Labuda, M. et al. Unique origin and specific ethnic distribution of the Friedreich ataxia GAA expansion. Neurology 54, 2322–2324 (2000).
Google Scholar
Vankan, P. Prevalence gradients of Friedreich’s ataxia and R1b haplotype in Europe co-localize, suggesting a common Palaeolithic origin in the Franco-Cantabrian ice age refuge. J. Neurochem. 126, 11–20 (2013).
Google Scholar
Koeppen, A. H. Nikolaus Friedreich and degenerative atrophy of the dorsal columns of the spinal cord. J. Neurochem. 126, 4–10 (2013).
Google Scholar
Depienne, C. & Mandel, J. L. 30 years of repeat expansion disorders: what have we learned and what are the remaining challenges? Am. J. Hum. Genet. 108, 764–785 (2021).
Google Scholar
Maio, N. & Rouault, T. A. Mammalian iron sulfur cluster biogenesis and human diseases. IUBMB Life 74, 705 (2022).
Google Scholar
Boesch, S. & Indelicato, E. Approval of omaveloxolone for Friedreich ataxia. Nat. Rev. Neurol. 20, 313–314 (2024).
Google Scholar
Campuzano, V. et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423–1427 (1996).
Google Scholar
Savellev, A., Everett, C., Sharpe, T., Webster, Z. & Festenstein, R. DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing. Nature 422, 909–913 (2003).
Google Scholar
Herman, D. et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat. Chem. Biol. 2, 551–558 (2006).
Google Scholar
Rodden, L. N. et al. Methylated and unmethylated epialleles support variegated epigenetic silencing in Friedreich ataxia. Hum. Mol. Genet. 29, 3818–3829 (2020).
Google Scholar
Campuzano, V. et al. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum. Mol. Genet. 6, 1771–1780 (1997).
Google Scholar
Galea, C. A. et al. Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia. Ann. Neurol. 79, 485–495 (2016).
Google Scholar
Shen, M. M., Rummey, C. & Lynch, D. R. Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort. Ann. Clin. Transl. Neurol. 11, 1110–1121 (2024).
Google Scholar
Candayan, A. et al. The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype. Neurogenetics 21, 73–78 (2020).
Google Scholar
Cossée, M. et al. Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation. Hum. Mol. Genet. 9, 1219–1226 (2000).
Google Scholar
Rummey, C. et al. Natural history of Friedreich ataxia: heterogeneity of neurologic progression and consequences for clinical trial design. Neurology 99, E1499–E1510 (2022).
Google Scholar
Indelicato, E. et al. Onset features and time to diagnosis in Friedreich’s ataxia. Orphanet J. Rare Dis. 15, 198 (2020).
Google Scholar
Parkinson, M. H., Boesch, S., Nachbauer, W., Mariotti, C. & Giunti, P. Clinical features of Friedreich’s ataxia: classical and atypical phenotypes. J. Neurochem. 126, 103–117 (2013).
Google Scholar
Fahey, M. C. et al. Vestibular, saccadic and fixation abnormalities in genetically confirmed Friedreich ataxia. Brain 131, 1035–1045 (2008).
Google Scholar
Spicker, S. et al. Fixation instability and oculomotor abnormalities in Friedreich’s ataxia. J. Neurol. 242, 517–521 (1995).
Google Scholar
Patel, M. et al. Body mass index and height in the Friedreich Ataxia Clinical Outcome Measures Study. Neurol. Genet. 7, e638 (2021).
Google Scholar
Simon, A. L. et al. Scoliosis in patients with Friedreich ataxia: results of a consecutive prospective series. Spine Deform. 7, 812–821 (2019).
Google Scholar
Helliwell, T. R. et al. The pathology of the lower leg muscles in pure forefoot pes cavus. Acta Neuropathol. 89, 552–559 (1995).
Google Scholar
Tamaroff, J. et al. Friedreich’s ataxia related diabetes: epidemiology and management practices. Diabetes Res. Clin. Pract. 186, 109828 (2022).
Google Scholar
Fichera, M. et al. Comorbidities in Friedreich ataxia: incidence and manifestations from early to advanced disease stages. Neurol. Sci. 43, 6831–6838 (2022).
Google Scholar
Cnop, M., Mulder, H. & Igoillo-Esteve, M. Diabetes in Friedreich ataxia. J. Neurochem. 126, 94–102 (2013).
