Clinical and genetic abnormalities in patients with Friedreich's ataxia
Clinical and genetic abnormalities in patients with Friedreich's ataxia
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DOI：
10.1056/nejm199610173351601
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发表时间：
1996-10-17
影响因子：
158.5
通讯作者：
Koenig, M
中科院分区：
文献类型：
--
作者：
Durr, A;Cossee, M;Koenig, M
弗里德赖希共济失调是最常见的遗传性共济失调，与9号染色体上fraataxin基因第一个内含子GAA重复序列不稳定扩增有关，该基因编码一种功能未知的蛋白质。方法对187例常染色体隐性共济失调患者进行分析，确定GAA扩增的大小，并分析其临床表现与GAA重复数和病程的关系。结果187例患者中有140例为纯合子，其GAA扩增具有120至1700个重复的三核苷酸，发病年龄在2至51岁之间。大约四分之一的患者，尽管是纯合子，但患有非典型弗里德赖希共济失调；患者就诊时年龄较大，肌腱反射完整。较大的GAA扩张与发病年龄较早和行动能力丧失时间较短相关。GAA扩张的大小（尤其是每对中较小的那对）与心肌病的发生频率和上肢反射丧失有关。GAA重复序列在传播过程中是不稳定的。结论弗里德赖希共济失调的临床谱系比以往认识的更为广泛，9号染色体GAA扩增的直接分子检测对该病的诊断、预后判断和遗传咨询具有重要意义。(C) 1996年，马萨诸塞州医学会。
Background Friedreich's ataxia, the most common inherited ataxia, is associated with a mutation that consists of an unstable expansion of GAA repeats in the first intron of the frataxin gene on chromosome 9, which encodes a protein of unknown function.Methods We studied 187 patients with autosomal recessive ataxia, determined the size of the GAA expansions, and analyzed the clinical manifestations in relation to the number of GAA repeats and the duration of disease.Results One hundred forty of the 187 patients, with ages at onset ranging from 2 to 51 years, were homozygous for a GAA expansion that had 120 to 1700 repeats of the trinucleotides. About one quarter of the patients, despite being homozygous, had atypical Friedreich's ataxia; they were older at presentation and had intact tendon reflexes. Larger GAA expansions correlated with earlier age at onset and shorter times to loss of ambulation. The size of the GAA expansions (and particularly that of the smaller of each pair) was associated with the frequency of cardiomyopathy and loss of reflexes in the upper limbs. The GAA repeats were unstable during transmission.Conclusions The clinical spectrum of Friedreich's ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion on chromosome 9 is useful for diagnosis, determination of prognosis, and genetic counseling. (C) 1996, Massachusetts Medical Society.