title: HFE p.C282Y heterozygosity is associated with earlier disease onset in Friedreich ataxia.
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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia; Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia; School of Psychology and Psychiatry, Monash University, Clayton, Victoria, Australia.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Delatycki
authors.forename: Geneieve
authors.initials: G
authors.lastname: Tai
authors.forename: Louise
authors.initials: L
authors.lastname: Corben
authors.forename: Eppie M
authors.initials: EM
authors.lastname: Yiu
authors.forename: Marguerite V
authors.initials: MV
authors.lastname: Evans-Galea
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Stephenson
authors.forename: Lyle
authors.initials: L
authors.lastname: Gurrin
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Allen
authors.forename: David
authors.initials: D
authors.lastname: Lynch
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lockhart
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D005260:Female; D005621:Friedreich Ataxia / Q000235:genetics*; D005838:Genotype; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics*; D055815:Young Adult; D000096923:Frataxin
chemical_list: D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D033862:Iron-Binding Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000096923:Frataxin; C103673:HFE protein, human
keywords: Friedreich ataxia; HFE; disease severity; genetic modifier; hemochromatosis