PHENOTYPIC VARIABILITY IN AUTOSOMAL-DOMINANT CEREBELLAR-ATAXIA TYPE-IIS UNRELATED TO GENETIC-HETEROGENEITY

Families with autosomal dominant cerebellar ataxia (ADCA), a heterogen eous group of diseases, were investigated prior to and during genetic linkage analysis. We report here on the clinical features of 122 affec ted individuals from 36 unrelated families with ADCA type I, the most common type. Our results indicate an anticipation expressed in a mean 9.4 year earlier age at onset and more rapid clinical progression in s uccessive generations. There was no imprinting, since age at onset, di sease duration and severity of the disease were independent of parenta l transmission. Progressive cerebellar ataxia was variably associated with signs such as ophthalmoplegia, dysphagia, sphincter disturbances, briskness or loss of tendon reflexes, decreased vibration sense and a myotrophy, a variability correlated with disease duration. Linkage ana lysis of 10 informative families with microsatellite markers, located on the short arm of the chromosome 6, allowed the identification of fo ur families showing positive linkage to the SCA1 (spinal cerebellar at axia 1) locus and six non-SCA1 families for whom linkage to this locus was excluded. This reflects non-allelic genetic heterogeneity. Thus, the analysis of clinical signs associated with cerebellar ataxia in SC A1 versus non-SCA1 kindreds did not distinguish between the two groups . The clinical picture of ADCA type I did not reflect the genetic hete rogeneity of the disease.