Skip to main content

Advertisement

SpringerLink
Log in

Recent Advances in the Genetics of Cerebellar Ataxias

  • (V Bonifati, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

The hereditary cerebellar ataxias are a clinically and genetically heterogeneous group of disorders that primarily affect the cerebellum; often there are additional features such as neuropathy, cognitive decline, or maculopathy that help define the clinical subtype of ataxia. They are commonly classified according to their mode of inheritance into autosomal dominant, autosomal recessive, X-linked, and mitochondrial forms. Great advances have been made in understanding the genetics of cerebellar ataxias in the last 15 years. At least 36 different forms of ADCA are known, 20 autosomal-recessive, two X-linked, and several forms of ataxia associated with mitochondrial defects are known to date. However, in about 40 % of suspected genetically determined ataxia cases, the underlying genetic defect remains undetermined. Although the majority of disease genes have been found in the last two decades, over the last 2 years the genetics has undergone a methodological revolution. New DNA sequencing technologies are enabling us to investigate the whole or large targeted proportions of the genome in a rapid, affordable, and comprehensive way. Exome and targeted sequencing has recently identified four new genes causing ataxia: TGM6, ANO10, SYT14, and rundataxin. This approach is likely to continue to discover new ataxia genes and make screening of existing genes more effective. Translating the genetic findings into isolated and overlapping disease pathways will help stratify patient groups and identify therapeutic targets for ataxia that have so far remained undiscovered.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9(9):885–94.

    Article  PubMed  CAS  Google Scholar 

  2. Juvonen V, Hietala M, Kairisto V, Savontaus M-L. The occurrence of dominant spinocerebellar ataxias among 251 Finnish ataxia patients and the role of predisposing large normal alleles in a genetically isolated population. Acta Neurol Scand. 2005;111(3):154–62.

    Article  PubMed  CAS  Google Scholar 

  3. Juvonen V, Hietala M, Päivärinta M, et al. Clinical and genetic findings in Finnish ataxia patients with the spinocerebellar ataxia 8 repeat expansion. Ann Neurol. 2000;48(3):354–61.

    Article  PubMed  CAS  Google Scholar 

  4. Kerber KA, Jen JC, Perlman S, Baloh RW. Late-onset pure cerebellar ataxia: differentiating those with and without identifiable mutations. J Neurol Sci. 2005;238(1–2):41–5.

    Article  PubMed  CAS  Google Scholar 

  5. Moseley ML, Benzow KA, Schut LJ, et al. Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology. 1998;51(6):1666–71.

    PubMed  CAS  Google Scholar 

  6. Schöls L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004;3(5):291–304.

    Article  PubMed  Google Scholar 

  7. Anheim M, Fleury M, Monga B, et al. Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management. Neurogenetics. 2010;11(1):1–12.

    Article  PubMed  CAS  Google Scholar 

  8. Harding AE. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the “the Drew family of Walworth.”. Brain. 1982;105(Pt 1):1–28.

    Article  PubMed  CAS  Google Scholar 

  9. Orr HT, Chung MY, Banfi S, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993;4(3):221–6.

    Article  PubMed  CAS  Google Scholar 

  10. Pulst SM, Nechiporuk A, Nechiporuk T, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996;14(3):269–76.

    Article  PubMed  CAS  Google Scholar 

  11. Kawaguchi Y, Okamoto T, Taniwaki M, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994;8(3):221–8.

    Article  PubMed  CAS  Google Scholar 

  12. Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997;15(1):62–9.

    Article  PubMed  CAS  Google Scholar 

  13. Nakamura K, Jeong SY, Uchihara T, et al. SCA17, A novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet. 2001;10(14):1441–8.

    Article  PubMed  CAS  Google Scholar 

  14. Chong SS, McCall AE, Cota J, et al. Gametic and somatic tissue-specific heterogeneity of the expanded SCA1 CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1995;10(3):344–50.

    Article  PubMed  CAS  Google Scholar 

  15. Koob MD, Moseley ML, Schut LJ, et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet. 1999;21(4):379–84.

    Article  PubMed  CAS  Google Scholar 

  16. Matsuura T, Yamagata T, Burgess DL, et al. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet. 2000;26(2):191–4.

    Article  PubMed  CAS  Google Scholar 

  17. Holmes SE, O’Hearn EE, McInnis MG, et al. Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12. Nat Genet. 1999;23(4):391–2.

    Article  PubMed  CAS  Google Scholar 

  18. Sato N, Amino T, Kobayashi K, et al. Spinocerebellar ataxia type 31 is associated with “inserted” penta-nucleotide repeats containing (TGGAA)n. Am J Hum Genet. 2009;85(5):544–57.

