogeneous group of diseases of low prevalence. Detailed epidemiological data are currently not available. The frequency of the disease is still reflected by reports of a handful affected families. Although the impressive clinical features of HSAN I are seen by neurologists, general practitioners, orthopedists, and dermatologists, the condition might still be under-recognized particularly for sporadic cases and patients who do not exhibit the characteristic clinical features.[1][2]
## History[edit]
The first description of sporadic and familial cases of a condition that is compatible with HSAN was made in French literature in the 19th century. The main feature of the familial case was ulcers at the sole of the feet.[44][45] In 1922, Hicks described a similar condition in a London family in which 10 persons suffered from perforating ulcers on their feet, lancinating and shooting pains, and deafness.[46] Subsequently, Jughenn et al.[47] and Denny-Brown[7] demonstrated that the pathological process underlying the clinical features seen in these conditions was a neuropathy, rather than an anatomical disorder as had been previously suggested. Since then, many other familial conditions with similar clinical features have been reported.[3][48][49][50][51][52][5][10][excessive citations]
The early names of the inherited neuropathies were given after the most prominent features or the suggested underlying mechanism of the diseases, such as mal perforant du pied, ulcero-mutilating neuropathy, hereditary perforating ulcers, familial trophoneurosis, familial syringomyelia, hereditary sensory radicular neuropathy, among others. In dermatological literature, the term Thèvenard syndrome is still used for familial forms, whereas Bureau-Barrière syndrome is for sporadic forms.[41]
In 1975, Dyck and Otha proposed a descriptive classification of the diseases and introduced the term hereditary sensory neuropathy (HSN) which later was changed to hereditary sensory and autonomic neuropathy (HSAN) given the substantial autonomic involvement in the diseases.[3] The diseases were categorized into five types HSAN I-V based on the mode of inheritance, the predominant clinical features, and the age at onset. The diseases that are characterized by autosomal dominant mode of inheritance and adolescence or adulthood disease onset are categorized in HSAN I.[41][40]
## See also[edit]
* Hereditary sensory and autonomic neuropathy
* Hereditary sensory and autonomic neuropathy type III (Familial dysautonomia)
* Hereditary sensory and autonomic neuropathy type IV (Congenital insensitivity to pain with anhidrosis)
* Hereditary motor and sensory neuropathy
* A Life Without Pain
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45. ^ Nélaton, M (1852). "Affection singulière des os du pied". Gazette Hopitaux Civils Militaires. 4: 13–20.
46. ^ Hicks, E (1922). "Hereditary perforating ulcer of the foot". Lancet. 199 (5138): 319–21. doi:10.1016/s0140-6736(01)27079-2.
47. ^ Jughenn, H; Krucke, W; Wadulla (1949). "Zur Frage der familiaren syringomyelie (Klinisch-anatomische Untersuchungen uber familiare neurovasculare Dystrophie der Extremitaten)". Arch Psychiat Nervenkr. 182: 153–76.
48. ^ Campbell, AM; Hoffman, HL (March 1964). "Sensory radicular neuropathy associated with muscle wasting in two cases". Brain : A Journal of Neurology. 87: 67–74. doi:10.1093/brain/87.1.67. PMID 14152213.
49. ^ Thèvenard, A (1942). "L'acropathie ulcero-mutilante familiale". Rev. Neurol. (Paris). 74: 193–203.
50. ^ Thèvenard, A (1953). "L'acropathie ulcero-mutilante familiale". Acta Neurol Belg. 53: 1–23.
51. ^ Jackson, M (Apr 2, 1949). "Familial lumbo-sacral syringomyelia and the significance of developmental errors of the spinal cord and column". The Medical Journal of Australia. 1 (14): 433–9. doi:10.5694/j.1326-5377.1949.tb67733.x. PMID 18129941.
52. ^ Wallace, DC (1965). "Observations upon a predominantly sensory hereditary neuropathy". Proceedings of the Australian Association of Neurologists. 3: 101–9. PMID 5881776.
## External links[edit]
Classification
D
* ICD-10: G60.8
* ICD-9-CM: 356.8
* OMIM: 162400 608088 613640 613708 614116
* DiseasesDB: 32501
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Hereditary sensory and autonomic neuropathy type I | c0020071 | 2,694 | wikipedia | https://en.wikipedia.org/wiki/Hereditary_sensory_and_autonomic_neuropathy_type_I | 2021-01-18T19:05:52 | {"mesh": ["D009477"], "orphanet": ["36386"], "wikidata": ["Q3338681"]} |
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Brachioradial pruritus (sometimes abbreviated BRP) is an intense itching sensation of the arm usually between the wrist and elbow of either or both arms.[1]:36 The itch can be so intense that sufferers will scratch their own skin to a bleeding condition.
The condition is becoming increasingly common, presenting in patients who are usually fair skinned and middle aged and indulge in golf, tennis, outdoor table tennis, sailing, or other leisure outdoor activities in sunny climates.[1]:64[2]:402
The cause is not known, although there are a few lines of thought on what causes it. No cure has been found, but good control with near 100% relief can be achieved. The intense itch/scratch cycle can be broken by applying a topical skin coolant gel like Biofreeze (or a substance containing menthol, camphor or other topical coolant) to affected itchy areas, and then consistently applying 100+SPF sunscreen to affected skin of arms, shoulders, neck, etc., whenever they are expected to be exposed to the sun. When combined, these treatments can bring almost full relief.
Many different medications and types of topical creams have been experimented with, but none seem to make any difference, except for the above. The application of ice packs to the affected area can also diminish the itch short-term.
## Contents
* 1 Causes
* 2 Treatments
* 3 See also
* 4 References
* 5 Further reading
## Causes[edit]
Brachioradial pruritus (BRP) is a localized pruritus of the dorsolateral aspect of the arm. BRP is an enigmatic condition with a controversial cause; some authors consider BRP to be a photodermatosis, whereas other authors attribute BRP to compression of cervical nerve roots.
BRP may be attributed to a neuropathy, such as chronic cervical radiculopathy. The possibility of an underlying neuropathy should be considered in the evaluation and treatment of all patients with BRP.
The main cause of BRP is not known, but there is evidence to suggest that BRP may arise in the nervous system. Cervical spine disease may also be an important contributing factor.
Patients with BRP may have underlying cervical spine pathology. Whether this association is causal or coincidental remains to be determined.
There is controversy regarding the cause of brachioradial pruritus: is it caused by a nerve compression in the cervical spine or is it caused by a prolonged exposure to sunlight?
In many patients, itching of the arms or shoulders is seasonal. Some patients reported neck pain.
BRP can be linked to the thyroid.[citation needed]
## Treatments[edit]
Symptom management may include the topical application of lidocaine or capsaicin, cervical traction, and good hygiene practices.[citation needed]
Treatment with lamotrigine has been reported.[3] Treatment by acupuncture has been reported.[4]
## See also[edit]
* List of cutaneous conditions
## References[edit]
1. ^ a b James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
2. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0.
3. ^ Crevits, L. (2006). "Brachioradial pruritus—A peculiar neuropathic disorder". Clinical Neurology and Neurosurgery. 108 (8): 803–5. doi:10.1016/j.clineuro.2005.12.001. PMID 16423451.
