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.