720例甲基丙二酸血症MMACHC基因c.609G>A突变患者临床特征及随访分析  

Clinical features and outcomes of patients with cblC type methylmalonic acidemia carrying MMACHC gene c.609G>A mutation

作　　者：于玥 凌诗颖 帅瑞雪 邱文娟[1] 张惠文[1] 梁黎黎[1] 季文君[1] 刘宇超 顾学范[1] 韩连书[1] YU Yue;LING Shiying;SHUAI Ruixue;QIU Wenjuan;ZHANG Huiwen;LIANG Lili;JIWenjun;LIU Yuchao;GU Xuefan;HAN Lianshu(Department of Pediatric Endocrino�logy and Genetic Metabolism,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai Institute for Pediatric Research,Shanghai 200092,China)

机构地区：[1]上海交通大学医学院附属新华医院上海市儿科医学研究所小儿内分泌遗传代谢科,上海200092

出　　处：《浙江大学学报（医学版）》2021年第4期436-443,共8页Journal of Zhejiang University(Medical Sciences)

基　　金：国家重点研发计划(2016YFC0901505)。

摘　　要：目的:分析携带MMACHC基因c.609G>A(p.W203X)突变的cblC型甲基丙二酸血症(MMA)患者的临床表现、治疗效果、预后及影响因素。方法:回顾性分析2007至2020年在上海交通大学医学院附属新华医院就诊的720例携带c.609G>A突变的cblC型MMA患者的临床及实验室检查资料。根据基因突变位点不同将患者分为三组,携带c.609G>A纯合突变的患者为A组(172例);携带c.609G>A与c.482G>A(p.R161Q)、c.80A>G(p.Q27R)及c.394C>T(p.R132X)中任一突变形成的复合杂合突变患者为B组(169例);携带c.609G>A与上述突变位点以外突变[如c.658_660delAAG(p.K220del)、c.315A>T(p.Y105X)、c.567dupT(p.I190fs*13)]的复合杂合突变患者为C组(379例)。对不同基因突变位点患者的临床表现,血酰基肉碱、血同型半胱氨酸、尿有机酸水平以及治疗效果进行比较,根据随访结果采用logistic回归分析患者预后的影响因素。结果:720例患者中306例(42.5%)来自新生儿筛查,其中156例发病;414例未进行新生儿筛查的患者中10例因同胞确诊后诊断(临床未发病),其余404例均为临床发病病例。560例发病患者中,发病年龄中位数为1.2个月(3 d~20岁)。B组发病年龄晚于A组和C组,三组间发病年龄差异有统计学意义(P<0.01)。患者临床症状各异,1岁以内发病患者多表现为呕吐、腹泻、喂养困难及抽搐,1岁以后发病患者多以运动障碍及智力落后为主要表现。肾脏疾病起病的患者均携带c.80A>G或c.482G>A突变,伴有肺动脉高压的患者均携带c.80A>G突变。长期随访患者621例,其中预后正常156例(25.1%),落后433例(69.7%),死亡32例(5.2%)。剔除失访、死亡及资料缺失的患者,对559例患者的预后影响因素进行logistic回归分析,结果显示新生儿筛查与否、发病与否、发病年龄及基因突变位点对预后的影响有统计学意义(P<0.05或P<0.01)。结论:MMACHC基因c.609G>A突变与早发型MMA相关,患者多于出生后1个月内起病。维生�Objective:To explore the clinical features and long-term outcomes of patients with cblC type methylmalonic acidemia(MMA)carrying c.609G>A(p.W203X)mutation of MMACHC gene.Methods:The clinical and laboratory findings of 720 patients with MMA carrying the c.609G>A mutation were retrospectively analyzed.There were 172 cases carrying homozygous mutations of c.609G>A(group A),169 cases carrying compound heterozygous mutations of c.609G>A with c.482G>A(p.R161Q),c.80A>G(p.Q27R)or c.394C>T(p.R132X)(group B),and 379 cases carrying compound heterozygous mutations of c.609G>A with c.658_660delAAG(p.K220del),c.315A>T(p.Y105X)or c.567dupT(p.I190fs*13)(group C).The clinical manifestations,the level of blood acylcarnitine,homocysteine and urinary organic acid,and the therapeutic efficacy were compared among groups.Logistic regression was used to analyze the factors influencing the prognosis of patients.Results:There were 306 patients(42.5%)detected from newborn screening,including 156 cases with disease onset;and 414 patients were not detected from the screening,among whom 10 cases were diagnosed by testing after the sibling confirmed,and the remaining 404 were clinical cases.In 560 patients with disease onset,the median onset age is 1.2 months(3 days to 20 years).The onset age of patients in group B was later than that in group A and group C(P<0.01).Patients aged<1 year mostly manifested as vomiting,diarrhea,feeding difficulties and convulsions,while those aged>1 year mostly manifested as movement disorders and mental retardation.Patients with renal disease all carried mutations of c.80A>G or c.482G>A,and patients with pulmonary hypertension all carried c.80A>G mutations.A total of 621 cases had long-term follow-up,156 cases(25.1%)developed well,433 cases(69.7%)had development delay and 32 cases(5.2%)died.The available data of 559 cases were analyzed by logistic regression,and the results showed that the neonatal screening,disease onset,age of onset and gene mutation site were significantly associated with the prognosis of pati

关 键 词：新生儿筛查 甲基丙二酸血症 MMACHC基因 钴胺素C缺乏 预后 影响因素 

分 类 号：R725.8[医药卫生—儿科]