4. ^ Stellon, Anthony (2002). "Neurogenic pruritus: an unrecognised problem? A retrospective case series of treatment by acupuncture". Acupuncture in Medicine. 20 (4): 186–90. doi:10.1136/aim.20.4.186. PMID 12512793.
## Further reading[edit]
* Walcyk, Patricia J.; Elpern, D.J. (1986). "Brachioradial pruritus: a tropical dermopathy". British Journal of Dermatology. 115 (2): 177–80. doi:10.1111/j.1365-2133.1986.tb05714.x. PMID 3741783.
* Orton, D.I.; Wakelin, S.H.; George, S.A. (1996). "Brachioradial photopruritus - a rare chronic photodermatosis in Europe". British Journal of Dermatology. 135 (3): 486–7. doi:10.1046/j.1365-2133.1996.d01-1030.x. PMID 8949453.
* Dermatology 1977;195:414-5.[full citation needed]
* Brachioradial Pruritus at eMedicine
* Veien, Niels K.; Hattel, Thais; Laurberg, Grete; Spaun, Eva (2001). "Brachioradial pruritus". Journal of the American Academy of Dermatology. 44 (4): 704–5. doi:10.1067/mjd.2001.112912. PMID 11260554.
* Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
* Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
* Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lippincott Williams & Wilkins 2004.
* Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
* DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
* Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
* Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
* Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| Brachioradial pruritus | c1304055 | 2,695 | wikipedia | https://en.wikipedia.org/wiki/Brachioradial_pruritus | 2021-01-18T18:47:03 | {"umls": ["C1304055"], "wikidata": ["Q4953340"]} |
Kearns–Sayre syndrome
Other namesOculocraniosomatic disorder or Oculocranionsomatic neuromuscular disorder with ragged red fibers
SpecialtyOphthalmology
Kearns–Sayre syndrome (KSS), Oculocraniosomatic disorder or Oculocranionsomatic neuromuscular disorder with ragged red fibers, is a mitochondrial myopathy with a typical onset before 20 years of age. KSS is a more severe syndromic variant of chronic progressive external ophthalmoplegia (abbreviated CPEO), a syndrome that is characterized by isolated involvement of the muscles controlling movement of the eyelid (levator palpebrae, orbicularis oculi) and eye (extra-ocular muscles). This results in ptosis and ophthalmoplegia respectively. KSS involves a combination of the already described CPEO as well as pigmentary retinopathy in both eyes and cardiac conduction abnormalities. Other symptoms may include cerebellar ataxia, proximal muscle weakness, deafness, diabetes mellitus, growth hormone deficiency, hypoparathyroidism, and other endocrinopathies.[1] In both of these diseases, muscle involvement may begin unilaterally but always develops into a bilateral deficit, and the course is progressive. This discussion is limited specifically to the more severe and systemically involved variant.
## Contents
* 1 Signs and symptoms
* 1.1 Pigmentary retinopathy
* 1.2 Cardiac conduction abnormalities
* 1.3 Cerebral folate deficiency
* 1.4 Cause and prevalence
* 2 Genetics
* 3 Diagnosis
* 3.1 Biopsy findings
* 3.2 Laboratory studies
* 4 Management
* 5 History
* 6 References
* 7 External links
## Signs and symptoms[edit]
Individuals with KSS present initially in a similar way to those with typical CPEO. Onset is in the first and second decades of life.[citation needed]
The first symptom of this disease is a unilateral ptosis, or difficulty opening the eyelids, that gradually progresses to a bilateral ptosis. As the ptosis worsens, the individual commonly extends their neck, elevating their chin in an attempt to prevent the eyelids from occluding the visual axis. Along with the insidious development of ptosis, eye movements eventually become limited causing a person to rely more on turning the head side to side or up and down to view objects in the peripheral visual field.[citation needed]
### Pigmentary retinopathy[edit]
Retinitis pigmentosa, mid stage
KSS results in a pigmentation of the retina, primarily in the posterior fundus. The appearance is described as a "salt-and-pepper" appearance. There is diffuse depigmentation of the retinal pigment epithelium with the greatest effect occurring at the macula. This is in contrast to retinitis pigmentosa where the pigmentation is peripheral. The appearance of the retina in KSS is similar to that seen in myotonic dystrophy type 1 (abbreviated DM1). Modest night-blindness can be seen in patients with KSS. Visual acuity loss is usually mild and only occurs in 40–50% of patients.[2]
### Cardiac conduction abnormalities[edit]
These most often occur years after the development of ptosis and ophthalmoplegia.[2] Atrioventricular (abbreviated "AV") block is the most common cardiac conduction deficit. This often progresses to a Third-degree atrioventricular block, which is a complete blockage of the electrical conduction from the atrium to the ventricle. Symptoms of heart block include syncope, exercise intolerance, and bradycardia.[citation needed]
### Cerebral folate deficiency[edit]
Kearns-Sayre patients are consistently found to have cerebral folate deficiency, a syndrome in which 5-MTHF levels are decreased in the cerebrospinal fluid despite being normal in serum.[3] Treatment with folinic acid can in some cases alleviate the associated symptoms and partially correct associated brain abnormalities, especially if started early in the course of illness.[4] The proposed cause of cerebral folate deficiency in the Kearns–Sayre syndrome is the failure of the mechanisms in the choroid plexus that are responsible for passage of folates from the serum to the cerebrospinal fluid.[5]
### Cause and prevalence[edit]
As characterized in Kearns' original publication in 1965 and in later publications, inconsistent features of KSS that may occur are weakness of facial, pharyngeal, trunk, and extremity muscles, hearing loss, small stature, electroencephalographic changes, cerebellar ataxia and elevated levels of cerebrospinal fluid protein.[citation needed]
Kearns–Sayre syndrome occurs spontaneously in the majority of cases. In some cases it has been shown to be inherited through mitochondrial, autosomal dominant, or autosomal recessive inheritance. There is no predilection for race or sex, and there are no known risk factors. As of 1992 there were only 226 cases reported in published literature.[6] Although NIH and other studies estimate occurrence in the population to be 1-3 and some as high as 9 in 100,000 individuals but a failure to be referred to specialist centres and recognise the disease symptoms is common [6]
## Genetics[edit]
KSS is the result of deletions in mitochondrial DNA (mtDNA) that cause a particular constellation of medical signs and symptoms. mtDNA is transmitted exclusively from the mother's ovum.[7] Mitochondrial DNA is composed of 37 genes found in the single circular chromosome measuring 16,569 base pairs in length. Among these, 13 genes encode proteins of the electron transport chain (abbreviated "ETC"), 22 encode transfer RNA (tRNA), and two encode the large and small subunits that form ribosomal RNA (rRNA). The 13 proteins involved in the ETC of the mitochondrion are necessary for oxidative phosphorylation. Mutations in these proteins results in impaired energy production by mitochondria. This cellular energy deficit manifests most readily in tissues that rely heavily upon aerobic metabolism such as the brain, skeletal and cardiac muscles, sensory organs, and kidneys. This is one factor involved in the presentation of mitochondrial diseases.[citation needed]
