儿童Leigh综合征的临床分析及 PDHA1基因变异功能初步研究  

Clinical analysis of Leigh syndrome in children and preliminary study of the function of PDHA1 mutant genes

作　　者：林婷 王珏[2,3] Lin Ting;Wang Jue(Department of Pediatrics,Fujian Provincial Government Hospital,Fuzhou 350001,China;Shengli Clinical Medical College of Fujian Medical University,Fuzhou 350001,China;Department of Pediatrics,Fujian Provincial Hospital,Fuzhou 350001,China)

机构地区：[1]福建省级机关医院儿科,福州350001 [2]福建医科大学省立临床学院,福州350001 [3]福建省立医院儿科,福州350001

出　　处：《国际遗传学杂志》2023年第6期413-420,共8页International Journal of Genetics

基　　金：福建省自然科学基金(2021J01371)。

摘　　要：目的回顾性分析儿童Leigh综合征(Leigh syndrome, LS)的临床及分子遗传学特点。方法收集2012年9月至2021年5月于福建省立医院儿科确诊为LS的9例患儿的临床资料及基因检测等结果进行分析和总结;同时利用计算机软件预测基因PDHA1(c.124G>A)变异型蛋白的三维结构, 对比野生型和变异型结构, 评估PDHA1基因变异对蛋白质结构的影响。结果 9例LS患儿男5例, 女4例, 中位起病年龄10个月;主要表现为精神运动发育迟缓或倒退、癫痫发作、喂养困难、营养不良、呼吸异常、听力异常等;颅脑MRI提示病变仅累及脑干4例, 其中2例病变进展并累及基底节或丘脑;基底节和小脑同时受累2例, 1例同时累及脑干、大脑皮层及乳头体;脑萎缩和脑积水各1例。核基因变异2例, 线粒体基因变异7例;与野生型PDHA1蛋白结构对比, 变异型PDHA1蛋白侧链结构发生变化。结论 LS具有显著的临床和遗传异质性;本文报道了LS可导致乳头体病变;报道2例核DNA(nDNA)变异, 分别是SDHA基因复合杂合变异(c. 393C>G;c. 448G>A)和PDHA1基因变异(c. 124G>A);对PDHA1基因变异进行蛋白结构功能预测, 发现此变异导致蛋白质侧链发生变化。Objective The clinical characteristics and molecular genetic analysis of Leigh syndrome in children were analyzed retrospectively.Methods The clinical date and genetic testing of 9 children diagnosed with LS from September 2012 to May 2021 in the pediatric department of Fujian Provincial Hospital were collected,and analyzed and summarized.Meanwhile,we used the computer software predicted 3 D structure of the mutation-type protein in the gene PDHA1(c.124G>A),and compared the wild-type to mutant type,assessed the effect of the mutations on the protein structure.Results In 9 cases,5 boys and 4 girls,the median onset age was 10 months.They mainly presented psychomotor development delayed or backward,epileptic seizure,feeding difficulties,malnutrition,abnormal breathing,abnormal muscular tension,etc.Brain MRI suggested that the lesions involved only brain stem in 4 cases,and 2 cases of them showed progression of brain stem lesions and involvement of basal ganglia or thalamus;the lesion involved both the basal ganglia and the cerebellum in 2 cases;involved brain stem,cerebral cortex and mammillary body involvement in 1 case;brain atrophy and hydrocephalus were each in one case.Two cases had nDNA mutations,and seven cases had mtDNA mutations.In contrast with the wild-type PDHA1 protein structure,large structural changes the protein side chain in mutant type PDHA1.Conclusions LS has significant clinical and genetic heterogeneity.This study reports that LS can cause mammillary body lesions;Two cases of nDNA mutation were reported for the first time,namely SDHA gene compound heterozygous mutation(c.393C>G;c.448G>A)and PDHA1 mutations(c.124G>A);It is the first time to predict the protein structure function of PDHA1 gene mutation,and it is found that this mutation causes the change of protein side chain.So the possible pathogenic variant PDHA1(c.124G>A)mutation could corrected to pathogenic variant.

关 键 词：LEIGH综合征 临床特征 PDHA1基因 SDHA基因 

分 类 号：R725.9[医药卫生—儿科]