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World J Cardiol. Jan 26, 2019; 11(1): 1-12
Published online Jan 26, 2019. doi: 10.4330/wjc.v11.i1.1
Heart disease in Friedreich’s ataxia
Emily Hanson, Mark Sheldon, Brenda Pacheco, Mohammed Alkubeysi, Veena Raizada
Emily Hanson, Mark Sheldon, Brenda Pacheco, Mohammed Alkubeysi, Veena Raizada, Department of Internal Medicine, Cardiology Section, University of New Mexico, Albuquerque, NM 87106, United States
Author contributions: Hanson E wrote the manuscript; Sheldon M, Pacheco B and Alkubeysi M contributed to the aim of the manuscript and the diagnostic process of the case study used in the manuscript; Raizada V contributed to writing and editing of the manuscript and is the corresponding author.
Conflict-of-interest statement: There are no conflicts of interest to report.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Veena Raizada, MD, Doctor, Professor, Department of Internal Medicine, Cardiology Section, University of New Mexico, 2211 Lomas Blvd NE, Albuquerque, NM 87131, United States. vraizada@salud.unm.edu
Telephone: +1-404-8230602
Received: November 14, 2018
Peer-review started: November 14, 2018
First decision: November 29, 2018
Revised: December 11, 2018
Accepted: January 5, 2019
Article in press: January 6, 2019
Published online: January 26, 2019
Abstract

Friedreich’s ataxia (FRDA), which occurs in 1/50000 live births, is the most prevalent inherited neuromuscular disorder. Nearly all FRDA patients develop cardiomyopathy at some point in their lives. The clinical manifestations of FRDA include ataxia of the limbs and trunk, dysarthria, diabetes mellitus, and cardiac diseases. However, the broad clinical spectrum makes FRDA difficult to identify. The diagnosis of FRDA is based on the presence of suspicious clinical factors, the use of the Harding criteria and, more recently, the use of genetic testing for identifying the expansion of a triplet nucleotide sequence. FRDA is linked to a defect in the mitochondrial protein frataxin; an epigenetic alteration interferes with the folding of this protein, causing a relative deficiency of frataxin in affected patients. Frataxins are small essential proteins whose deficiency causes a range of metabolic disturbances, including oxidative stress, iron-sulfur cluster deficits, and defects in heme synthesis, sulfur amino acid metabolism, energy metabolism, stress responses, and mitochondrial function. The cardiac involvement seen in FRDA is a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. The walls of the left ventricle become thickened, and different phenotypic manifestations are seen, including concentric or asymmetric hypertrophy and (less commonly) dilated cardiomyopathy. Dilated cardiomyopathy and arrhythmia are associated with mortality in patients with FRDA, whereas hypertrophic cardiomyopathy is not. Systolic function tends to be low-normal in FRDA patients, with an acute decline at the end of life. However, the literature includes only a few long-term prospective studies of cardiac progression in FRDA, and the cause of death is often attributed to heart failure and arrhythmia postmortem. Cardiomyopathy tends to be correlated with the clinical neurologic age of onset and the nucleotide triplet repeat length (i.e., markers of phenotypic disease severity) rather than the duration of disease or the severity of neurologic symptoms. As most patients are wheelchair-bound within 15 years of diagnosis, the clinical determination of cardiac involvement is often complicated by comorbidities. Researchers are currently testing targeted therapies for FRDA, and a centralized database, patient registry, and natural history study have been launched to support these clinical trials. The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in FRDA patients and then introduces gene-targeted and pathology-specific therapies as well as screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.

Keywords: Friedreich’s ataxia, Mitochondrial disorder, Nonischemic cardiomyopathy, Cardiac disease

Core tip: The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in Friedreich’s Ataxia, and introduces gene-targeted and pathology-specific therapies, in addition to the screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.