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HFE p.C282Y heterozygosity is associated with earlier disease onset in Friedreich ataxia

Authors

  • Martin B. Delatycki FRACP, PhD,

    Corresponding author
    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    2. Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia
    3. Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
    4. School of Psychology and Psychiatry, Monash University, Clayton, Victoria, Australia
    • 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

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  • Geneieve Tai BBiomedSci (Hons),

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
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  • Louise Corben PhD,

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    2. School of Psychology and Psychiatry, Monash University, Clayton, Victoria, Australia
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  • Eppie M. Yiu FRACP,

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
    3. Children's Neuroscience Centre, Royal Children's Hospital, Parkville, Victoria, Australia
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  • Marguerite V. Evans-Galea PhD,

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
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  • Sarah E.M. Stephenson BSci (Hons),

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
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  • Lyle Gurrin PhD,

    1. Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Parkville, Victoria, Australia
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  • Katrina J. Allen FRACP, PhD,

    1. Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
    2. Gastro and Food Allergy, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    3. Department of Allergy and Immunology, Royal Children's Hospital, Parkville, Victoria, Australia
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  • David Lynch MD, PhD,

    1. Department of Neurology, University of Pennsylvania School of Medicine and the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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  • Paul J. Lockhart PhD

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
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  • 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.

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. © 2014 International Parkinson and Movement Disorder Society

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