ALS risk but not phenotype is affected by ataxin-2 intermediate length polyglutamine expansion

TDP-43 is the major disease protein in amyotrophic lateral sclerosis (ALS).1 Recently, ataxin-2, a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2 (SCA2),2 has been shown to interfere with TDP-43 toxicity in ALS animal models and to abnormally localize in ALS spinal cord neurons.3 An increased risk for ALS and an earlier age at disease onset were observed in patients with an intermediatelength CAG expansion (24 –33) [(CAG)24 –33] in ataxin-2 encoding gene (ATXN2). To test the hypothesis that ATXN2 (CAG)24–33 expansion is a clinical modifier in ALS, we determined the length of the polyQ expansion in 247 patients with ALS and correlated clinical phenotype in the (CAG)24–33 expansion patients with those with a CAG expansion below 24 repeats.