Objective: To characterize a distinct form of spinocerebellar ataxia (
SCA) clinically and genetically. Background: The SCAs are a geneticall
y heterogeneous group of neurodegenerative disorders affecting the cer
ebellum and its connections. The mutations for SCAI, 2, 3, 6, and 7 ha
ve been identified and shown to be due to expansion of a CAG repeat in
the coding region of these genes. Two additional SCA loci on chromoso
mes 16 and 11 have been designated SCA4 and SCA5. However, up to 20% o
f individuals with autosomal dominant forms of ataxias cannot be assig
ned any of these genotypes, implying the presence of other unidentifie
d genes that may be involved in the development of ataxia. Methods: We
ascertained and clinically characterized a six-generation pedigree se
gregating an autosomal dominant trait for SCA. We performed direct mut
ation analysis and linkage analysis for all known SCA loci. Results: T
he mutation analysis excludes SCA1, 2, 3, 6, and 7, and genetic linkag
e analysis excludes SCA4 and SCA5 (multipoint location scores <-2 acro
ss the candidate region). Clinical analysis of individuals in this fam
ily shows that all affected members have dysarthria, gait and limb ata
xia, and nystagmus. No individuals have major brainstem or long-tract
findings. Analysis of age at disease onset through multiple generation
s suggests anticipation.; Conclusion: This pedigree represents a genet
ically distinct form of SCA with a phenotype characterized by predomin
antly cerebellar symptoms and signs.