MMACHC c.609G>A纯合变异cblC型甲基丙二酸血症合并同型半胱氨酸尿症患者的表型差异  

Factors affecting phenotypes in the patients with MMACHC gene c.609G>A homozygous variant cblC type methylmalonic acidemia combined with homocysteinuria

作　　者：贺薷萱 莫若 张尧[1] 沈鸣 康路路 陈哲晖 刘怡 宋金青[1] 张宏武[6] 姚红新 刘玉鹏[7] 董慧[1] 金颖[1] 李梦秋 秦炯[7] 郑宏[8] 陈永兴 卫海燕[9] 李东晓 李溪远 郑荣秀[12] 张会丰[13] 黄敏 张春燕[3] 姜玉武[1] 梁德生[15] 田亚平[3] 杨艳玲[1] He Ruxuan;Mo Ruo;Zhang Yao;Shen Ming;Kang Lulu;Chen Zhehui;Liu Yi;Song Jinqing;Zhang Hongwu;Yao Hongxin;Liu Yupeng;Dong Hui;Jin Ying;Li Mengqiu;Qin Jiong;Zheng Hong;Chen Yongxing;Wei Haiyan;Li Dongxiao;Li Xiyuan;Zheng Rongxiu;Zhang Huifeng;Huang Min;Zhang Chunyan;Jiang Yuwu;Liang Desheng;Tian Yaping;Yang Yanling(Department of Pediatrics,Peking University First Hospital,Beijing 100034,China;Department of Pediatric,Tsinghua Changgung Hospital,Beijing 102218,China;Translational Medicine Laboratory,Chinese People’s Liberation Army General Hospital,Beijing 100045,China;Department of Pediatrics,the First Affiliated Hospital of Zhengzhou University,Zhengzhou,Henan 450052,China;Clinical Laboratory,China-Japan Friendship Hospital,Beijing 100029,China;Department of Pediatric Surgery,Peking University First Hospital,Beijing 100034,China;Department of Pediatrics,Peking University People’s Hospital,Beijing 100044,China;Department of Pediatrics,First Affiliated Hospital of Henan University of Traditional Chinese Medicine,Zhengzhou,Henan 450000,China;Department of Endocrinology and Inherited Metabolic,Henan Children’s Hospital,Zhengzhou,Henan 450000,China;Department of Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases,Children’s Hospital Affiliated to Zhengzhou University,Zhengzhou,Henan 450003,China;Precision Medicine Center,General Hospital of Tianjin Medical University,Tianjin 300020,China;Department of Pediatrics,General Hospital,Tianjin Medical University,Tianjin 300052,China;Department of Pediatrics,Hebei Medical University Second Hospital,Shijiazhuang,Hebei 050000,China;Similan Clinic,Beijing 100703,China;Center for Medical Genetics,School of Life Sciences,Central South University,Changsha,Hunan 430074,China)

机构地区：[1]北京大学第一医院儿科,北京100034 [2]北京清华长庚医院儿科,北京102218 [3]中国人民解放军总医院转化医学实验室,北京100045 [4]郑州大学第一附属医院小儿内科,郑州450000 [5]中日友好医院检验科,北京100029 [6]北京大学第一医院儿外科,北京100034 [7]北京大学人民医院儿科,北京100044 [8]河南中医药大学第一附属医院儿科,郑州450000 [9]郑州大学附属儿童医院内分泌遗传代谢科,郑州450000 [10]郑州大学附属儿童医院遗传代谢性疾病重点实验室,郑州450000 [11]天津医科大学总医院精准医学中心,天津300020 [12]天津医科大学总医院儿科,天津300052 [13]河北医科大学第二医院儿科,石家庄050000 [14]北京福佑龙惠专科门诊部,北京100703 [15]中南大学生命科学学院医学遗传学研究中心,长沙430074

