Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2
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Abstract
Objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons that results in progressive muscle weakness and limits survival to 2–5 years after disease onset. Intermediate CAG repeat expansions in ataxin 2 (ATXN2), the causative gene of spinocerebellar ataxia type 2 (SCA2), have been implicated in sporadic ALS. We studied ATXN2 in a large cohort of patients with sporadic and familial ALS.
Methods: We determined ATXN2 CAG repeat size in 1,948 sporadic and familial ALS cases and 2,002 controls from Belgium and the Netherlands.
Results: In controls, the maximal ATXN2 repeat size was 31. In sporadic ALS, a significant amount of longer repeat sizes (≥32, range 32–39) were encountered (in 0.5% or 10/1,845 ALS cases, vs 0% in controls, p = 0.0006). Receiver operating characteristic analysis showed that a cutoff of ≥29 appeared optimal to discriminate ALS from control (p = 0.036, odds ratio [OR] 1.92, 95% confidence interval [CI] 1.04–3.64). A meta-analysis with the previously published results from the United States showed that the association between a repeat length of ≥29 and ALS became stronger (p < 0.0001, OR 2.93, 95% CI 1.73–4.98). In unexplained familial ALS, we found an intermediate repeat expansion of 31 and a homozygous repeat expansion of 33 each in 1.1% of families. The phenotype of patients with ALS with expanded repeat sizes ranged from rapidly progressive typical ALS to slowly progressive ALS with reduced sensory nerve action potentials.
Conclusion: Our data reveal a novel genetic overlap between ALS and SCA2.
Footnotes
↵* These authors shared first authorship.
↵‡ These authors shared last authorship.
Study funding: Supported by the Health Seventh Framework Programme (FP7/2007–2013, grant agreement no. 259867), the Interuniversity Attraction Poles (IUAP) programme P6/43 of the Belgian Federal Science Policy Office, and the University of Leuven (GOA 11/014 and Methusalem). P.V.D., B.D., and V.T. hold a clinical investigatorship from the FWO-Vlaanderen. W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, B.D. through the Biogen Idec Chair Translational Research in Multiple Sclerosis and the Bayer Schering Pharma Chair on Fundamental Research regarding the Neuroimmunological Aspects of Multiple Sclerosis. J.H.V. is supported by the Brain Foundation of the Netherlands. L.v.d.B. is supported by the Prinses Beatrix Fonds, Netherlands ALS Foundation, VSB Fonds, and Adessium Foundation.
Editorial, page 2050
See page 2062
Supplemental data at www.neurology.org
-
- ALS
- amyotrophic lateral sclerosis
- CI
- confidence interval
- GWAS
- genome-wide association studies
- OR
- odds ratio
- SCA
- spinocerebellar ataxia
- Received October 5, 2010.
- Accepted January 19, 2011.
- Copyright © 2011 by AAN Enterprises, Inc.
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