Journal of Neurology

, Volume 251, Issue 8, pp 913– 922 | Cite as

A pathogenetic classification of hereditary ataxias: Is the time ripe?



Harding’s classification takes credits for defining the homogeneous phenotypes that have been essential for the genetic linkage studies and it is still useful for didactic purposes. The advances in pathogenetic knowledge make it now possible to modify Harding’s classification. Five main pathogenetic mechanisms may be distinguished: 1) mitochondrial; 2) metabolic; 3) defective DNA repair; 4) abnormal protein folding and degradation; 5) channelopathies. The present attempt to classify ataxia disorders according to their pathogenetic mechanism is a work in progress, since the pathogenesis of several disorders is still unknown. A pathogenetic classification may be useful in clinical practice and when new therapeutic strategies become available.

Key words

hereditary ataxias classification pathogenesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Babcock R, deSilva D, Oaks R, et al. (1997) Regulation of mitochondrial iron accumulation by Yfh1p, a putative homologue of frataxin. Science 276:1709–1712CrossRefPubMedGoogle Scholar
  2. 2.
    Baloh RW, Yue Q, Furman JM, et al. (1997) Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann Neurol 41:8–16PubMedGoogle Scholar
  3. 3.
    Benomar A, Yahyaoui M, Meggouh F, et al. (2002) Clinical comparison between AVED patients with 744 del A mutation and Friedreich ataxia with GAA expansion in 15 Moroccan families. J Neurol Sci 198:25–29CrossRefPubMedGoogle Scholar
  4. 4.
    Boder E (1985) Ataxia-telangiectasia: an overview. In: Gatti RA, Swift M (eds) Ataxia-telangiectasia: genetics, neuropathy, and immunology of a degenerative disease of childhood. Alan R Liss,New York, pp 1–63Google Scholar
  5. 5.
    Bouchard JP, Richter A, Mathieu J, et al. (1998) Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Neuromuscul Disord 8:474–479PubMedGoogle Scholar
  6. 6.
    Browne DL, Gancher ST, Nutt JG, et al. (1994) Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet 8:136–140PubMedGoogle Scholar
  7. 7.
    Campuzano V, Montermini L, Moltò MD, et al. (1996) Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271:1423–1427Google Scholar
  8. 8.
    Chen DH, Brkanac Z, Verlinde CL, et al. (2003) Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet 72:839–849 921CrossRefPubMedGoogle Scholar
  9. 9.
    Cleaver JE, Thompson LH, Richardson AS, et al. (1999) A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Hum Mutat 14:9–22PubMedGoogle Scholar
  10. 10.
    Coppola G, Filla A (2004) Disorders of the cerebellum. In: Joynt RJ,Griggs RC (eds) Baker and Joynt’s Clinical Neurology on CD-ROM Lippincott, Williams and Wilkins, PhiladelphiaGoogle Scholar
  11. 11.
    Cossee M, Durr A, Schmitt M, et al. (1999) Friedreich’s ataxia: point mutations and clinical presentation of compound heterozygotes. Ann Neurol 45:200–206PubMedGoogle Scholar
  12. 12.
    De Michele G, Filla A, Cavalcanti F, et al. (1994) Late onset Friedreich’s disease: clinical features and mapping of mutation to FRDA locus. J Neurol Neurosurg Psychiatry 57:977–979PubMedGoogle Scholar
  13. 13.
    DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668 CrossRefPubMedGoogle Scholar
  14. 14.
    Durr A, Cossee M, Agid Y, et al. (1996) Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med 335:1169–1175PubMedGoogle Scholar
  15. 15.
    Engert JC, Berube P, Mercier J, et al. (2000) ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet 24:120–125PubMedGoogle Scholar
  16. 16.
    Filla A, De Michele G, Cavalcanti F, et al. (1996) The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet 59:554–560Google Scholar
  17. 17.
    Geschwind DH, Perlman S, Figueroa KP, et al. (1997) Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations. Neurology 49:1247–1251PubMedGoogle Scholar
  18. 18.
    Ghetti B, Dlouhy SR, Giaccone G, et al. (1995) Gerstmann-Straussler-Scheinker disease and the Indiana kindred. Brain Pathol 5:61–75PubMedGoogle Scholar
  19. 19.
    Gomez CM, Thompson RM, Gammack JT, et al. (1997) Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. Ann Neurol 42:933–950PubMedGoogle Scholar
