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Genetic ataxias: update on classification and diagnostic approaches

  • Movement Disorders (T. Simuni, Section Editor)
  • Published:
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Abstract

Ataxia encompasses a large group of rare disorders characterized by irregular movements, decreased coordination, imbalance, kinetic tremor, wide-based stance, and dysarthria. Evaluating ataxia can be challenging considering the volume of disorders and their complex pathologies involving diverse genetic and clinical factors. This is a comprehensive review of the genetic ataxia literature, presenting updated guidelines for differential diagnosis. Age, time course, and family history provide initial guidance for evaluation of ataxia. As genetic testing is increasingly utilized, new genes are discovered and phenotypes for existing disorders are expanded. This review assists physicians by offering a diagnostic roadmap for suspected hereditary ataxia based on the current literature.

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References

  1. Schols L, Szymanski S, Peters S, Przuntek H, Epplen JT, Hardt C, et al. Genetic background of apparently idiopathic sporadic cerebellar ataxia. Hum Genet. 2000;107(2):132–7.

    Article  CAS  Google Scholar 

  2. Hadjivassiliou M, Martindale J, Shanmugarajah P, Grunewald RA, Sarrigiannis PG, Beauchamp N, et al. Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. J Neurol Neurol Neurosurg Psychiatry. 2017;88(4):301–9.

    Article  CAS  Google Scholar 

  3. Horton RH, Lucassen AM. Recent developments in genetic/genomic medicine. Clin Scie (Lond). 2019;133(5):697–708.

    Article  Google Scholar 

  4. Sun M, Johnson AK, Nelakuditi V, Guidugli L, Fischer D, Arndt K, et al. Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes. Genet Med. 2019;21(1):195–206.

    Article  CAS  Google Scholar 

  5. Brandsma R, Verschuuren-Bemelmans CC, Amrom D, Barisic N, Baxter P, Bertini E, et al. A clinical diagnostic algorithm for early onset cerebellar ataxia. Eur J Paediatr Neurol. 2019;23(5):692–706.

    Article  CAS  Google Scholar 

  6. Adam MP AH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle: University of Washington, Seattle 1993–2020.

  7. Evidente VG, Gwinn-Hardy KA, Caviness JN, Gilman S. Hereditary ataxias. Mayo Clinic Proc. 2000;75(5):475–90.

    Article  CAS  Google Scholar 

  8. Rasmussen A, Gomez M, Alonso E, Bidichandani SI. Clinical heterogeneity of recessive ataxia in the Mexican population. J Neurol Neurol Neurosurg Psychiatry. 2006;77(12):1370–2.

    Article  CAS  Google Scholar 

  9. Cortese A, Simone R. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019;51(4):649–58.

    Article  CAS  Google Scholar 

  10. Infante J, Garcia A, Serrano-Cardenas KM, Gonzalez-Aguado R, Gazulla J, de Lucas EM, et al. Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) with chronic cough and preserved muscle stretch reflexes: evidence for selective sparing of afferent Ia fibres. J Neurol. 2018;265(6):1454–62.

    Article  Google Scholar 

  11. Ashizawa T, Oz G, Paulson HL. Spinocerebellar ataxias: prospects and challenges for therapy development. Nature Rev Neurol. 2018;14(10):590–605.

    Article  Google Scholar 

  12. Bird T. Hereditary Ataxia Overview: GeneReviews®; 2019 [updated 2019 Jul 25; cited 2020 Mar 3]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1138/.

  13. McLoughlin HS, Moore LR, Paulson HL. Pathogenesis of SCA3 and implications for other polyglutamine diseases. Neurobiol Dis. 2020;134:104635.

    Article  CAS  Google Scholar 

  14. Martier R, Sogorb-Gonzalez M, Stricker-Shaver J, Hubener-Schmid J, Keskin S, Klima J, et al. Development of an AAV-based microRNA gene therapy to treat Machado-Joseph disease. Molecular therapy Methods & clinical development. 2019;15:343–58.

    Article  CAS  Google Scholar 

  15. Szpisjak L, Zadori D, Klivenyi P, Vecsei L. Clinical characteristics and possible drug targets in autosomal dominant spinocerebellar ataxias. CNS Neurol Disord Drug TargetS. 2019;18(4):279–93.

    Article  CAS  Google Scholar 

  16. Fesahat F, Montazeri F, Hoseini SM. Preimplantation genetic testing in assisted reproduction technology. J Gynecol Obstet Hum Reprod. 2020:101723.

  17. Cahn S, Rosen A, Wilmot G. Spinocerebellar ataxia patient perceptions regarding reproductive options. Mov Disord Clin Pract. 2020;7(1):37–44.

    Article  Google Scholar 

  18. Carroll LS, Massey TH, Wardle M, Peall KJ. Dentatorubral-pallidoluysian atrophy: an update. Tremor Other Hyperkinet Mov (N Y). 2018;8:577.

    Article  Google Scholar 

  19. Burke JR, Wingfield MS, Lewis KE, Roses AD, Lee JE, Hulette C, et al. The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family. Nature Genet. 1994;7(4):521–4.

    Article  CAS  Google Scholar 

  20. Rodriguez-Porcel F, Ciarlariello VB, Dwivedi AK, Lovera L, Da Prat G, Lopez-Castellanos R, et al. Movement disorders in prionopathies: a systematic review. Tremor Other Hyperkinet Mov (N Y). 2019;9.

  21. Paucar M, Xiang F, Moore R, Walker R, Winnberg E, Svenningsson P. Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation. Prion. 2013;7(6):501–10.

