甲基丙二酸血症合并同型半胱氨酸尿症导致脑积水76例诊断和治疗分析  

Clinical and genetic studies on 76 patients with hydrocephalus caused by methylmalonic acidemia combined with homocysteinuria

作　　者：贺薷萱 董慧[1] 张宏武[2] 张尧[1] 康路路 李辉[2] 沈鸣 莫若 宋金青[1] 刘玉鹏[5] 陈哲晖 刘怡 金颖[1] 李梦秋 郑宏[7] 李东晓 秦炯[5] 张会丰[9] 黄敏 郑荣秀[11] 梁德生[12] 田亚平[4] 姚红新[2] 杨艳玲[1] He Ruxuan;Dong Hui;Zhang Hongwu;Zhang Yao;Kang Lulu;Li Hui;Shen Ming;Mo Ruo;Song Jinqing;Liu Yupeng;Chen Zhehui;Liu Yi;Jin Ying;Li Mengqiu;Zheng Hong;Li Dongxiao;Qin Jiong;Zhang Huifeng;Huang Min;Zheng Rongxiu;Liang Desheng;Tian Yaping;Yao Hongxin;Yang Yanling(Department of Pediatrics,Peking University First Hospital,Beijing 100034,China;Department of Pediatric Surgery,Peking University First Hospital,Beijing 100034,China;Department of Pediatrics,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China;Translational Medicine Laboratory,Chinese People’s Liberation Army General Hospital,Beijing 100045,China;Department of Pediatrics,Peking University People's Hospital,Beijing 100044,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 Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases,Children^Hospital Affiliated to Zhengzhou University,Zhengzhou 450003,China;Department of Pediatrics,Hebei Medical University Second Hospital,Shijiazhuang 050000,China;Similan Clinic,Beijing 100703,China;Department of Pediatrics,General Hospital,Tianjin Medical University,Tianjin 300052,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]北京大学第一医院小儿外科,100034 [3]郑州大学第一附属医院小儿内科,450052 [4]解放军总医院转化医学实验室,北京100045 [5]北京大学人民医院儿科,100044 [6]中曰友好医院检验科,北京100029 [7]河南中医药大学第一附属医院儿科,郑州450000 [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]河北医科大学第二医院儿科,石家庄050000 [10]北京福佑龙惠遗传病诊所,100703 [11]天津医科大学总医院儿科,300052 [12]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》2021年第6期459-465,共7页Chinese Journal of Pediatrics

基　　金：国家重点研发计划(2016YFC0905102,2017YFC1001700,2019YFC1005100)。

摘　　要：目的探讨甲基丙二酸血症合并同型半胱氨酸尿症引起脑积水患儿的临床特征、遗传学特点以及诊疗和防控策略。方法回顾性分析1998年1月至2020年12月于北京大学第一医院等11家医院诊治的甲基丙二酸血症合并同型半胱氨酸尿症继发脑积水的76例患儿,经过生化、影像及基因分析确诊,根据是否接受脑室-腹腔分流术治疗分为手术组与非手术组。对其临床特征、实验室检查、基因变异类型、治疗随访情况进行分析。组间比较采用秩和检验或χ^(2)检验。结果76例患儿中男51例、女25例,新生儿筛查发现5例,71例为发病后临床诊断;早发型(发病年龄≤1岁)68例(96%),晚发型(发病年龄>1岁)3例(4%)。其中74例患儿资料齐全,主要临床表现为智力、运动落后74例(100%)、视力障碍74例(100%)、癫痫44例(59%)、贫血31例(42%)、肌张力低下或肌张力增高21例(28%)、喂养困难19例(26%)和意识障碍17例(23%)。76例患儿均为MMACHC基因缺陷,其中MMACHC c.609G>A纯合变异30例(39%)。最常见的变异为c.609G>A[94次(62.7%)],然后依次为c.658_660del[18次(12.0%)]、c.567dupT[9次(6.0%)]和c.217C>T[8次(5.3%)]。诊断后采用钴胺素注射,补充左卡尼汀、甜菜碱。41例手术组与31例非手术组的起病年龄、确诊年龄、血总同型半胱氨酸、血蛋氨酸及尿液甲基丙二酸浓度差异均无统计学意义(均P>0.05)。41例手术组患儿术后长期随访,智力及运动落后、癫痫、视力障碍等症状逐渐好转。结论甲基丙二酸血症合并同型半胱氨酸尿症引起脑积水常见临床表现为智力及运动发育落后、视力障碍、癫痫等神经系统损伤,主要见于早发型cblC型,最常见的MMACHC基因致病变异为c.609G>A,部分患儿脑积水在代谢干预治疗后好转,对于严重脑积水,需及时进行脑室-腹腔分流术治疗,以改善预后。Objective To analyze the clinical features,genetic characteristics,treatment and follow-up results of patients with hydrocephalus caused by methylmalonic acidemia combined with homocysteinuria,and to discuss the optimal strategies for assessing and treating such patients.Methods From January 1998 to December 2020,76 patients with hydrocephalus due to methylmalonic acidemia combined with homocysteinuria in the Department of Pediatrics in 11 hospitals including Peking University First Hospital were diagnosed by biochemical,genetic analysis and brain imaging examination.The patients were divided into operation-group and non-operation-group according to whether they underwent ventriculoperitoneal shunt.The clinical features,laboratory examinations,genotype,and follow-up data were retrospectively analyzed.Data were compared between the two groups using rank sum test,and categorical data were compared usingχ^(2) test.Results Among the 76 patients(51 male,25 female),5 were detected by newborn screening,while 71 were diagnosed after clinical onset,68 cases(96%)had early-onset,3 cases(4%)had late-onset.The most common clinical manifestations of 74 cases with complete data were psychomotor retardation in 74 cases(100%),visual impairment in 74 cases(100%),epilepsy in 44 cases(59%),anemia in 31 cases(42%),hypotonia or hypertonia in 21 cases(28%),feeding difficulties in 19 cases(26%)and disturbance of consciousness in 17 cases(23%).Genetic analysis was performed in 76 cases,all of whom had MMACHC gene variations,including 30 homozygous variations of MMACHC c.609G>A.The most common variations were c.609G>A(94,62.7%),followed by c.658_660del(18,12.0%),c.567dupT(9,6.0%)and c.217C>T(8,5.3%).Therapy including cobalamin intramuscular injection,L-carnitine and betaine were initiated immediately after diagnosis.A ventriculoperitoneal shunt operation was performed in 41 cases(operation group),and 31 patients improved after metabolic intervention(non-operation group).There was no significant difference in the age of onset,the age of d

关 键 词：甲基丙二酸 高同型半胱氨酸血症 脑积水 脑室腹膜分流术 

分 类 号：R589[医药卫生—内分泌]