Schöls L, Amoiridis G, Przuntek H, Frank G, Epplen J T, Epplen C
Department of Neurology, St Josef Hospital, Bochum, Germany.
Brain. 1997 Dec;120 ( Pt 12):2131-40. doi: 10.1093/brain/120.12.2131.
Friedreich's ataxia is an autosomal recessively inherited neurodegenerative disorder caused by expansions of an unstable GAA trinucleotide repeat in the STM7/X25 gene on chromosome 9q. We studied the (GAA)n polymorphism in 178 healthy controls and 102 patients with idiopathic ataxia. The repeat size ranged from 7 to 29 (GAA)n motifs on normal chromosomes and from 66 to 1360 trinucleotide repetitions in Friedreich's ataxia patients. Meiotic instability of expanded alleles was observed without significant differences in maternal and paternal transmissions. Thirty-six of 102 patients were typed homozygous for expanded (GAA)n alleles. Twenty-seven of these presented with the typical Friedreich's ataxia symptoms and nine patients with an atypical Friedreich's ataxia phenotype. Before molecular genetic diagnosis had been performed seven of these patients had been classified as early onset cerebellar ataxia and two as idiopathic sporadic cerebellar ataxia of late onset. In contrast, in one family with typical Friedreich's ataxia phenotype we did not find an expanded allele; this suggests that there can be either point mutations in the X25 gene on both chromosomes or locus heterogeneity in Friedreich's ataxia. The phenotypic spectrum of Friedreich's ataxia is much broader than considered before. Early onset, areflexia, extensor plantar responses and reduced vibration sense should no longer be considered essential diagnostic criteria of Friedreich's ataxia. In comparison with the non-Friedreich's ataxia group hypertrophic cardiomyopathy seems to be the only symptom specific for Friedreich's ataxia. However, it is not obligatory. The phenotype is significantly influenced by the number of GAA repeats with close genotype-phenotype relationships when the smaller of the two alleles is considered. Repeat length correlated inversely with age at onset, onset of dysarthria and progression rate. In conclusion, molecular genetic analysis appears mandatory for the diagnosis and genetic counselling of Friedreich's ataxia. The molecular genetic test should be applied not only to patients with typical Friedreich's ataxia phenotype but also in all cases of idiopathic autosomal recessive or sporadic ataxia.
弗里德赖希共济失调是一种常染色体隐性遗传的神经退行性疾病，由9号染色体长臂上STM7/X25基因中不稳定的GAA三核苷酸重复序列扩增引起。我们研究了178名健康对照者和102名特发性共济失调患者的（GAA）n多态性。正常染色体上的重复序列大小范围为7至29个（GAA）n基序，弗里德赖希共济失调患者的三核苷酸重复序列为66至1360个。观察到扩增等位基因的减数分裂不稳定性，母系和父系传递无显著差异。102名患者中有36名被检测为扩增（GAA）n等位基因纯合子。其中27名表现出典型的弗里德赖希共济失调症状，9名患者表现出非典型的弗里德赖希共济失调表型。在进行分子遗传学诊断之前，这些患者中有7名被归类为早发性小脑共济失调，2名被归类为晚发性特发性散发性小脑共济失调。相反，在一个具有典型弗里德赖希共济失调表型的家族中，我们未发现扩增等位基因；这表明两条染色体上的X25基因可能存在点突变，或者弗里德赖希共济失调存在基因座异质性。弗里德赖希共济失调的表型谱比以前认为的要广泛得多。早发性、无反射、跖伸反应和振动觉减退不应再被视为弗里德赖希共济失调的必要诊断标准。与非弗里德赖希共济失调组相比，肥厚型心肌病似乎是弗里德赖希共济失调唯一的特异性症状。然而，并非必然出现。当考虑两个等位基因中较小的那个时，表型受GAA重复序列数量的显著影响，基因型与表型关系密切。重复长度与发病年龄、构音障碍发作和进展速度呈负相关。总之，分子遗传学分析对于弗里德赖希共济失调的诊断和遗传咨询似乎是必不可少的。分子遗传学检测不仅应应用于具有典型弗里德赖希共济失调表型的患者，也应应用于所有特发性常染色体隐性或散发性共济失调病例。