Google Scholar
Dürr, A. et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N. Engl. J. Med. 335, 1169–1175 (1996).
Google Scholar
Reetz, K. et al. Biological and clinical characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) cohort: a cross-sectional analysis of baseline data. Lancet Neurol. 14, 174–182 (2015).
Google Scholar
Patel, M. et al. Progression of Friedreich ataxia: quantitative characterization over 5 years. Ann. Clin. Transl. Neurol. 3, 684–694 (2016).
Google Scholar
Reetz, K. et al. Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study. Lancet Neurol. 15, 1346–1354 (2016).
Google Scholar
Rummey, C., Farmer, J. M. & Lynch, D. R. Predictors of loss of ambulation in Friedreich’s ataxia. EClinicalMedicine 18, 100213 (2020).
Google Scholar
Sharma, R. et al. Friedreich ataxia in carriers of unstable borderline GAA triplet-repeat alleles. Ann. Neurol. 56, 898–901 (2004).
Google Scholar
Ragno, M. et al. Broadened Friedreich’s ataxia phenotype after gene cloning: minimal GAA expansion causes late-onset spastic ataxia. Neurology 49, 1617–1620 (1997).
Google Scholar
Indelicato, E. et al. Predictors of survival in Friedreich’s ataxia: a prospective cohort study. Mov. Disord. 39, 510–518 (2024).
Google Scholar
Epplen, C. et al. Differential stability of the (GAA)n tract in the Friedreich ataxia (STM7) gene. Hum. Genet. 99, 834–836 (1997).
Google Scholar
Tai, G., Yiu, E. M., Corben, L. A. & Delatycki, M. B. A longitudinal study of the Friedreich ataxia impact scale. J. Neurol. Sci. 352, 53–57 (2015).
Google Scholar
Brandsma, R. et al. A clinical diagnostic algorithm for early onset cerebellar ataxia. Eur. J. Paediatr. Neurol. 23, 692–706 (2019).
Google Scholar
Van de Warrenburg, B. P. C. et al. EFNS/ENS consensus on the diagnosis and management of chronic ataxias in adulthood. Eur. J. Neurol. 21, 552–562 (2014).
Google Scholar
Fleszar, Z. et al. Short-read genome sequencing allows ‘en route’ diagnosis of patients with atypical Friedreich ataxia. J. Neurol. 270, 4112–4117 (2023).
Google Scholar
Uppili, B. et al. Sequencing through hyperexpanded Friedreich’s ataxia-GAA repeats by nanopore technology: implications in genotype-phenotype correlation. Brain Commun. 5, fcad020 (2023).
Google Scholar
Bidichandani, S. I., Ashizawa, T. & Patel, P. I. The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. Am. J. Hum. Genet. 62, 111–121 (1998).
Google Scholar
Ohshima, K., Montermini, L., Wells, R. D. & Pandolfo, M. Inhibitory effects of expanded GAA·TTC triplet repeats from intron I of the Friedreich ataxia gene on transcription and replication in vivo. J. Biol. Chem. 273, 14588–14595 (1998).
Google Scholar
Sakamoto, N. et al. Sticky DNA: self-association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich’s ataxia. Mol. Cell 3, 465–475 (1999).
Google Scholar
Soragni, E. et al. Epigenetic therapy for Friedreich ataxia. Ann. Neurol. 76, 489–508 (2014).
Google Scholar
Cavadini, P., Adamec, J., Taroni, F., Gakh, O. & Isaya, G. Two-step processing of human frataxin by mitochondrial processing peptidase. Precursor and intermediate forms are cleaved at different rates. J. Biol. Chem. 275, 41469–41475 (2000).
Google Scholar
Schmucker, S. et al. Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex. PLoS ONE 6, e16199 (2011).
Google Scholar
Pastore, A. & Puccio, H. Frataxin: a protein in search for a function. J. Neurochem. 126, 43–52 (2013).
Google Scholar
Babcock, M. et al. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science 276, 1709–1712 (1997).
Google Scholar
Yoon, T. & Cowan, J. A. Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins. J. Am. Chem. Soc. 125, 6078–6084 (2003).
Google Scholar
Adamec, J. et al. Iron-dependent self-assembly of recombinant yeast frataxin: implications for Friedreich ataxia. Am. J. Hum. Genet. 67, 549–562 (2000).
