MOLECULAR AND CLINICAL CORRELATIONS IN SPINOCEREBELLAR ATAXIA TYPE-I - EVIDENCE FOR FAMILIAL EFFECTS ON THE AGE AT ONSET

The spinocerebellar ataxias are a group of debilitating neurodegenerat ive diseases for which a clinical classification system has proved unr eliable. We have recently isolated the gene for spinocerebellar ataxia type 1 (SCA1) and have shown that the disease is caused by an expande d, unstable, CAG trinucleotide repeat within an expressed gene. Normal alleles have a size range of 19-36 repeats, while SCA1 alleles have 4 2-81 repeats. In this study, we examined the frequency and variability of the SCA1 repeat expansion in 87 kindreds with diverse ethnic backg rounds and dominantly inherited ataxia. All nine families for which li nkage to the SCA1 region of 6p had previously been established showed repeat expansion, while 3 of the remaining 78 showed a similar abnorma lity. For 113 patients from the families with repeat expansion, invers e correlations between CAG repeat size and both age at onset and disea se duration were observed. Repeat size accounted for 66% of the variat ion in age at onset in these patients. After correction for repeat siz e, interfamilial differences in age at onset remained significant, sug gesting that additional genetic factors affect the expression of the S CA1 gene product.