Bit-Avragim N, Perrot A, Schöls L, Hardt C, Kreuz F R, Zühlke C, Bubel S, Laccone F, Vogel H P, Dietz R, Osterziel K J
Charité/Franz-Volhard Clinic at the Max-Delbrück Centre for Molecular Medicine, Humboldt University Berlin, Germany. bit_avragim@fvk-berlin-de
J Mol Med (Berl). 2001;78(11):626-32. doi: 10.1007/s001090000162.
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 GAA 1 allele and 11+/-5 repeats on GAA 2 allele; dilated cardiomyopathy, 7+/-2 repeats on GAA 1 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.
弗里德赖希共济失调是一种常染色体隐性疾病，其特征为脊髓小脑变性。它由位于9号染色体（9q13）上的frataxin基因第一内含子中的不稳定GAA三核苷酸重复序列扩增（>120次重复）引起，且两个等位基因均如此。同心性左心室肥厚已被确认为弗里德赖希共济失调的主要心脏表现。我们的目的是研究frataxin重复序列长度对弗里德赖希共济失调患者以及肥厚型和扩张型心肌病患者心脏肥厚的影响。通过心电图和二维M型超声心动图对31例弗里德赖希共济失调患者、86例肥厚型心肌病患者、134例扩张型心肌病患者以及32名无心脏病的健康个体进行了分析。然后，通过聚合酶链反应（PCR）和琼脂糖凝胶电泳确定frataxin重复序列的大小。肥厚型和扩张型心肌病患者的GAA重复次数与无心脏病患者的长度无差异（肥厚型心肌病，GAA 1等位基因上为8±2次重复，GAA 2等位基因上为11±5次重复；扩张型心肌病，GAA 1等位基因上为7±2次重复，GAA 2等位基因上为11±5次重复；对照组，GAA 1等位基因上为9±1次重复，GAA 2等位基因上为12±6次重复）。这些患者的室间隔和后壁厚度与GAA重复序列长度无关。所有弗里德赖希共济失调患者均有两个扩增的等位基因，其平均GAA重复序列长度分别为757±316和1012±231。两个等位基因的长度均显著大于对照组（P<0.0001）、肥厚型心肌病患者（P<0.0001）和扩张型心肌病患者（P<0.0001）。在较小的等位基因中，室间隔肥厚与frataxin重复序列长度之间存在显著相关性。此外，室间隔与后壁厚度之比与较小等位基因上的GAA重复序列大小显著相关。总之，frataxin基因中较小等位基因上的GAA重复序列大小与弗里德赖希共济失调患者的左心室肥厚程度相关，但与肥厚型心肌病的严重程度无关。
