Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2
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.
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Supplementary Material
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Copyright © 2011 by AAN Enterprises, Inc.
Publication History
Received: October 5, 2010
Accepted: January 19, 2011
Published online: May 11, 2011
Published in print: June 14, 2011
Disclosure
Dr. Van Damme holds a clinical research fellowship from FWO-Vlaanderen. Dr. Veldink has received funding for travel from Baxter International Inc. Dr. van Blitterwijk, Dr. Corveleyn, and Dr. van Vught report no disclosures. Dr. Thijs serves on scientific advisory boards for SYGNIS Pharma AG, Merck & Co., Inc., Shire plc, and Boehringer Ingelheim; has received funding for travel from Shire plc and Boehringer Ingelheim; serves as an Associate Editor for Acta Neurologica Belgica; serves on the speakers' bureaus of Shire plc, Abbott, Pfizer Inc, Boehringer Ingelheim, and Medtronic, Inc.; receives research support from SERVIER, Schering-Plough Corp., SYGNIS Pharma AG, CoAxia, Inc., Medtronic, Inc., Novo Nordisk, Bristol-Myers Squibb, Pfizer Inc, Shire plc, AstraZeneca, ThromboGenics NV, Eli Lilly and Company, sanofi-aventis, Boehringer Ingelheim, Daiichi Sankyo, Asubio Pharmaceuticals, Inc., FWO Flanders, and Vlaams Instituut voor Biotechnologie; and holds stock in Novo Nordisk. Dr. Dubois serves on a scientific advisory board for Biogen Idec; has received funding for travel from Novartis, Merck Serono, Bayer Schering Pharma, sanofi-aventis, and Biogen Idec; and receives research support from Bayer Schering Pharma, Merck Serono, and Biogen Idec. Dr. Matthijs reports no disclosures. Dr. van den Berg serves on the scientific advisory board of ARISLA (the Italian ALS Association); serves as a consultant for and has received funding for travel from Baxter International Inc.; and receives research support from the Prinses Beatrix Fonds, Netherlands ALS Foundation, VSB Fonds, and Adessium Foundation. Dr. Robberecht serves on scientific advisory boards for the T. Latran Foundation, the Packard Center, Motor Neurone Disease Association, UK, and GlaxoSmithKline; serves on the editorial boards of the Journal of Neuropathology and Experimental Neurology and Amyotrophic Lateral Sclerosis; and receives research support from Neuronova, TEVA, Trophos, FWO Flanders, the T. Latran Foundation, Paris (France), and the Packard Center for ALS research (USA).
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