Charles A Galea1,2, Aamira Huq2, Paul J Lockhart2,3, Geneieve Tai2, Louise A Corben2,3,4, Eppie M Yiu2,3,5, Lyle C Gurrin6, David R Lynch7, Sarah Gelbard7, Alexandra Durr8,9,10, Francoise Pousset11, Michael Parkinson12, Robyn Labrum13, Paola Giunti12,13, Susan L Perlman14, Martin B Delatycki2,3,4,15, Marguerite V Evans-Galea2,3. 1. Medicinal Chemistry and Drug Delivery, Disposition and Dynamics (D4), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. 2. Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia. 3. Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia. 4. School of Psychological Sciences, Monash University, Clayton, Victoria, Australia. 5. Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia. 6. Center for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. 7. Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, PA. 8. APHP, Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 9. Institut du Cerveau et de la Moelle épinière (ICM), Pitié-Salpêtrière University Hospital, Paris, France. 10. Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S_1127, ICM, F-75013, France. 11. APHP, Cardiology Department, AP-HP Pitie-Salpétrière Hospital, Paris, France. 12. Department of Molecular Neuroscience, University College London Institute of Neurology, London, United Kingdom. 13. Department of Neurogenetics, University College London Hospital, Institute of Neurology, London, United Kingdom. 14. 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. 15. Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia.
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. INTERPRETATION: 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.
OBJECTIVE:Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by ataxia and cardiomyopathy. Homozygous GAAtrinucleotide 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. INTERPRETATION: 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: Vijayendran Chandran; Kun Gao; Vivek Swarup; Revital Versano; Hongmei Dong; Maria C Jordan; Daniel H Geschwind Journal: Elife Date: 2017-12-19 Impact factor: 8.140
Authors: Marie Beaudin; Mario Manto; Jeremy D Schmahmann; Massimo Pandolfo; Nicolas Dupre Journal: Nat Rev Neurol Date: 2022-03-24 Impact factor: 42.937