Google Scholar
Rotig, A. et al. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat. Genet. 17, 215–217 (1997).
Google Scholar
Rouault, T. A. & Tong, W. H. Iron-sulfur cluster biogenesis and human disease. Trends Genet. 24, 398–407 (2008).
Google Scholar
Fox, N. G. et al. Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism. Nat. Commun. 10, 2210 (2019).
Google Scholar
Schulz, V. et al. Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2. Nat. Commun. 15, 3269 (2024).
Google Scholar
Gervason, S. et al. Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin. Nat. Commun. 10, 3566 (2019).
Google Scholar
Uzarska, M. A. et al. During FeS cluster biogenesis, ferredoxin and frataxin use overlapping binding sites on yeast cysteine desulfurase Nfs1. J. Biol. Chem. 298, 101570 (2022).
Google Scholar
Steinhilper, R. et al. Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex. Nat. Commun. 15, 10559 (2024).
Google Scholar
Belbellaa, B., Reutenauer, L., Messaddeq, N., Monassier, L. & Puccio, H. High levels of frataxin overexpression lead to mitochondrial and cardiac toxicity in mouse models. Mol. Ther. Methods Clin. Dev. 19, 120–138 (2020).
Google Scholar
Huichalaf, C. et al. In vivo overexpression of frataxin causes toxicity mediated by iron-sulfur cluster deficiency. Mol. Ther. Methods Clin. Dev. 24, 367–378 (2022).
Google Scholar
Ast, T. et al. Hypoxia rescues frataxin loss by restoring iron sulfur cluster biogenesis. Cell 177, 1507–1521.e16 (2019).
Google Scholar
Puccio, H. et al. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat. Genet. 27, 181–186 (2001).
Google Scholar
González-Cabo, P. & Palau, F. Mitochondrial pathophysiology in Friedreich’s ataxia. J. Neurochem. 126, 53–64 (2013).
Google Scholar
Lodi, R. et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc. Natl Acad. Sci. USA 96, 11492–11495 (1999).
Google Scholar
Indelicato, E. et al. Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich’s ataxia. Front. Neurosci. 17, 1289027 (2023).
Google Scholar
Indelicato, E. et al. Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich’s ataxia. Hum. Mol. Genet. 32, 2241–2250 (2023).
Google Scholar
Gurgel-Giannetti, J. et al. A novel complex neurological phenotype due to a homozygous mutation in FDX2. Brain 141, 2289–2298 (2018).
Google Scholar
Crooks, D. R. et al. Tissue specificity of a human mitochondrial disease: differentiation-enhanced mis-splicing of the Fe-S scaffold gene ISCU renders patient cells more sensitive to oxidative stress in ISCU myopathy. J. Biol. Chem. 287, 40119–40130 (2012).
Google Scholar
Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
Google Scholar
Lynch, D. R., Deutsch, E. C., Wilson, R. B. & Tennekoon, G. Unanswered questions in Friedreich ataxia. J. Child. Neurol. 27, 1223–1229 (2012).
Google Scholar
De Biase, I. et al. Progressive GAA expansions in dorsal root ganglia of Friedreich’s ataxia patients. Ann. Neurol. 61, 55–60 (2007).
Google Scholar
Long, A. et al. Somatic instability of the expanded GAA repeats in Friedreich’s ataxia. PLoS One 12, e0189990 (2017).
Google Scholar
Koeppen, A. H., Becker, A. B., Qian, J., Gelman, B. B. & Mazurkiewicz, J. E. Friedreich ataxia: developmental failure of the dorsal root entry zone. J. Neuropathol. Exp. Neurol. 76, 969–977 (2017).
Google Scholar
Koeppen, A. H. & Mazurkiewicz, J. E. Friedreich ataxia: neuropathology revised. J. Neuropathol. Exp. Neurol. 72, 78–90 (2013).
Google Scholar
Koeppen, A. H., Ramirez, R. L., Becker, A. B. & Mazurkiewicz, J. E. Dorsal root ganglia in Friedreich ataxia: satellite cell proliferation and inflammation. Acta Neuropathol. Commun. 4, 46 (2016).
Google Scholar
Harding, I. H. et al. Brain structure and degeneration staging in Friedreich ataxia: magnetic resonance imaging volumetrics from the ENIGMA-Ataxia working group. Ann. Neurol. 90, 570–583 (2021).
