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The wide spectrum of spinocerebellar ataxias (SCAs)

Abstract

Spinocerebellar ataxias (SCAs) are a clinically heterogeneous group of disorders. Current molecular classification corresponds to the order of gene description (SCA1-SCA 25). The prevalence of SCAs is estimated to be 1–4/100.000. Patients exhibit usually a slowly progressive cerebellar syndrome with various combinations of oculomotor disorders, dysarthria, dysmetria/kinetic tremor, and/or ataxic gait. They can present also with pigmentary retinopathy, extrapyramidal movement disorders (parkinsonism, dyskinesias, dystonia, chorea), pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioral symptoms), peripheral neuropathy. SCAs are also genetically heterogeneous and the clinical diagnosis of subtypes of SCAs is complicated by the salient overlap of the phenotypes between genetic subtypes. The following clinical features have some specific values for predicting a gene defect: slowing of saccades in SCA2, ophthalmoplegia in SCA1, SCA2 and SCA3, pigmentary retinopathy in SCA7, spasticity in SCA3, dyskinesias associated with a mutation in the fibroblast growth factor 14 (FGF14) gene, cognitive impairment/behavioral symptoms in SCA17 and DRPLA, seizures in SCA10, SCA17 and DRPLA, peripheral neuropathy in SCA1, SCA2, SCA3, SCA4, SCA8, SCA18 and SCA25. Neurophysiological findings are compatible with a dying-back axonopathy and/or a neuronopathy. Three patterns of atrophy can be identified on brain MRI: a pure cerebellar atrophy, a pattern of olivopontocerebellar atrophy, and a pattern of global brain atrophy. A remarkable observation is the presence of dentate nuclei calcifications in SCA20, resulting in a low signal on brain MRI sequences. Several identified mutations correspond to expansions of repeated trinucleotides (CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7, SCA17 and DRPLA, CTG repeats in SCA8). A pentanucleotide repeat expansion (ATTCT) is associated with SCA10. Missense mutations have also been found recently. Anticipation is a main feature of SCAs, due to instability of expanded alleles. Anticipation may be particularly prominent in SCA7. It is estimated that extensive genetic testing leads to the identification of the causative gene in about 60–75 % of cases. Our knowledge of the molecular mechanisms of SCAs is rapidly growing, and the development of relevant animal models of SCAs is bringing hope for effective therapies in human.

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References

  1. 1.

    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;105:1–28.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Leone M, Bottacchi E, D’Alessandro G, Kustermann S. Hereditary ataxias and paraplegias in Valle d’Aosta, Italy: A study of prevalence and disability. Acta Neurol Scand. 1995;91:183–7.

    PubMed  CAS  Google Scholar 

  3. 3.

    Silva MC, Coutinho P, Pinheiro CD, Neves JM, Serrano P. Hereditary ataxias and spastic paraplegias: methodological aspects of a prevalence study in Portugal. J Clin Epidemiol. 1997;50:1377–84.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    van de Warrenburg BP, Sinke RJ, Verschuuren-Bemelmans CC, et al. Spinocerebellar ataxias in the Netherlands: Prevalence and age at onset variance analysis. Neurology. 2002;58:702–8.

    PubMed  Google Scholar 

  5. 5.

    Orozco Diaz G, Nodarse Fleites A, Cordoves Sagaz R, Auburger G. Autosomal dominant cerebellar ataxia: Clinical analysis of 263 patients from a homogeneous population in HolguÃ-n, Cuba. Neurology. 1990;40:1369–75.

    Google Scholar 

  6. 6.

    Silveira I, Coutinho P, Maciel P, et al. Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families. Am J Med Genet. 1998;81: 134–8.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Schols L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: Clinical features, genetics, and pathogenesis. Lancet Neurol. 2004;3: 291–304.

    PubMed  Article  Google Scholar 

  8. 8.

    Zuhlke C, Gehlken U, Hellenbroich Y, Schwinger E, Burk K. Phenotypical variability of expanded alleles in the TATA-binding protein gene. Reduced penetrance in SCA17? J Neurol. 2003;250:161–3.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Ikeda Y, Dalton JC, Moseley ML, et al. Spinocerebellar ataxia type 8: Molecular genetic comparisons and haplotype analysis of 37 families with ataxia. Am J Hum Genet. 2004;75:3–16.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Knight MA, Gardner RJ, Bahlo M, Matsuura T, Dixon JA, Forrest SM, Storey E. Dominantly inherited ataxia and dysphonia with dentate calcification: Spinocerebellar ataxia type 20. Brain. 2004;127:1172–81.

    PubMed  Article  Google Scholar 

  11. 11.

    Schols L, Amoiridis G, Epplen JT, Langkafel M, Przuntek H, Riess O. Relations between genotype and phenotype in German patients with the Machado-Joseph disease mutation. J Neurol Neurosurg Psychiatry. 1996;61:466–70.

    PubMed  CAS  Article  Google Scholar 

  12. 12.

    Matsumura R, Futamura N, Fujimoto Y, Yanagimoto S, Horikawa H, Suzumura A, Takayanagi T. Spinocerebellar ataxia type 6. Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology. 1997;49:1238–43.

    PubMed  CAS  Google Scholar 

  13. 13.

