Medicine:Gerstmann–Sträussler–Scheinker syndrome

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Short description: Human neurodegenerative disease
Not to be confused with Gerstmann syndrome.
Gerstmann–Sträussler–Scheinker syndrome
A person with inherited prion disease has cerebellar atrophy. This is typical for GSS.
A person with inherited prion disease has cerebellar atrophy. This is quite typical of GSS.
Symptomsdifficulty speaking, developing dementia, memory loss, vision loss, ataxia
Complicationsaspiration pneumonia, akinetic mutism
Usual onset30s to 50s
Duration2-10 years, usually 5-6 years, ranging from 3 months to 13 years[1]
TypesTypical GSS, GSS with areflexia and paresthesia, pure dementia GSS, Creutzfeldt-Jakob disease-like GSS
CausesPrion, specifically PrPGSS
Risk factorsPRNP mutations, usually a replacement of proline with leucine at codon 102 of PRNP (P102L)
Diagnostic methodPRNP gene sequencing
Differential diagnosisCreutzfeldt-Jakob disease
PreventionGene editing of children at risk
TreatmentNone
MedicationNone
PrognosisUniversally fatal, life expectancy is typically 5-6 years from diagnosis, with a range of 3 months to 13 years[1]
Frequency1-10 of every 100 million people
DeathsUnknown

Gerstmann–Sträussler–Scheinker syndrome (GSS) is an extremely rare, invariably fatal neurodegenerative disease that usually affects patients from 35 to 55 years in age. It is exclusively heritable in an autosomal dominant manner, and is found in only a few families around the world.[2] GSS is considered a transmissible spongiform encephalopathy (TSE) due to the causative role played by the PRNP gene, which encodes for the human prion protein.[3] It was discovered by Josef Gerstmann, Ernst Sträussler, and Ilya Scheinker in 1936.[4][5]

Certain symptoms are common to GSS, such as progressive ataxia, pyramidal signs, and dementia; they worsen as the disease progresses.[6] Much like Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome has significant variety in presentation.[7]

Symptoms and signs

Symptoms start with slowly developing dysarthria (difficulty speaking) and cerebellar truncal ataxia (unsteadiness) before the progressive dementia becomes more evident. In the early stages of GSS, people with the condition may also exhibit clumsiness and difficulty walking. As the condition progresses, symptoms of ataxia become more pronounced.[8] Loss of memory can be the first symptom of GSS.[9] Extrapyramidal and pyramidal symptoms and signs may occur, and the disease may mimic spinocerebellar ataxias in the beginning stages. Myoclonus (spasmodic muscle contraction) is less frequently seen than in Creutzfeldt–Jakob disease. Many patients also exhibit nystagmus (involuntary movement of the eyes), visual disturbances, and blindness or deafness.[10] The neuropathological findings of GSS include widespread deposition of amyloid plaques composed of misfolded prion proteins.[9]

Four clinical phenotypes are recognized: typical GSS, GSS with areflexia and paresthesia, pure dementia GSS and Creutzfeldt-Jakob disease-like GSS.[11]

Causes

GSS is part of a group of diseases called transmissible spongiform encephalopathies. These diseases are caused by prions, which are a class of pathogenic proteins that are resistant to proteases. These prions then form clusters in the brain, which are responsible for the neurodegenerative effects seen in patients.[12]

The P102L mutation, which causes a substitution of proline to a leucine in codon 102, has been found in the prion protein gene (PRNP, on chromosome 20) of most affected individuals.[13] Therefore, it appears this genetic change is usually required for the development of the disease.[14][15][16]

Diagnosis

GSS can be identified through genetic testing.[10] Testing for GSS involves a blood and DNA examination in order to detect the mutated gene at certain codons. If the genetic mutation is present, the patient will eventually develop GSS.

Treatment

Prognosis

GSS is a disease that progresses slowly, lasting from roughly 2 to 10 years, with an average of approximately five years.[9][2]

Symptoms, such as clumsiness and unsteadiness when walking, appear at the beginning of the illness. Muscle jerking (myoclonus) is much less common than in Creutzfeldt-Jakob disease. Speaking becomes difficult (called dysarthria), and dementia develops. Nystagmus (rapid movement of the eyes in one direction, followed by a slower drift back to the original position) and deafness may develop. Muscle coordination is lost (called ataxia), which may cause muscles to become stiff. Usually, the muscles that control breathing and coughing are impaired, resulting in a high risk of pneumonia, which is the most common cause of death.

The disease ultimately results in death, most commonly from the patient either going into a coma, or from a secondary infection due to the patient's loss of bodily functions.[2]

Research

Prion diseases, also called transmissible spongiform encephalopathies (TSEs), are neurodegenerative diseases of the brain thought to be caused by a protein that converts to an abnormal form called a prion.[17][18] GSS is a very rare TSE, making its genetic origin nearly impossible to determine. It is also challenging to find any patients with GSS, as the disease tends to be underreported, due to its clinical similarity to other diseases, and has been found in only a few countries.[19] In 1989, the first mutation of the prion protein gene was identified in a GSS family.[16] The largest of these families affected by GSS is the Indiana Kindred, spanning over 8 generations, and includes over 3,000 people, with 57 individuals known to be affected.[15] GSS was later realized to have many different gene mutation types, varying in symptom severity, timing and progression. Doctors in different parts of the world are in the process of uncovering more generations and families who have the mutation.

