探讨线粒体翻译优化因子(MTO)1基因变异，所致常染色体隐性遗传联合氧化磷酸化缺陷症10型(COXPD10)患儿的临床表型和遗传学特征。

选择2022年7月中山市小榄人民医院儿科收治的1例以运动发育迟缓为主诉的COXPD10患儿(患儿1)为研究对象。回顾性分析其临床资料，采用全外显子组测序(WES)对患儿1及其父母进行遗传学分析。根据美国医学遗传学与基因组学学会(ACMG)制定的《序列变异解释的标准和指南》(以下简称为ACMG指南)，对检出变异致病性进行分析。分别以"MTO1基因""联合氧化磷酸化缺陷症10型""复合氧化磷酸化缺陷症10型""COXPD10"，以及"MTO1""combined oxidative phosphorylation deficiency-10""COXPD10"为中、英文关键词，在万方数据知识服务平台、中国知网及Web of Science和PubMed数据库中，检索MTO1基因变异所致COXPD10患儿。文献检索年限设定为各数据库建库至2023年3月。对检索文献中COXPD10患儿MTO1基因变异情况与临床表现等进行复习。本研究遵循的程序符合中山市小榄人民医院医学伦理委员会的规定，并通过该伦理委员会审查及批准(审批文号：ZSXL-ll2023-002)，患儿1监护人签署临床研究知情同意书。

①患儿1为8个月龄女婴。其本次入院相关检查结果显示，Alberta婴儿运动量表(AIMS)评分为18分(低于同龄儿AIMS评分第5百分位数)；头颅MRI检查提示，双侧丘脑、中脑呈对称性片状异常信号，T1加权成像(WI)呈稍低信号，T2WI呈稍高信号，T2-液体衰减反转恢复(FLAIR)呈低信号，扩散加权成像(DWI)呈高信号；心脏彩色多普勒超声检查提示，左心室增大，卵圆孔未闭；血清乳酸浓度为9.39 mmol/L(异常增高)；尿液有机酸分析结果无异常；2022年9月复查尿液有机酸结果显示，尿液有机酸异常增高。其WES检测结果提示，携带MTO1基因c.134G>A(p.Gly45Glu)和c.578C>G(p.Thr193Ser)杂合变异，分别遗传自其父、母亲。这2种变异在万方数据知识服务平台、中国知网、Web of Science、PubMed数据库及基因组聚合数据库(gnomAD)中均未见报道。根据ACMG指南，将这2种变异判断为可能致病性变异(PS4＋PM2＋PM3)。结合临床表现与遗传学检测结果，患儿1被诊断为COXPD10患儿。②文献复习结果：共计纳入MTO1基因变异所致COXPD10患儿相关文献18篇，涉及44例患儿(患儿2～45)，加上患儿1，共计45例COXPD10患儿。这45例患儿中，发生MTO1基因变异30种，分布于10个外显子中，其中8号外显子发生变异最多，为11种，并且均为错义变异；主要临床表现：高乳酸血症(42例，93.3%)，心血管疾病(38例，84.4%)，线粒体复合体缺乏症(34例，75.6%)，发育迟缓(30例，66.7%)等。

MTO1基因c.134G>A(p.Gly45Glu)和c.578C>G(p.Thr193Ser)杂合变异是患儿1的致病原因。本研究丰富了MTO1基因变异所致COXPD10患儿的基因变异谱，为临床诊断、产前诊断COXPD10患儿提供了依据。对于运动发育迟缓、头颅MRI检查结果异常、血清乳酸水平异常增高的患儿，需警惕COXPD10可能，应尽早完善基因检查明确病因。

To explore the clinical phenotype and genetic characteristics of a child with autosomal recessive combined oxidative phosphorylation deficiency type 10 (COXPD10) caused by mitochondrial translation optimization factor (MTO)1 gene variation.

A child with COXPD10 (patient-1) who was admitted to the Department of Pediatrics, Xiaolan People′s Hospital of Zhongshan in July 2022 and complained of delayed motor development was selected as research subject. The clinical data of patient-1 were retrospectively analyzed, and whole-exome sequencing (WES) was used to perform genetic analysis on patient-1 and her parents. The pathogenicity of the detected variants was analyzed in accordance with the Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as the ACMG guideline). Related literature of children with COXPD10 caused by MTO1 gene variation was reviewed with " MTO1 gene" " combined oxidative phosphorylation deficiency type 10" " complex oxidative phosphorylation deficiency type 10" and " COXPD10" both in Chinese and English as keywords in Wanfang Data Knowledge Service Platform, CNKI, Web of Science and PubMed, and search time was set from the inception of each database to March 2023. The MTO1 gene variations and manifestations of COXPD10 children in retrieved literature were reviewed. The procedures followed in this study complied with the regulations of the Medical Ethics Committee of Xiaolan People′s Hospital of Zhongshan, and were reviewed and approved by the ethics committee (Approval No. ZSXL-ll2023-002). The guardian of patient-1 signed the clinical research informed consent form.

①Patient-1 was an 8-month-old girl. The relevant auxiliary examination results of patient-1 at admission showed that the Alberta Infant Motor Scale (AIMS) score was 18 points (lower than the 5th percentile of AIMS scores for children of the same age); the brain MRI showed symmetrical patchy abnormal signals in the bilateral thalamus and midbrain, slightly hypointense on T1-weighted imaging (WI), slightly hyperintense on T2WI, hypointense on T2-fluid-attenuated inversion recovery (FLAIR), and hyperintense on diffusion-weighted imaging (DWI); cardiac color Doppler ultrasound showed that the left ventricle was enlarged and the foramen ovale was patent; the serum lactic acid concentration was 9.39 mmol/L (abnormally increased); the urine organic acid analysis results at admission showed no abnormalities, but in September 2022, the urine organic acid re-examination results showed an abnormal increase. WES test results showed that she carried heterozygous mutations c. 134G>A(p.Gly45Glu) and c. 578C>G(p.Thr193Ser) in MTO1 gene, which inherited from her father and mother, respectively. These two mutations have not been reported in Wanfang Data Knowledge Service Platform, CNKI, Web of Science, PubMed database and Genome Aggregation Database (gnomAD). According to the ACMG guideline, these two variants were judged to be possible pathogenic variants (PS4+ PM2+ PM3). Based on the clinical manifestations and genetic test results, patient-1 was diagnosed as COXPD10. ②Literature review results: a total of 18 pieces of relevant literature on children with COXPD10 caused by MTO1 gene mutations were included, involving 44 cases (patient 2-45), and together with patient-1, a total of 45 children with COXPD10 were included. Among these 45 children, 28 mutations occurred in the MTO1 gene, distributed across 10 exons, and exon 8 had the most mutations, with 11 different types, all of which were missense mutations. The main clinical manifestations: hyperlactatemia (42 cases, 93.3%), cardiovascular diseases (38 cases, 84.4%), mitochondrial complex deficiency (34 cases, 75.6%), developmental delay (30 cases, 66.7%), and so on.

The heterozygous variants of c. 134G>A (p.Gly45Glu) and c. 578C>G (p.Thr193Ser) in MTO1 gene are the causative factors of patient-1. This study enriches the gene variation spectrum of COXPD10 children caused by MTO1 gene variation and provides a basis for clinical diagnosis and prenatal diagnosis of COXPD10 children. For children with delayed motor development, abnormal brain MRI examination results, and abnormally increased serum lactic acid levels, caution should be exercised for the possibility of COXPD10. Early and comprehensive genetic testing is recommended to confirm the cause.