Friedreich's ataxia-a rare multisystem disease.

Miguel Pishnamaz, Kerstin Konrad, Claire Didszun, David R Lynch, Imis Dogan, Jennifer Farmer, Jörg B Schulz, Massimo Pandolfo, Kathrin Reetz, Louise A Corben, Stella A Lischewski, Katharina Marx-Schütt

Journal: The Lancet. Neurology 2025;24(7):614-624

PMID: 40541211

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Abstract

Friedreich's ataxia is a rare autosomal recessive neurodegenerative disease. Most patients have a homozygous GAA repeat expansion in the FXN gene, resulting in a deficiency of the mitochondrial protein frataxin. Disease onset occurs typically in adolescence but can vary widely, ranging from early childhood to late adulthood. Friedreich's ataxia is increasingly recognised as a multisystem disorder, affecting not only the nervous system, but also the heart and musculoskeletal system, and metabolism. Common extraneural manifestations include cardiomyopathy, which is the most common cause of mortality, and also scoliosis and diabetes. Despite research advances, the phenotypical heterogeneity of patients with Friedrich's ataxia remains inadequately explained by current knowledge of the underlying genetics. The approval of omaveloxolone by the US Food and Drug Administration and the European Medicines Agency has been a pharmacological milestone; however, further research addressing complex interorgan interactions is crucial for a better understanding of the multisystem nature of Friedreich's ataxia and the development of targeted treatment approaches.

Address: Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Research Centre Juelich GmbH, Aachen, Germany. Electronic address: [email protected].; Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Research Centre Juelich GmbH, Aachen, Germany.; Department for Orthopaedics, Trauma and Reconstructive Surgery, University Hospital, RWTH Aachen, Germany.; Section Child Neuropsychology, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, RWTH Aachen, Germany.; Department of Internal Medicine I, Cardiology, RWTH Aachen University, Aachen, Germany.; Friedreich's Ataxia Research Alliance, Downingtown, PA, USA.; Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.; Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia.; McGill University, Montreal, QC, Canada.

DOI: 10.1016/S1474-4422(25)00175-9