Google Scholar
Martínez, A. C. & Anciones, B. Central motor conduction to upper and lower limbs after magnetic stimulation of the brain and peripheral nerve abnormalities in 20 patients with Friedreich’s ataxia. Acta Neurol. Scand. 85, 323–326 (1992).
Google Scholar
Caruso, G. et al. Friedreich’s ataxia: electrophysiological and histological findings. Acta Neurol. Scand. 67, 26–40 (1983).
Google Scholar
Rezende, T. J. R. et al. Progressive spinal cord degeneration in Friedreich’s ataxia: results from ENIGMA-Ataxia. Mov. Disord. 38, 45–56 (2023).
Google Scholar
Joers, J. M. et al. Spinal cord magnetic resonance imaging and spectroscopy detect early-stage alterations and disease progression in Friedreich ataxia. Brain Commun. 4, fcac246 (2022).
Google Scholar
Rezende, T. J. R. et al. Developmental and neurodegenerative damage in Friedreich’s ataxia. Eur. J. Neurol. 26, 483–489 (2019).
Google Scholar
Ward, P. G. D. et al. Longitudinal evaluation of iron concentration and atrophy in the dentate nuclei in Friedreich ataxia. Mov. Disord. 34, 335–343 (2019).
Google Scholar
Adanyeguh, I. M. et al. Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia. Brain Commun. 5, fcad19 (2023).
Google Scholar
Tsou, A. Y. et al. Mortality in Friedreich ataxia. J. Neurol. Sci. 307, 46–49 (2011).
Google Scholar
Koeppen, A. H. et al. The pathogenesis of cardiomyopathy in Friedreich ataxia. PLoS ONE 10, e0116396 (2015).
Google Scholar
Eigentler, A., Boesch, S., Schneider, R., Dechant, G. & Nat, R. Induced pluripotent stem cells from Friedreich ataxia patients fail to upregulate frataxin during in vitro differentiation to peripheral sensory neurons. Stem Cell Dev. 22, 3271–3282 (2013).
Google Scholar
Dionisi, C. et al. Proprioceptors-enriched neuronal cultures from induced pluripotent stem cells from Friedreich ataxia patients show altered transcriptomic and proteomic profiles, abnormal neurite extension, and impaired electrophysiological properties. Brain Commun. 5, fcad007 (2023).
Google Scholar
Lai, J. I. et al. Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures. J. Biol. Chem. 294, 1846–1859 (2019).
Google Scholar
Boesch, S. & Indelicato, E. Experimental drugs for Friedrich’s ataxia: progress and setbacks in clinical trials. Expert. Opin. Invest. Drugs 32, 967–969 (2023).
Google Scholar
Perdomini, M., Hick, A., Puccio, H. & Pook, M. A. Animal and cellular models of Friedreich ataxia. J. Neurochem. 126, 65–79 (2013).
Google Scholar
Rai, M. et al. HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS ONE 3, e1958 (2008).
Google Scholar
Piguet, F. et al. Rapid and complete reversal of sensory ataxia by gene therapy in a novel model of Friedreich ataxia. Mol. Ther. 26, 1940–1952 (2018).
Google Scholar
Perdomini, M. et al. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich’s ataxia. Nat. Med. 20, 542–547 (2014).
Google Scholar
Salami, C. O. et al. Stress-induced mouse model of the cardiac manifestations of Friedreich’s ataxia corrected by AAV-mediated gene therapy. Hum. Gene Ther. 31, 819–827 (2020).
Google Scholar
Sivakumar, A. & Cherqui, S. Advantages and limitations of gene therapy and gene editing for Friedreich’s ataxia. Front. Genome Ed. 4, 903139 (2022).
Google Scholar
Li, Y. et al. Excision of expanded GAA repeats alleviates the molecular phenotype of Friedreich’s ataxia. Mol. Ther. 23, 1055–1065 (2015).
Google Scholar
Li, J. et al. Excision of the expanded GAA repeats corrects cardiomyopathy phenotypes of iPSC-derived Friedreich’s ataxia cardiomyocytes. Stem Cell Res. 40, 101529 (2019).
Google Scholar
Mishra, P. et al. Gene editing improves endoplasmic reticulum-mitochondrial contacts and unfolded protein response in Friedreich’s ataxia iPSC-derived neurons. Front. Pharmacol. 15, 1323491 (2024).
