McDaniel D O, Keats B, Vedanarayanan V V, Subramony S H
Department of Surgery, The University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Mov Disord. 2001 Nov;16(6):1153-8. doi: 10.1002/mds.1210.
Friedreich's ataxia, the most common autosomal recessive inherited ataxia, is characterized by progressive gait and limb ataxia. Friedreich's ataxia is known for its occurrence within the first or second decade of life and is associated with hypertrophic cardiomyopathy, and in some cases with diabetes. Genetically, it is identified by the expression of an unstable trinucleotide GAA repeat expansion located in the first intron of the X25 gene on chromosome 9. Two brothers with very late adult-onset ataxia, and their unaffected sister, were examined for the clinical presentation of FA and for the presence of the mutated FA gene. The relationship of the expanded gene sequence to the severity of disease and age of onset were evaluated. Clinical examination revealed that the two brothers had mild ataxia and proprioceptive loss, with age of onset between 60 and 70 years of age. DNA from peripheral blood nucleated cells demonstrated a small homozygous expansion, with approximately 120-130 GAA repeats in the X25 gene in both patients. The expanded repeats were interrupted either with GAAGAG, GAAGGA, or GAAGAAAA sequences. The unaffected sister carried a normal FA genotype with 8-uninterrupted GAA repeat, observed by sequence analysis. In addition, the levels of FA gene transcript in both brothers were relatively lower than that in the unaffected sister. No detectable cardiomyopathy or diabetes was observed. Phenotypic diversity of FA is increasingly expanding. The age of onset and the structure of GAA repeat expansion plays an important role in determining the clinical features and the differential diagnosis of FA. The confirmation of the FA gene mutation in the atypical case, broadens the clinical spectrum of FA, and supports the idea that patients with even a mild form of ataxia of late adult onset should be considered for molecular testing.
弗里德赖希共济失调是最常见的常染色体隐性遗传性共济失调，其特征为进行性步态和肢体共济失调。弗里德赖希共济失调以在生命的第一个或第二个十年内发病而闻名，与肥厚型心肌病相关，在某些情况下还与糖尿病有关。从基因角度来看，它是由位于9号染色体X25基因第一个内含子中的不稳定三核苷酸GAA重复序列扩增所表达的。对两名成年晚期起病的共济失调兄弟及其未受影响的妹妹进行了弗里德赖希共济失调（FA）的临床表现及突变的FA基因检测。评估了扩增的基因序列与疾病严重程度和发病年龄的关系。临床检查发现，这两名兄弟有轻度共济失调和本体感觉丧失，发病年龄在60至70岁之间。外周血有核细胞的DNA显示出小的纯合扩增，两名患者的X25基因中均有大约120 - 13 GAA重复序列。扩增的重复序列被GAAGAG、GAAGGA或GAAGAAAA序列打断。通过序列分析观察到，未受影响的妹妹携带正常的FA基因型，有8个不间断的GAA重复序列。此外，两名兄弟中FA基因转录本的水平相对低于未受影响的妹妹。未观察到可检测到的心肌病或糖尿病。FA的表型多样性正在不断扩大。发病年龄和GAA重复序列扩增的结构在确定FA的临床特征和鉴别诊断中起着重要作用。非典型病例中FA基因突变的证实拓宽了FA的临床谱，并支持这样一种观点，即即使是轻度成年晚期起病的共济失调患者也应考虑进行分子检测。
