Skip to main content

Advertisement

SpringerLink
Log in

Inherited Cerebellar Ataxias: 5-Year Experience of the Irish National Ataxia Clinic

  • Original Article
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

Establishing a molecular diagnosis in patients with progressive ataxia is often challenging due to significant genetic and clinical heterogeneity and requires a methodical approach with expert clinical evaluation and investigations. We describe the 5-year experience of the National Ataxia Clinic (NAC), Ireland. All adults with ataxia attending the NAC between 2014 and 2019 were evaluated. All individuals underwent detailed clinical assessment and investigations including, where appropriate, genetic testing using next-generation sequencing. For all patients, acquired causes were ruled out. A total of 254 patients from 196 families were assessed; with growth of the clinic cohort by 82% from 133 to 242 over the 5-year period. The underlying genetic cause was identified in 128/196 probands (65.3%). The detection rate for repeat expansion disorder gene testing was 47.7% (82/172) and using NGS gene panel, a genetic diagnosis was obtained in 30/84 (35.7%). Whole exome sequencing identified the molecular diagnosis in 4/20 (20%), and whole genome sequencing provided genetic diagnosis in 1/5 (20%). The commonest diagnosis was Friedreich’s ataxia (68/128, 53.1%). SPG7-associated ataxia was the second most common diagnosis (21/128, 16.4%), followed by ANO10-associated spastic ataxia, ataxia telangiectasia (AT), and other rarer phenotypes. Our results highlight that careful clinical phenotyping in a dedicated ataxia clinic is crucial for appropriate genetic testing in selected patients in a timely manner. Advanced genetic testing has significantly improved the diagnostic yield in patients with suspected genetic ataxia and should be considered in all individuals with negative repeat expansion testing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet. 1983;1(8334):1151–5.

    Article  CAS  Google Scholar 

  2. Jayadev S, Bird TD. Hereditary ataxias: overview. Gen Med. 2013;15:673–83.

    CAS  Google Scholar 

  3. Beaudin M, Matilla-Dueñas A, Soong BW, Pedroso JL, Barsottini OG, Mitoma H, et al. The classification of autosomal recessive cerebellar ataxias: a consensus statement from the society for research on the cerebellum and ataxias task force. Cerebellum. 2019;18(6):1098–125.

    Article  CAS  Google Scholar 

  4. Pfeffer G, Pyle A, Griffin H, Miller J, Wilson V, Turnbull L, et al. SPG7 mutations are a common cause of undiagnosed ataxia. Neurology. 2015;84(11):1174–6.

    Article  Google Scholar 

  5. Chun HH, Gatti RA. Ataxia–telangiectasia, an evolving phenotype. DNA Repair (Amst). 2004;3(8–9):1187–96.

    Article  CAS  Google Scholar 

  6. le Ber I, Brice A, Dürr A. New autosomal recessive cerebellar ataxias with oculomotor apraxia. Curr Neurol Neurosci Rep. 2005;5(5):411–7.

    Article  Google Scholar 

  7. Palau F, Espinós C. Autosomal recessive cerebellar ataxias. Orphanet J Rare Dis. 2006;1:47.

    Article  Google Scholar 

  8. Yokoseki A, Ishihara T, Koyama A, Shiga A, Yamada M, Suzuki C, et al. Genotype-phenotype correlations in early onset ataxia with ocular motor apraxia and hypoalbuminaemia. Brain. 2011;134(pt 5):1387–99.

    Article  Google Scholar 

  9. Velázquez-Pérez L, Medrano-Montero J, Rodríguez-Labrada R, et al. Hereditary ataxias in Cuba: a nationwide epidemiological and clinical study in 1001 patients. Cerebellum. 2020;19(2):252–64.

    Article  Google Scholar 

  10. Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014;42(3):174–83.

    Article  Google Scholar 

  11. de Silva RN, Vallortigara J, Greenfield J, Hunt B, Giunti P, Hadjivassiliou M. Diagnosis and management of progressive ataxia in adults. Pract Neurol. 2019;19:196–207.

    Article  Google Scholar 

  12. Fogel B, Lee H, Deignan J, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurology. 2014;71(10):1237–46.

    Article  Google Scholar 

  13. Choquet K, Tétreault M, Yang S, La Piana R, Dicaire MJ, et al. SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases. Eur J Hum Genet. 2016;24(7):1016–21.

    Article  CAS  Google Scholar 

  14. Roxburgh RH, Marquis-Nicholson R, Ashton F, George AM, Lea RA, Eccles D, et al. The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry. J Neurol. 2013;260(5):1286–94.

    Article  CAS  Google Scholar 

  15. Bogdanova-Mihaylova P, Alexander MD, Murphy RP, Chen H, Healy DG, Walsh RA, et al. Clinical spectrum of AIFM1-associated disease in an Irish family, from mild neuropathy to severe cerebellar ataxia with colour blindness. J Peripher Nerv Syst. 2019;24(4):348–53.

    Article  CAS  Google Scholar 

  16. Kang C, Liang C, Ahmad KE, Gu Y, Siow SF, Colebatch JG, et al. High degree of genetic heterogeneity for hereditary cerebellar ataxias in Australia. Cerebellum. 2019;18:137–46.

    Article  CAS  Google Scholar 

  17. Hadjivassiliou M, Martindale J, Shanmugarajah P, et al. Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. J Neurol Neurosurg Psychiatry. 2016;88(4):301–9.

    Article  Google Scholar 

  18. Gebus O, Montaut S, Monga B, Wirth T, Cheraud C, Alves Do Rego C, et al. Deciphering the causes of sporadic late-onset cerebellar ataxias: a prospective study with implications for diagnostic work. J Neurol. 2017;264:1118–26.