Notes

  1. ↑ 1.0 1.1 Park, Min Jeong; Jo, Hee Young; Cheon, Sang-Myung; Choi, Sun Seob; Kim, Yong-Sun; Kim, Jae Woo (March 27, 2010). "A case of gerstmann-sträussler-scheinker disease". Journal of Clinical Neurology 6 (1): 46–50. doi:10.3988/jcn.2010.6.1.46. PMID 20386644. PMC 2851297. https://pmc.ncbi.nlm.nih.gov/articles/PMC2851297/. 
  2. ↑ 2.0 2.1 2.2 "Gerstmann-Straussler-Scheinker Disease Information Page". National Institute of Neurological Disorders and Stroke. U.S. Department of Health & Human Services. https://www.ninds.nih.gov/Disorders/All-Disorders/Gerstmann-Straussler-Scheinker-Disease-Information-Page. 
  3. ↑ "Gerstmann-Sträussler-Scheinker Disease". Neurodegenerative Diseases. Advances in Experimental Medicine and Biology. 724. 2012. pp. 128–37. doi:10.1007/978-1-4614-0653-2_10. ISBN 978-1-4614-0652-5. 
  4. ↑ synd/2269 at Who Named It?
  5. ↑ "Über eine eigenartige hereditär-familiäre Erkrankung des Zentralnervensystems. Zugleich ein Beitrag zur Frage des vorzeitigen lokalen Alterns". Zeitschrift für die gesamte Neurologie und Psychiatrie 154: 736–762. 1936. doi:10.1007/bf02865827. 
  6. ↑ "Gerstmann-Sträussler-Scheinker disease. I. Extending the clinical spectrum". Neurology 39 (11): 1446–52. November 1989. doi:10.1212/wnl.39.11.1446. PMID 2812321. 
  7. ↑ Riudavets, Miguel A.; Sraka, María Alejandra; Schultz, Marcelo; Rojas, Estefanía; Martinetto, Horacio; Begué, Christian; Noher de Halac, Inés; Poleggi, Anna et al. (March 27, 2014). "Gerstmann-Sträussler-Scheinker syndrome with variable phenotype in a new kindred with PRNP-P102L mutation". Brain Pathology 24 (2): 142–147. doi:10.1111/bpa.12083. PMID 23944754. PMC 8029128. https://pmc.ncbi.nlm.nih.gov/articles/PMC8029128/. 
  8. ↑ "Gerstmann-Straussler-Scheinker Disease" (in en). https://www.ninds.nih.gov/health-information/disorders/gerstmann-straussler-scheinker-disease. 
  9. ↑ 9.0 9.1 9.2 "Gerstmann-Sträussler-Scheinker syndrome,fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies". Journal of Clinical Neuroscience 8 (5): 387–97. September 2001. doi:10.1054/jocn.2001.0919. PMID 11535002. 
  10. ↑ 10.0 10.1 "Gerstmann–Sträussler–Scheinker Disease". The Merck Manuals: Online Medical Library. http://www.merckmanuals.com/home/sec06/ch090/ch090d.html. 
  11. ↑ "Clinical Variability in P102L Gerstmann-Sträussler-Scheinker Syndrome". Annals of Neurology 86 (5): 643–652. November 2019. doi:10.1002/ana.25579. PMID 31397917. 
  12. ↑ "Prion protein misfolding, strains, and neurotoxicity: an update from studies on Mammalian prions". International Journal of Cell Biology 2013. 2013. doi:10.1155/2013/910314. PMID 24454379. 
  13. ↑ "Early clinical signs and imaging findings in Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu)". Neurology 66 (11): 1672–8. June 2006. doi:10.1212/01.wnl.0000218211.85675.18. PMID 16769939. 
  14. ↑ "Clinicopathological Correlates in a PRNP P102L Mutation Carrier with Rapidly Progressing Parkinsonism-dystonia". Movement Disorders Clinical Practice 3 (4): 355–358. 2016-02-18. doi:10.1002/mdc3.12307. PMID 27617269. 
  15. ↑ 15.0 15.1 "Prion protein amyloidosis". Brain Pathology 6 (2): 127–45. April 1996. doi:10.1111/j.1750-3639.1996.tb00796.x. PMID 8737929. 
  16. ↑ 16.0 16.1 "Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome". Nature 338 (6213): 342–5. March 1989. doi:10.1038/338342a0. PMID 2564168. Bibcode: 1989Natur.338..342H. 
  17. ↑ "Prions in variably protease-sensitive prionopathy: an update". Pathogens 2 (3): 457–71. July 2013. doi:10.3390/pathogens2030457. PMID 25437202. 
  18. ↑ "Creationism and evolutionism in prions". The American Journal of Pathology 182 (3): 623–7. March 2013. doi:10.1016/j.ajpath.2012.12.016. PMID 23380581. 
  19. ↑ "Hereditary prion protein amyloidoses". Clinics in Laboratory Medicine 23 (1): 65–85, viii. March 2003. doi:10.1016/s0272-2712(02)00064-1. PMID 12733425. 
Classification

Template:Prion diseases



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