The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich's ataxia

Abstract.

Friedreich's ataxia is an autosomal recessive disorder characterized by spinocerebellar degeneration. It is caused by an unstable GAA trinucleotide repeat expansion (>120 repeats) in the first intron of the frataxin gene on chromosome 9 (9q13) in both alleles. Concentric left ventricular hypertrophy has been recognized as the major cardiac manifestation of Friedreich's ataxia. Our aim was to investigate the influence of the frataxin repeat length on cardiac hypertrophy in patients with Friedreich's ataxia and in patients with hypertrophic and dilated cardiomyopathy. Thirty-one patients with Friedreich's ataxia, 86 patients with hypertrophic cardiomyopathy, 134 patients with dilated cardiomyopathy, and 32 healthy individuals without cardiac disease were analysed by electrocardiography and 2D-M-mode echocardiography. Then, the size of the frataxin repeat was determined by polymerase chain reaction (PCR) and agarose gel electrophoresis. The number of GAA repeats in patients with hypertrophic and dilated cardiomyopathy was not different from the length in patients without cardiac disease (hypertrophic cardiomyopathy, 8±2 repeats on GAA1 allele and 11±5 repeats on GAA 2 allele; dilated cardiomyopathy, 7±2 repeats on GAA1 allele and 11±5 repeats on GAA 2 allele; Control, 9±1 repeats on GAA 1 allele and 12±6 repeats on GAA 2 allele). The septal and posterior wall thickness of these patients was not related to the GAA repeat length. All patients with Friedreich's ataxia had two enlarged alleles with a mean GAA repeat length of 757±316 and 1012±231, respectively. The lengths of both alleles were significantly greater than the lengths in the controls (P<0.0001), patients with hypertrophic cardiomyopathy (P<0.0001) and dilated cardiomyopathy (P<0.0001). A significant correlation was revealed between interventricular septal hypertrophy and frataxin repeat length in the smaller allele. Furthermore, the ratio of septal to posterior wall thickness was significantly correlated to GAA repeat size on the smaller allele. In conclusion, the size of the GAA repeat on the smaller allele in the frataxin gene is associated with the degree of left ventricular hypertrophy in patients with Friedreich's ataxia but is not related to the severity of hypertrophic cardiomyopathy.