There are other factors involved in the manifestation of a mitochondrial disease besides the size and location of a mutation. Mitochondria replicate during each cell division during gestation and throughout life. Because the mutation in mitochondrial disease most often occurs early in gestation in these diseases, only those mitochondria in the mutated lineage are defective. This results in an uneven distribution of dysfunctional mitochondria within each cell, and among different tissues of the body. This describes the term heteroplasmic which is characteristic of mitochondrial diseases including KSS. The distribution of mutated mtDNA in each cell, tissue, and organ, is dependent on when and where the mutation occurs.[8] This may explain why two patients with an identical mutation in mtDNA can present with entirely different phenotypes and in turn different syndromes. A publication in 1992 by Fischel-Ghodsian et al. identified the same 4,977-bp deletion in mtDNA in two patients presenting with two entirely different diseases. One of the patients had characteristic KSS, while the other patient had a very different disease known as Pearson marrow pancreas syndrome.[9] Complicating the matter, in some cases Pearson's syndrome has been shown to progress into KSS later in life.[10]
More recent studies have concluded that mtDNA duplications may also play a significant role in determining what phenotype is present. Duplications of mtDNA seem to be characteristic of all cases of KSS and Pearson's syndrome, while they are absent in CPEO.[10][11]
Deletions of mtDNA in KSS vary in size (1.3–8kb), as well as position in the mitochondrial genome. The most common deletion is 4.9kb and spans from position 8469 to position 13147 on the genome. This deletion is present in approximately ⅓ of people with KSS[citation needed]
## Diagnosis[edit]
An example of ragged red fibers
A neuro-ophthalmologist is usually involved in the diagnosis and management of KSS. An individual should be suspected of having KSS based upon clinical exam findings. Suspicion for myopathies should be increased in patients whose ophthalmoplegia does not match a particular set of cranial nerve palsies (oculomotor nerve palsy, fourth nerve palsy, sixth nerve palsy). Initially, imaging studies are often performed to rule out more common pathologies. Diagnosis may be confirmed with muscle biopsy, and may be supplemented with PCR determination of mtDNA mutations.[citation needed]
### Biopsy findings[edit]
It is not necessary to biopsy an ocular muscle to demonstrate histopathologic abnormalities. Cross-section of muscle fibers stained with Gömöri trichrome stain is viewed using light microscopy. In muscle fibers containing high ratios of the mutated mitochondria, there is a higher concentration of mitochondria. This gives these fibers a darker red color, causing the overall appearance of the biopsy to be described as "ragged red fibers. Abnormalities may also be demonstrated in muscle biopsy samples using other histochemical studies such as mitochondrial enzyme stains, by electron microscopy, biochemical analyses of the muscle tissue (ie electron transport chain enzyme activities), and by analysis of muscle mitochondrial DNA. "[12]
### Laboratory studies[edit]
Blood lactate and pyruvate levels usually are elevated as a result of increased anaerobic metabolism and a decreased ratio of ATP:ADP. CSF analysis shows an elevated protein level, usually >100 mg/dl, as well as an elevated lactate level.[6]
## Management[edit]
Currently there is no curative treatment for KSS. Because it is a rare condition, there are only case reports of treatments with very little data to support their effectiveness. Several promising discoveries have been reported which may support the discovery of new treatments with further research. Satellite cells are responsible for muscle fiber regeneration. It has been noted that mutant mtDNA is rare or undetectable in satellite cells cultured from patients with KSS. Shoubridge et al. (1997) asked the question whether wildtype mtDNA could be restored to muscle tissue by encouraging muscle regeneration. In the forementioned study, regenerating muscle fibers were sampled at the original biopsy site, and it was found that they were essentially homoplasmic for wildtype mtDNA.[8] Perhaps with future techniques of promoting muscle cell regeneration and satellite cell proliferation, functional status in KSS patients could be greatly improved.[citation needed]
One study described a patient with KSS who had reduced serum levels of coenzyme Q10. Administration of 60–120 mg of Coenzyme Q10 for 3 months resulted in normalization of lactate and pyruvate levels, improvement of previously diagnosed first degree AV block, and improvement of ocular movements.[13]
A screening ECG is recommended in all patients presenting with CPEO. In KSS, implantation of pacemaker is advised following the development of significant conduction disease, even in asymptomatic patients.[14]
Screening for endocrinologic disorders should be performed, including measuring serum glucose levels, thyroid function tests, calcium and magnesium levels, and serum electrolyte levels. Hyperaldosteronism is seen in 3% of KSS patients.[15]
## History[edit]
The triad of CPEO, bilateral pigmentary retinopathy, and cardiac conduction abnormalities was first described in a case report of two patients in 1958 by Thomas P. Kearns (1922-2011), MD., and George Pomeroy Sayre (1911-1992), MD.[16] A second case was published in 1960 by Jager and co-authors reporting these symptoms in a 13-year-old boy.[17] Previous cases of patients with CPEO dying suddenly had been published, occasionally documented as from a cardiac dysrhythmia. Other cases had noted a peculiar pigmentation of the retina, but none of these publications had documented these three pathologies occurring together as a genetic syndrome.[18] Kearns published a defining case in 1965 describing 9 unrelated cases with this triad.[18] In 1988, the first connection was made between KSS and large-scale deletions of muscle mitochondrial DNA (abbreviated mtDNA)[19][20] Since this discovery, numerous deletions in mitochondrial DNA have been linked to the development of KSS.[21][22][23]
## References[edit]
1. ^ Harvey JN, Barnett D (July 1992). "Endocrine dysfunction in Kearns-Sayre syndrome". Clin. Endocrinol. 37 (1): 97–103. doi:10.1111/j.1365-2265.1992.tb02289.x. PMID 1424198.
2. ^ a b Miller, Neil R.; Newman, Nancy J., eds. (2007). Walsh & Hoyt's Clinical Neuro-Ophthalmology: The Essentials. Lippincott Williams & Wilkins.
3. ^ Garcia-Cazorla A, Quadros EV, Nascimento A, Garcia-Silva MT, Briones P, Montoya J, et al. (2008). "Mitochondrial diseases associated with cerebral folate deficiency". Neurology. 70 (16): 1360–2. doi:10.1212/01.wnl.0000309223.98616.e4. PMID 18413591. S2CID 44622892.
4. ^ Quijada-Fraile P, O'Callaghan M, Martín-Hernández E, Montero R, Garcia-Cazorla À, de Aragón AM, et al. (2014). "Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome". Orphanet J Rare Dis. 9: 217. doi:10.1186/s13023-014-0217-2. PMC 4302586. PMID 25539952.
5. ^ Spector R, Johanson CE (2010). "Choroid plexus failure in the Kearns-Sayre syndrome". Cerebrospinal Fluid Res. 7: 14. doi:10.1186/1743-8454-7-14. PMC 2939631. PMID 20731822.
6. ^ a b c Kearns-Sayre Syndrome at eMedicine
7. ^ Fine PE (September 1978). "Mitochondrial inheritance and disease". Lancet. 2 (8091): 659–62. doi:10.1016/S0140-6736(78)92764-2. PMID 80581. S2CID 40192499.