Google Scholar
Mazzara, P. G. et al. Frataxin gene editing rescues Friedreich’s ataxia pathology in dorsal root ganglia organoid-derived sensory neurons. Nat. Commun. 11, 4178 (2020).
Google Scholar
Rocca, C. J. et al. Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia. Sci. Transl. Med. 9, eaaj2347 (2017).
Google Scholar
Reetz, K. et al. Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 4-year cohort study. Lancet. Neurol. 20, 362–372 (2021).
Google Scholar
Subramony, S. H. et al. Measuring Friedreich ataxia: interrater reliability of a neurologic rating scale. Neurology 64, 1261–1262 (2005).
Google Scholar
Schmitz-Hübsch, T. et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66, 1717–1720 (2006).
Google Scholar
Rummey, C. et al. Psychometric properties of the Friedreich ataxia rating scale. Neurol. Genet. 5, 371 (2019).
Google Scholar
Lynch, D. R. et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe Study). Ann. Neurol. 89, 212–225 (2021).
Google Scholar
Lynch, D. R. et al. Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data. Ann. Clin. Transl. Neurol. 11, 4–16 (2024).
Google Scholar
Center for Drug Evaluation and Research. Clinical review(s). Application number: 216718Orig1s000. CDER https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216718Orig1s000MedR.pdf (2023).
Gunther, K. & Lynch, D. R. Pharmacotherapeutic strategies for Friedreich ataxia: a review of the available data. Expert. Opin. Pharmacother. 25, 529–539 (2024).
Google Scholar
Abeysekara, L. L. et al. A novel feature from instrumented utensils for clinical assessment of Friedreich ataxia. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. 2023, 1–4 (2023).
Google Scholar
Corben, L. A. et al. Developing an instrumented measure of upper limb function in Friedreich ataxia. Cerebellum 20, 430–438 (2021).
Google Scholar
Kadirvelu, B. et al. A wearable motion capture suit and machine learning predict disease progression in Friedreich’s ataxia. Nat. Med. 29, 86–94 (2023).
Google Scholar
Németh, A. H. et al. Using smartphone sensors for ataxia trials: consensus guidance by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers. Cerebellum 23, 912–923 (2024).
Google Scholar
Center for Drug Evaluation and Research. Patient-focused drug development: collecting comprehensive and representative input. FDA https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-focused-drug-development-collecting-comprehensive-and-representative-input (2020).
Tai, G., Corben, L. A., Yiu, E. M. & Delatycki, M. B. A longitudinal study of the SF-36 version 2 in Friedreich ataxia. Acta Neurol. Scand. 136, 41–46 (2017).
Google Scholar
Seabury, J. et al. Friedreich’s ataxia-health index: development and validation of a novel disease-specific patient-reported outcome measure. Neurol. Clin. Pract. 13, e200180 (2023).
Google Scholar
Seabury, J. et al. Friedreich Ataxia Caregiver-Reported Health Index: development of a novel, disease-specific caregiver-reported outcome measure. Neurol. Clin. Pract. 14, e200303 (2024).
Google Scholar
Payne, R. M. Cardiovascular research in Friedreich ataxia: unmet needs and opportunities. JACC Basic. Transl. Sci. 7, 1267–1283 (2022).
Google Scholar
Weidemann, F. et al. The heart in Friedreich ataxia: definition of cardiomyopathy, disease severity, and correlation with neurological symptoms. Circulation 125, 1626–1634 (2012).
Google Scholar
Takazaki, K. A. G. et al. Pre-clinical left ventricular myocardial remodeling in patients with Friedreich’s ataxia: a cardiac MRI study. PLoS ONE 16, e0246633 (2021).
Google Scholar
Hutchens, J. A., Johnson, T. R. & Payne, R. M. Myocardial perfusion reserve in children with Friedreich ataxia. Pediatr. Cardiol. 42, 1834–1840 (1234).
Google Scholar
Pousset, F. et al. A 22-year follow-up study of long-term cardiac outcome and predictors of survival in Friedreich ataxia. JAMA Neurol. 72, 1334–1341 (2015).
Google Scholar
Hewer, R. L. Study of fatal cases of Friedreich’s ataxia. Br. Med. J. 3, 649 (1968).
Google Scholar
Mejia, E. et al. Ectopic burden via Holter monitors in Friedreich’s ataxia. Pediatr. Neurol. 117, 29 (2021).
