The combination of spinocerebellar ataxia and motor neuron disease associated with SOD1 gene mutation
https://doi.org/10.25557/2073-7998.2023.09.53-58
Abstract
We report a clinical case of the patient with a rare phenotype presented by progressive cerebellar ataxia in combination with upper and lower motor neuron involvement. Target panel sequencing revealed the previously described pathogenic mutation c.272A>C (p.D91A, rs80265967) in the 4th exon of the SOD1 gene. Mutations in this gene are a common cause of the hereditary forms of amyotrophic lateral sclerosis (ALS, MIM #105400). The combination of ALS with cerebellar ataxia is an extremely rare, and cases of association of this mutation with cerebellar ataxia have not been previously described. The presented clinical observation and literature data expand the understanding of the genetic and phenotypic “overlap” of hereditary ataxias and motor neuron diseases. The development of drugs for SOD1-ALS gene therapy, including the use of antisense oligonucleotides aimed at suppressing SOD1 gene expression, is currently underway. In this regard, it is necessary to include the study of the SOD1 gene in the algorithms for diagnosing hereditary cerebellar ataxia in the presence of a characteristic clinical phenotype.
Keywords
spinocerebellar ataxia,
amyotrophic lateral sclerosis,
motor neuron disease,
SOD1 gene,
clinical presentation
Supporting agencies: The research was carried out within the state assignment of Ministry of Science and Higher Education of the Russian Federation.
About the Authors
E. P. Nuzhnyi
Research Center of Neurology
Russian Federation
Russian Federation
80, Volokolamskoye shosse, 125367, Moscow
I. V. Minaev
Research Center of Neurology
Russian Federation
Russian Federation
80, Volokolamskoye shosse, 125367, Moscow
A. O. Protopopova
Research Center of Neurology
Russian Federation
Russian Federation
80, Volokolamskoye shosse, 125367, Moscow
N. Y. Abramycheva
Research Center of Neurology
Russian Federation
Russian Federation
80, Volokolamskoye shosse, 125367, Moscow
E. Y. Fedotova
Research Center of Neurology
Russian Federation
Russian Federation
80, Volokolamskoye shosse, 125367, Moscow
S. N. Illarioshkin
Research Center of Neurology
Russian Federation
Russian Federation
80, Volokolamskoye shosse, 125367, Moscow
References
1. Nuzhnyi, E.P., Abramycheva, N.Y., Safonov, D.G. et al. Massive Parallel Sequencing and the Problem of Overlapping Phenotypes in Hereditary Spastic Paraplegias and Spinocerebellar Ataxias. Russ J Genet. 2022; 58: 456–461.
2. Abramycheva N.Yu., Lysogorskaya E.V., Shpilyukova Yu.A. et al. Molekulyarnaya struktura bokovogo amiotroficheskogo skleroza v rossiyskoy populyatsii. [Molecular structure of amyotrophic lateral sclerosis in Russian population]. Nervno-myshechnyye bolezni [Neuromuscular Diseases] 2016; 6 (4): 21-27. (In Russ.)
3. Al-Chalabi A., van den Berg L.H., Veldink J. Gene discovery in amyotrophic lateral sclerosis: implications for clinical management. Nat Rev Neurol. 2017; 13 (2): 96–104.
4. Semenova O.V., Klyushnikov S.A., Pavlov E.V. et al. Klinicheskiy sluchay bolezni Teya-Saksa s pozdnim nachalom. [Clinical case of the late onset Tay–Sachs disease]. Nervnyye bolezni [Nervous Diseases]. 2016; 3: 57-60. (In Russ.)
5. Kume K., Morino H., Komure O. et al. C-terminal mutations in SYNE1 are associated with motor neuron disease in patients with SCAR8. J Neurol Sci. 2019; 402: 118-120.
6. Lysogorskaya E.V., Rossokhin A.V., Abramycheva N.Y. et al. Mutatsii v gene SOD1 pri bokovom amiotroficheskom skleroze: vozmozhnosti metoda molekulyarnogo modelirovaniya. [SOD1 gene mutations in patients with amyotrophic lateral sclerosis: potential for the method of molecular modeling]. Molekulyarnaya biologiya [Molecular Biology]. 2013; 47 (5): 861–867. (In Russ.)