8. ^ a b Shoubridge EA, Johns T, Karpati G (December 1997). "Complete restoration of a wild-type mtDNA genotype in regenerating muscle fibres in a patient with a tRNA point mutation and mitochondrial encephalomyopathy". Hum. Mol. Genet. 6 (13): 2239–42. doi:10.1093/hmg/6.13.2239. PMID 9361028.
9. ^ Fischel-Ghodsian N, Bohlman MC, Prezant TR, Graham JM, Cederbaum SD, Edwards MJ (June 1992). "Deletion in blood mitochondrial DNA in Kearns-Sayre syndrome". Pediatr. Res. 31 (6): 557–60. doi:10.1203/00006450-199206000-00004. PMID 1635816.
10. ^ a b Poulton J, Morten KJ, Weber K, Brown GK, Bindoff L (June 1994). "Are duplications of mitochondrial DNA characteristic of Kearns-Sayre syndrome?". Hum. Mol. Genet. 3 (6): 947–51. doi:10.1093/hmg/3.6.947. PMID 7951243.
11. ^ Miller, Neil R.; Newman, Nancy J.; Bioussee, Valerie; Kerrison, John B. (2008). "Ch. 20, adapted from a chapter 22 by Paul N. Hoffman". Walsh and Hoyt's Clinical Neuro-ophthalmology: the essentials. Philadelphia: Lippincott Williams & Wilkins. pp. 432–6.
12. ^ Rubin, Richard M.; Sadun, Alfredo A. (2008). "Ch. 9.17 Ocular Myopathies". In Yanoff, Myron; Duker, Jason (eds.). Ophthalmology (Online Textbook) (3rd ed.). Mosby.
13. ^ Ogasahara S, Yorifuji S, Nishikawa Y, et al. (March 1985). "Improvement of abnormal pyruvate metabolism and cardiac conduction defect with coenzyme Q10 in Kearns-Sayre syndrome". Neurology. 35 (3): 372–7. doi:10.1212/WNL.35.3.372. PMID 3974895. S2CID 27569662.
14. ^ Gregoratos G, Abrams J, Epstein AE, et al. (October 2002). "ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines)". Circulation. 106 (16): 2145–61. doi:10.1161/01.CIR.0000035996.46455.09. PMID 12379588.
15. ^ Kearns-Sayre Syndrome~diagnosis at eMedicine
16. ^ Kearns TP, Sayre GP (August 1958). "Retinitis pigmentosa, external ophthalmophegia, and complete heart block: unusual syndrome with histologic study in one of two cases". AMA Arch Ophthalmol. 60 (2): 280–9. doi:10.1001/archopht.1958.00940080296016. PMID 13558799.
17. ^ Jager BV, Fred HL, Butler RB, Carnes WH (November 1960). "Occurrence of retinal pigmentation, ophthalmoplegia, ataxia, deafness and heart block. Report of a case, with findings at autopsy". Am. J. Med. 29 (5): 888–93. doi:10.1016/0002-9343(60)90122-4. PMID 13789175.
18. ^ a b Kearns TP (1965). "External Ophthalmoplegia, Pigmentary Degeneration of the Retina, and Cardiomyopathy: A Newly Recognized Syndrome". Trans Am Ophthalmol Soc. 63: 559–625. PMC 1310209. PMID 16693635.
19. ^ Zeviani M, Moraes CT, DiMauro S, et al. (September 1988). "Deletions of mitochondrial DNA in Kearns-Sayre syndrome". Neurology. 38 (9): 1339–46. doi:10.1212/wnl.38.9.1339. PMID 3412580. S2CID 30046555.
20. ^ Lestienne P, Ponsot G (April 1988). "Kearns-Sayre syndrome with muscle mitochondrial DNA deletion". Lancet. 1 (8590): 885. doi:10.1016/S0140-6736(88)91632-7. PMID 2895391. S2CID 6811844.
21. ^ Carod-Artal FJ, Lopez Gallardo E, Solano A, Dahmani Y, Herrero MD, Montoya J (September 2006). "[Mitochondrial DNA deletions in Kearns-Sayre syndrome]". Neurologia (in Spanish). 21 (7): 357–64. PMID 16977556.
22. ^ Lertrit P, Imsumran A, Karnkirawattana P, et al. (1999). "A unique 3.5-kb deletion of the mitochondrial genome in Thai patients with Kearns-Sayre syndrome". Hum. Genet. 105 (1–2): 127–31. doi:10.1007/s004390051074. PMID 10480366. Archived from the original on 2000-09-29.
23. ^ Soga F, Ueno S, Yorifuji S (September 1993). "[Deletions of mitochondrial DNA in Kearns-Sayre syndrome]". Nippon Rinsho (in Japanese). 51 (9): 2386–90. PMID 8411717.
## External links[edit]
* kearns_sayre at NINDS
* Kearns Sayre syndrome at NIH's Office of Rare Diseases
Classification
D
* ICD-10: H49.8
* ICD-10-CM: H49.81
* ICD-9-CM: 277.87
* OMIM: 530000
* MeSH: D007625
* DiseasesDB: 7137
External resources
* eMedicine: article/950897
* GeneReviews: Mitochondrial DNA Deletion Syndromes
* Orphanet: 480
* v
* t
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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
* Diseases of the human eye
Adnexa
Eyelid
Inflammation
* Stye
* Chalazion
* Blepharitis
* Entropion
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Eyelash
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Lacrimal apparatus
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Orbit
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* Orbital lymphoma
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Conjunctiva
* Conjunctivitis
* allergic
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Globe
Fibrous tunic
Sclera
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Cornea
* Keratitis
* herpetic
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* Fuchs'
* Meesmann
* Corneal ectasia
* Keratoconus
* Pellucid marginal degeneration
* Keratoglobus
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* Post-LASIK ectasia
* Keratoconjunctivitis
* sicca
* Corneal opacity
* Corneal neovascularization
* Kayser–Fleischer ring
* Haab's striae
* Arcus senilis
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Vascular tunic
* Iris
* Ciliary body
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* Intermediate uveitis
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Choroid
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Lens
* Cataract
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Retina
* Retinitis
* Chorioretinitis
* Cytomegalovirus retinitis
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* Ocular ischemic syndrome / Central retinal vein occlusion
* Central retinal artery occlusion
* Branch retinal artery occlusion
* Retinopathy
* diabetic
* hypertensive
* Purtscher's
* of prematurity
* Bietti's crystalline dystrophy
* Coats' disease
* Sickle cell
* Macular degeneration
* Retinitis pigmentosa
* Retinal haemorrhage
* Central serous retinopathy
* Macular edema
* Epiretinal membrane (Macular pucker)
* Vitelliform macular dystrophy
* Leber's congenital amaurosis
* Birdshot chorioretinopathy
Other
* Glaucoma / Ocular hypertension / Primary juvenile glaucoma
* Floater
* Leber's hereditary optic neuropathy
* Red eye
* Globe rupture
* Keratomycosis
* Phthisis bulbi
* Persistent fetal vasculature / Persistent hyperplastic primary vitreous
* Persistent tunica vasculosa lentis
* Familial exudative vitreoretinopathy
Pathways
Optic nerve
Optic disc
* Optic neuritis
* optic papillitis
* Papilledema
* Foster Kennedy syndrome
