title: Compound heterozygous FXN mutations and clinical outcome in friedreich ataxia.
abstract: OBJECTIVE
  Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by ataxia and cardiomyopathy. Homozygous GAA trinucleotide repeat expansions in the first intron of FXN occur in 96% of affected individuals and reduce frataxin expression. Remaining individuals are compound heterozygous for a GAA expansion and a FXN point/insertion/deletion mutation. We examined disease-causing mutations and the impact on frataxin structure/function and clinical outcome in FRDA.
  
  
  METHODS
  We compared clinical information from 111 compound heterozygotes and 131 individuals with homozygous expansions. Frataxin mutations were examined using structural modeling, stability analyses and systematic literature review, and categorized into four groups: (1) homozygous expansions, and three compound heterozygote groups; (2) null (no frataxin produced); (3) moderate/strong impact; and (4) minimal impact. Mean age of onset and the presence of cardiomyopathy and diabetes mellitus were compared using regression analyses.
  
  
  RESULTS
  Mutations in the hydrophobic core of frataxin affected stability whereas surface residue mutations affected interactions with iron sulfur cluster assembly and heme biosynthetic proteins. The null group of compound heterozygotes had significantly earlier age of onset and increased diabetes mellitus, compared to the homozygous expansion group. There were no significant differences in mean age of onset between homozygotes and the minimal and moderate/strong impact groups.
  
  
  CONCLUSIONS
  In compound heterozygotes, expression of partially functional mutant frataxin delays age of onset and reduces diabetes mellitus, compared to those with no frataxin expression from the non-expanded allele. This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provide a definitive resource for investigating disease pathogenesis in FRDA.
authors.affiliation: Medicinal Chemistry and Drug Delivery, Disposition and Dynamics (D4), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.|Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Galea
authors.affiliation: Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Aamira
authors.initials: A
authors.lastname: Huq
authors.affiliation: Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lockhart
authors.affiliation: Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Geneieve
authors.initials: G
authors.lastname: Tai
authors.affiliation: Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.|School of Psychological Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Corben
authors.affiliation: Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.|Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Eppie M
authors.initials: EM
authors.lastname: Yiu
authors.affiliation: Center for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Lyle C
authors.initials: LC
authors.lastname: Gurrin
authors.affiliation: Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch
authors.affiliation: Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gelbard
authors.affiliation: APHP, Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.|Institut du Cerveau et de la Moelle épinière (ICM), Pitié-Salpêtrière University Hospital, Paris, France.|Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S_1127, ICM, F-75013, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: APHP, Cardiology Department, AP-HP Pitie-Salpétrière Hospital, Paris, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Pousset
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Parkinson
authors.affiliation: Department of Neurogenetics, University College London Hospital, Institute of Neurology, London, United Kingdom.
authors.forename: Robyn
authors.initials: R
authors.lastname: Labrum
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, London, United Kingdom.|Department of Neurogenetics, University College London Hospital, Institute of Neurology, London, United Kingdom.
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.affiliation: Ataxia Center and Huntington Disease Center of Excellence, Department of Neurology, David Geffen School of Medicine at the University of California at Los Angeles, CA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Perlman
authors.affiliation: Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.|School of Psychological Sciences, Monash University, Clayton, Victoria, Australia.|Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Delatycki
authors.affiliation: Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Marguerite V
authors.initials: MV
authors.lastname: Evans-Galea
mesh_terms: D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D015984:Causality; D002648:Child; D002675:Child, Preschool; D015897:Comorbidity; D003920:Diabetes Mellitus / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D005621:Friedreich Ataxia / Q000453:epidemiology* / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D015994:Incidence; D007223:Infant; D033862:Iron-Binding Proteins / Q000235:genetics*; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D011379:Prognosis; D012307:Risk Factors; D017678:Sex Distribution; D014739:Victoria / Q000453:epidemiology; D055815:Young Adult; D000096923:Frataxin
chemical_list: D005819:Genetic Markers; D033862:Iron-Binding Proteins; D000096923:Frataxin