GOSR2-related progressive myoclonus ataxia

GOSR2-related progressive myoclonus ataxia
Other namesEPM6, PME type 6, Progressive myoclonic epilepsy type 6, North Sea progressive myoclonus epilepsy, Progressive myoclonus epilepsy type 6
SpecialtyMedical genetics
SymptomsMyoclonic epilepsy with progressive ataxia
Usual onsetEarly
DurationLifelong
CausesMutation in GOSR2
Diagnostic methodGenetic testing
TreatmentPhysical therapy
Frequencyvery rare, only 12 cases have been described in medical literature

GOSR2-related progressive myoclonus ataxia, also known as Progressive myoclonic epilepsy type 6, is a rare genetic type of progressive myoclonus ataxia which is characterized by progressive myoclonic epilepsy with an early onset which is associated with generalized tonic-clonic seizures, petit mal seizures, and drop attacks, variable degrees of scoliosis, areflexia, high levels of creatine kinase serum, and late-onset cognitive decline.[1][2]

According to OMIM,[3] only 12 cases have been described in medical literature.[4][5][6]

Symptoms

EPM6 is classically characterised by first beginning motor delay, decreased muscle tone, gait issues, absent reflexes.[7] At around age 4, patients usually develop ataxia; later (around age 6), they develop myoclonus. Myoclonus is more prominient in upper extremity than in lower, also they can experience myoclonus of tongue and around the mouth.[7] Before age 20, patients might also develop epileptic seizures, also during the first decade, patients experience dysarthric speech; later, around the second/third decade, some patients experience dysphagia.[7] Scoliosis (abnormal curvature of spine) can be seen in patients before first/second decade, also most of the patients became wheelchair-bound (around at the age 13).[7][8][9] Increased creatine kinase levels can be seen, in addition patients usually have preserved cognition until late course of the disorder.[1][9]

Diagnosis

PME6 can be suspected by symptoms and confirmed by genetic testing.[10]

Cause

It is caused by autosomal recessive loss of function mutations in the GOSR2 gene, in chromosome 17.[4] Most patients share the common mutation, specifically p.Gly144Trp.[11] Rarely patients can present with congenital muscular dystrophy and PME at the same time.[12][11]

Pathophysiology

GOSR2 is a protein that is classified as a t-SNARE and includes SNARE domain which is important for vesicle fusion; in EPM6, GOSR2 function is compromised.[11] In Drosophila model, GOSR2 mutation might cause deficiency in dendritic growth and disrupts evoked and spontaneous release of neurotransmitter.[13]

Treatment

Treatment is only symptomatic.[7]

