Genetic characterization of Spinocerebellar ataxia 1 in a South Indian cohort

Abstract

BackgroundSpinocerebellar ataxia type 1 (SCA1) is a late onset autosomal dominant cerebellar ataxia, caused by CAG triplet repeat expansion in the ATXN1 gene. The frequency of SCA1 occurrence is more in Southern India than in other regions as observed from hospital-based studies. However there are no reports on variability of CAG repeat expansion, phenotype-genotype association and founder mutations in a homogenous population from India.MethodsGenomic DNA isolated from buccal mouthwash of the individuals in the cohort was used for PCR-based diagnosis of SCA1. Subsequently SNP’s found within the ATXN1 loci were identified by Taqman allelic discrimination assays. Significance testing of the genotype-phenotype associations was calculated by Kruskal-Wallis ANOVA test with post-hoc Dunnett’s test and Pearson’s correlation coefficient.ResultsBy genetic analysis of an affected population in Southern India we identified 21 pre-symptomatic individuals including four that were well past the average age of disease onset of 44 years, 16 symptomatic and 63 normal individuals. All pre-symptomatic cases harbor “pure” expansions of greater than 40 CAGs. Genotyping to test for the presence of two previously identified SNPs showed a founder effect of the same repeat carrying allele as in the general Indian population. We show that SCA1 disease onset is significantly delayed when transmission of the disease is maternal.ConclusionsOur finding of early disease onset in individuals with a paternally inherited allele could serve as valuable information for clinicians towards early detection of SCA1 in patients with affected fathers. Identification of older pre-symptomatic individuals (n = 4) in our cohort among individuals with a shared genetic and environmental background, suggests that second site genetic or epigenetic modifiers might significantly affect SCA1 disease progression. Moreover, such undetected SCA1 cases could underscore the true prevalence of SCA1 in India.

Spinocerebellar ataxia 1: case and cohort-based studies in India

“…Expanded repeats were in the range 50-65. An inverse correlation of age of onset with CAG repeat size was observed here as seen in previous studies 19,37 . These studies were primarily aimed at frequency estimation of different ADCAs and concluded that SCA2 was the most prevalent form in India.…”

“…However, in southern India, four independent studies point to a higher incidence of SCA1 over other SCAs 13,14,19,38 . When the frequencies of SCA1 patients from hospitals were compared amongst the ADCAs, they were twice in southern India (33%, 20/60 families) than in northern India (15%, 17/107 families) 13 .…”

“…This study also revealed 60% of the patients to be asymptomatic, indicating pre-symptomatic carriers who are likely to manifest the disease at a later stage. Additionally, a recent study in an ethnic in-breeding population in South India identified 21 symptomatic (age 17-60 years) and 16 pre-symptomatic SCA1 (age 34-60 years) cases with repeat sizes above 40 CAG from DNA isolated from buccal mouthwashes 19 . To summarize, three groups have conducted exclusive studies on SCA1 in India.…”

“…Specific cohortbased studies on the natural history and clinical characteristics of SCAs are gaining importance because such studies could help in understanding the preclinical stages of SCA, where therapy is likely to be most effective. Such cohort-based studies exploring the clinical and biological characteristics of at-risk cases of SCA1 have so far been conducted in the US, Europe, South Africa [16][17][18] and more recently in India 19 .…”

Spinocerebellar ataxia 1: case and cohort-based studies in India

“…Specific cohortbased studies on the natural history and clinical characteristics of SCAs are gaining importance because such studies could help in understanding the preclinical stages of SCA, where therapy is likely to be most effective. Such cohort-based studies exploring the clinical and biological characteristics of at-risk cases of SCA1 have so far been conducted in the US, Europe, South Africa [16][17][18] and more recently in India 19 .…”