Google Scholar
Weidemann, F. et al. The cardiomyopathy in Friedreich’s ataxia – new biomarker for staging cardiac involvement. Int. J. Cardiol. 194, 50–57 (2015).
Google Scholar
Indelicato, E. & Bösch, S. Emerging therapeutics for the treatment of Friedreich’s ataxia. Expert Opin. Orphan Drugs 6, 57–67 (2018).
Google Scholar
Libri, V. et al. Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich’s ataxia: an exploratory, open-label, dose-escalation study. Lancet 384, 504–513 (2014).
Google Scholar
Boesch, S. & Indelicato, E. Erythropoietin and Friedreich ataxia: time for a reappraisal? Front. Neurosci. 13, 386 (2019).
Google Scholar
Gottesfeld, J. M. Molecular mechanisms and therapeutics for the GAA·TTC expansion disease Friedreich ataxia. Neurotherapeutics 16, 1032–1049 (2019).
Google Scholar
Trantham, S. J. et al. Perspectives of the Friedreich ataxia community on gene therapy clinical trials. Mol. Ther. Methods Clin. Dev. 32, 101179 (2024).
Google Scholar
Design Therapeutics. Design Therapeutics reports initial results from phase 1 multiple-ascending dose study of DT-216 for the treatment of Friedreich ataxia. Design Therapeutics https://investors.designtx.com/news-releases/news-release-details/design-therapeutics-reports-initial-results-phase-1-multiple (2023).
Clayton, R. et al. Safety, pharmacokinetics, and pharmacodynamics of nomlabofusp (CTI‐1601) in Friedreich’s ataxia. Ann. Clin. Transl. Neurol. 11, 540 (2024).
Google Scholar
Larimar Therapeutics. Larimar Therapeutics: corporate deck (June 2024). Larimar Therapeutics https://investors.larimartx.com/static-files/6aaf56f2-3c60-4164-a7ea-865cdb0ae356 (2024).
Reisman, S. A. et al. Pharmacokinetics and pharmacodynamics of the novel NrF2 activator omaveloxolone in primates. Drug. Des. Devel. Ther. 13, 1259–1270 (2019).
Google Scholar
Paupe, V. et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS ONE 4, e4253 (2009).
Google Scholar
Abeti, R., Baccaro, A., Esteras, N. & Giunti, P. Novel Nrf2-inducer prevents mitochondrial defects and oxidative stress in Friedreich’s ataxia models. Front. Cell. Neurosci. 12, 188 (2018).
Google Scholar
Lynch, D. R. et al. Efficacy of omaveloxolone in Friedreich’s ataxia: delayed-start analysis of the MOXIe extension. Mov. Disord. 38, 313–320 (2023).
Google Scholar
Pane, C. et al. Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety, and tolerability of dimethyl fumarate in Friedreich ataxia (DMF-FA-201). Front. Neurosci. 17, 1260977 (2023).
Google Scholar
Linker, R. A. et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134, 678–692 (2011).
Google Scholar
Hayashi, G. et al. Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. Hum. Mol. Genet. 26, 2864–2873 (2017).
Google Scholar
Jasoliya, M. et al. Dimethyl fumarate dosing in humans increases frataxin expression: a potential therapy for Friedreich’s ataxia. PLoS ONE 14, e0217776 (2019).
Google Scholar
La Rosa, P., Petrillo, S., Fiorenza, M. T., Bertini, E. S. & Piemonte, F. Ferroptosis in Friedreich’s ataxia: a metal-induced neurodegenerative disease. Biomolecules 10, 1551 (2020).
Google Scholar
Wenzel, S. E. et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171, 628–641.e26 (2017).
Google Scholar
Friedreich’s Ataxia Research Alliance. Drug development pipeline. FARA https://www.curefa.org/drug-development/ (2024).
Parkinson, M. H., Schulz, J. B. & Giunti, P. Co-enzyme Q10 and idebenone use in Friedreich’s ataxia. J. Neurochem. 126, 125–141 (2013).
Google Scholar
Boddaert, N. et al. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood 110, 401–408 (2007).
Google Scholar
Pandolfo, M. et al. Deferiprone in Friedreich ataxia: a 6-month randomized controlled trial. Ann. Neurol. 76, 509–521 (2014).
Google Scholar
Martelli, A. et al. Iron regulatory protein 1 sustains mitochondrial iron loading and function in frataxin deficiency. Cell Metab. 21, 311–323 (2015).
