Wang Yanjun, He Juan, Dong Fangling, Shou Weihua, Feng Xingxing, Yang Ya, Li Cuifen, Wang Jingjing, Li Bin, Xiao Shufang
Pediatric Intensive Care Unit, Kunming Children's Hospital, Children's Hospital Affiliated to Kunming Medical University, Kunming, China.
Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming, China.
Heliyon. 2024 Mar 2;10(6):e27199. doi: 10.1016/j.heliyon.2024.e27199. eCollection 2024 Mar 30.
Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) is a rare mitochondrial disease caused by mutations in the gene. The rare incidence of the disease and the high clinical heterogeneity pose challenges in making a precise diagnosis. Investigations into the rare COXPD23 patients are of pathophysiological and etiological value. In this study, we investigated the genotype-phenotype relationship in a COXPD23 patient from a Manchu family, with mutations.
Routine physical examinations, laboratory assays and imaging analyses were performed. The metabolic profiles of amino acids in blood, acylcarnitine in blood and organic acids in urine were used to determine the presence of inherited metabolic diseases. Genetic variations in the family were investigated using whole-exome sequencing and Sanger sequencing. Splicing disruption by a mutation was predicted and verified using a minigene assay.
The patient presented with severe lactic acidosis, neurological symptoms, multiple symmetrical lesions in the brain and serious mitochondrial energy metabolism disturbances. The c.689A > C (p.Q230P) and c.809-1_809delinsA compound heterozygous mutations were detected in . The novel c.809-1_809delinsA mutation was located at the splicing site of exon 7 and intron 6 and multiple tools predicted that it would disrupt the normal splicing. The minigene assay proved that the novel mutation resulted in two aberrant transcripts that created premature termination codons.
The clinical manifestations, brain imaging change, mitochondrial metabolism disturbances and the detection and validation of the mutations expand the profile of COXPD23 and the pathogenic mutation spectrum. Our study improves the understanding of the pathophysiology and etiology of COXPD23.
联合氧化磷酸化缺陷23（COXPD23）是一种由该基因中的突变引起的罕见线粒体疾病。该疾病的罕见发病率和高度的临床异质性给精确诊断带来了挑战。对罕见的COXPD23患者进行研究具有病理生理学和病因学价值。在本研究中，我们调查了一名来自满族家庭且存在突变的COXPD23患者的基因型-表型关系。
进行了常规体格检查、实验室检测和影像学分析。利用血液中氨基酸、血液中酰基肉碱和尿液中有机酸的代谢谱来确定遗传性代谢疾病的存在。使用全外显子测序和桑格测序研究该家庭中的基因变异。使用小基因检测预测并验证突变导致的剪接破坏。
该患者表现为严重乳酸酸中毒、神经症状、脑部多发对称性病变以及严重的线粒体能量代谢紊乱。在该基因中检测到c.689A>C（p.Q230P）和c.809-1_809delinsA复合杂合突变。新的c.809-1_809delinsA突变位于外显子7和内含子6的剪接位点，多种工具预测它会破坏正常剪接。小基因检测证明该新突变导致了两个产生过早终止密码子的异常转录本。
该患者的临床表现、脑影像学改变、线粒体代谢紊乱以及突变的检测和验证扩展了COXPD23的特征和致病突变谱。我们的研究提高了对COXPD23病理生理学和病因学的认识。
