Heart disease in Friedreich’s ataxia

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.

Stress-Induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy

“…9,11,[13][14][15][16]30,31 Despite this, for most of the early clinical course, the cardiac manifestations remain subclinical as exogenous stress is limited due to the inactivity associated with the neurologic disease, limiting oxygen demands. 1,7,8,11,14,32,33 These limited energy demands limit the stress on the heart and the cardiacassociated clinical sequelae are typically delayed. 9,15 In this context, we hypothesized that assessment of new therapies directed at FA-associated cardiac disease would benefit from an animal model that reconstitutes the mild For (A, B), shown is the mean and standard error of percent change with dobutamine-induced stress from the resting state.…”

“…A substantial number of patients with FA develop severe cardiomyopathy and 60% of patients die from cardiac causes, typically in the third to fourth decade. 11,33,34 There is a correlation between the GAA repeat number and the onset and severity of clinical symptoms with higher repeat numbers signaling an earlier onset and more severe cardiomyopathy. 13,14,30,32,35 The cardiomyopathy associated with FA is characterized by arrhythmias, heart failure, and intolerance of cardiovascular stress, such as surgery.…”

“…Histologically, the LV myocardium is commonly moderately to severely hypertrophied and has a high degree of fibrosis and cardiomyocyte loss at the time of death. 1,33,34,36,37 To date, despite trials of antioxidant and iron chelation therapies, there is no effective therapy for the cardiac manifestations of FA. 10,38,39 Models of FA cardiac disease…”

Molecular Defects in Friedreich’s Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities

“…Cardiomyopathy is the most common cause of death in FRDA patients (∼59%) and typically occurs after two decades of disease progression ( Tsou et al, 2011 ). Cardiomyopathy includes fibrosis of cardiac wall tissue at later disease stages with thickening of the left ventricle wall ( Hanson et al, 2019 ). Patients often succumb to disease due to resulting arrhythmia and dilated cardiomyopathy ( Casazza and Morpurgo, 1996 ; Kipps et al, 2009 ).…”

Molecular and Cellular Substrates for the Friedreich Ataxia. Significance of Contactin Expression and of Antioxidant Administration

“…The corresponding tissue alteration affects sensory as well as spino-cerebellar functions [ 2 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ] and, as such, it results in an ataxic phenotype [ 9 , 14 , 15 , 16 ]. Due to concomitant myocardiocyte damage, neurological symptoms are associated with a cardiovascular phenotype [ 4 , 5 , 17 , 18 , 19 ], resulting in ventricular failure. The neural and the cardiovascular phenotypes share a common pathogenic mechanism, based on the evidence that FA is a mitochondrial disorder, affecting at the same time the nervous and the hearth tissue [ 6 , 12 , 20 , 21 , 22 , 23 ] as a consequence of the mutation of the gene encoding the mitochondrial protein Frataxin [ 24 ].…”