Recessive mutations in the mitochondrial copper-binding protein SCO2, cytochrome c oxidase (COX) assembly protein, have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency. Significantly expanding the known phenotypic spectrum, we identified compound heterozygous variants in SCO2 in two unrelated patients with axonal polyneuropathy, also known as Charcot-Marie-Tooth disease type 4. Different from previously described cases, our patients developed predominantly motor neuropathy, they survived infancy, and they have not yet developed the cardiomyopathy that causes death in early infancy in reported patients. Both of our patients harbour missense mutations near the conserved copper-binding motif (CXXXC), including the common pathogenic variant E140K and a novel change D135G. In addition, each patient carries a second mutation located at the same loop region, resulting in compound heterozygote changes E140K/P169T and D135G/R171Q. Patient fibroblasts showed reduced levels of SCO2, decreased copper levels and COX deficiency. Given that another Charcot-Marie-Tooth disease gene, ATP7A, is a known copper transporter, our findings further underline the relevance of copper metabolism in Charcot-Marie-Tooth disease.

中文翻译：

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SCO2突变会导致与细胞铜缺乏有关的早发性轴索性Charcot-Marie-Tooth病

线粒体铜结合蛋白SCO2，细胞色素c氧化酶（COX）组装蛋白的隐性突变已在几例患有COX缺乏的致命性婴儿性脑脊髓病的病例中报道。显着扩展了已知的表型谱，我们确定了SCO2中的化合物杂合变异体在两名不相关的轴索性多发性神经病患者中，也称为4型Charcot-Marie-Tooth疾病。与先前描述的病例不同，我们的患者主要发展为运动神经病，在婴儿期幸存下来，尚未发展出可导致早期死亡的心肌病。报告患者的婴儿期。我们的两名患者均在保守的铜结合基序（CXXXC）附近怀有错义突变，包括常见的致病变异E140K和新的D135G。另外，每位患者在同一环区域携带第二个突变，导致复合杂合子改变E140K / P169T和D135G / R171Q。患者成纤维细胞显示SCO2水平降低，铜水平降低和COX缺乏症。考虑到另一个Charcot-Marie-Tooth病基因ATP7A，是一种已知的铜转运蛋白，我们的发现进一步强调了铜代谢与Charcot-Marie-Tooth病的相关性。