    Ogawa M. Pharmacological treatments of cerebellar ataxia. Cerebellum. 2004;3:107–11.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Pirker W, Back C, Gerschlager W, Laccone F, Alesch F. Chronic thalamic stimulation in a patient with spinocerebellar ataxia type 2. Mov Disord. 2003;18:222–5.

    PubMed  Article  Google Scholar 

  15. 15.

    Xia H, Mao Q, Eliason SL, Harper SQ, Martins IH, Orr HT, Paulson HL, Yang L, Kotin RM, Davidson BL. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med. 2004;10:816–20.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Cummings CJ, Sun Y, Opal P, Antalffy B, Mestril R, Orr HT, Dillmann WH, Zoghbi HY. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet. 2001;10:1511–18.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Steffan JS, Kazantsev A, Spasic-Boskovic O, et al. The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci USA. 2000;97:6763–8.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Valazquez-Perez L, Seifried C, Santos-Falcon N, et al. Saccade velocity is controlled by polyglutamine size in spinocerebellar ataxia type 2. Ann Neurol. 2004;56:444–7.

    Article  Google Scholar 

  19. 19.

    van de Warrenburg BP, Notermans NC, Schelhaas HJ, van Alfen N, Sinke RJ, Knoers NV, Zwarts MJ, Kremer BP. Peripheral nerve involvement in spinocerebellar ataxias. Arch Neurol. 2004;61:257–61.

    PubMed  Article  Google Scholar 

  20. 20.

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

    PubMed  Article  CAS  Google Scholar 

  21. 21.

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

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    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;8:221–8.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert MF, Kaplan C, Ptacek LJ. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): Clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet. 1996;59:392–9.

    PubMed  CAS  Google Scholar 

  24. 24.

    Ranum LP, Schut LJ, Lundgren JK, Orr HT, Livingston DM. Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet. 1994;8:280–4.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997;15:62–9.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    David G, Abbas N, Stevanin G, et al. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet. 1997;17:65–70.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, Ranum LP. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet. 1999;21:379–84.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

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

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Worth PF, Giunti P, Gardner-Thorpe C, Dixon PH, Davis MB, Wood NW. Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14-21.3. Am J Hum Genet. 1999; 65:420–6.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    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;23:391–2.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Herman-Bert A, Stevanin G, Netter JC, et al. Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3-q13.4 in a family with autosomal dominant cerebellar ataxia and mental retardation. Am J Hum Genet. 2000;67:229–35.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Yamashita I, Sasaki H, Yabe I, et al. A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter. Ann Neurol. 2000;48:156–63.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Knight MA, Kennerson ML, Anney RJ, Matsuura T, Nicholson GA, Salimi-Tari P, Gardner RJ, Storey E, Forrest SM. Spinocerebellar ataxia type 15 (sca15) maps to 3p24.2–3pter: exclusion of the ITPR1 gene, the human orthologue of an ataxic mouse mutant. Neurobiol Dis. 2003;13:147–57.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Miyoshi Y, Yamada T, Tanimura M, Taniwaki T, Arakawa K, Ohyagi Y, Furuya H, Yamamoto K, Sakai K, Sasazuki T, Kira J. A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q22.1–24.1. Neurology. 2001;57:96–100.

    PubMed  CAS  Google Scholar 

  35. 35.

    Koide R, Kobayashi S, Shimohata T, Ikeuchi T, Maruyama M, Saito M, Yamada M, Takahashi H, Tsuji S. A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum Mol Genet. 1999;8:2047–53.

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Brkanac Z, Fernandez M, Matsushita M, Lipe H, Wolff J, Bird TD, Raskind WH. Autosomal dominant sensory/motor neuropathy with Ataxia (SMNA): Linkage to chromosome 7q22-q32. Am J Med Genet. 2002;114:450–7.

    PubMed  Article  Google Scholar 

  37. 37.

    Verbeek DS, Schelhaas JH, Ippel EF, Beemer FA, Pearson PL, Sinke RJ. Identification of a novel SCA locus (SCA19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region 1p21-q21. Hum Genet. 2002;111:388–93.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Vuillaume I, Devos D, Schraen-Maschke S, et al. A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3-p15.1. Ann Neurol. 2002;52:666–70.

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Chung MY, Lu YC, Cheng NC, Soong BW. novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23. Brain. 2003;126:1293–9.

    PubMed  Article  Google Scholar 

  40. 40.

    Verbeek DS, van de Warrenburg BP, Wesseling P, Pearson PL, Kremer HP, Sinke RJ. Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3. Brain. 2004;127:2551–7.

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    van Swieten JC, Brusse E, de Graaf BM, Krieger E, van de Graaf R, de Koning I, Maat-Kievit A, Leegwater P, Dooijes D, Oostra BA, Heutink P. A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia. Am J Hum Genet. 2003;72:191–9.

    PubMed  Article  Google Scholar 

  42. 42.

    Stevanin G, Bouslam N, Thobois S, et al. Spinocerebellar ataxia with sensory neuropathy (SCA25) maps to chromosome 2p. Ann Neurol. 2004;55:97–104.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Koide R, Ikeuchi T, Onodera O, et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet. 1994;6:9–13.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Mario-Ubaldo Manto.

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Manto, MU. The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum 4, 2 (2005). https://doi.org/10.1080/14734220510007914

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Key words

  • Ataxia
  • dysarthria
  • nystagmus
  • ataxic gait
  • cerebellar atrophy
  • ADCA
  • polyglutamine
  • expansions