  20. 20.
    Griggs RC, Moxley RT 3rd, Lafrance RA, et al. (1978) Hereditary paroxysmal ataxia: response to acetazolamide. Neurology 28:1259–1264PubMedGoogle Scholar
  21. 21.
    Gwinn-Hardy K, Singleton A, O’Suilleabhain P, et al. (2001) Spinocerebellar ataxia type 3 phenotypically resembling Parkinson disease in a black family. Arch Neurol 58:296–299PubMedGoogle Scholar
  22. 22.
    Harding AE (1984) The hereditary ataxias and related disorders. Churchill Livingstone, EdinburghGoogle Scholar
  23. 23.
    Holmes SE, O’Hearn EE, McInnis MG, et al. (1999) Expansion of a novel CAG trinucleotide repeat in the 5’ region of PPP2R2B is associated with SCA12. Nat Genet 23:391–392 CrossRefGoogle Scholar
  24. 24.
    Jones B, Jones EL, Bonney SA, et al. (2003) Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet 34:29–31CrossRefPubMedGoogle Scholar
  25. 25.
    Klement IA, Skinner PJ, Kaytor MD, et al. (1998) Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95:41–53CrossRefPubMedGoogle Scholar
  26. 26.
    Koob MD, Moseley ML, Schut LJ, et al. (1999) An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet 21:379–384PubMedGoogle Scholar
  27. 27.
    Lamarche JB, Cote M, Lemieux B (1980) The cardiomyopathy of Friedreich’s ataxia: morphological observations in 3 cases. Can J Neurol Sci 7:389–396PubMedGoogle Scholar
  28. 28.
    Le Ber I, Bouslam N, Rivaud-Pechoux S, et al. (2004) Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic study in 18 patients. Brain Jan 21 (Epub)Google Scholar
  29. 29.
    Le Ber I, Moreira MC, Rivaud-Pechoux S, et al. (2003) Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies. Brain 26:2761–2772CrossRefGoogle Scholar
  30. 30.
    Lin X, Antalffy B, Kang D, et al. (2000) Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci 3:157–163CrossRefPubMedGoogle Scholar
  31. 31.
    Lodi R, Hart PE, Rajagopalan B, et al. (2001) Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich’s ataxia. Ann Neurol 49:590–596CrossRefPubMedGoogle Scholar
  32. 32.
    Margolis RL (2002) The spinocerebellar ataxias: order emerges from chaos. Curr Neurol Neurosci Rep 2:447–456PubMedGoogle Scholar
  33. 33.
    Mariotti C, Solari A, Torta D, Marano L, Fiorentini C, Di Donato S (2003) Idebenone treatment in Friedreich patients: one-year-long randomized placebo-controlled trial. Neurology 60:1676–1679PubMedGoogle Scholar
  34. 34.
    Matsuura T, Achari M, Khajavi M, et al. (1999) Mapping of the gene for a novel spinocerebellar ataxia with pure cerebellar signs and epilepsy. Ann Neurol 45:407–411CrossRefPubMedGoogle Scholar
  35. 35.
    Moreira M, Barbot C, Tachi N, et al. (2001) The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nat Genet 29:1–5PubMedGoogle Scholar
  36. 36.
    Moreira MC, Klur S, Watanabe M, et al. (2004) Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet 36:225–227CrossRefPubMedGoogle Scholar
  37. 37.
    Naito H, Oyanagi S (1982) Familial myoclonus epilepsy and choreoathetosis: hereditary dentatorubral-pallidoluysian atrophy. Neurology 32:798–807PubMedGoogle Scholar
  38. 38.
    Nakamura K, Jeong SY, Uchihara T, et al. (2001) SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TAT-Abinding protein. Hum Mol Genet 10:1441–1448CrossRefPubMedGoogle Scholar
  39. 39.
    Nemes JP, Benzow KA, Moseley ML, et al. (2000) The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1). Hum Mol Genet 9:1543–1551CrossRefPubMedGoogle Scholar
  40. 40.
    Online Mendelian Inheritance in Man, OMIM™ (2000) McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD). World Wide Web URL: Scholar
  41. 41.
    Ophoff RA, Terwindt GM, Vergouwe MN, et al. (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87:543–552CrossRefPubMedGoogle Scholar
  42. 42.
    Ouahchi K, Arita M, Kayden H, et al. (1995) Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet 9:141–145PubMedGoogle Scholar
  43. 43.
    Palau F, De Michele G, Vilchez J, et al. (1995) Early onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreich’s ataxia locus on chromosome 9q. Ann Neurol 37:359–362PubMedGoogle Scholar
  44. 44.
