Repeat length and disease progression in spinocerebellar ataxia type 3

Abstract

Spinocerebellar ataxia type 3 (SCA3 or Machado-Joseph disease) belongs to a group of autosomal dominant hereditary neurodegenerative disorders that are caused by unstable expansions of trinucleotide CAG repeats coding for polyglutamine. 1 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: 221-228 Crossref PubMed Scopus (1539) Google Scholar This group of disorders also comprises Huntington's disease, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxia type 1. CAG repeat disorders share the common feature of an inverse correlation between repeat length and age at disease onset, with the largest expansions occurring in patients with juvenile disease onset. 2 La Spada AR Paulson HL Fischbeck KH Trinucleotide repeat expansion in neurological disease. Ann Neurol. 1994; 36: 814-822 Crossref PubMed Scopus (175) Google Scholar In addition, repeat length influences the clinical phenotype of the respective disorders. In SCA3, patients with large repeats often have clinical features of pyramidal tract and basal ganglia involvement. By contrast, SCA3 patients with intermediate repeat length show mainly ataxia and gaze palsy, whereas patients with smaller expansions have signs of peripheral neuropathy with loss of tendon reflexes, amyotrophy, and decreased vibration sense. 3 Maciel P Gaspar C DeStefano AL et al. Correlation between CAG repeat length and clinical features in Machado-Joseph disease. Am J Hum Genet. 1995; 57: 54-61 PubMed Google Scholar Clinical observations in CAG repeat disorders suggest that larger repeats are often associated with a more severe phenotype and rapid clinical deterioration. These observations prompted us to study the relation between repeat length and disease progression in SCA3.