See also

References

  1. 1 2 "Orphanet: Progressive myoclonic epilepsy type 6". www.orpha.net. Retrieved 2022-06-16.
  2. ↑ "GOSR2-related progressive myoclonus ataxia | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". 2021-03-21. Archived from the original on 2021-03-21. Retrieved 2022-06-16.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
  3. ↑ "OMIM Entry - # 614018 - Epilepsy, Progressive Myoclonic, 6; EPM6". omim.org. Retrieved 2022-06-16.
  4. 1 2 Corbett, Mark A.; Schwake, Michael; Bahlo, Melanie; Dibbens, Leanne M.; Lin, Meng; Gandolfo, Luke C.; Vears, Danya F.; O'Sullivan, John D.; Robertson, Thomas; Bayly, Marta A.; Gardner, Alison E. (2011-05-13). "A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia". American Journal of Human Genetics. 88 (5): 657–663. doi:10.1016/j.ajhg.2011.04.011. ISSN 1537-6605. PMC 3146720. PMID 21549339.
  5. ↑ van Egmond, Martje E.; Verschuuren-Bemelmans, Corien C.; Nibbeling, Esther A.; Elting, Jan Willem J.; Sival, Deborah A.; Brouwer, Oebele F.; de Vries, Jeroen J.; Kremer, Hubertus P.; Sinke, Richard J.; Tijssen, Marina A.; de Koning, Tom J. (January 2014). "Ramsay Hunt syndrome: clinical characterization of progressive myoclonus ataxia caused by GOSR2 mutation". Movement Disorders. 29 (1): 139–143. doi:10.1002/mds.25704. ISSN 1531-8257. PMID 24458321. S2CID 22595640.
  6. ↑ Praschberger, Roman; Balint, Bettina; Mencacci, Niccolo E.; Hersheson, Joshua; Rubio-Agusti, Ignacio; Kullmann, Dimitri M.; Bettencourt, Conceição; Bhatia, Kailash; Houlden, Henry (September 2015). "Expanding the Phenotype and Genetic Defects Associated with the GOSR2 Gene". Movement Disorders Clinical Practice. 2 (3): 271–273. doi:10.1002/mdc3.12190. ISSN 2330-1619. PMC 6178697. PMID 30363482.
  7. 1 2 3 4 5 Polet, Sjoukje S.; Anderson, David G.; Koens, Lisette H.; Egmond, Martje E. van; Drost, Gea; Brusse, Esther; Willemsen, Michèl AAP; Sival, Deborah A.; Brouwer, Oebele F.; Kremer, Hubertus PH; Vries, Jeroen J. de; Tijssen, Marina AJ; Koning, Tom J. de (2020-03-01). "A detailed description of the phenotypic spectrum of North Sea Progressive Myoclonus Epilepsy in a large cohort of seventeen patients". Parkinsonism & Related Disorders. 72: 44–48. doi:10.1016/j.parkreldis.2020.02.005. hdl:11370/3a96be43-955a-418e-b315-b79d3903c55d. ISSN 1353-8020. PMID 32105965.
  8. ↑ "Adolescent idiopathic scoliosis: MedlinePlus Genetics". medlineplus.gov. Retrieved 2026-04-12.
  9. 1 2 Boissé Lomax, Lysa; Bayly, Marta A.; Hjalgrim, Helle; Møller, Rikke S.; Vlaar, Annemarie M.; Aaberg, Kari M.; Marquardt, Iris; Gandolfo, Luke C.; Willemsen, Michèl; Kamsteeg, Erik-Jan; O'Sullivan, John D.; Korenke, G. Christoph; Bloem, Bastiaan R.; de Coo, Irenaeus F.; Verhagen, Judith M. A. (2013-02-18). "'North Sea' progressive myoclonus epilepsy: phenotype of subjects with GOSR2 mutation". Brain: A Journal of Neurology. 136 (Pt 4): 1146–1154. doi:10.1093/brain/awt021. ISSN 1460-2156. PMID 23449775.
  10. ↑ Hentrich, Lea; Parnes, Mered; Lotze, Timothy Edward; Coorg, Rohini; de Koning, Tom J.; Nguyen, Kha M.; Yip, Calvin K.; Jungbluth, Heinz; Koy, Anne; Dafsari, Hormos Salimi (2023-09-25). "Novel Genetic and Phenotypic Expansion in GOSR2-Related Progressive Myoclonus Epilepsy". Genes. 14 (10): 1860. doi:10.3390/genes14101860. ISSN 2073-4425. PMC 10606070. PMID 37895210.
  11. 1 2 3 Polet, Sjoukje S.; Siegal, Elisabeth Z.; Fuchs, Sabine A.; Tijssen, Marina A. J.; de Koning, Tom J. (2025-11-25). "The Genotypic and Phenotypic Spectrum of GOSR2 Mutations: Clinical and Pathophysiological Insights". Journal of Inherited Metabolic Disease. 48 (6) e70115. doi:10.1002/jimd.70115. ISSN 0141-8955. PMC 12631098. PMID 41261947.
  12. ↑ Arroyo, Monica S.; Fuller, Christine; Schorry, Elizabeth K.; Ulm, Elizabeth; Tian, Cuixia (2024-07-14). "Compound Heterozygous Variants of GOSR2 Associated With Congenital Muscular Dystrophy and Progressive Myoclonus Epilepsy". Neurology Genetics. 10 (4) e200177. doi:10.1212/NXG.0000000000200177. PMC 11259530. PMID 39035823.
  13. ↑ Praschberger, Roman; Lowe, Simon A.; Malintan, Nancy T.; Giachello, Carlo N. G.; Patel, Nian; Houlden, Henry; Kullmann, Dimitri M.; Baines, Richard A.; Usowicz, Maria M.; Krishnakumar, Shyam S.; Hodge, James J. L.; Rothman, James E.; Jepson, James E. C. (2017-10-03). "Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity". Cell Reports. 21 (1): 97–109. doi:10.1016/j.celrep.2017.09.004. ISSN 2211-1247. PMC 5640804. PMID 28978487.
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