* Optic atrophy
* Optic disc drusen
Optic neuropathy
* Ischemic
* anterior (AION)
* posterior (PION)
* Kjer's
* Leber's hereditary
* Toxic and nutritional
Strabismus
Extraocular muscles
Binocular vision
Accommodation
Paralytic strabismus
* Ophthalmoparesis
* Chronic progressive external ophthalmoplegia
* Kearns–Sayre syndrome
palsies
* Oculomotor (III)
* Fourth-nerve (IV)
* Sixth-nerve (VI)
Other strabismus
* Esotropia / Exotropia
* Hypertropia
* Heterophoria
* Esophoria
* Exophoria
* Cyclotropia
* Brown's syndrome
* Duane syndrome
Other binocular
* Conjugate gaze palsy
* Convergence insufficiency
* Internuclear ophthalmoplegia
* One and a half syndrome
Refraction
* Refractive error
* Hyperopia
* Myopia
* Astigmatism
* Anisometropia / Aniseikonia
* Presbyopia
Vision disorders
Blindness
* Amblyopia
* Leber's congenital amaurosis
* Diplopia
* Scotoma
* Color blindness
* Achromatopsia
* Dichromacy
* Monochromacy
* Nyctalopia
* Oguchi disease
* Blindness / Vision loss / Visual impairment
Anopsia
* Hemianopsia
* binasal
* bitemporal
* homonymous
* Quadrantanopia
subjective
* Asthenopia
* Hemeralopia
* Photophobia
* Scintillating scotoma
Pupil
* Anisocoria
* Argyll Robertson pupil
* Marcus Gunn pupil
* Adie syndrome
* Miosis
* Mydriasis
* Cycloplegia
* Parinaud's syndrome
Other
* Nystagmus
* Childhood blindness
Infections
* Trachoma
* Onchocerciasis
* 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
| Kearns–Sayre syndrome | c0022541 | 2,696 | wikipedia | https://en.wikipedia.org/wiki/Kearns%E2%80%93Sayre_syndrome | 2021-01-18T18:37:24 | {"gard": ["6817"], "mesh": ["D007625"], "umls": ["C0022541"], "icd-9": ["277.87"], "orphanet": ["480"], "wikidata": ["Q2605012"]} |
Anal dysplasia is a pre-cancerous condition which occurs when the lining of the anal canal undergoes abnormal changes. It can be classified as low grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL).[1] Most cases are not associated with symptoms, but people may notice lumps in and around the anus.[2]
## Contents
* 1 Causes
* 2 Diagnosis
* 3 See also
* 4 References
## Causes[edit]
Anal dysplasia is most commonly linked to human papillomavirus (HPV), a usually sexually-transmitted infection.[3] HPV is the most common sexually transmitted infection in the United States[4] while genital herpes (HSV) was the most common sexually transmitted infection globally.[5]
## Diagnosis[edit]
This section is empty. You can help by adding to it. (October 2018)
## See also[edit]
* Human papillomavirus
* Anal cancer
## References[edit]
1. ^ Darragh, Teresa (October 2012). "The Lower Anogenital Squamous Terminology. Standardization Project for HPV-Associated Lesions:". Arch Pathol Lab Med. 136: 1266–1297.
2. ^ Salit, Irving. "Fact Sheets: Anal dyspasia". Canadian Aids Treatment Information Exchange. Archived from the original on 2009-02-01. Retrieved 2009-02-22.
3. ^ Palefsky, Joel M.; Holly, Elizabeth A.; Ralston, Mary L.; Jay, Naomi (February 1988). "Prevalence and Risk Factors for Human Papillomavirus Infection of the Anal Canal in Human Immunodeficiency Virus (HIV)–Positive and HIV-Negative Homosexual Men" (PDF). Departments of Laboratory Medicine, Stomatology, and Epidemiology Biostatistics, University of California, San Francisco. The Journal of Infectious Diseases. Retrieved 2 March 2014.
4. ^ "CDC Fact Sheet - Incidence, Prevalence, and Cost of Sexually Transmitted Infections in the United States" (PDF). CDC. February 2013. Retrieved 2 March 2014.
5. ^ Antonio C Gerbase; Jane T Rowley; Thierry E Merten (1998). "Global epidemiology of sexually transmitted diseases". Lancet. 352: S2–S4. doi:10.1016/S0140-6736(98)90001-0.
* v
* t
* e
Diseases of the digestive system
Upper GI tract
Esophagus
* Esophagitis
* Candidal
* Eosinophilic
* Herpetiform
* Rupture
* Boerhaave syndrome
* Mallory–Weiss syndrome
* UES
* Zenker's diverticulum
* LES
* Barrett's esophagus
* Esophageal motility disorder
* Nutcracker esophagus
* Achalasia
* Diffuse esophageal spasm
* Gastroesophageal reflux disease (GERD)
* Laryngopharyngeal reflux (LPR)
* Esophageal stricture
* Megaesophagus
* Esophageal intramural pseudodiverticulosis
Stomach
* Gastritis
* Atrophic
* Ménétrier's disease
* Gastroenteritis
* Peptic (gastric) ulcer
* Cushing ulcer
* Dieulafoy's lesion
* Dyspepsia
* Pyloric stenosis
* Achlorhydria
* Gastroparesis
* Gastroptosis
* Portal hypertensive gastropathy
* Gastric antral vascular ectasia
* Gastric dumping syndrome
* Gastric volvulus
* Buried bumper syndrome
* Gastrinoma
* Zollinger–Ellison syndrome
Lower GI tract
Enteropathy
Small intestine
(Duodenum/Jejunum/Ileum)
* Enteritis
* Duodenitis
* Jejunitis
* Ileitis
* Peptic (duodenal) ulcer
* Curling's ulcer
* Malabsorption: Coeliac
* Tropical sprue
* Blind loop syndrome
* Small bowel bacterial overgrowth syndrome
* Whipple's
* Short bowel syndrome
* Steatorrhea
* Milroy disease
* Bile acid malabsorption
Large intestine
(Appendix/Colon)
* Appendicitis
* Colitis
* Pseudomembranous
* Ulcerative
* Ischemic
* Microscopic
* Collagenous
* Lymphocytic
* Functional colonic disease
* IBS
* Intestinal pseudoobstruction / Ogilvie syndrome
* Megacolon / Toxic megacolon
* Diverticulitis/Diverticulosis/SCAD
Large and/or small
* Enterocolitis
* Necrotizing
* Gastroenterocolitis
* IBD
* Crohn's disease
* Vascular: Abdominal angina
* Mesenteric ischemia
* Angiodysplasia
* Bowel obstruction: Ileus
* Intussusception
* Volvulus
* Fecal impaction
* Constipation
* Diarrhea
* Infectious
* Intestinal adhesions
Rectum
* Proctitis
* Radiation proctitis
* Proctalgia fugax
* Rectal prolapse
* Anismus
Anal canal
* Anal fissure/Anal fistula
* Anal abscess
* Hemorrhoid
* Anal dysplasia
* Pruritus ani
GI bleeding
* Blood in stool
* Upper
* Hematemesis
* Melena
* Lower
* Hematochezia
Accessory
Liver
* Hepatitis
* Viral hepatitis
* Autoimmune hepatitis
* Alcoholic hepatitis
* Cirrhosis
* PBC
* Fatty liver
* NASH
* Vascular
* Budd–Chiari syndrome
* Hepatic veno-occlusive disease
* Portal hypertension
* Nutmeg liver
* Alcoholic liver disease
* Liver failure
* Hepatic encephalopathy
* Acute liver failure
* Liver abscess
* Pyogenic
* Amoebic
* Hepatorenal syndrome
* Peliosis hepatis
* Metabolic disorders
* Wilson's disease
* Hemochromatosis
Gallbladder
* Cholecystitis
* Gallstone / Cholelithiasis
* Cholesterolosis
* Adenomyomatosis
* Postcholecystectomy syndrome
* Porcelain gallbladder
Bile duct/
Other biliary tree
