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Predictors of Left Ventricular Dysfunction in Friedreich’s Ataxia in a 16-Year Observational Study

A Letter to the Editor to this article was published on 25 July 2020

A Letter to the Editor to this article was published on 25 July 2020



Friedreich’s ataxia (FRDA) is a cerebellar ataxia due to GAA repeat expansions in the FXN gene, and in affected patients, lower left ventricular ejection fraction (LVEF) leads to poorer prognosis. We aimed to identify patients likely to develop worsening LVEF at an early stage.


We included 115 FRDA patients aged 30 ± 10 years with 620 ± 238 GAA repeats on the shorter allele and disease onset of 15 ± 7 years.


At baseline, left ventricular (LV) hypertrophy was present in 53%, with LVEF 65 ± 7%, LV end diastolic diameter (LVEDD) 43 ± 5 mm, septal wall thickness (SWT) 11.8 ± 2.7 mm, and posterior wall thickness 11.1 ± 2.5 mm. After a mean follow-up of 13 ± 6 years, LVEF ≤ 50% was observed in 12 patients. The main determinants of LVEF ≤ 50% were GAA repeat number on the shorter allele (odds ratio [OR] 1.007, 95% confidence interval [CI] 1.003–1.012, p = 0.002), LVEDD (OR 1.217, 95% CI 1.058–1.399, p = 0.006), and SWT (OR 1.352, 95% CI 1.016–1.799, p = 0.04). High-risk patients were predicted 5 years before LVEF ≤ 50% occurred: area under the curve of 0.91, 95% CI 0.85–0.97. Patients with GAA repeats > 800 were categorized as high risk, patients with 500 < GAA < 800 were high risk if LVEDD was ≥ 52.6 mm and SWT was ≥ 13.3 mm, and patients with GAA < 500 were low risk if LVEDD was < 52.6 mm and SWT was < 13.3 mm.


Echocardiographic follow-up combined with size assessment of GAA repeat expansions is a powerful tool to identify patients at high risk of developing LV systolic dysfunction up to 5 years before clinical symptoms. Further studies are mandatory to investigate if these patients would benefit from cardiac interventions.

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  1. Durr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med. 1996;335(16):1169–75.

    CAS  Article  PubMed  Google Scholar 

  2. Pousset F, Legrand L, Monin ML, Ewenczyk C, Charles P, Komajda M, Brice A, Pandolfo M, Isnard R, Tezenas du Montcel S, Durr A. A 22-year follow-up study of long-term cardiac outcome and predictors of survival in Friedreich ataxia. JAMA Neurol. 2015;72(11):1334–41.

    Article  PubMed  Google Scholar 

  3. Filla A, De Michele G, Cavalcanti F, Pianese L, Monticelli A, Campanella G, Cocozza S. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet. 1996;59(3):554–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Isnard R, Kalotka H, Durr A, Cossee M, Schmitt M, Pousset F, Thomas D, Brice A, Koenig M, Komajda M. Correlation between left ventricular hypertrophy and GAA trinucleotide repeat length in Friedreich’s ataxia. Circulation. 1997;95(9):2247–9.

    CAS  Article  PubMed  Google Scholar 

  5. Tai G, Corben LA, Yiu EM, Milne SC, Delatycki MB. Progress in the treatment of Friedreich ataxia. Neurol Neurochir Pol. 2018;52(2):129–39.

    Article  PubMed  Google Scholar 

  6. Perdomini M, Belbellaa B, Monassier L, Reutenauer L, Messaddeq N, Cartier N, Crystal RG, Aubourg P, Puccio H. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich’s ataxia. Nat Med. 2014;20(5):542–7.

    CAS  Article  PubMed  Google Scholar 

  7. Piguet F, de Montigny C, Vaucamps N, Reutenauer L, Eisenmann A, Puccio H. Rapid and complete reversal of sensory ataxia by gene therapy in a novel model of Friedreich ataxia. Mol Ther. 2018;26(8):1940–52.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Deverman BE, Ravina BM, Bankiewicz KS, Paul SM, Sah DWY. Gene therapy for neurological disorders: progress and prospects. Nat Rev Drug Discov. 2018;17(10):767.

    CAS  Article  PubMed  Google Scholar 

  9. Tsou AY, Paulsen EK, Lagedrost SJ, Perlman SL, Mathews KD, Wilmot GR, Ravina B, Koeppen AH, Lynch DR. Mortality in Friedreich ataxia. J Neurol Sci. 2011;307(1–2):46–9.

    Article  PubMed  Google Scholar 

  10. Weidemann F, Liu D, Hu K, Florescu C, Niemann M, Herrmann S, Kramer B, Klebe S, Doppler K, Uceyler N, Ritter CO, Ertl G, Stork S. The cardiomyopathy in Friedreich’s ataxia—new biomarker for staging cardiac involvement. Int J Cardiol. 2015;194:50–7.

