An observational study of pleiotropy and penetrance of amyotrophic lateral sclerosis associated with CAG-repeat expansion of ATXN2

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Abstract Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are both associated with a CAG-repeat expansion in ATXN2 and with TDP-43-positive neuronal cytoplasmic inclusions. The two disorders have been viewed as distinct entities, where an intermediate length expansion of 31–33 CAG-repeats is associated with sporadic ALS and a full length expansion of ≧ 34 CAG-repeats is associated with SCA2. We report the clinical phenotype of ATXN2-positive patients and their relatives, identified in three specialist ALS clinics, which force a reconsideration of this dichotomy. We also report the frequency of ATXN2 expansions in two large cohorts of ALS patients and in a population-matched cohort of controls. We report ten cases of familial ALS in which disease is associated with either an intermediate or a full-length ATXN2 CAG-repeat expansion. Pedigrees and patients feature additional phenotypes including parkinsonism, dementia and essential tremor (ET). We conclude that CAG-repeat expansions in ATXN2 exhibit pleiotropy and are associated with a disease spectrum that includes ALS, SCA2, and parkinsonism; to recognise this complexity we propose the new term ‘ATXN2 spectrum disorder’. We also observed sporadic ALS associated with full-length expansions. We conclude that ATXN2 CAG-repeat expansions, irrespective of length, should be considered a risk factor for both familial and sporadic ALS. Interrupted CAG-repeats were not perfectly aligned with an ALS phenotype in our data. Our findings have relevance for researchers, patients and families linked to CAG-repeat expansions in ATXN2.

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