Molecular genetics of hereditary ataxias

Baillieres Clin Neurol. 1994 Aug;3(2):281-95.


The hereditary ataxias are a very heterogeneous group of disorders characterized by cerebellar dysfunction that can be either isolated or accompanied by other neurological manifestations. The classification of the hereditary ataxias based on clinical or histopathological findings has been difficult because of the significant overlap of phenotypes among the various genotypes. The patterns of inheritance observed in ataxias include autosomal dominant, autosomal recessive and X-linked. Friedreich's ataxia, the most frequent form among the recessive ataxias, has been mapped to the long arm of chromosome 9 based on close linkage to the markers D9S5 and D9S15. This close linkage allows the use of these two DNA markers for prenatal diagnosis in families with one affected offspring. In the past year, significant research progress has been accomplished by applying molecular genetic studies to the dominantly inherited spinocerebellar ataxias. Spinocerebellar ataxia type 1 (SCA1), which maps to the short arm of chromosome 6, has been found to be caused by expansion of an unstable trinucleotide (CAG) repeat. This mutational mechanism explains the presence of the clinical phenomenon of anticipation in some families with SCA1. The finding of an unstable repeat in SCA1 will facilitate the diagnosis of SCA1 in familial and isolated cases and will allow preclinical and prenatal diagnosis in families with this disease. In addition to the cloning of the SCA1 gene, two dominantly inherited ataxias have been genetically mapped: SCA2, to the long arm of chromosome 12, and Machado-Joseph disease (MJD), to the long arm of chromosome 14. Given that anticipation has been observed in patients with SCA2 and MJD, it is likely that trinucleotide repeat expansion could be a common mechanism involved in all the spinocerebellar ataxias. Last, significant research progress has been accomplished in the field of hereditary ataxias associated with DNA repair defects which should facilitate our understanding of mechanisms involved in cerebellar degeneration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Ataxia / genetics*
  • DNA Repair
  • Friedreich Ataxia / genetics
  • Genes, Dominant
  • Genetic Linkage
  • Humans
  • Molecular Biology
  • Spinocerebellar Degenerations / genetics
  • X Chromosome