Clinical features and genetic analysis of a new form of spinocerebellar ataxia

Background: The autosomal dominant cerebellar ataxias (ADCA) are a clinical ly heterogeneous group of disorders. The mutations for SCA1, SCA2, SCA3, SC A6, SCA7, SCA8, and SCA-12 are identified and caused by an expansion of a C AG or a CTG repeat sequence of these genes. Six additional loci for SCA4, S CA5, SCA-10, SCA-11, SCA-13, and SCA-14 are mapped. The growing heterogenei ty of the autosomal dominant forms of these diseases shows that the genetic etiologies of at least 20% of ADCA have yet to be elucidated. Methods: The authors ascertained and clinically characterized a four-generation pedigre e segregating an autosomal dominant phenotype for SCA. Direct mutation anal ysis, repeat expansion detection analysis, and linkage analysis for all kno wn SCA loci were performed. Results: Direct mutational analysis excluded SC A1, 2, 3, 6, 7, 8, and 12; genetic linkage analysis excluded SCA4, 5,10, 11 , 13, and 14, giving significant negative lod scores. Examination of the fa mily showed that all affected members had gait ataxia and akinesia with var iable features of dysarthria, hyporeflexia, and mild intellectual impairmen t. Eye movements were normal. Head MRI showed atrophy of the cerebellum wit hout involvement of the brainstem. In 10 parent-child pairs, median onset o ccurred 10.5 years earlier in offspring than in their parents, suggesting a nticipation. Conclusion.: This family is distinct from other families with SCA and is characterized by cerebellar ataxia and extrapyramidal signs.