HFE p.C282Y heterozygosity is associated with earlier disease onset in Friedreich ataxia
Funding agencies: This study was supported by the Friedreich Ataxia Research Association (Australasia), Friedreich Ataxia Research Alliance (USA), Muscular Dystrophy Association, Australian Rotary Health Fund, and Collier Charitable Fund as well as the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.
Relevant conflicts of interest/financial disclosures: Martin B. Delatycki is a Practitioner Fellow, Louise Corben is an Early Career Fellow, and Lyle Gurrin and Paul J. Lockhart are Career Development Fellows all of the National Health and Medical Research Council. Katrina J. Allen is a Viertel Senior Medical Research Fellow.
Full financial disclosures and author roles may be found in the online version of this article.
Friedreich ataxia (FRDA) generally results from reduced frataxin, a mitochondrial protein involved in iron metabolism. We assessed whether HFE p.C282Y and/or p.H63D heterozygosity modifies age at disease onset or disease severity in individuals with FRDA.
One hundred seventy individuals with FRDA were assessed for the association of HFE p.C282Y and p.H63D with (1) age at disease onset and (2) Friedreich Ataxia Rating Scale (FARS) score.
After adjusting for the smaller FXN GAA repeat size and sex, individuals with FRDA and heterozygous for p.C282Y had disease onset on average 3.72 years earlier than those homozygous for the wild-type amino acid (P = 0.02). Neither mutation affected disease severity as measured by FARS.
It is hypothesized that the association between p.C282Y heterozygosity and an earlier age at FRDA onset relates to exacerbation of the already dysregulated iron metabolism that plays a major role in the pathogenesis of FRDA. © 2014 International Parkinson and Movement Disorder Society