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

Abstract

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 intermediate-length 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. ### Methods. Considered in the present study were patients with ALS according to the El Escorial criteria4 evaluated at the ALS Clinic of Padova from January 2004 to August 2010. Patient data entered included sex, age and site of onset (bulbar or spinal), disease duration at ALS diagnosis, forced vital capacity (FVC, expressed as percentage of the expected value) at first assessment, survival defined as the time from onset to …