Autosomal dominant cerebellar ataxia: SCA2 is the most frequent mutation in eastern India

Abstract

Objective: Spinocerebellar ataxia type 2 (SCA2) has been reported as the commonest dominant hereditary ataxia in India. However, India is an ethnically and religiously diverse population. Previous studies have not clearly indicated exact ethnic and religious origins, and must therefore be interpreted with caution. The purpose of this study was to determine the prevalence of different SCA mutations in a relatively homogeneous population from eastern India. Methods: We identified 28 families with autosomal dominant cerebellar ataxia from eastern India. Each underwent full clinical evaluation and were analysed for the presence of SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and SCA17 mutations. In addition, haplotype analysis was carried out in seven of the 16 families with SCA2. Results: Seven patients from four (14%) families were positive for an expansion in SCA1 and 26 patients from 16 (57%) families were positive for an expansion in SCA2. No mutations were detected in the remaining eight families (29%). Most of the SCA1 and SCA2 families were Hindu from the state of Bihar. Five out of 26 SCA2 patients in this study did not have slow saccades. In addition, four of seven SCA1 patients had slow saccades. We found an association between the SCA2 CAG repeat expansion and the 285 base pair (bp) allele of microsatellite marker D12S1672, and also data supportive of the association between the expansion and the 225 bp allele of D12S1333, which has been previously described. Conclusions: We conclude that (1) although slow ocular saccades are highly suggestive of SCA2, that they are not universal, nor are they exclusive to this disorder and (2) SCA2 is likely to be the commonest dominant ataxia in eastern India, with further evidence for a founder effect.

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles

“…This may be relevant for the understanding of SCA2 origin in Cuba, because though the prevalence of SCA2 in Cuba is the highest worldwide, 5 the basis for this 31 is poorly understood yet. The frequency of large ANs in Cuba is the highest compared with other populations having a high prevalence of SCA2 20,21 and even other populations with a high frequency of such alleles. 18 This highly significant frequency of large ANs and other alleles distinct from 22 CAG suggests that the SCA2 locus in Cuba is highly polymorphic.…”

“…Furthermore, the comparison disclosed highly significant differences and strong effect of the CAG length in the somatic mosaicism, assessed either as mosaicism index (MI) or as peak numbers (F(1,243)¼131.57, P¼0.00, ANOVA followed by Bonferroni post hoc test, 20-26 vs 27-31 CAG range, MI ± SEM: 0.00 ± 0.016, 0.385 ± 0.028, respectively, P¼0.000) (Supplementary Figures S3a and b). According to our current results with regard to the differences between somatic mosaicism and the known phenotypic range of SCA2, we extended the previous comparison to a cohort of 551 alleles with the following ranges: normal (20)(21)(22)(23)(24)(25)(26), large (27)(28)(29)(30)(31), intermediate (32)(33)(34) and expanded . In addition to the differences in normal CAG repeat ranges, the levels of somatic mosaicism of 32-34 CAG alleles were lower than those observed in the full penetrant expanded alleles (35-79 CAG) (MI±SEM: 0.632±0.11 and 2.51±0.25, respectively, P¼0.000) (Figures 3a-c).…”

“…Normal genetic polymorphism according to CAG repeat length (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) The normal CAG repeat size from 2695 (K-S, Po0.01) chromosomes of the Cuban NM population shows a modal distribution (Figure 1a) (mode and median¼22 CAG), with 22 28 The range of the CAG is distributed continuously from 13 to 31 CAG and encompasses almost all the expected allelic classes in this numeric series (17 observed/18 expected) -with a kurtosis of 11.66 and a variance of 3.04 vs 1.21 for other populations worldwide. 27 The allele with 13 CAG repeats is exclusively found in the Cuban population and that with 26 CAG in both Cuban and Czech populations.…”

“…The high odds ratio and the specificity seen in the 27-31 CAG alleles suggest that instabilities would be associated to 27-31 CAG alleles and are more likely to occur in these rather than in the shorter ones (20)(21)(22)(23)(24)(25)(26). The proposed 27 CAG as the lower threshold for intermediate or indeterminate penetrance alleles is in agreement with the situation in SCA7, for which de novo mutations have been proven, and the lower threshold for mitotic and meiotic instabilities has been set at 27 CAG.…”

“…17 Later, some authors suggested that it is biased to only use CAG length as a marker for determining the propensity of certain alleles to be predisposed or prone to undergo expansion reaching the pathological range. 18 This argument is also supported by the fact that in East India, where SCA2 prevalence is high, [19][20][21] large ANs are spared and clustered to limited ethnic groups. 22 Therefore, the role of large ANs as a possible source of SCA2 expansion and the mechanism by which this might happen is poorly understood.…”