* Cholangitis
* Primary sclerosing cholangitis
* Secondary sclerosing cholangitis
* Ascending
* Cholestasis/Mirizzi's syndrome
* Biliary fistula
* Haemobilia
* Common bile duct
* Choledocholithiasis
* Biliary dyskinesia
* Sphincter of Oddi dysfunction
Pancreatic
* Pancreatitis
* Acute
* Chronic
* Hereditary
* Pancreatic abscess
* Pancreatic pseudocyst
* Exocrine pancreatic insufficiency
* Pancreatic fistula
Other
Hernia
* Diaphragmatic
* Congenital
* Hiatus
* Inguinal
* Indirect
* Direct
* Umbilical
* Femoral
* Obturator
* Spigelian
* Lumbar
* Petit's
* Grynfeltt-Lesshaft
* Undefined location
* Incisional
* Internal hernia
* Richter's
Peritoneal
* Peritonitis
* Spontaneous bacterial peritonitis
* Hemoperitoneum
* Pneumoperitoneum
This oncology 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
| Anal dysplasia | c0347129 | 2,697 | wikipedia | https://en.wikipedia.org/wiki/Anal_dysplasia | 2021-01-18T18:59:36 | {"umls": ["C0347129"], "wikidata": ["Q4750997"]} |
## Description
Apolipoprotein A-II, like apolipoprotein A-I (APOA1; 107680), is a major apolipoprotein in high density lipoprotein (HDL).
Cloning and Expression
Sakaguchi et al. (1984) and Lackner et al. (1984) isolated the gene for apolipoprotein A-II from a human cDNA library using synthetic oligonucleotides as probes.
Mapping
Sakaguchi et al. (1984) and Lackner et al. (1984) isolated a restriction fragment of 300 bp from an apoA-II cDNA clone and used it as a probe in filter hybridization assay of DNA from human-mouse somatic cell hybrids. Restriction digestion was performed with HindIII. They found that apoA-II segregates with chromosome 1. The gene was regionalized to 1p21-qter and may reside in a conserved linkage group with renin and peptidase C.
Moore et al. (1984) confirmed the assignment of the APOA2 gene to chromosome 1. By in situ hybridization, Middleton-Price et al. (1988) mapped the APOA2 gene to 1q21-q23. Southern hybridization to the DNA from somatic cell hybrids made from cells carrying a balanced translocation between X and 1 confirmed the localization as proximal to 1q23. In the course of creating a physical map of human 1q21-q23, Oakey et al. (1992) confirmed this assignment. Using a cDNA probe, Rogne et al. (1989) found tight linkage with Duffy blood group (FY; 110700). No recombination was found in 19 meioses examined, giving a maximal lod score of 4.2 at theta = 0.0. This information, combined with other data, made the most likely distance between FY and APOA2 about 10% recombination, with a combined lod score of 5.6 for both sexes.
In the mouse, the genes for apoA-I and apoA-II are on separate chromosomes (Lusis et al., 1983)--mouse chromosomes 9 and 1, respectively. Thus, in man, apoA-II was presumably not coded by 11q, the site of the APOA1 gene.
Gene Function
Apolipoprotein A-II is the second most abundant protein of high density lipoprotein particles. Warden et al. (1993) showed that in both mice and humans, the APOA2 gene is linked to a gene that controls plasma levels of apoA-II and that the APOA2 gene or its product influences, by an unknown mechanism, plasma levels of free fatty acids (FFA).
Allayee et al. (2003) studied 18 extended families of Dutch Caucasian descent with familial combined hyperlipidemia (FCHL; 144250) and found that, despite having lower levels of HDLC, FCHL subjects had higher apoA-II levels compared with unaffected relatives (p less than 0.00016). Triglyceride and HDL-C levels were significant predictors of apoA-II levels, demonstrating that apoA-II variation is associated with several FCHL-related traits. After adjustment for multiple covariates, there was evidence for the heritability of apoA-II levels (h-squared = 0.15; p less than 0.02) in this sample. A genome scan for apoA-II levels identified significant evidence (lod = 3.1) for linkage to a locus on chromosome 1q41, coincident with a suggestive linkage for triglycerides (lod = 1.4), suggesting that this locus may have pleiotropic effects on apoA-II and FCHL traits. Allayee et al. (2003) concluded that apoA-II is biochemically and genetically associated with FCHL and may serve as a useful marker for understanding the mechanism by which FCHL develops.
Sontag and Reardon (2014) noted that mouse Apoa2 shares only 55% amino acid identity with human APOA2 and exists as a monomer, since it lacks the cysteine residue in human APOA2. They purified the 2 most common polymorphic variants of mouse Apoa2, which differ at 3 amino acid sites, and showed that the polymorphisms altered the physical and functional nature of Apoa2.
Fager et al. (1981) found an inverse relationship between serum apoA-II and a risk of myocardial infarction.
Molecular Genetics
Kessling et al. (1988) studied the high density lipoprotein-cholesterol concentrations (HDLC) along with RFLPs in the APOA2 and APOA1-APOC3-APOA4 gene cluster in 109 men selected from a random sample of 1,910 men aged 45 to 59 years. They found no significant difference in allelic frequencies at either locus between the groups of individuals with high and low HDL-C levels. They did find an association between a PstI RFLP associated with apoA-I and genetic variation determining the plasma concentration of apoA-I. No significant association was found between alleles for the apoA-II MspI RFLP and apoA-II or HDL concentrations.
In a brother and sister with apolipoprotein A-II deficiency, Deeb et al. (1990) identified homozygosity for a mutation in the APOA2 gene (107670.0001).
Through molecular study of a 1,135-member American Caucasian familial hypercholesterolemia (143890) kindred, Takada et al. (2002) demonstrated that a SNP of the promoter of the APOA2 gene, -265T-C (107670.0002), influenced the level of total cholesterol and low density lipoprotein (LDL) cholesterol in members with a mutation in the LDLR gene causing hypercholesterolemia (606945.0063).
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-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
| APOLIPOPROTEIN A-II | c3888202 | 2,698 | omim | https://www.omim.org/entry/107670 | 2019-09-22T16:44:49 | {"omim": ["107670"]} |
A number sign (#) is used with this entry because autosomal recessive limb-girdle muscular dystrophy-2 (LGMDR2) is caused by homozygous or compound heterozygous mutation in the DYSF gene (DYSF; 603009), encoding the skeletal muscle protein dysferlin, on chromosome 2p13.
