Marked variation in the cardiomyopathy associated with Friedreich's ataxia

Abstract

Objective: To document the cardiac phenotype associated with Friedreich's ataxia, a recessively inherited disorder characterised by spinocerebellar degeneration.

Setting: Individuals with Friedreich's ataxia who accepted the invitation to participate in the study.

Hypothesis: The cardiomyopathy associated with Friedreich's ataxia may offer a human model for the study of factors modulating cardiac hypertrophy.

Methods: 55 patients (mean (SD) age 30 (9) years) with a clinical diagnosis of Friedreich's ataxia were studied by clinical examination, electrocardiography, cross sectional and Doppler echocardiography, and analysis of the GAA repeat in the first intron of the frataxin gene.

Results: A wide variety of cardiac morphology was documented. Subjects with normal frataxin alleles had no evidence of cardiomyopathy. In homozygous subjects, a relation was found between the thickness of the interventricular septum (r = 0.53, p < 0.005), left ventricular mass (r = 0.48, p < 0.01), and the number of GAA repeats on the smaller allele of the frataxin gene. No relation was shown between the presence of electrocardiographic abnormalities (mainly repolarisation changes) and either the pattern of ventricular hypertrophy (if present) and degree of neurological disability or the length of time since diagnosis. No tendency to ventricular thinning or dilatation with age was found. Although ventricular systolic function appeared impaired in some cases, Doppler studies of ventricular filling were within the normal range for age.

Conclusions: The cardiomyopathy associated with Friedreich's ataxia shows a variable phenotype which is not concordant with the presence of ECG abnormalities or the neurological features of the condition. As the genetic basis for Friedreich's ataxia has been established, further studies will help to clarify the molecular mechanisms of the cardiac hypertrophy.

Figure 1

Twelve lead electrocardiogram from an 18 year old patient with Friedreich's ataxia (800 and 1160 GAA repeats on the frataxin alleles), showing inferolateral T wave and deep S waves in the septal leads.

Figure 2

Parasternal long axis echocardiogram of the patient whose ECG is shown in fig 1, illustrating hypertrophy of the proximal interventricular septum (14.2 mm) and normal dimensions of the left ventricle (LV) and atrium (LA), aorta (AO), and right ventricular outflow (RVO).

Figure 3

Relation between (A) the thickness of the interventricular septum (in diastole, r = 0.53, p < 0.005), and (B) left ventricular (LV) mass (r = 0.48, p < 0.01) and the number of GAA repeats on the smaller allele of the frataxin gene in the 45 subjects homozygous for the GAA expansion. The 95% confidence intervals are shown by the dotted lines.