7. Chipika R.H., Mulkerrin G., Pradat P.F. et al. Cerebellar pathology in motor neuron disease: neuroplasticity and neurodegeneration. Neural Regen Res. 2022; 17 (11): 2335-2341.
8. Fedotova E.Y., Abramycheva N.Y., Moroz A.A. et al. Geny ATXN2 i C9ORF72 kak universal’nyye faktory razvitiya razlichnykh neyrodegenerativnykh zabolevaniy. [Genes ATXN2 and C9ORF72 as universal factors of different neurological disorders development]. Nevrologicheskiy zhurnal [Neurological Journal]. 2016; 21 (6): 323–329. (In Russ.)
9. Rudenskaya G.E., Nikitin S.S., Shatokhina O.L., Shchagina O.A. Yuvenil’nyy bokovoy amiotroficheskiy skleroz 4-go tipa: klinicheskoye nablyudeniye i obzor literatury. [Juvenile amyotrophic lateral sclerosis type 4: case report and review]. Nervno-myshechnyye bolezni [Neuromuscular Diseases]. 2022; 12 (3): 52-58. (In Russ.)
10. Bharti K., Khan M., Beaulieu C. et al. Involvement of the dentate nucleus in the pathophysiology of amyotrophic lateral sclerosis: A multi-center and multi-modal neuroimaging study. Neuroimage Clin. 2020; 28: 102385.
11. Gentile G., Perrone B., Morello G., et al. Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients. Genes 2021; 12: 1843.
12. Bernard E., Pegat A., Svahn J. et al. Clinical and Molecular Landscape of ALS Patients with SOD1 Mutations: Novel Pathogenic Variants and Novel Phenotypes. A Single ALS Center Study. Int. J. Mol. Sci. 2020; 21: 6807.
13. Yasser S., Fecto F., Siddique T. et al. An unusual case of familial ALS and cerebellar ataxia. Amyotrophic Lateral Sclerosis. 2010; 11: 568–570.
14. Sequeira M., Faustino P., Lourenço J. Amyotrophic Lateral Sclerosis with SOD1 mutation presenting with progressive cerebellar ataxia [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/amyotrophic-lateral-sclerosis-with-sod1-mutation-presenting-with-progressive-cerebellar-ataxia/. Accessed July 17, 2023.
15. Marsili L., Davis J.L., Espay A.J. et al. SOD1-Related Cerebellar Ataxia and Motor Neuron Disease: Cp Variant as Functional Modifier? Cerebellum. 2023 Feb 9. doi: 10.1007/s12311-023-01527-3.
16. Gagliardi D., Ripellino P., Meneri M. et al. Clinical and molecular features of patients with amyotrophic lateral sclerosis and SOD1 mutations: a monocentric study. Front. Neurol. 2023; 14: 1169689.
17. Shpilyukova Y.A., Fedotova E.Y., Illarioshkin S.N. Geneticheskoye raznoobraziye lobno-visochnoy dementsii. [Genetic diversity of frontotemporal dementia]. Molekulyarnaya biologiya [Molecular Biology]. 2020; 54 (1): 17-28. (In Russ.)
18. Kovrazhkina YE.A., Razinskaya O.D., Gubskiy L.V. Klinicheskiy polimorfizm bokovogo amiotroficheskogo skleroza. [Clinical polymorphism of amyotrophic lateral sclerosis]. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova [S.S. Korsakov Journal of Neurology and Psychiatry]. 2017; 117 (8): 4-10. (In Russ.)
19. Ungaro C., Sprovieri T., Morello G. et al. Genetic investigation of amyotrophic lateral sclerosis patients in south Italy: A two-decade analysis. Neurobiol. Aging. 2021; 99:99.e7–99.e14.
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For citations:
Nuzhnyi E.P., Minaev I.V., Protopopova A.O., Abramycheva N.Y., Fedotova E.Y., Illarioshkin S.N. The combination of spinocerebellar ataxia and motor neuron disease associated with SOD1 gene mutation. Medical Genetics. 2023;22(9):53-58. (In Russ.) https://doi.org/10.25557/2073-7998.2023.09.53-58
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