儿童MELAS线粒体基因突变异质性水平与临床特征的关系

ASSOCIATION OF HETEROGENEITY LEVEL OF MITOCHONDRIAL MELAS MUTATION WITH CLINICAL FEATURES IN CHILDREN

目的探讨儿童线粒体脑肌病伴乳酸血症和卒中样发作(MELAS)线粒体基因A3243G点突变异质性水平与临床特征的关系,以期为尽早明确MELAS临床诊断及临床遗传咨询提供依据。方法研究对象为临沂市人民医院收治的7例MELAS病儿及其家系。回顾性分析病儿的临床表现、实验室检查、线粒体位点点突变检测结果,并根据相关文献报道分析遗传的异质性及阈效应。结果7例病儿中6例以抽搐为首发症状,1例以头痛、呕吐起病;伴体型瘦小者7例,多毛6例,发热4例,视力障碍3例,智力运动发育落后1例。7例病儿血乳酸水平均升高(5.52~12.00 mmol/L)。7例病儿颅脑MRI均示顶、枕、颞叶异常信号,不符合解剖学血管支配分布。脑电图特点以背景活动慢化为主,1例部分性发作起始部位与颅脑影像学病变部位有高度相关性。7例线粒体脑肌病致病基因均为MT-TL 1基因A3243G突变,其中2例为双胞胎兄弟,先症者基因明确诊断后其胞弟基因明确。MELAS病儿A3243G突变率与血乳酸水平呈正相关(r=0.89,P<0.01),与起病年龄呈负相关(r=-0.84,P<0.05)。结论早期筛查家系以及基因检测有助于MELAS的诊断,病儿A3243G突变率高低可能与起病年龄、血乳酸水平存在相关性。

Objective To investigate the association of the heterogeneity level of mitochondrial gene A3243G mutation with clinical features in children with mitochondrial encephalopathy,lactic acidosis,and stroke-like episodes(MELAS),and to provide evidence for early clinical diagnosis of MELAS and clinical genetic counseling.Methods Seven children with MELAS who were admitted to Linyi People’s Hospital and their family members were enrolled as subjects,and a retrospective analysis was performed for their clinical data including clinical manifestations,laboratory findings,and mitochondrial gene point mutations.Related articles were reviewed to analyze the genetic heterogeneity and threshold effect.Results Of all 7 children,6 had convulsion as the initial symptom,and 1 had headache and vomiting at disease onset;of all children,7 had a lean body type,6 had excessive hairiness,4 had pyrexia,3 had visual impairment,and 1 had intellectual and motor developmental delay.All 7 children had an increase in blood lactate level(5.52-12.00 mmol/L).Brain MRI showed abnormal signals in the parietal,occipital,and temporal lobes in all children,which did not correspond to anatomic vascular distribution.Slow background activity was the main feature of electroencephalography,and 1 child showed high correlation between the location of origin of partial episodes and the location of lesions on brain imaging.The MT-TL 1 gene with A3243G mutation was the pathogenic gene for mitochondrial encephalopathy in all 7 children,among whom 2 were twin brothers,and the gene mutation was clarified in the younger bother after a confirmed diagnosis was made based on gene detection in the elder bother.In the children with MELAS,A3243G mutation rate was positively correlated with blood lactate level(r=0.89,P<0.01)and was negatively correlated with onset age(r=-0.84,P<0.05).Conclusion Early screening of pedigrees and gene detection may help with the diagnosis of MELAS,and A3243G mutation rate may be correlated with onset age and blood lactate level.