    Article  PubMed  CAS  Google Scholar 

  19. Worth PF, Houlden H, Giunti P, Davis MB, Wood NW. Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia. Nat Genet. 2000;24(3):214–5.

    Article  PubMed  CAS  Google Scholar 

  20. Brussino A, Graziano C, Giobbe D, et al. Spinocerebellar ataxia type 12 identified in two Italian families may mimic sporadic ataxia. Mov Disord. 2010;25(9):1269–73.

    Article  PubMed  Google Scholar 

  21. Wang Y-C, Lee C-M, Lee L-C, et al. Mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of spinocerebellar ataxia type 12 (SCA12). J Biol Chem. 2011;286(24):21742–54.

    Article  PubMed  CAS  Google Scholar 

  22. Kobayashi H, Abe K, Matsuura T, et al. Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. Am J Hum Genet. 2011;89(1):121–30.

    Article  PubMed  CAS  Google Scholar 

  23. Ikeda Y, Dick KA, Weatherspoon MR, et al. Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet. 2006;38(2):184–90.

    Article  PubMed  CAS  Google Scholar 

  24. Houlden H, Johnson J, Gardner-Thorpe C, et al. Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet. 2007;39(12):1434–6.

    Article  PubMed  CAS  Google Scholar 

  25. Bauer P, Stevanin G, Beetz C, et al. Spinocerebellar ataxia type 11 (SCA11) is an uncommon cause of dominant ataxia among French and German kindreds. J Neurol Neurosurg Psychiatr. 2010;81(11):1229–32.

    Article  PubMed  Google Scholar 

  26. Bouskila M, Esoof N, Gay L, et al. TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development. Biochem J. 2011;437(1):157–67.

    Article  PubMed  CAS  Google Scholar 

  27. Issa FA, Mazzochi C, Mock AF, Papazian DM. Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish. J Neurosci. 2011;31(18):6831–41.

    Article  PubMed  CAS  Google Scholar 

  28. Figueroa KP, Minassian NA, Stevanin G, et al. KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients. Hum Mutat. 2010;31(2):191–6.

    Article  PubMed  CAS  Google Scholar 

  29. Waters MF, Minassian NA, Stevanin G, et al. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet. 2006;38(4):447–51.

    Article  PubMed  CAS  Google Scholar 

  30. Yabe I, Sasaki H, Chen D-H, et al. Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C gamma. Arch Neurol. 2003;60(12):1749–51.

    Article  PubMed  Google Scholar 

  31. van de Leemput J, Chandran J, Knight MA, et al. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet. 2007;3(6):e108.

    Article  PubMed  Google Scholar 

  32. Hara K, Shiga A, Nozaki H, et al. Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families. Neurology. 2008;71(8):547–51.

    Article  PubMed  CAS  Google Scholar 

  33. van de Leemput J, Wavrant-De Vrièze F, Rafferty I, et al. Sequencing analysis of the ITPR1 gene in a pure autosomal dominant spinocerebellar ataxia series. Mov Disord. 2010;25(6):771–3.

    Article  PubMed  Google Scholar 

  34. Knight MA, Hernandez D, Diede SJ, et al. A duplication at chromosome 11q12.2–11q12.3 Is associated with spinocerebellar ataxia type 20. Hum Mol Genet. 2008;17(24):3847–53.

    Article  PubMed  CAS  Google Scholar 

  35. Bakalkin G, Watanabe H, Jezierska J, et al. Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23. Am J Hum Genet. 2010;87(5):593–603.

    Article  PubMed  CAS  Google Scholar 

  36. Misceo D, Fannemel M, Barøy T, et al. SCA27 caused by a chromosome translocation: further delineation of the phenotype. Neurogenetics. 2009;10(4):371–4.

    Article  PubMed  CAS  Google Scholar 

  37. Di Bella D, Lazzaro F, Brusco A, et al. Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nat Genet. 2010;42(4):313–21.

    Article  PubMed  Google Scholar 

  38. Cagnoli C, Stevanin G, Brussino A, et al. Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5 % of European autosomal dominant cerebellar ataxias. Hum Mutat. 2010;31(10):1117–24.

    Article  PubMed  CAS  Google Scholar 

  39. •• Wang JL, Yang X, Xia K, et al. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain. 2010;133(Pt 12):3510–8. This article demonstrates how NGS in combination with linkage analysis can be applied to identify new ataxia genes. This approach will most likely lead to the discovery of several more genes in the near future.

