Abstract
We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37–3.94]; p = 6 × 10−18), with an exponential relationship between repeat length and ALS risk for alleles of 29–32 repeats (R2 = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.
Highlights
Spinocerebellar ataxia type 2 is a trinucleotide repeat disease in which neurodegeneration is a consequence of expansion of a repeated CAG sequence in the ATXN2 gene
Trinucleotide repeat expansion in the ATXN2 gene is a risk factor for amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of upper and lower motor neurons, but this association is only seen for repeats of intermediate size, below the range usually associated with spinocerebellar ataxia (34 repeats or more) but above the normal range (Elden et al, 2010)
Based on literature searches (Fig. 2), we identified all known studies examining ATXN2 repeat expansion in ALS, contacting authors for raw data where necessary, and including studies for analysis based on strict criteria (Supplementary Table 1)
Summary
Spinocerebellar ataxia type 2 is a trinucleotide repeat disease in which neurodegeneration is a consequence of expansion of a repeated CAG sequence in the ATXN2 gene. Trinucleotide repeat expansion in the ATXN2 gene is a risk factor for amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of upper and lower motor neurons, but this association is only seen for repeats of intermediate size, below the range usually associated with spinocerebellar ataxia (34 repeats or more) but above the normal range (Elden et al, 2010). Such pleiotropy is not seen in other trinucleotide repeat diseases and means that the usually observed relationship between repeat size, age of onset, and severity, might not be straightforward. We investigate the size range defining ALS risk and test the relationship of phenotype with repeat size
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