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

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-related neurodegeneration'. 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 ALS. Interrupted CAG-repeats were associated with an ALS phenotype in our data but we also identified ALS cases with uninterrupted expansions. Our findings have relevance for researchers, patients and families linked to CAG-repeat expansions in ATXN2.

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Publication Details

Journal
European Journal of Human Genetics
Published
2025-02-16
DOI
https://doi.org/10.1038/s41431-025-01811-2
Citations
6
Primary Topic
Genetic Neurodegenerative Diseases
Type
article
Field-Weighted Citation Impact
5.45

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article

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

Guy Armand Rouleau, Tobias Moll, David O’Brien, Philip Van Damme et al.
6 citations
European Journal of Human Genetics
Genetic Neurodegenerative Diseases
5.45
article

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

Guy Armand Rouleau, Tobias Moll, David O’Brien, Philip Van Damme, Andrea Western, Jan Willem Dankbaar, Calum Harvey, Michael Benatar, Johnathan Cooper‐Knock, Luke Drury, Wouter Koole, Patrick A. Dion, Sali M.K. Farhan, Joke J.F.A. van Vugt, R. Jeroen Pasterkamp, Koen C. Demaegd, Jan H. Veldink, Leonard H. van den Berg, Wouter van Rheenen, Michael A. van Es, Paul J. Parsons, Esther Hobson, Jeroen Hendrikse, Janine Kirby, Charlotte de Bie, Pamela J. Shaw, Sarah Gornall, Bruce McLean, Bart van de Warrenburg, Aoife Kernan
article en
6 citations

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-related neurodegeneration'. 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 ALS. Interrupted CAG-repeats were associated with an ALS phenotype in our data but we also identified ALS cases with uninterrupted expansions. Our findings have relevance for researchers, patients and families linked to CAG-repeat expansions in ATXN2.

European Journal of Human GeneticsVol. 33(9)
University of North Carolina at Chapel Hill (US), Montreal Neurological Institute and Hospital (CA), University of Miami (US), Radboud University Nijmegen (NL), Utrecht University (NL), Sheffield Teaching Hospitals NHS Foundation Trust (GB), Exact Sciences (United States) (US), Sheffield Children's NHS Foundation Trust (GB), Altrecht GGZ (NL), McGill University (CA), University of Sheffield (GB), KU Leuven (BE)
Wellcome, Fondation Thierry Latran, Cure for MND Foundation, Ionis Pharmaceuticals, Motor Neurone Disease Association, ZonMw, National Institutes of Health
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Openalex Percentile: Top 4%
Genetic Neurodegenerative Diseases
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