Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy with a prevalence of 1 in 2500 individuals worldwide. Here, we report three Turkish siblings from consanguineous parents presenting with a CMT-like phenotype who carry a homozygous c.493C>T, p.Arg165Cys mutation in the FXN gene that is the only known causative gene for Friedreich’s ataxia (FRDA). The identified missense mutation has been reported previously in two FRDA cases in compound heterozygosity with the common GAA repeat expansion in the first intron of the FXN gene. Analysis of skin biopsy samples from our family indicated that the mutation does not affect the expression levels of the frataxin, pointing to functional impairment of the corresponding protein. The CMT phenotype in the siblings was associated with visual impairment, optic nerve atrophy, and dysarthria. To the best of our knowledge, this family represents the first FXN missense mutation in homozygosity and challenges the notion that missense mutations have not been reported yet due to their embryonic lethality. Furthermore, this finding poses an interesting genetic overlap between autosomal recessive CMT and FRDA that we believe may have important implications on understanding the pathogenesis of these neurological disorders.

中文翻译：

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在具有Charcot-Marie-Tooth样表型的近亲土耳其家庭中，FXN基因中的第一个等位基因错义突变。

Charcot-Marie-Tooth（CMT）病是最常见的遗传性神经病，全球2500人中有1人患病。在这里，我们报道了来自三个近亲的土耳其同胞，他们表现出类似于CMT的表型，他们在FXN基因中携带纯合的c.493C> T，p.Arg165Cys突变，这是Friedreich共济失调（FRDA）唯一已知的致病基因。先前已在两个FRDA病例中以复合杂合性报道了已发现的错义突变，在FXN基因的第一个内含子中有共同的GAA重复扩增。对来自我们家庭的皮肤活检样品的分析表明，该突变不影响frataxin的表达水平，表明相应蛋白质的功能受损。兄弟姐妹中的CMT表型与视觉障碍，视神经萎缩和构音障碍有关。据我们所知，该家族代表纯合性中的第一个FXN错义突变，并挑战了由于其胚胎致死性尚未报道错义突变的观念。此外，这一发现在常染色体隐性隐性CMT和FRDA之间引起了有趣的遗传重叠，我们认为这可能对理解这些神经系统疾病的发病机理具有重要意义。