Objective: To investigate the clinically and genetic characteristics of children with Leigh syndrome. Method: Patients with clinically diagnosed Leigh syndrome(LS)in the department of Neurology, Beijing Children's Hospital from January 2013 to February 2016 underwent the mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) detecting with next generation sequencing (NGS) technology. The clinical data of gene confirmed cases were retrospectively collected and analyzed. The differences in the onset age, clinical manifestations, lactic acid level and MRI results between the mtDNA variation and nDNA variation were compared and analyzed.t test, Chi-square test and Fisher's exact test were used for statistical analysis. Result: Thirty-five cases were diagnosed by gene detection, including 20 males and 15 females. The median onset age was 1 year (ranging from the neonatal period to 4.4 years old). The age of onset within 2 years accounted for 74%(26 cases). The onset age of initial symptoms, including developmental delay, developmental regression, and seizures, were 6 (4, 12) months, 12 (8, 14) months, and 6 (1, 23) months respectively. The onset age of ptosis, extrapyramidal symptoms and ataxia were 26 (18, 44) months, 28 (23, 40) months and 28 (19, 35) months, respectively. There were significant differences in the onset age between the three groups (H=21.919, P=0.01). Within the 35 cases, 29 were manifested with developmental delay (83%), 26 with dystonia (74%), 18 with growth retardation, 15 with myasthenia, 13 with developmental regression, 11 with dysphagia, 10 with feeding difficulties, 4 with skeletal dysplasia, and 2 with digestive tract symptoms; nystagmus and respiratory abnormalities were observed in 9 cases respectively; extrapyramidal symptoms, peripheral nerve injury, ptosis, seizures were observed in 8 cases respectively; and ataxia, ophthalmoplegia and hypertrichiasis were found in 5 cases respectively.The blood lactic acid was measured in 32 LS patients, within which 23 cases (72%) had increased results; 8 out of 11 cases who underwent were cerebrospinal fluid lactic acid test had increased results. The results of neuroimaging revealed that all the patients were involved in the brainstem and (or) basal ganglia, of whom 27 (77%) had brainstem involvement, 24 (69%) had basal ganglia involvement. Thirteen out of 14 patients who had medulla oblongata involvement had nDNA variation; while 7 out of 8 patients with cerebellar involvement had nDNA variation. Genetic etiology was confirmed in all patients, among whom there were 17 cases (49%) with mtDNA mutation, including 8993T>C/G (n=5), 14487T>C (n=4), 13513G>A (n=2), 9176T>C, 10158T>C, 3697G>A, 10191T>C, 14459A>G and 11777C>A (n=1) respectively. Remaining 18 cases(51%) had nDNA mutation, including SURF1 gene(n=10), PDHA1 gene(n=3) and one case each of NDUFV1, NDUFAF6, NDUFAF5, NDUFS1 and COQ7 genes. In this study, 27 types of mutations were founded, 15 of which had not been previously reported. Respiratory chain gene mutations have been found in 31 cases(89%); 3 cases had PDHc gene mutations, and 1 case had other mutation. Conclusion: LS usually occurs in infants. The most common primary symptoms are age-dependent abnormal movements, ocular symptoms, and seizures. Respiratory chain defects is the most common causes of LS.SURF1 is the most common variation, followed by 8993T>C/G, 14487 T>C and 13513G>A mutation.
目的：了解儿童Leigh综合征(LS)临床和遗传学特征。 方法：对2013至2016年在北京儿童医院神经内科临床诊断LS的患儿，应用靶向基因捕获二代测序(NGS)技术对线粒体基因(mtDNA)组和LS相关的核基因(nDNA)进行测序，对基因确诊病例的临床资料进行回顾性总结。采用t检验、方差分析以及Fisher确切概率检验，对mtDNA和nDNA变异两组发病年龄、临床表现、乳酸和头颅磁共振成像(MRI)进行比较。 结果：经基因确诊LS 35例，其中男20例、女15例。起病年龄为新生儿～4.4岁，中位起病年龄1岁。2岁之内发病26例(74%)。首发症状包括发育落后、发育倒退和抽搐发作，其发生年龄分别为6(4，12)，12(8，14)和6(1，23)月龄；眼睑下垂、椎体外系症状和共济失调发病年龄分别为26(18，44)，28(23，40)和28(19，35)月龄。各首发症状发病年龄差异有统计学意义(H＝21.919，P＝0.01)。35例中临床表现发育落后29例(83%)，肌张力异常26例(74%)，生长落后18例，肌无力15例，发育倒退13例，吞咽困难11例，喂养困难10例，眼球震颤及呼吸异常各9例，锥体外系表现、周围神经损害、眼睑下垂、抽搐各8例，共济失调、眼外肌麻痹和多毛各5例，骨骼发育异常4例，消化道症状2例。32例LS患儿行血乳酸测定，23例(72%)升高，11例行脑脊液乳酸测定，8例升高。头颅磁共振成像(MRI)均累及脑干和(或)基底节区，其中27例(77%)脑干受累，24例(69%)基底节区受累，14例累及延髓，13例为nDNA变异；8例累及小脑，7例为nDNA变异。35例基因变异中mtDNA变异17例(49%)，分别为8993 T>C/G 5例、14487T>C 4例、13513 G>A 2例，9176 T>C、10158 T>C、3697 G>A、10191T>C、14459A>G，11777C>A各1例；nDNA变异18例(51%)，其中SURF1基因10例、PDHA1基因3例、NDUFV1、NDUFAF6、NDUFAF5、NDUFS1和COQ7基因各1例。共发现27种变异类型，15种为新发。涉及呼吸链酶复合物基因变异31例(89%)，丙酮酸脱氢酶复合物(PDHc)变异3例，其他1例。 结论： LS为婴幼儿好发，首发症状主要表现为运动异常、眼部症状和癫痫发作，具有年龄依赖性；呼吸链酶复合物基因变异是LS最常见原因，其中以SURF1最多，其次为8993 T>C/G、14487 T>C与13513 G>A。.
Keywords: Child; Clinical features; Heredity; Leigh disease.