The heart in Friedreich's Ataxia: Basic findings and clinical implications

Abstract

Friedreich’s Ataxia is the most common inherited ataxia in man. It is a mitochondrial disease caused by severely reduced expression of the iron binding protein, frataxin. A large GAA triplet expansion in the human FRDA gene encoding this protein inhibits expression of this gene. It is inherited in an autosomal recessive pattern and typically diagnosed in childhood. The primary symptoms include severe and progressive neuropathy, and a hypertrophic cardiomyopathy that may cause death. The cardiomyopathy is difficult to treat and is frequently associated with arrhythmias, heart failure, and intolerance of cardiovascular stress, such as surgeries. Innovative approaches to therapy, such as histone deacetylase inhibitors, and enzyme replacement with cell penetrant peptide fusion proteins, hold promise for this and other similar mitochondrial disorders. This review will focus on the basic findings of this disease, and the cardiomyopathy associated with its diagnosis.

The Progression of Cardiomyopathy in the Mitochondrial Disease, Friedreich’s Ataxia

“…Analysis of hearts from the FA knockout animals have also shown higher apoptosis counts than the age-matched wild-type mice, which is evidence for ongoing cardiomyocyte loss (Payne 2011). In addition, the use of apoptosis inhibitors is able to improve the viability of frataxin-deficient cells in vitro (Wong et al 1999).…”

“…Patients are often found with left ventricular hypertrophy which can progress to the more fatal dilated cardiomyopathy, and adequate systolic function is usually maintained until shortly before death (Puccio et al 2001;Papanikolaou and Pantopoulos 2005;Payne 2011). Both ventricles are affected, and arrhythmias of atrial origin are common and important in determining the prognosis of the patient, as they are indicative of left ventricular dysfunction (Santos et al 2010;Bourke and Keane 2011).…”

“…Both ventricles are affected, and arrhythmias of atrial origin are common and important in determining the prognosis of the patient, as they are indicative of left ventricular dysfunction (Santos et al 2010;Bourke and Keane 2011). Microscopically, it has been found that cardiomyocyte hypertrophy, focal necrosis and diffuse fibrosis occur in the left ventricle (Payne 2011).…”

“…Moreover, a significant decrease in myocardial energy generation was shown to correlate with the degree of hypertrophy (Payne 2011). Accordingly, short term studies have shown that the use of idebenone has been successful in improving myocardial energy deficiency and decreasing hypertrophy (Rustin et al 1999;Payne 2011).…”

“…Accordingly, short term studies have shown that the use of idebenone has been successful in improving myocardial energy deficiency and decreasing hypertrophy (Rustin et al 1999;Payne 2011). However, longer term studies have failed to show a decrease in arrhythmias or progression of heart failure (Payne 2011;Velasco-Sánchez et al 2011). Another possible treatment method for cardiomyopathy in FA is cardiac transplants.…”