    Article  PubMed  Google Scholar 

  40. Jen JC. Hereditary episodic ataxias. Ann N Y Acad Sci. 2008;1142:250–3.

    Article  PubMed  CAS  Google Scholar 

  41. Campuzano V, Montermini L, Moltò MD, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271(5254):1423–7.

    Article  PubMed  CAS  Google Scholar 

  42. Zühlke C, Laccone F, Cossée M, et al. Mutation of the start codon in the FRDA1 gene: linkage analysis of three pedigrees with the ATG to ATT transversion points to a unique common ancestor. Hum Genet. 1998;103(1):102–5.

    Article  PubMed  Google Scholar 

  43. Dupré N, Gros-Louis F, Chrestian N, et al. Clinical and genetic study of autosomal recessive cerebellar ataxia type 1. Ann Neurol. 2007;62(1):93–8.

    Article  PubMed  Google Scholar 

  44. Attali R, Warwar N, Israel A, et al. Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Hum Mol Genet. 2009;18(18):3462–9.

    Article  PubMed  CAS  Google Scholar 

  45. Lagier-Tourenne C, Tazir M, López LC, et al. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am J Hum Genet. 2008;82(3):661–72.

    Article  PubMed  CAS  Google Scholar 

  46. Horvath R, Czermin B, Gulati S, et al. Adult-onset cerebellar ataxia due to mutations in CABC1/ADCK3. J Neurol Neurosurg Psychiatry. 2012;83(2):174–8.

    Article  PubMed  Google Scholar 

  47. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995;268(5218):1749–53.

    Article  PubMed  CAS  Google Scholar 

  48. Ahmed M, Rahman N. ATM and breast cancer susceptibility. Oncogene. 2006;25(43):5906–11.

    Article  PubMed  CAS  Google Scholar 

  49. Anheim M, Monga B, Fleury M, et al. Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. Brain. 2009;132(Pt 10):2688–98.

    Article  PubMed  CAS  Google Scholar 

  50. Al Tassan N, Khalil D, Shinwari J, et al. A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia. Hum Mutat. 2012;33(2):351–4.

    Article  PubMed  CAS  Google Scholar 

  51. Doi H, Yoshida K, Yasuda T, et al. Exome sequencing reveals a homozygous SYT14 mutation in adult-onset, autosomal-recessive spinocerebellar ataxia with psychomotor retardation. Am J Hum Genet. 2011;89(2):320–7.

    Article  PubMed  CAS  Google Scholar 

  52. Vermeer S, Hoischen A, Meijer RP, Gilissen C, Neveling K, Wieskamp N, et al. Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia. Am J Hum Genet. 2010;87(6):813–9.

    Article  PubMed  CAS  Google Scholar 

  53. Assoum M, Salih MA, Drouot N, et al. Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia. Brain. 2010;133(Pt 8):2439–47.

    Article  PubMed  Google Scholar 

  54. Ouahchi K, Arita M, Kayden H, et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet. 1995;9(2):141–5.

    Article  PubMed  CAS  Google Scholar 

  55. Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57(1):127–30.

    PubMed  CAS  Google Scholar 

  56. Rodriguez-Revenga L, Madrigal I, Pagonabarraga J, et al. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet. 2009;17(10):1359–62.

    Article  PubMed  CAS  Google Scholar 

  57. • Garcia-Arocena D, Hagerman PJ. Advances in understanding the molecular basis of FXTAS. Hum Mol Genet. 2010;19(R1):R83–9. This paper gives a good example of how different mutational mechanisms in the same gene can give rise to different phenotypes.

    Article  PubMed  CAS  Google Scholar 

  58. Cohen BH, Naviaux RK. The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders. Methods. 2010;51(4):364–73.

    Article  PubMed  CAS  Google Scholar 

  59. Schicks J, Synofzik M, Schulte C, Schöls L. POLG, but not PEO1, is a frequent cause of cerebellar ataxia in central Europe. Mov Disord. 2010;25(15):2678–82.

    Article  PubMed  Google Scholar 

  60. O’Sullivan SS, Massey LA, Williams DR, et al. Clinical outcomes of progressive supranuclear palsy and multiple system atrophy. Brain. 2008;131(Pt 5):1362–72.

    PubMed  Google Scholar 

  61. Hardy J, Cai H, Cookson MR, Gwinn-Hardy K, Singleton A. Genetics of Parkinson’s disease and parkinsonism. Ann Neurol. 2006;60(4):389–98.