出　　处：《中华医学遗传学杂志》2022年第6期565-570,共6页Chinese Journal of Medical Genetics

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

摘　　要：探讨MMACHC c.609G>A纯合变异cblC型甲基丙二酸血症合并同型半胱氨酸尿症患者的复杂表型差异,分析可能的影响因素。方法回顾性研究1998年1月至2020年12月就诊的164例MMACHC c.609G>A纯合变异cblC型甲基丙二酸血症合并同型半胱氨酸尿症患者,经生化及基因分析确诊,对临床表现、并发症、治疗和预后情况进行分析。结果164例MMACHC c.609G>A纯合变异cblC型患者中,2例为胎儿期诊断,日龄1天时开始治疗,现3岁和12岁,智力运动发育正常。21例经新生儿筛查发现,其中15例于生后2周无症状时开始治疗,发育正常;6例于1~3个月发病后开始治疗,发育落后。141例为发病后临床诊断,于出生后数分钟到6岁发病,其中早发型110例(78.0%),晚发型31例(22.0%)。5例患者死亡,24例失访。在发病后临床诊断的患者中,130例(92.2%)发育迟滞,69例(48.9%)合并癫痫,39例(27.7%)贫血,30例(21.3%)视力损伤,27例(19.1%)合并脑积水,26例(18.4%)喂养困难,7例(5.0%)肝损害,5例(3.5%)合并代谢综合征。早发型中癫痫和脑积水发生率高,晚发型多因发育迟滞就诊。合并癫痫的患者尿甲基丙二酸浓度明显升高。在长期随访中,癫痫未控制组患者的血浆总同型半胱氨酸水平显著高于癫痫控制组,差异有统计学意义(P<0.05)。结论MMACHC c.609G>A纯合变异所致cblC型患者多为早发型,致死及致残率很高。如未能及时获得症状前治疗,多数患者发生神经系统损害,导致癫痫、智力运动落后、脑积水及多脏器损害。早期诊断和及时规范化的治疗是避免脑损害的关键。新生儿筛查和产前诊断是改善预后的关键。Objective To investigate the factors affecting phenotypes in the patients of methylmalonic acidemia combined with homocysteinemia cblC type with MMACHC c.609G>A homologous variant.Methods A retrospective study on the clinical manifestations,complications,treatment,and outcome in 164patients of cblC type with MMACHC c.609G>A homologous variant was conducted.The patients were diagnosed by biochemical and genetic analysisfrom January 1998 to December 2020.Results Among the 164 patients,2 cases were prenatally diagnosed and began treatment after birth.They are 3 and 12 years old with normal physical and mental development.Twenty-one cases were diagnosed by newborn screening.Among them,15 cases had with normal development.They were treated fromthe age of two weeks at the asymptomatic period.Six cases began treatment aged 1 to 3 months after onset.Their development was delayed.One hundred and forty-one cases were clinically diagnosed.Their onset age ranges from a few minutes after birth to 6 years old.110 cases had early-onset(78.0%).31 cases had late-onset(22.0%).Five of them died.24 patients lost to follow-up.Of the 141 clinically diagnosed patients,130(92.2%)with psychomotor retardation,69(48.9%)with epilepsy,39(27.7%)with anemia,30(21.3%)had visual impairment,27(19.1%)had hydrocephalus,26(18.4%)had feeding difficulties,7(5.0%)with liver damage,and 5(3.5%)with metabolic syndrome.The frequency of hydrocephalus and seizures was significantly higher in the early-onset group.The urinary methylmalonic acid increased significantly in the patients with epilepsy.During the long-term follow-up,the level of plasma total homocysteine in the seizure-uncontrolled group was significantly higher than that in the seizure-controlled group,the difference had a statistical significance(P<0.05).Conclusion Most of the patients with MMACHC c.609G>A homozygous variant had early-onset disease,with a high mortality and disability rate.If not treated in time,it will lead to neurological damage,resulting in epilepsy,mental retardation,hydroce

关 键 词：甲基丙二酸血症 同型半胱氨酸尿症 MMACHC基因 cblC型 c.609G>A纯合变异 

分 类 号：R725.8[医药卫生—儿科]