Google Scholar
Grander, M. et al. Genetic determined iron starvation signature in Friedreich’s ataxia. Mov. Disord. 39, 1088–1098 (2024).
Google Scholar
Harding, I. H. et al. Localized changes in dentate nucleus shape and magnetic susceptibility in Friedreich ataxia. Mov. Disord. 39, 1109–1118 (2024).
Google Scholar
Patel, M. et al. Open-label pilot study of oral methylprednisolone for the treatment of patients with Friedreich ataxia. Muscle Nerve 60, 571–575 (2019).
Google Scholar
Yiu, E. M. et al. An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels. J. Neurol. 262, 1344–1353 (2015).
Google Scholar
Lynch, D. R. et al. Randomized, double-blind, placebo-controlled study of interferon-γ 1b in Friedreich ataxia. Ann. Clin. Transl. Neurol. 6, 546–553 (2019).
Google Scholar
Lynch, D. R. et al. Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia. J. Neurol. 270, 1615–1623 (2023).
Google Scholar
Metz, G. et al. Rating disease progression of Friedreich’s ataxia by the International Cooperative Ataxia Rating Scale: analysis of a 603-patient database. Brain 136, 259 (2013).
Google Scholar
Pandolfo, M. et al. Efficacy and safety of leriglitazone in patients with Friedreich ataxia: a phase 2 double-blind, randomized controlled trial (FRAMES). Neurol. Genet. 8, e200034 (2022).
Google Scholar
Marmolino, D. et al. PGC-1α down-regulation affects the antioxidant response in Friedreich’s ataxia. PLoS ONE 5, e10025 (2010).
Google Scholar
Rodríguez-Pascau, L. et al. PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich ataxia. Neurobiol. Dis. 148, 105162 (2021).
Google Scholar
Chevis, C. F. et al. Spinal cord atrophy correlates with disability in Friedreich’s ataxia. Cerebellum 12, 43–47 (2013).
Google Scholar
Dogan, I. et al. Structural characteristics of the central nervous system in Friedreich ataxia: an in vivo spinal cord and brain MRI study. J. Neurol. Neurosurg. Psychiatry 90, 615–617 (2019).
Google Scholar
Georgiou-Karistianis, N. et al. A natural history study to track brain and spinal cord changes in individuals with Friedreich’s ataxia: TRACK-FA study protocol. PLoS ONE 17, e0269649 (2022).
Google Scholar
Lynch, D. R., Perlman, S. L. & Meier, T. A phase 3, double-blind, placebo-controlled trial of idebenone in Friedreich ataxia. Arch. Neurol. 67, 941–947 (2010).
Google Scholar
Rummey, C., Perlman, S., Subramony, S. H., Farmer, J. & Lynch, D. R. Evaluating mFARS in pediatric Friedreich’s ataxia: insights from the FACHILD study. Ann. Clin. Transl. Neurol. 11, 1290–1300 (2024).
Google Scholar
Roche, B. et al. Test-retest reliability of an instrumented electronic walkway system (GAITRite) for the measurement of spatio-temporal gait parameters in young patients with Friedreich’s ataxia. Gait Posture 66, 45–50 (2018).
Google Scholar
Park, S. Y. et al. Cardiac, skeletal, and smooth muscle mitochondrial respiration: are all mitochondria created equal? Am. J. Physiol. Hear. Circ. Physiol. 307, H346 (2014).
Google Scholar
Vorgerd, M. et al. Mitochondrial impairment of human muscle in Friedreich ataxia in vivo. Neuromuscul. Disord. 10, 430–435 (2000).
Google Scholar
Nachbauer, W. et al. Bioenergetics of the calf muscle in Friedreich ataxia patients measured by 31P-MRS before and after treatment with recombinant human erythropoietin. PLoS ONE 8, e69229 (2013).
Google Scholar
Sival, D. A. et al. In children with Friedreich ataxia, muscle and ataxia parameters are associated. Dev. Med. Child. Neurol. 53, 529–534 (2011).
Google Scholar
Nachbauer, W. et al. Skeletal muscle involvement in Friedreich ataxia and potential effects of recombinant human erythropoietin administration on muscle regeneration and neovascularization. J. Neuropathol. Exp. Neurol. 71, 708–715 (2012).
Google Scholar
