Spinocerebellar ataxia type 1 in China - Molecular analysis and genotype-phenotype correlation in 5 families

Background: Twelve genetic types of autosomal dominant hereditary ataxia ha ve been recently identified and the genes responsible for most of them clon ed. Molecular identification of the type of ataxia is important to determin e the disease prevalence and its natural history in various populations. Objectives: To perform molecular analysis of 75 Chinese families affected w ith spinocerebellar ataxia (SCA) and to evaluate the spectrum of mutations in these genes and the correlation between genotypes and phenotypes in Chin ese patients. Setting: Neurogenetics Unit, China-Japan Friendship Hospital, Beijing, Chin a. Methods: One hundred nine patients from 75 kindreds diagnosed as having aut osomal dominant SCA, 16 patients with sporadic SCA or spastic paraplegia, 2 80 control chromosomes of the Chinese population, and 120 control chromosom es of the Sakha population were selected for this study. We conducted detai led mutational analysis by direct sequencing of polymerase chain reaction p roducts amplified from genomic DNA. Results: Spinocerebellar ataxia type 1 (SCA1) was identified in 5 families with 12 studied patients. All affected family members were heterozygous for a CAG repeat expansion in the SCAI gene containing 51 to 64 trinucleotide repeats. Normal alleles had 26 to 35 repeats. Spinocerebellar ataxia type 1 accounted for 7% of the studied Chinese families with ataxia. In addition, we determined the frequency of a single vs double CAT interruption in 120 control chromosomes of the Siberian Sakha population, which has the highest known prevalence of SCA1, and compared this with 280 control chromosomes f rom the Chinese populations. The results show that 64.7% of the Siberian no rmal alleles contain a single CAT interruption whereas 92% of the Chinese h ad more than 1 interruption. Conclusions: Spinocerebellar ataxia type 1 is responsible for 7% of affecte d families in the Chinese population. A correlation between the prevalence of SCA1 and the number of CAT interruptions in the trinucleotide chain sugg ests that a CAT-to-GAG substitution may have been the initial event contrib uting to the generation of expanded alleles and influencing relative preval ence of SCA1.