    Article  PubMed  CAS  Google Scholar 

  62. Simón-Sánchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet. 2009;41(12):1308–12.

    Article  PubMed  Google Scholar 

  63. Scholz SW, Houlden H, Schulte C, et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol. 2009;65(5):610–4.

    Article  PubMed  CAS  Google Scholar 

  64. • Montenegro G, Powell E, Huang J, et al. Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. Ann Neurol. 2011;69(3):464–70. This article demonstrates the ability of NGS to rapidly identify causal mutations within a large number of candidate genes. This approach is likely to be used in clinical genetics for mutational screening in heterogeneous diseases such as ataxia.

    Article  PubMed  CAS  Google Scholar 

  65. Hildebrandt F, Heeringa SF, Rüschendorf F, et al. A systematic approach to mapping recessive disease genes in individuals from outbred populations. PLoS Genet. 2009;5(1):e1000353.

    Article  PubMed  Google Scholar 

  66. Shao J, Diamond MI. Polyglutamine diseases: emerging concepts in pathogenesis and therapy. Hum Mol Genet. 2007;16(Spec No. 2):R115–23.

    Article  PubMed  CAS  Google Scholar 

  67. Xia H, Mao Q, Eliason SL, et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med. 2004;10(8):816–20.

    Article  PubMed  CAS  Google Scholar 

  68. Tsou W-L, Soong B-W, Paulson HL, Rodríguez-Lebrón E. Splice isoform-specific suppression of the CaV2.1 variant underlying spinocerebellar ataxia type 6. Neurobiol Dis. 2011;43(3):533–42.

    Article  PubMed  CAS  Google Scholar 

  69. Todd PK, Oh SY, Krans A, et al. Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome. PLoS Genet. 2010;6(12):e1001240.

    Article  PubMed  Google Scholar 

  70. Herman D, Jenssen K, Burnett R, et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat Chem Biol. 2006;2(10):551–8.

    Article  PubMed  CAS  Google Scholar 

  71. Rai M, Soragni E, Jenssen K, et al. HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS One. 2008;3(4):e1958.

    Article  PubMed  Google Scholar 

  72. Boesch S, Sturm B, Hering S, et al. Neurological effects of recombinant human erythropoietin in Friedreich’s ataxia: a clinical pilot trial. Mov Disord. 2008;23(13):1940–4.

    Article  PubMed  Google Scholar 

  73. Schmucker S, Puccio H. Understanding the molecular mechanisms of Friedreich’s ataxia to develop therapeutic approaches. Hum Mol Genet. 2010;19(R1):R103–10.

    Article  PubMed  CAS  Google Scholar 

  74. Liu J, Tang T-S, Tu H, et al. Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci. 2009;29(29):9148–62.

    Article  PubMed  CAS  Google Scholar 

  75. Hourez R, Servais L, Orduz D, et al. Aminopyridines correct early dysfunction and delay neurodegeneration in a mouse model of spinocerebellar ataxia type 1. J Neurosci. 2011;31(33):11795–807.

    Article  PubMed  CAS  Google Scholar 

  76. Pineda M, Arpa J, Montero R, Aracil A, Domínguez F, Galván M, et al. Idebenone treatment in paediatric and adult patients with Friedreich ataxia: long-term follow-up. Eur J Paediatr Neurol. 2008;12(6):470–5

    Google Scholar 

  77. Lagedrost SJ, Sutton MS, Cohen MS, Satou GM, Kaufman BD, Perlman SL, et al. Idebenone in Friedreich ataxia cardiomyopathy-results from a 6-month phase III study (IONIA). Am Heart J. 2011;161(3):639–645.e1

    Google Scholar 

  78. Schulz JB, Di Prospero NA, Fischbeck K. Clinical experience with high-dose idebenone in Friedreich ataxia. J Neurol. 2009;256(Suppl 1):42–5.

    Google Scholar 

Download references

Acknowledgments

We are grateful to the patients and families who support our research. We would also like to thank the following for essential grant support: The Multiple System Atrophy (MSA) Trust, The Medical Research Council (MRC), The Brain Research Trust (BRT), AFM, DMRF, and The Wellcome Trust and Ataxia UK. This study was also supported by the NIHR UCLH/UCL Comprehensive Biomedical Research Centre.

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom

    Anna Sailer & Henry Houlden

Authors
  1. Anna Sailer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Henry Houlden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Henry Houlden.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sailer, A., Houlden, H. Recent Advances in the Genetics of Cerebellar Ataxias. Curr Neurol Neurosci Rep 12, 227–236 (2012). https://doi.org/10.1007/s11910-012-0267-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-012-0267-6

Keywords

Search

Navigation