MOLECULAR AND CLINICAL CORRELATIONS IN SPINOCEREBELLAR ATAXIA-2 - A STUDY OF 32 FAMILIES

Spinocerebellar ataxia 2 (SCA2) is caused by the expansion of an unsta ble CAG repeat encoding a polyglutamine tract, One hundred and eighty four index patients with autosomal dominant cerebellar ataxia type I w ere screened for this mutation, We found expansion in 109 patients fro m 30 families of different geographical origins (15%) and in two isola ted cases with no known family histories (2%). The SCA2 chromosomes co ntained from 34 to 57 repeats and consisted of a pure stretch of CAG, whereas all tested normal chromosomes (14-31 repeats), except one with 14 repeats, were interrupted by 1-3 repeats of CAA. As in other disea ses caused by unstable mutations, a strong negative correlation was ob served between the age at onset and the size of the CAG repeat (r = -0 .81), The frequency of several clinical signs such as myoclonus, dysto nia and myokymia increased with the number of CAG repeats whereas the frequency of others was related to disease duration, The CAG repeat wa s highly unstable during transmission with variations ranging from -8 to +12, and a mean increase of +2.2, but there was no significant diff erence according to the parental sex. This instability was confirmed b y the high degree of gonadal mosaicism observed in sperm DNA of one pa tient.