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Original Investigation
November 2015

A 22-Year Follow-up Study of Long-term Cardiac Outcome and Predictors of Survival in Friedreich Ataxia

Author Affiliations
  • 1Department of Cardiology, Assistance Publique–Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière Charles-Foix, Paris, France
  • 2Department of Genetics and Cytogenetics, Assistance Publique–Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière Charles-Foix, Paris, France
  • 3Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie, University Paris 06, Unité Mixte de Recherche (UMR) 1127, Institut National de la Santé et de la Récherche Médicale (INSERM) Unité 1127, Centre National de la Recherche Scientifique UMR 7225, Groupe Hospitalier Pitié-Salpêtrière Charles-Foix, Paris, France
  • 4Sorbonne Universités, Université Pierre et Marie Curie, University Paris 06, UMR 1166, INSERM, Paris, France
  • 5Department of Neurology, Université Libre de Bruxelles, Hôpital Erasme, Brussels, Belgium
  • 6Institute for Cardiometabolism and Nutrition, Paris, France
  • 7Sorbonne Universités, Université Pierre et Marie Curie, University Paris 06, UMR 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Paris, France
  • 8INSERM, UMR 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Paris, France
  • 9Biostatistics Unit, Assistance Publique–Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
JAMA Neurol. 2015;72(11):1334-1341. doi:10.1001/jamaneurol.2015.1855
Abstract

Importance  Friedreich ataxia (FRDA) is the most common genetic sensory ataxia, and myocardial involvement is a major determinant of survival.

Objective  To assess FRDA survival and cardiac outcome to adapt future therapeutic trials.

Design, Setting, and Participants  In a longitudinal follow-up study, all patients with genetically confirmed FRDA seen in the reference center and referred for cardiac evaluation (standard 12-lead electrocardiogram and transthoracic echocardiography) to the cardiology department were enrolled and followed up from April 27, 1990, to July 31, 2013. The setting was the French National Reference Center for Rare Diseases and the Department of Cardiology, Salpêtrière University Hospital, Paris, France. In total, 138 patients with FRDA were followed up. Among 133 patients homozygous for expanded GAA repeats, the mean (SD) age was 31 (10) years (age range, 11-62 years), with a mean (SD) age at disease onset of 16 (8) years (age range, 3-50 years) and a mean (SD) age at first wheelchair use of 26 (9) years (age range, 11-64 years). Cardiac hypertrophy was present in 57.9% (77 of 133), and electrocardiography was normal in 6.8% (9 of 133).

Main Outcomes and Measures  Long-term cardiac outcome and predictors of survival in FRDA.

Results  After a mean (SD) follow-up of 10.5 (5.5) years (range, 0.6-23.0 years), the 10-year survival rate was 88.5%. In 80.0% of patients (12 of 15), death was due to cardiac causes. Predictors of survival were a shorter GAA repeat length on the smaller allele of the frataxin gene (hazard ratio [HR], 1.85; 95% CI, 1.28-2.69), left ventricular ejection fraction (HR, 0.42; 95% CI, 0.20-0.89), and left ventricular mass index (HR, 1.19; 95% CI, 1.04-1.36). Two cardiac evolutions were distinguished with a group-based trajectory model, including a low-risk cardiac group (78.6% [81 of 103] with normal ejection fraction at baseline that declined slightly over time but remained within the normal range) and a high-risk cardiac group (21.4% [22 of 103] in which the ejection fraction progressively declined during follow-up). The patients with the worse cardiac evolution had longer GAA repeats. Neurological impairment was not predictive of cardiac change over time.

Conclusions and Relevance  Survival in FRDA is determined by cardiac complications, which are dependent on the mutation (ie, the size of the expanded GAA repeat). Patients with progressive decline of the left ventricular ejection fraction had a worse prognosis. This finding demonstrates that cardiac follow-up is important in FRDA to identify individuals at risk for further cardiac complications.

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