Molecular analysis of CAG repeats at five different spinocerebellar ataxia loci: correlation and alternative explanations for disease pathogenesis.

Spinocerebellar ataxias (SCAs) are caused by expansion of (CAG)n triplet repeats. These repeats occur as polymorphic forms in general population; however, beyond a threshold size they become pathogenic. The sizes and distributions of repeats at the SCA1, SCA2, SCA3, SCA7 and DRPLA loci were assessed by molecular analysis of 124 unrelated ataxia patients and 44 controls, and the association of larger normal (LN) alleles with disease prevalence was evaluated. Triplet repeat expansions in the disease range were detected in 8% (10/124) of the cases, with the majority having expansion at the SCA1 locus. Normal allele ranges in the cohort studied were similar to the Caucasian and North Indian populations but differed from the Korean and Japanese populations at various loci. The percentage of individuals with LN alleles at the SCA1 and SCA2 loci was higher than reported in Indians, Japanese and Caucasians. LN alleles showed a good correlation with the incidence of SCA1, indicating that SCA1 is the most prevalent ataxia in our population. The majority of cases with clinical symptoms of SCA could not be diagnosed by established CAG repeat criteria, suggesting that there may be an alternative basis for disease pathogenesis: (i) Repeats lower than the normal range may also result in abnormal phenotypes (ii) LN alleles at different loci in the same individual may contribute to symptoms (iii) Exogenous factors may play a role in triggering disease symptoms in individuals with LN alleles (iv) Triplet repeats may reach the disease range in the brain but not in the blood.

Pathological repeat variation at the SCA17/TBP gene in south Indian patients.

Despite the intense debate around the repeat instability reported on the large group of neurological disorders caused by trinucleotide repeat expansions, little is known about the mutation process underlying alleles in the normal range, diseases range, large normal alleles (LNAs). In this study, we assessed the CAG repeats at SCA17 in 188 clinical SCA patients and 100 individuals without any neurological signs. This highly polymorphic population displayed high variability in the CAG repeats and ranged from 19-38 CAG repeats in patients with mode of 20 and 19-32 CAG repeats in controls with mode of 24. The triplet repeat expansion was not detected in any of the 188 patients, as per the reference pathogenic range (>43 repeats); however, 2.7% of the patients had >33 CAG repeats with a clinical phenotype close to what is expected of SCA 17 patients. The findings of this study implicate a more sophisticated interpretation of SCA17 gene and raise the question about the diagnostic thresh hold between normal and expanded repeats in our population.

Role of dynamic and mitochondrial mutations in neurodegenerative diseases with ataxia: lower repeats and LNAs at multiple loci as alternative pathogenesis.

Spinocerebellar ataxia is a growing group of hereditary neurodegenerative diseases for which ≥30 different genetic loci have been identified. In this study, we assessed the repeats at eight spinocerebellar ataxia (SCA) loci in 188 clinical SCA patients and 100 individuals without any neurological signs. Results from the present study were able to identify 16/188 (8.5%) clinical ataxia patients with repeat expansions in the pathological range of SCA genes, with the majority having expansion at the SCA1, 2, and 3 loci. The present study further evaluated two mitochondrial mutations associated with ataxia, i.e., T8993G and A8344G. Six patients were identified with A8344G mutation and none had the mutation in ATPase 6 gene; however, G8994A variation was found in three cases. Overall, three cases had triplet repeat expansions as well as mitochondrial (mt) mutations, which indicates potential association of triplet repeat expansions and mitochondrial mutations. Both the molecular analysis of several SCA loci and two relevant mt mutations indicated that the majority of ataxia cases were still undiagnosed; hence, the following hypotheses were proposed and tested based on available data: (i) lower repeats than normal range and (ii) large normal alleles (LNAs) at multiple loci may be an alternative basis for disease pathogenesis.