314例单纯型甲基丙二酸血症的临床表型和基因型研究  

The phenotypes and genotypes in 314 patients with isolated methylmalonic acidemia

作　　者：康路路 刘玉鹏[2] 沈鸣 陈哲晖 宋金青[1] 贺薷萱 刘怡 张尧[1] 董慧[1] 李梦秋 金颖[1] 郑宏[5] 王峤[6] 丁圆 李溪远 李东晓 李海霞[9] 刘雪芹[1] 肖慧捷[1] 姜玉武[1] 熊晖[1] 张春燕[3] 王朝霞[10] 袁云[10] 梁德生[11] 田亚平[3] 杨艳玲[1] Kang Lulu;Liu Yupeng;Shen Ming;Chen Zhehui;Song Jinqing;He Ruxuan;Liu Yi;Zhang Yao;Dong Hui;Li Mengqiu;Jin Ying;Zheng Hong;Wang Qiao;Ding Yuan;Li Xiyuan;Li Dongxiao;Li Haixia;Liu Xueqin;Xiao Huijie;Jiang Yuivu;Xiong Hui;Zhang Chunyan;Wang Zhaoxia;Yuan Yun;Liang Desheng;Tian Yaping;Yang Yanling(Department of Pediatrics,Peking University First Hospital,Beijing 100034,China;Department of Pediatrics,Peking University People's Hospital,Beijing 100044.China;Translational Medicine Laboratory,Chinese People's Liberation Army General Hospital,Beijing 100045,China;Clinical Laboratory,China-Japan Friendship Hospital,Beijing 100029,China;Department of Pediatrics,First Affiliated Hospital of Henan University of Traditional Chinese Medicine,Zhengzhou 450000,China;Department of Endocrinology and Genetic Beijing Children's Hospital,Capital Medical University,Beijing 100045,China;Precision Medicine Center,General Hospital of Tianjin Medical University,Tianjin 300020,China;Department of Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases,Children1 s Hospital Affiliated to Zhengzhou University,Zhengzhou 450003,China;Clinical Laboratory,Peking University First Hospital,Beijing 100034,China;Depart merit of Neurology,Peking University First Hospital,Beijing 100034,China;Center for Medical Genetics,School of Life Sciences,Central South University,Changsha 430074,China)

机构地区：[1]北京大学第一医院儿科,100034 [2]北京大学人民医院儿科,100044 [3]解放军总医院转化医学实验室,北京100045 [4]中日友好医院检验科,北京100029 [5]河南中医药大学第一附属医院儿科,郑州450000 [6]首都医科大学附属北京儿童医院内分泌遗传代谢科,100045 [7]天津医科大学总医院精准医学中心,300020 [8]郑州大学附属儿童医院遗传代谢性疾病重点实验室,450003 [9]北京大学第一医院检验科,100034 [10]北京大学第一医院神经内科,100034 [11]中南大学生命科学学院医学遗传学研究中心,长沙430074

出　　处：《中华儿科杂志》2020年第6期468-475,共8页Chinese Journal of Pediatrics

基　　金：国家重点研发计划(2016YFC0905102、2017YFC1001700、2019YFC1005100);国家自然科学基金(81471097);北京市科技计划(BZ0317、Z151100003915126)。

