To describe the long-term follow-up and pathogenesis in a child with leukoencephalopathy and cytochrome c oxidase (COX) deficiency due to a novel homozygous nonsense mutation in APOPT1/COA8.

The patient was clinically investigated at 3, 5, 9, and 25 years of age. Brain MRI, repeat muscle biopsies with biochemical, morphologic, and protein expression analyses were performed, and whole-genome sequencing was used for genetic analysis.

Clinical investigation revealed dysarthria, dysphagia, and muscle weakness following pneumonia at age 3 years. There was clinical regression leading to severe loss of ambulation, speech, swallowing, hearing, and vision. The clinical course stabilized after 2.5 years and improved over time. The MRI pattern in the patient demonstrated cavitating leukoencephalopathy, and muscle mitochondrial investigations showed COX deficiency with loss of complex IV subunits and ultrastructural abnormalities. Genetic analysis revealed a novel homozygous mutation in the APOPT1/COA8 gene, c.310T>C; p.(Gln104*).

We describe a novel nonsense mutation in APOPT1/COA8 and provide additional experimental evidence for a COX assembly defect in human muscle causing the complex IV deficiency. The long-term outcome of the disease seems in general to be favorable, and the characteristic MRI pattern with cavitating leukoencephalopathy in combination with COX deficiency should prompt for testing of the APOPT1/COA8 gene.

描述因APOPT1/COA8中新的纯合无义突变导致白质脑病和细胞色素 c 氧化酶 (COX) 缺乏症儿童的长期随访和发病机制。

患者在 3、5、9 和 25 岁时接受了临床调查。进行了脑 MRI、重复肌肉活检以及生化、形态学和蛋白质表达分析，并使用全基因组测序进行遗传分析。

临床调查显示 3 岁时肺炎后出现构音障碍、吞咽困难和肌肉无力。临床消退导致行走、言语、吞咽、听力和视力严重丧失。临床病程在 2.5 年后趋于稳定，并随着时间的推移而改善。患者的 MRI 模式显示空洞性白质脑病，肌肉线粒体检查显示 COX 缺乏伴复杂 IV 亚基丢失和超微结构异常。遗传分析揭示了APOPT1/COA8基因中的一个新的纯合突变，c.310T>C；p.(Gln104*)。

我们描述了APOPT1/COA8中的一种新的无义突变，并为人类肌肉中的 COX 组装缺陷导致复杂的 IV 缺乏提供了额外的实验证据。该疾病的长期结果似乎总体上是有利的，空洞性白质脑病和 COX 缺乏的特征性 MRI 模式应该提示检测APPT1/COA8基因。