UNSTABLE TRIPLET REPEAT AND PHENOTYPIC VARIABILITY OF SPINOCEREBELLARATAXIA TYPE-1

A Siberian kindred with spinocerebellar ataxia genetically linked to t he SCA1 locus on chromosome 6p has been screened for the CAG triplet e xpansion within the coding region of the SCA1 gene. The kindred includ es 1,484 individuals, 225 affected and 656 at risk, making this collec tion the largest spinocerebellar ataxia type 1 (SCA1) pedigree known. Each of the studied 78 SCA1 patients carried an expanded allele contai ning a stretch of 39 to 72 uninterrupted CAG repeats. Normal alleles h ad 25 to 37 trinucleotide repeats. Expanded alleles containing 40 to 5 5 repeats were found in 26 at-risk relatives. The number of CAG repeat s in the mutated allele was inversely correlated with age at disease o nset. Cerebellar deficiency was present in each patient and its severi ty was moderately affected by the number of CAG repeats. In contrast, the associated signs, dysphagia, diffuse skeletal muscle atrophy with fasciculations, and tongue atrophy were absent or mild in patients wit h low CAG repeat numbers, but severely complicated the course of illne ss in patients with a larger number of repeat units. One female mutati on carrier was asymptomatic at age 66, more than 2 standard deviations beyond the average age of risk, suggesting incomplete penetrance. In 2 symptomatic individuals who had an expanded number of CAG repeats on both chromosomes, age at onset, rate of progression, and clinical man ifestation corresponded to the size of the larger allele.