See also Miyoshi myopathy (MDM1; 254130) and distal myopathy with anterior tibial onset (DMAT; 606768), allelic disorders characterized by more distal muscle involvement.
For a general phenotypic description and a discussion of genetic heterogeneity of LGMD, see LGMDR1 (253600).
Nomenclature
At the 229th ENMC international workshop, Straub et al. (2018) reviewed, reclassified, and/or renamed forms of LGMD. The proposed naming formula was 'LGMD, inheritance (R or D), order of discovery (number), affected protein.' Under this formula, LGMD2B was renamed LGMDR2.
In a review of the limb-girdle muscular dystrophies, including 8 autosomal dominant and 5 autosomal recessive forms, Bushby (1999) referred to Miyoshi myopathy and LGMD2B as 'dysferlinopathies.'
Clinical Features
Bashir et al. (1994) reported 2 unrelated consanguineous families, 1 of Palestinian and 1 of Sicilian origin, with autosomal recessive LGMD. Age at onset ranged from 15 to 25 years with difficulty in climbing stairs, fatigue, weakness, and markedly elevated serum creatine kinase. EMG showed myopathic changes and skeletal muscle biopsies showed severe myopathic changes with variation of fiber size, fiber splitting, increased connective tissue, and some necrotic changes. Disease progression was relatively slow.
Weiler et al. (1996) reported a large, inbred, aboriginal Canadian kindred in which 7 patients presented with limb-girdle muscular dystrophy, whereas 2 manifested predominantly distal wasting and weakness consistent with Miyoshi myopathy. Those with LGMD all developed distal involvement and all but 1 were wheelchair-bound. Those with distal presentation later showed proximal muscle involvement. Age at onset of weakness was in adolescence. Both types of disorder showed increased serum creatine kinase and similar dystrophic changes on muscle biopsy. There was no evidence of cardiac involvement.
Illarioshkin et al. (1996) reported a 6-generation consanguineous family originating from an isolated mountainous village in the Russian province of Daghestan with 2 forms of progressive muscular dystrophy. Seven patients developed classical LGMD with disease onset between 15 and 30 years and loss of ambulation within a 25-year course. The second group included 3 patients with a slowly progressive distal myopathy first manifested in the late teens and confined to the tibial and calf muscles. Each of these phenotypes segregated independently as an autosomal recessive trait and muscle biopsies showed non-specific myopathic changes.
Bashir et al. (1998) reported 8 Libyan Jewish families with LGMD2B. The 25 patients in these families showed onset of the disease between 12 and 39 years of age (mean 19.5 +/- 5 years). All had lower limb involvement on average 9 years before upper limb symptoms. Thirteen patients (52%) presented with distal lower limb muscle weakness, mostly of the gastrocnemius, with some complaining of transient calf enlargement. Intrafamilial variability was seen in the distribution of muscle weakness. Only 6 patients had lost the ability to walk independently; all of these were older than 35 years. Muscle biopsy showed chronic myopathic changes, and creatine kinase was elevated to 10-25 times normal in all affected individuals.
Passos-Bueno et al. (1999) studied 140 patients from 40 Brazilian families with one of 7 autosomal recessive limb-girdle muscular dystrophies (LGMDs). All LGMD2E (LGMDR4; 604286) and LGMD2F (LGMDR6; 601287) patients had a severe phenotype; considerable inter- and intrafamilial variability was observed in all other types of LGMD. Among the sarcoglycanopathies, serum CK levels were highest in the LGMD2D (LGMDR3; 608099) patients. Comparison between 40 LGMD2A (LGMDR1; 253600) patients and 52 LGMD2B patients showed that LGMD2A patients had a more severe course and higher frequency of calf hypertrophy (86% vs 13%), and that LGMD2B patients were more likely to be unable to walk on toes (70% vs 18%).
McNally et al. (2000) reported a large inbred pedigree of Yemenite Jewish descent with LGMD2B. These patients had slowly progressive muscular weakness of the lower limbs, both distal and proximal, beginning in the late second decade of life. Most developed upper limb involvement within 10 years. Three of 6 patients became wheelchair-bound. The patients had markedly elevated serum creatine kinase levels, and 2 of the 4 patients from whom muscle biopsies were available demonstrated an inflammatory process, a finding not previously described in LGMD. Mutation analysis demonstrated a homozygous mutation in the DYSF gene (609003.0008).
Illa et al. (2007) reported a 54-year-old woman who presented with a 3-year history of progressive fatigue while walking and difficulty climbing stairs. She had proximal muscle weakness of the lower limbs, increased serum creatine kinase and evidence of fatty infiltration of the lower limb muscles on MRI; mutation analysis showed that she was a heterozygous mutation carrier (D625Y; 603009.0013). Her brother had a full LGMD2B phenotype and was compound heterozygous the D625Y mutation and a second missense mutation (603009.0014) in the DYSF gene. Although immunostaining and Western blot analysis showed decreased dysferlin levels in the woman's muscle, RT-PCR showed normal levels of DYSF mRNA. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder.
Spuler et al. (2008) reported 2 sibs with LGMD2B caused by compound heterozygosity for mutations in the DYSF gene (G299R, 603009.0017; 603009.0020). Skeletal muscle biopsy showed amyloid fibrils on skeletal muscle biopsy. Amyloid was located in the sarcolemma of muscle cells as well as in blood vessel walls and interstitium. Spuler et al. (2008) postulated that the G299R mutation destabilized the protein structure of dysferlin and increased the propensity to form amyloid fibrils.
### Clinical Variability
Paradas et al. (2009) reported 2 Spanish sibs, aged 2 and 5 years, with a congenital muscular dystrophy associated with a homozygous truncating mutation in the DYSF gene (2779delG; 603009.0021). Both showed hypotonia in infancy and difficulty walking, running, and climbing stairs. There was neck and pelvic muscle weakness. The older patient developed increased serum creatine kinase after age 3. There were no abnormalities in muscle bulk or facial or bulbar motor functions, and no skeletal abnormalities. MRI of the older patient at age 5 showed myoedema of the hamstrings and medial gastrocnemius; these changes were not observed in the other affected sib at age 2. Muscle biopsy showed mild dystrophic features and absent dysferlin expression. Paradas et al. (2009) emphasized the early onset of the disorder in these sibs, and suggested that they have a novel phenotype not previously associated with DYSF mutations, which may be due to genetic modifiers.
Diagnosis
Cacciottolo et al. (2011) found that all of 55 patients with an undetermined LGMD clinical phenotype and 10 patients with a Miyoshi myopathy phenotype who had less than 20% dysferlin on skeletal muscle biopsy determined by Western blot analysis had pathogenic mutations in the DYSF gene. Exhaustive mutation analysis was performed, including genomic DNA sequencing, mRNA analysis, array CGH, and PCR. Sixty-five different mutations were identified throughout the gene and there were no mutation hotspots. Cacciottolo et al. (2011) noted the difficulty of sequencing the DYSF gene because of its larger size, and concluded that protein analysis showing a dysferlin reduction to 20% of normal values in skeletal muscle or in peripheral blood monocytes can be used to identify LGMD2B/MMD1 caused by DYSF mutations with 100% accuracy.