摘　　要：目的总结单纯型甲基丙二酸血症的临床表型及分子遗传学特点,探讨诊断、治疗及预防对策。方法回顾性收集我国26个省市1998年1月至2020年3月确诊的单纯型甲基丙二酸血症患儿314例(男180例、女134例),采用Sanger测序、靶向捕获二代测序或者全外显子测序分析、多重连接依赖探针扩增技术、定量PCR等技术进行基因诊断。根据发病年龄,分为早发型(发病年龄≤12月龄)和晚发型(发病年龄>12月龄)。根据个体情况,给予钴胺素、左卡尼汀、特殊饮食及对症治疗。采用χ2检验进行组间比较。结果314例单纯型甲基丙二酸血症患儿中58例(18.5%)通过液相串联质谱法新生儿筛查发现,5例(1.6%)为尸检确诊,251例(79.9%)患儿为发病后临床诊断。发病年龄为3小时龄~18岁,其中早发型159例(71.0%),晚发型65例(29.0%)。较常见的临床表现是代谢危象、智力运动落后、癫痫、贫血和多脏器损伤。早发型较晚发型患儿代谢性酸中毒及贫血常见[20.8%(33/159)比9.2%(6/65),34.6%(55/159)比16.9%(11/65),χ^2=4.261、6.930,P=0.039、0.008]。236例(75.2%)接受了基因分析,227例(96.2%)获得了基因诊断,在7个基因(MMUT、MMAA、MMAB、MMADHC、SUCLG1、SUCLA2、MCEE)上共发现127个变异,其中49个为新变异。MMUT变异导致的甲基丙二酰辅酶A变位酶缺乏(mut型)211例(93.0%),常见的MMUT变异是c.729_730insTT、c.1106G>A、c.914T>C。c.914T>C在早发型中发生的频率较晚发型高[8.3%(18/216)比1.6%(1/64),χ^2=3.859,P=0.037]。mut型较其他类型患儿代谢危象常见[72.6%(114/157)比3/13,χ^2=13.729,P=0.001]。发育落后、肌张力低下在mut型患儿中比其他类型患儿少见[38.2%(60/157)比9/13、25.5%(40/157)比8/13,χ^2=4.789、7.705,P=0.030、0.006]。58例新生儿筛查发现的患儿中44例(75.9%)从无症状时开始治疗,发育正常;14例(24.1%)临床发病后才开始接受治疗,遗留有不同程度的智力、运动发育落后。结论分析了我国�Objectives To summarize the clinical and genetic characteristics of the patients with isolated methylmalonic acidemia and investigate the strategies for the diagnosis,treatment and prevention.Methods Three hundred and fourteen patients(180 males,134 females)with isolated methylmalonic acidemia were ascertained from 26 provinces or cities across the mainland of China during January 1998 to March 2020.Genetic analysis was performed by Sanger sequencing,gene panel sequencing,whole exome sequencing,multiplex ligation-dependent probe amplification or quantitative PCR.According to the age of onset,the patients were divided to early-onset group(≤12 months of age)and the late-onset group(>12 months of age).They were treated by cobalamin,L-carnitine and(or)special diet and symptomatic treatment.Statistical analysis was done using Chi-square test.Results Fifty-eight of 314(18.5%)patients were detected by Newborn screening using liquid chromatography tandem mass spectrometry.Five cases(1.6%)had a postmortem diagnosis.Two hundred and fifty-one patients(79.9%)were clinically diagnosed with an age of onset ranged from 3 hours after birth to 18 years.One hundred and fifty-nine patients(71.0%)belonged to early-onset groups,65 patients(29.0%)belonged to the late-onset group.The most common symptoms were metabolic crises,psychomotor retardation,epilepsy,anemia and multiple organ damage.Metabolic acidosis and anemia were more common in early-onset patients than that in late-onset patients(20.8%(33/159)vs.9.2%(6/65),34.6%(55/159)vs.16.9%(11/165),χ2=4.261,6.930,P=0.039,0.008).Genetic tests were performed for 236 patients(75.2%),96.2%(227/236)had molecular confirmation.One hundred and twenty-seven variants were identified in seven genes(MMUT,MMAA,MMAB,MMADHC,SUCLG1,SUCLA2,and MCEE),of which 49 were novel.The mut type,caused by the deficiency of methylmalonyl-CoA mutase,was the most common(n=211,93%)cause of this condition.c.729_730insTT,c.1106G>A and c.914T>C were the three most frequent mutations in MMUT gene.The frequency of c.91

关 键 词：甲基丙二酸 甲基丙二酸单酰CoA变位酶 新生儿筛查 串联质谱法 

分 类 号：R725.8[医药卫生—儿科]