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Nadia A. Sutedja, MD; Richard J. Sinke, PhD; Paul W. J. Van Vught, MSc; Michiel W. Van der Linden, MD, PhD; John H. J. Wokke, MD, PhD; Cornelia M. Van Duijn, PhD; Omer T. Njajou, DSc, PhD; Yvonne T. Van der Schouw, PhD; Jan H. Veldink, MD, PhD; Leonard H. Van den Berg, MD, PhD

Arch Neurol. 2007;64(1):63-67.

Background  Mutations in HFE, a gene defect that can disrupt iron metabolism, have been implicated in increasing the risk of developing amyotrophic lateral sclerosis (ALS).

Objective  To further establish the association between ALS and HFE mutations by investigating whether HFE mutations are associated with an increased risk of developing ALS in a population in the Netherlands and by pooling our results with those from previous studies.

Design  Retrospective study.

Setting  Tertiary referral center for neuromuscular disorders.

Participants  Genotyping for 2 common HFE mutations was performed in 289 patients with ALS and 5886 population-based controls in the Netherlands between January 1, 2000, and December 31, 2004.

Main Outcome Measures  Development of ALS and clinical phenotype were compared among the different HFE genotypes, adjusting for known prognostic factors such as age at onset and sex.

Results  Homozygosity for H63D was associated with an increased risk of developing ALS (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1- 4.1). After pooling our results with those from previous studies, a positive association between H63D homozygotes (OR, 2.7; 95% CI, 1.7-4.4), heterozygotes (OR, 1.5; 95% CI, 1.0-2.1), and mutation carriers (OR, 1.7; 95% CI, 1.1-2.5) was found. Within the patient group, heterozygosity for the H63D mutation was associated with a higher age at onset.

Conclusions  These findings suggest that H63D mutations in HFE play a role in the pathogenesis of ALS in various populations. This association might involve a later-onset subset of ALS.

Author Affiliations: Departments of Neurology (Drs Sutedja, Van Vught, Wokke, Veldink, and Van den Berg) and Medical Genetics (Dr Sinke) and Julius Center for Health Sciences and Primary Care (Drs Van der Linden and Van der Schouw), University Medical Center Utrecht, Utrecht, and Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam (Drs Van Duijn and Njajou), the Netherlands.

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