    Article  CAS  Google Scholar 

  22. Genis D, Ortega-Cubero S, San Nicolas H, Corral J, Gardenyes J, de Jorge L, et al. Heterozygous STUB1 mutation causes familial ataxia with cognitive affective syndrome (SCA48). Neurology. 2018;91(21):e1988–e98.

    Article  CAS  Google Scholar 

  23. Hoche F, Guell X, Vangel MG, Sherman JC, Schmahmann JD. The cerebellar cognitive affective/Schmahmann syndrome scale. Brain : a. J Neurol. 2018;141(1):248–70.

    Google Scholar 

  24. De Michele G, Lieto M, Galatolo D, Salvatore E, Cocozza S, Barghigiani M, et al. Spinocerebellar ataxia 48 presenting with ataxia associated with cognitive, psychiatric, and extrapyramidal features: a report of two Italian families. Parkinsonism Relat Disord. 2019;65:91–6.

    Article  Google Scholar 

  25. Hall DA, Berry-Kravis E. Fragile X syndrome and fragile X-associated tremor ataxia syndrome. Handb Clin Neurol. 2018;147:377–91.

    Article  Google Scholar 

  26. Hall DA, Hagerman RJ. Fragile X-associated tremor/ataxia syndrome: unmet needs and a path for the future. Front Genet. 2018;9:100.

    Article  Google Scholar 

  27. Finsterer J, Zarrouk-Mahjoub S. Mitochondrial multiorgan disorder syndrome score generated from definite mitochondrial disorders. Neuropsychiatr Dis Treat. 2017;13:2569–79.

    Article  CAS  Google Scholar 

  28. Cohen BH, Chinnery PF, Copeland WC. POLG-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, et al., editors. GeneReviews((R)). Seattle: University of Washington.

  29. Bargiela D, Shanmugarajah P, Lo C, Blakely EL, Taylor RW, Horvath R, et al. Mitochondrial pathology in progressive cerebellar ataxia. Cerebellum Ataxias. 2015;2:16.

    Article  Google Scholar 

  30. Rahman S, Copeland WC. POLG-related disorders and their neurological manifestations. Nature Rev Neurol. 2019;15(1):40–52.

    Article  CAS  Google Scholar 

  31. Yan C, Duanmu X, Zeng L, Liu B, Song Z. Mitochondrial DNA: distribution, mutations, and elimination. PLoS One. 2019;8(4).

  32. Atorino L, Silvestri L, Koppen M, Cassina L, Ballabio A, Marconi R, et al. Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia. J Cell Biol. 2003;163(4):777–87.

    Article  CAS  Google Scholar 

  33. Wedding IM, Koht J, Tran GT, Misceo D, Selmer KK, Holmgren A, et al. Spastic paraplegia type 7 is associated with multiple mitochondrial DNA deletions. PLoS one. 2014;9(1):e86340.

    Article  Google Scholar 

  34. Coarelli G, Schule R, van de Warrenburg BPC, De Jonghe P, Ewenczyk C, Martinuzzi A, et al. Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7. Neurology. 2019;92(23):e2679–e90.

    Article  CAS  Google Scholar 

  35. Fadic R, Russell JA, Vedanarayanan VV, Lehar M, Kuncl RW, Johns DR. Sensory ataxic neuropathy as the presenting feature of a novel mitochondrial disease. Neurology. 1997;49(1):239–45.

    Article  CAS  Google Scholar 

  36. Milone M, Massie R. Polymerase gamma 1 mutations: clinical correlations. Neurologist. 2010;16(2):84–91.

    Article  Google Scholar 

  37. Set KK, Sen K, Huq AHM, Agarwal R. Mitochondrial disorders of the nervous system: a review. Clin Pediat. 2019;58(4):381–94.

    Article  Google Scholar 

  38. Davison JE, Rahman S. Recognition, investigation and management of mitochondrial disease. Dis Child. 2017;102(11):1082–90.

    Article  Google Scholar 

  39. North American Mitochondrial Disease Consortium: Rare disease clinical research network; 2020 [cited 2020 Mar 22]. Available from: https://www.rarediseasesnetwork.org/cms/namdc.

  40. Eggink H, Kuiper A, Peall KJ, Contarino MF, Bosch AM, Post B, et al. Rare inborn errors of metabolism with movement disorders: a case study to evaluate the impact upon quality of life and adaptive functioning. Orphanet J Rare Dis. 2014;9:177.

    Article  Google Scholar 

  41. Online Mendelian Inheritance in Man: An online catalog of human genes and genetic disorders Mar 2020 [updated Mar 19 2020]. Available from: https://www.ncbi.nlm.nih.gov/omim.

  42. GTR: Genetic Testing Registry 8600 Rockville Pike, Bethesda MD, 20894 USA: National Center for Biotechnology Information, U.S. National Library of Medicine; 2020. Available from: https://www.ncbi.nlm.nih.gov/gtr/.

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Authors and Affiliations

  1. Rush Parkinson’s Disease and Movement Disorders Program, 1725 W Harrison St. Suite 755, Chicago, IL, 60612, USA

    Natalie Witek, Jacob Hawkins & Deborah Hall

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  1. Natalie Witek
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  2. Jacob Hawkins
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Correspondence to Natalie Witek.

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Witek, N., Hawkins, J. & Hall, D. Genetic ataxias: update on classification and diagnostic approaches. Curr Neurol Neurosci Rep 21, 13 (2021). https://doi.org/10.1007/s11910-021-01092-4

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