Journal
NEUROLOGY
Volume 76, Issue 24, Pages 2066-2072Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e31821f445b
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Funding
- Health Seventh Framework Programme [FP7/2007-2013, 259867]
- Belgian Federal Science Policy Office [P6/43]
- University of Leuven [GOA 11/014]
- E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
- Biogen Idec Chair Translational Research in Multiple Sclerosis
- Bayer Schering Pharma Chair on Fundamental Research
- Brain Foundation of the Netherlands
- Prinses Beatrix Fonds
- Netherlands ALS Foundation
- VSB Fonds
- Adessium Foundation
- FWO-Vlaanderen
- Baxter International Inc.
- Shire plc
- Boehringer Ingelheim
- SERVIER
- Schering-Plough Corp.
- SYGNIS Pharma AG
- CoAxia, Inc.
- Medtronic, Inc.
- Novo Nordisk
- Bristol-Myers Squibb
- Pfizer Inc
- AstraZeneca
- ThromboGenics NV
- Eli Lilly and Company
- sanofi-aventis
- Daiichi Sankyo
- Asubio Pharmaceuticals, Inc.
- FWO Flanders
- Vlaams Instituut voor Biotechnologie
- Novartis
- Merck Serono
- Bayer Schering Pharma
- Biogen Idec
- Neuronova
- TEVA
- Trophos
- T. Latran Foundation, Paris (France)
- Packard Center for ALS research (USA)
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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. Neurology (R) 2011; 76: 2066-2072
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