Mapping
In a study of 11 large Brazilian LGMD families of different racial backgrounds, Passos-Bueno et al. (1993) excluded 6 families from linkage to the LGMD2A locus on 15q. The findings indicated genetic heterogeneity in LGMD.
Bashir et al. (1994) mapped a form of LGMD (LGMD2B) to short tandem repeat polymorphisms D2S134 and D2S136 on chromosome 2p16-p13. The maximum lod score was 3.57 at zero recombination. The phenotype in the 2 families was similar, with onset in the pelvic girdle musculature in the late teens and usually relatively slow progression.
Passos-Bueno et al. (1995) confirmed the assignment to 2p in their Brazilian families with autosomal recessive LGMD. Haplotypes generated from 5 chromosome 2 markers from all of the known large families linked to 2p were reported together with the recombinants which showed the most likely location of the LGMD2B gene to be between D2S292 and D2S286, a region of approximately 4 cM located 9-cM distal to the linked markers originally described.
Bashir et al. (1996) assembled a 6-cM YAC contig spanning the LGMD2B locus and mapped 7 genes and 13 anonymous polymorphic microsatellites to it. Using haplotype analysis in the linked families, they narrowed the region of interest to an interval between D2S2113 and D2S2112/D2S145. By fluorescence in situ hybridization mapping of YACs positive for closely linked markers, they defined the distal and proximal boundaries of the LGMD2B gene to be 2p13.3 and 2p13.1, respectively.
In an aboriginal Canadian family that segregated both LGMD and Miyoshi myopathy, Weiler et al. (1996) found significant linkage to a locus spanning the region of LGMD2B on chromosome 2p (lod scores greater than 3.0). Although the family was highly consanguineous, 2 different core haplotypes were identified. Six patients, including the 2 with MM, were homozygous for a haplotype encompassing a 4-cM region spanned by D2S291-D2S2145-D2S286. The 3 other patients were compound heterozygous for the 4-cM haplotype and an additional haplotype. The findings indicated that there were 2 mutant alleles of independent origin in this kindred. However, since the haplotypes did not distinguish between the LGMD and MM phenotypes, Weiler et al. (1996) concluded that LGMD and MM in this aboriginal Canadian population are caused by the same mutation in LGMD2B and that additional factors, both genetic and nongenetic, must have contributed to the clinical phenotype.
By linkage analysis of a consanguineous family with both proximal and distal AR muscular dystrophy, Illarioshkin et al. (1996) found linkage to a 6-cM region on 2p between D2S292 and D2S286 (maximum lod score of 5.64 at D2S291). The authors also demonstrated homozygosity by descent at the critical chromosomal region in all patients, thus providing evidence for a common genetic basis of the 2 clinical phenotypes. Illarioshkin et al. (1997) reported extended haplotypes generated from 15 microsatellite markers, including 7 new markers, and thereby narrowed the locus on 2p13 to a region between D2S327 and D2S2111.
Molecular Genetics
In affected members of 8 Libyan Jewish families with LGMD2B, Bashir et al. (1998) identified a homozygous mutation in the DYSF gene (603009.0005). In a ninth Libyan Jewish family, with a single affected member, the mutation was detected in single copy; one of the parents, who did not carry the mutation, was of Romanian origin.
In a large Canadian aboriginal kindred reported by Weiler et al. (1996), Weiler et al. (1999) found that both patients with LGMD2B and patients with MM were homozygous for a mutation in the dysferlin gene (P791R; 603009.0007). Four additional patients from 2 previously unpublished families also had this mutation and haplotype analysis suggested a common origin of the mutation in all patients. On Western blots of muscle, LGMD2B and MM patients showed a similar abundance of dysferlin staining of 15% and 11%, respectively. Normal tissue sections showed that dysferlin localizes to the sarcolemma, while tissue sections from MM and LGMD patients showed minimal staining which was indistinguishable between the 2 types.
In a large inbred Russian family with both LGMD2B and Miyoshi myopathy reported by Illarioshkin et al. (1996), Illarioshkin et al. (2000) identified a homozygous mutation in the DYSF gene (V67D; 603009.0009).
In affected members from 5 families from Sueca, Spain, with a dysferlinopathy, Vilchez et al. (2005) identified a homozygous mutation in the DYSF gene (R1905X; 603009.0012). Two families presented with Miyoshi myopathy, 2 presented with distal myopathy with anterior tibial onset, and 1 presented with LGMD2B. Although the same mutation resulted in different phenotypes, affected members of each family expressed the same phenotype. Haplotype analysis indicated a founder effect. Sueca was founded in 1245 by 17 settlers belonging to the Hospital Order, which received land from King James I of Aragon as a reward for help in reconquering Valencia from the Moors.
Population Genetics
Guglieri et al. (2008) found that LGMD2B was the second most common form of LGMD after LGMD2A among 155 Italian probands. LGMD2B occurred in 18.7% of probands, whereas LGMD2A occurred in 28.4%. In LGMD2B, there was a correlation between mutation type, age at onset, and protein levels. Patients with truncating mutations in the DYSF gene had an earlier age at onset and an absence of protein on muscle biopsy, whereas patients with missense mutations had some residual protein.
In 6 unrelated Portuguese male patients with LGMD2B, Santos et al. (2010) identified a mutation in the DYSF gene (5492G-A; 603009.0022). A seventh Portuguese patient was compound heterozygous for the 5492G-A mutation and another pathogenic DYSF mutation. The 5492G-A mutation was not found in 240 control alleles, and haplotype analysis supported a founder effect for the mutation. All 7 patients originated or resided in a confined region of the northern interior part of Portugal. Although most patients had a limb-girdle muscular dystrophy, there was some phenotypic variation: 1 patient presented with distal muscle weakness in the lower limbs, and another had cardiac arrhythmia.
INHERITANCE \- Autosomal recessive MUSCLE, SOFT TISSUES \- Proximal muscle weakness \- Primarily affects lower limbs \- Difficulty climbing stairs \- Difficulty running \- Increased fatigue \- Upper limb involvement occurs later or not at all \- EMG shows myopathic changes \- Muscle biopsy shows dystrophic changes \- Increased variation in fiber size \- Fiber splitting \- Increased connective tissue and fat in muscles \- Necrotic changes \- Amyloid deposition in muscle fibers occurs rarely LABORATORY ABNORMALITIES \- Increased serum creatine kinase MISCELLANEOUS \- Age at onset 15 to 25 years \- Slow progression \- Many patients lose independent mobility after 25 years \- Onset in infancy was reported in 1 family \- Heterozygous mutation carriers may have late-onset of mild symptoms \- Allelic disorder to Miyoshi myopathy ( 254130 ) and distal myopathy with anterior tibial onset ( 606768 ) MOLECULAR BASIS \- Caused by mutation in the dysferlin gene (DYSF, 603009.0003 ) ▲ 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
| MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2 | c1850889 | 2,699 | omim | https://www.omim.org/entry/253601 | 2019-09-22T16:24:47 | {"doid": ["0110276"], "mesh": ["C535899"], "omim": ["253601"], "orphanet": ["268"], "synonyms": ["Alternative titles", "MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2B", "MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 3"], "genereviews": ["NBK1303"]} |
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