HFE p.C282Y Heterozygosity Is Associated With Earlier Disease Onset in Friedreich Ataxia Martin B. Delatycki, FRACP, PhD, 1,2,3,4 * Geneieve Tai, BBiomedSci (Hons), 1 Louise Corben, PhD, 1,4 Eppie M. Yiu, FRACP, 1,3,5 Marguerite V. Evans-Galea, PhD, 1,3 Sarah E.M. Stephenson, BSci (Hons), 1,3 Lyle Gurrin, PhD, 6 Katrina J. Allen, FRACP, PhD, 3,7,8 David Lynch, MD, PhD 9 and Paul J. Lockhart, PhD 1,3 1 Bruce Lefroy Centre for Genetic Health Research, Murdoch Child- rens Research Institute, Parkville, Victoria, Australia 2 Clinical Genet- ics, Austin Health, Heidelberg, Victoria, Australia 3 Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Park- ville, Victoria, Australia 4 School of Psychology and Psychiatry, Mon- ash University, Clayton, Victoria, Australia 5 Children’s Neuroscience Centre, Royal Children’s Hospital, Parkville, Victoria, Australia 6 Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Parkville, Victoria, Australia 7 Gastro and Food Allergy, Murdoch Childrens Research Institute, Parkville, Victoria, Australia 8 Department of Allergy and Immunology, Royal Children’s Hospital, Parkville, Victoria, Australia 9 Department of Neu- rology, University of Pennsylvania School of Medicine and the Child- ren’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA ABSTRACT Background: 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. Methods: 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. Results: After adjusting for the smaller FXN GAA repeat size and sex, individuals with FRDA and hetero- zygous for p.C282Y had disease onset on average 3.72 years earlier than those homozygous for the wild- type amino acid (P 5 0.02). Neither mutation affected disease severity as measured by FARS. Conclusions: It is hypothesized that the association between p.C282Y heterozygosity and an earlier age at FRDA onset relates to exacerbation of the already dys- regulated iron metabolism that plays a major role in the pathogenesis of FRDA. V C 2014 International Par- kinson and Movement Disorder Society Key Words: Friedreich ataxia; HFE; hemochromato- sis; genetic modifier; disease severity Friedreich ataxia (FRDA), the most common inher- ited ataxia, results from mutations in the FXN gene. Affected individuals have onset of symptoms on aver- age at 10 to 15 years of age and have a median life expectancy of 36 years. 1 Greater than 90% of affected individuals with FRDA are homozygous for an FXN intron 1 GAA expansion, with the rest being compound heterozy- gous for a GAA expansion and a point mutation/dele- tion. 1 The size of the smaller of the 2 GAA repeats (GAA1) inversely correlates with age at disease onset and accounts for approximately 50% of the variation in this clinical parameter. 1 Little is known about the etiology of the remaining 50% in variation, although epigenetic changes in FXN are known to associate with FRDA phenotype. 2 FXN encodes the mitochondrial protein frataxin (FXN), which is involved in cellular iron homeosta- sis. 3 Deletion of the yeast frataxin homologue Dyfh1 results in marked elevation of mitochondrial iron and loss of respiration, 4 and increased iron has been dem- onstrated in fibroblast mitochondria 5 and the cerebel- lum 6,7 of individuals with FRDA. Frataxin plays a key role in the synthesis and assembly of iron–sulfur clus- ters, 8 and a number of other roles in iron homeostasis have been identified for this protein. 3 Homozygous/compound heterozygous mutations in HFE can result in hereditary hemochromatosis, an iron-overload disorder. 9 The 2 major mutations are c.845G>A resulting in p.C282Y and c.187C>G result- ing in p.H63D. Heterozygosity for one of these HFE mutations has been reported to modify a number of unrelated neurological conditions including Alzheimer’s ------------------------------------------------------------ *Correspondence to: Professor Martin Delatycki, Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Flemington Rd, Parkville, Victoria 3052, Australia; martin.delatycki@ghsv.org.au 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 ver- sion of this article. Received: 27 July 2013; Revised: 26 November 2013; Accepted: 3 December 2013 Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/mds.25795 BRIEF REPORT Movement Disorders, Vol. 00, No. 00, 2013 1