    Article  CAS  Google Scholar 

  19. Németh A, Kwasniewska A, Lise S, et al. Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model. Brain. 2013;136(10):3106–18.

    Article  Google Scholar 

  20. Coutelier M, Hammer M, Stevanin G, et al. Efficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurology. 2018;75(5):591–9.

    Article  Google Scholar 

  21. Wardle M, Majounie E, Muzaimi M, Williams N, Morris H, Robertson N. The genetic aetiology of late-onset chronic progressive cerebellar ataxia. J Neurol. 2009;256(3):343–8.

    Article  Google Scholar 

  22. Vankan P. Prevalence gradients of Friedreich’s Ataxia and R1b haplotype in Europe co-localize, suggesting a common Palaeolithic origin in the Franco-Cantabrian ice age refuge. J Neurochem. 2013;126(Suppl 1):11–20.

    Article  CAS  Google Scholar 

  23. Mallaret M, Renaud M, Redin C, Drouot N, Muller J, Severac F, et al. Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases. J Neurol. 2016;263(7):1314–22.

    Article  CAS  Google Scholar 

  24. Iqbal Z, Rydning S, Wedding I, et al. Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. PLoS One. 2017;12(3):e0174667.

    Article  Google Scholar 

  25. van Gassen KL, van der Heijden CD, de Bot ST, et al. Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort. Brain. 2012;135:2994–3004.

    Article  Google Scholar 

  26. Hewamadduma CA, Hoggard N, O'Malley R, Robinson MK, Beauchamp NJ, Segamogaite R, et al. Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations. Neurol Genet. 2018;4:e279.

    Article  CAS  Google Scholar 

  27. Van de Warrenburg B, Schouten M, de Bot S, et al. Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene–disease associations and unanticipated rare disorders. Eur J Hum Genet. 2016;24(10):1460–6.

    Article  Google Scholar 

  28. Ngo KJ, Rexach JE, Lee H, Petty LE, Perlman S, Valera JM, et al. A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders. Hum Mutat. 2019;41:487–501. https://doi.org/10.1002/humu.23946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pyle A, Smertenko T, Bargiela D, Griffin H, Duff J, Appleton M, et al. Exome sequencing in undiagnosed inherited and sporadic ataxias. Brain. 2015;138:276–83.

    Article  Google Scholar 

  30. Sun M, Johnson AK, Nelakuditi V, et al. Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes. Gen Med. 2018;21:195–206.

    Google Scholar 

  31. Kim A, Kumar KR, Davis RL, Mallawaarachchi AC, Gayevskiy V, Minoche AE, et al. Increased diagnostic yield of spastic paraplegia with or without cerebellar ataxia through whole-genome sequencing. Cerebellum. 2019;18(4):781–90.

    Article  CAS  Google Scholar 

  32. Kumar KR, Davis RL, Tchan MC, et al. Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes. Parkinsonism Relat Disord. 2019;69:111–8.

    Article  Google Scholar 

  33. Fogel BL, Satya-Murti S, Cohen BH. Clinical exome sequencing in neurologic disease. Neurol Clin Pract. 2016;6(2):164–76.

    Article  Google Scholar 

  34. Vissers LELM, van Nimwegen KJM, Schieving JH, Kamsteeg EJ, Kleefstra T, Yntema HG, et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017;19(9):1055–63.

    Article  Google Scholar 

  35. Stubbe C, Bogdanova-Mihaylova P, Austin N, Murphy S, Walsh R. NGS-based molecular diagnosis of hereditary ataxia is cost efficient: an illustrative case. QJM: An international journal of medicine. 2016;109(8):551–2.

    Article  CAS  Google Scholar 

  36. Schofield D, Alam K, Douglas L, et al. Cost-effectiveness of massively parallel sequencing for diagnosis of paediatric muscle diseases. NPJ Genom Med. 2017;2:4.

    Article  Google Scholar 

  37. Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, et al. 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 

Download references

Funding

PBM and SMM received research funding support from Ataxia Ireland.

Author information

Author notes

  1. Richard A Walsh and Sinéad M Murphy are joint senior authors

Authors and Affiliations

  1. National Ataxia Clinic, Department of Neurology, Tallaght University Hospital, Dublin, 24, Ireland

    Petya Bogdanova-Mihaylova, Josephine Hebert, Sharon Moran, Michael Murphy, Richard A. Walsh & Sinéad M. Murphy

  2. Department of Cardiology, Tallaght University Hospital, Dublin, 24, Ireland

    Deirdre Ward

  3. Academic Unit of Neurology, Trinity College Dublin, Dublin, Ireland

    Richard A. Walsh & Sinéad M. Murphy

Authors
  1. Petya Bogdanova-Mihaylova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Josephine Hebert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sharon Moran
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Deirdre Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard A. Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sinéad M. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Petya Bogdanova-Mihaylova.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Standard

The study was conducted according to the Ethical standards stated in the declaration of Helsinki.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Petya Bogdanova-Mihaylova and Josephine Hebert are joint first authors

Electronic Supplementary Material

Supplementary Table 1

(DOCX 16 kb)

Supplementary Table 2

(DOCX 19.6 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bogdanova-Mihaylova, P., Hebert, J., Moran, S. et al. Inherited Cerebellar Ataxias: 5-Year Experience of the Irish National Ataxia Clinic. Cerebellum 20, 54–61 (2021). https://doi.org/10.1007/s12311-020-01180-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-020-01180-0

Keywords

Search

Navigation