    Article  PubMed  Google Scholar 

  11. Reetz K, Abbas Z, Costa AS, Gras V, Tiffin-Richards F, Mirzazade S, Holschbach B, Frank RD, Vassiliadou A, Kruger T, Eitner F, Gross T, Schulz JB, Floege J, Shah NJ. Increased cerebral water content in hemodialysis patients. PLoS One. 2015;10(3):e0122188.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Reetz K, Dogan I, Hilgers RD, Giunti P, Mariotti C, Durr A, Boesch S, Klopstock T, de Rivera FJ, Schols L, Klockgether T, Burk K, Rai M, Pandolfo M, Schulz JB, EFACTS Study Group. Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study. Lancet Neurol. 2016;15(13):1346–54.

    Article  PubMed  Google Scholar 

  13. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ, G. Chamber Quantification Writing Group, American Society of Echocardiography’s Guidelines and Standards Committee, European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440–63.

    Article  PubMed  Google Scholar 

  14. Foppa M, Duncan BB, Rohde LE. Echocardiography-based left ventricular mass estimation. How should we define hypertrophy. Cardiovasc Ultrasound. 2005;3:17.

    Article  PubMed  PubMed Central  Google Scholar 

  15. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33(14):1787–847.

    Article  PubMed  Google Scholar 

  16. Henry WL, Gardin JM, Ware JH. Echocardiographic measurements in normal subjects from infancy to old age. Circulation. 1980;62(5):1054–61.

    CAS  Article  PubMed  Google Scholar 

  17. Weidemann F, Rummey C, Bijnens B, Stork S, Jasaityte R, Dhooge J, Baltabaeva A, Sutherland G, Schulz JB, Meier T, Mitochondrial Protection with Idebenone in Cardiac or Neurological Outcome (MICONOS) Study Group. The heart in Friedreich ataxia: definition of cardiomyopathy, disease severity, and correlation with neurological symptoms. Circulation. 2012;125(13):1626–34.

    Article  PubMed  Google Scholar 

  18. Kipps A, Alexander M, Colan SD, Gauvreau K, Smoot L, Crawford L, Darras BT, Blume ED. The longitudinal course of cardiomyopathy in Friedreich’s ataxia during childhood. Pediatr Cardiol. 2009;30(3):306–10.

    Article  PubMed  Google Scholar 

  19. McCormick A, Shinnick J, Schadt K, Rodriguez R, Addonizio L, Hirano M, Perlman S, Lin KY, Lynch DR. Cardiac transplantation in Friedreich ataxia: extended follow-up. J Neurol Sci. 2017;375:471–3.

    Article  PubMed  Google Scholar 

  20. Long A, Napierala JS, Polak U, Hauser L, Koeppen AH, Lynch DR, Napierala M. Somatic instability of the expanded GAA repeats in Friedreich’s ataxia. PLoS One. 2017;12(12):e0189990.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB, Clinical Management Guidelines Writing Group. Consensus clinical management guidelines for Friedreich ataxia. Orphanet J Rare Dis. 2014;9:184.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dedobbeleer C, Rai M, Donal E, Pandolfo M, Unger P. Normal left ventricular ejection fraction and mass but subclinical myocardial dysfunction in patients with Friedreich’s ataxia. Eur Heart J Cardiovasc Imaging. 2012;13(4):346–52.

    Article  PubMed  Google Scholar 

  23. St John Sutton M, Ky B, Regner SR, Schadt K, Plappert T, He J, D’souza B, Lynch DR. Longitudinal strain in Friedreich ataxia: a potential marker for early left ventricular dysfunction. Echocardiography. 2014;31(1):50–7.

    Article  PubMed  Google Scholar 

  24. Adabag AS, Maron BJ, Appelbaum E, Harrigan CJ, Buros JL, Gibson CM, Lesser JR, Hanna CA, Udelson JE, Manning WJ, Maron MS. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol. 2008;51(14):1369–74.

    Article  PubMed  Google Scholar 

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The authors would like to thank all patients who participated in the study. Special thanks go to Sandra Benaich and Fabien Lesne, who helped with data handling, and Rachel Peat, for English editing.

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Correspondence to Francoise Pousset.

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This study was supported by FP7 (7th Framework Programme) Grant HEALTH-F2-2010-242193 from the European Commission.

Conflict of interest

Lise Legrand, Abdourahmane Diallo, Marie-Lorraine Monin, Claire Ewenczyk, Perrine Charles, Richard Isnard, Eric Vicaut, Gilles Montalescot, Alexandra Durr, and Francoise Pousset declare that they have no potential conflicts of interest that might be relevant to this work.

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Legrand, L., Diallo, A., Monin, ML. et al. Predictors of Left Ventricular Dysfunction in Friedreich’s Ataxia in a 16-Year Observational Study. Am J Cardiovasc Drugs 20, 209–216 (2020).

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