The association between H63D mutations in HFE and amyotrophic lateral sclerosis in a Dutch population

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.