Abstract
We examined the clinical features of Friedreich ataxia (FRDA) patients who present first with cardiac disease in order to understand the earliest features of the diagnostic journey in FRDA. We identified a group of subjects in the FACOMS natural history study whose first identified clinical feature was cardiac. Only 0.5% of the total cohort belonged to this group, which was younger on average at the time of presentation. Their cardiac symptoms ranged from asymptomatic features to heart failure with severe systolic dysfunction. Two of those individuals with severe dysfunction proceeded to heart transplantation, but others spontaneously recovered. In most cases, diagnosis of FRDA was not made until well after cardiac presentation. The present study shows that some FRDA patients present based on cardiac features, suggesting that earlier identification of FRDA might occur through enhancing awareness of FRDA among pediatric cardiologists who see such patients. This is important in the context of newly identified therapies for FRDA.
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References
Bidichandani SI, Delatycki MB. Friedreich Ataxia. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2023 Nov 13]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1281/
Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F et al (1996) Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271(5254):1423–1427
Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S et al (1997) Frataxin is reduced in friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 6(11):1771–1780
Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC et al (2021) Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe study). Ann Neurol 89(2):212–225
The FA Clinical Outcome Measures Study (FA-COMS) - ClinicalTrials.gov [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT03090789
R Core Team. R: A language and environment for statistical computing [Internet]. Vienna, Austria; 2023. Available from: https://www.R-project.org/
McCormick A, Shinnick J, Schadt K, Rodriguez R, Addonizio L, Hirano M et al (2017) Cardiac transplantation in Friedreich ataxia: extended follow-up. J Neurol Sci 15(375):471–473
Norrish G, Rance T, Montanes E, Field E, Brown E, Bhole V et al (2021) Friedreich’s ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study. Arch Dis Child 2021:322455
Leonard H, Forsyth R (2001) Friedreich’s ataxia presenting after cardiac transplantation. Arch Dis Child 84(2):167–168
Rummey C, Corben LA, Delatycki M, Wilmot G, Subramony SH, Corti M et al (2022) Natural history of Friedreich ataxia: heterogeneity of neurologic progression and consequences for clinical trial design. Neurology 99(14):e1499–e1510
Koeppen AH (2011) Friedreich’s ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci 303(1–2):1–12
Tadros HJ, Miyake CY, Kearney DL, Kim JJ, Denfield SW (2023) The many faces of arrhythmogenic cardiomyopathy: an overview. Appl Clin Genet 16:181–203
Lees JG, Napierala M, Pébay A, Dottori M, Lim SY (2022) Cellular pathophysiology of Friedreich’s ataxia cardiomyopathy. Int J Cardiol. 346:71–78
Koeppen AH, Ramirez RL, Becker AB, Bjork ST, Levi S, Santambrogio P et al (2015) The pathogenesis of cardiomyopathy in Friedreich ataxia. PLoS One. 10(3):e0116396
Friedman LS, Schadt KA, Regner SR, Mark GE, Lin KY, Sciascia T et al (2013) Elevation of serum cardiac troponin I in a cross-sectional cohort of asymptomatic subjects with Friedreich ataxia. Int J Cardiol 167(4):1622–1624
Takazaki KAG, Quinaglia T, Venancio TD, Martinez ARM, Shah RV, Neilan TG et al (2021) Pre-clinical left ventricular myocardial remodeling in patients with Friedreich’s ataxia: a cardiac MRI study. PLoS One. 16(3):e0246633
Lota AS, Hazebroek MR, Theotokis P, Wassall R, Salmi S, Halliday BP et al (2022) Genetic architecture of acute myocarditis and the overlap with inherited cardiomyopathy. Circulation 146(15):1123–1134
Weidemann F, Störk S, Liu D, Hu K, Herrmann S, Ertl G et al (2013) Cardiomyopathy of Friedreich Ataxia. J Neurochem 126:88–93
Del Franco A, Menale S, Chiti C, Biagioni G, Tomberli A, Zampieri M et al (2023) The evolving paradigm and current perception of hypertrophic cardiomyopathy: implications for management. Prog Cardiovasc Dis 80:8–13
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The present work was supported by the Friedreich Ataxia Research Alliance.
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Drs DRL, SS, KYL, and CR conceived the work. Drs DRL, SS, KM, SP and GY contributed patients. Drs. DRL and CR drafted the original manuscript. All authors provided critical review.
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The present work was sponsored by grants from the Friedreich Ataxia Research Alliance to each of the authors.
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Lynch, D.R., Subramony, S., Lin, K.Y. et al. Characterization of Cardiac-Onset Initial Presentation in Friedreich Ataxia. Pediatr Cardiol (2024). https://doi.org/10.1007/s00246-024-03429-5
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DOI: https://doi.org/10.1007/s00246-024-03429-5