    Paulson HL, Perez MK, Trottier Y, et al. (1997) Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19:333–344CrossRefGoogle Scholar
  45. 45.
    Pianese L, Cavalcanti F, De Michele G, et al. (1997) The effect of parental gender on the GAA dynamic mutation in the FRDA gene. Am J Hum Genet 60:460–463PubMedGoogle Scholar
  46. 46.
    Puccio H, Simon D, Cossee M, et al. (2001) Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet 27:181–186CrossRefPubMedGoogle Scholar
  47. 47.
    Pulst SM (2002) Spinocerebellar ataxia type 2. In:Manto MU, Pandolfo M (eds) The cerebellum and its disorders. University Press, Cambridge, pp 419–427Google Scholar
  48. 48.
    Rapin I, Lindenbaum Y, Dickson DW, et al. (2000) Cockayne syndrome and xeroderma pigmentosum. Neurology 55:1442–1449PubMedGoogle Scholar
  49. 49.
    Rötig A, deLonlay P, Chretien D, et al. (1997) Frataxin gene expansion causes aconitase and mitochondrial iron-sulfur protein deficiency in Friedreich ataxia. Nat Genet 17:215–217PubMedGoogle Scholar
  50. 50.
    Rowe PC, Newman SL, Brusilow SW (1986) Natural history of symptomatic partial ornithine transcarbamylase deficiency. N Engl J Med 314:541–547PubMedGoogle Scholar
  51. 51.
    Rubinsztein DC (2002) Lessons from animal models of Huntington’s disease. Trends Genet 18:202–209 PubMedGoogle Scholar
  52. 52.
    Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, et al. (1999) Effect of idebenone on cardiomyopathy in Friedreich’s ataxia: a preliminary study. Lancet 354:477–479CrossRefPubMedGoogle Scholar
  53. 53.
    Santoro L, De Michele G, Perretti A, et al. (1999) Relation between trinucleotide GAA repeat length and sensory neuropathy in Friedreich’s ataxia. J Neurol Neurosurg Psychiatry 66:93–96Google Scholar
  54. 54.
    Savitsky K, Bar-Shira A, Gilad S, et al. (1995) A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268:1749–1753PubMedGoogle Scholar
  55. 55.
    Schols L, Amoiridis G, Buttner T, et al. (1997) Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol 42:924–932PubMedGoogle Scholar
  56. 56.
    Scriver CR, Sly WS, Childs B, et al. (2001) The metabolic and molecular bases of inherited disease (ed 8).Mc-Graw-Hill, New YorkGoogle Scholar
  57. 57.
    Shan DE, Soong BW, Sun CM, et al. (2001) Spinocerebellar ataxia type 2 presenting as familial levodopa-responsive parkinsonism. Ann Neurol 50:812–815CrossRefPubMedGoogle Scholar
  58. 58.
    Singh N, Zanusso G, Chen SG, et al. (1997) Prion protein aggregation reverted by low temperature in transfected cells carrying a prion protein gene mutation. J Biol Chem 272:28461–28470CrossRefPubMedGoogle Scholar
  59. 59.
    Stevanin G, Lebre AS, Zander C, Cancel G, Durr A, Brice A (2002) Autosomal dominant cerebellar ataxia with progressive pigmentary macular distrophy. In:Manto MU, Pandolfo M (eds) The cerebellum and its disorders. University Press, Cambridge, pp 459–468Google Scholar
  60. 60.
    Subramony SH, Filla A (2001) Autosomal dominant spinocerebellar ataxias ad infinitum? Neurology 56:287–289PubMedGoogle Scholar
  61. 61.
    Subramony SH, Vig PJS (2002) Spinocerebellar ataxia type 3. In:Manto MU, Pandolfo M (eds) The cerebellum and its disorders.University Press, Cambridge, pp 428–439Google Scholar
  62. 62.
    Takashima H, Boerkoel CF, John J, et al. (2002) Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet 32:267–272Google Scholar
  63. 63.
    Worth PF, Houlden H, Giunti P, et al. (2000) Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia. Nat Genet 24:214–215PubMedGoogle Scholar
  64. 64.
    Zhuchenko O, Bailey J, Bonnen P, et al. (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 15:62–69PubMedGoogle Scholar
  65. 65.
    Zoghbi HY, Orr HAT (2000) Glutamine repeats and neurodegeneration. Ann Rev Neurosci 23:217–247Google Scholar

Copyright information

© Steinkopff Verlag 2004

Authors and Affiliations

  • G. De Michele
    • 1
  • G. Coppola
    • 1
  • S. Cocozza
    • 2
  • A. Filla
    • 1
  1. 1.Dipartimento di Scienze NeurologicheUniversità degli Studi di Napoli Federico IINapoliItaly
  2. 2.Molecular and Cellular Biology and Pathology and CEOS, CNR Federico II UniversityNaplesItaly

Personalised recommendations