新生儿甲基丙二酸血症的筛查与基因突变分析  

Screening and gene mutations analysis for neonates with methylmalonic aciduria

作　　者：王秀利 顾茂胜 周伟 杨丹艳 武娇 Wang Xiuli;Gu Maosheng;Zhou Wei;Yang Danyan;Wu Jiao(Screening Center for Neonatal Diseases,Xuzhou Maternity and Child Health Care Hospital,Xuzhou 221009,China)

机构地区：[1]徐州市妇幼保健院新生儿疾病筛查中心,221009

出　　处：《中华围产医学杂志》2018年第8期541-550,共10页Chinese Journal of Perinatal Medicine

基　　金：徐州市科技项目（KC16SH073）

摘　　要：目的 探讨甲基丙二酸血症（methylmalonic aciduria,MMA）患儿的临床表现、生化检查、基因突变特点及治疗随访. 方法 利用液相色谱串联质谱技术对徐州市2016年1月至2017年12月出生的207 308例新生儿进行酰基肉碱谱筛查,结合气相色谱质谱技术检测尿有机酸及二代基因测序技术进行确诊.单纯型MMA患儿给予饮食控制及左卡尼汀治疗,MMA合并同型半胱氨酸血症（简称合并型MMA）患儿给予维生素B12、左卡尼汀、甜菜碱及亚叶酸钙治疗.对确诊患儿的临床表现、生化检查、影像学异常、基因突变特点及治疗预后进行分析.采用配对样本t检验对患儿治疗前后的生化指标进行比较. 结果 共确诊12例MMA患儿,其中单纯型MMA3例,均为维生素B12无效型,确诊时均无任何临床症状;合并型MMA 9例,均为维生素B12有效型,其中4例确诊时均无任何临床症状,5例确诊前已发病,主要表现为反应差、反复呕吐、喂养困难、呼吸困难、贫血、黄疸等.12例均行头颅MRI,异常表现为双侧基底节对称性病变、脑外间隙增宽、脑室扩张及脑白质改变.12例患儿均进行基因突变分析,其中MUT基因突变3例,MMA CHC基因突变9例.MUT基因突变类型共5种,分别为c.ll06G＞A、c.1880A＞G、c.441T＞A、c.581C＞T、c.1741C＞T.MMA CHC基因突变类型共8种,分别为c.609G＞A、c.658_660delAAG、c.482G＞A、c.1A＞G、c.567dupT、c.80A＞G、c.276＋lG＞A、c.228_231delTGAC,其中c.609G＞A为最常见的基因突变,c.276＋lG＞A和c.228_23 ldelTGAC为新突变.3例单纯型MMA患儿中,1例因家长拒绝治疗而死亡;2例治疗1个月后血丙酰肉碱、丙酰肉碱与乙酰肉碱比值、同型半胱氨酸及尿甲基丙二酸、甲基枸橼酸水平明显下降,随访过程中l例生长发育正常,1例生长发育迟缓.9例合并型MMA患儿治疗1个月后血丙酰肉碱、丙酰肉碱与乙酰肉碱比值、同型半胱氨酸及尿甲基丙二酸、甲基枸橼酸水平[Objective To investigate the characteristics of neonatal methylmalonic aciduria （MMA）regarding clinical manifestations,laboratory findings,gene mutations,treatments and prognosis.Methods Acylcamitine levels in blood samples of 207 308 neonates born from January 2016 to December 2017 in Xuzhou were detected by liquid chromatography tandem mass spectrometry and the abnormal results were further confirmed by detecting organic acids in urine samples with gas chromatography-mass spectrometry and gene sequencing analysis.Patients with isolated MMA were treated with dietary control and levocarnitine,while those complicated by homocysteinemia were treated with vitamin B12,levocarnitine,glycine betaine and calcium folinate.Clinical manifestations,laboratory findings,imaging features,genotypes,treatments and prognosis of patients with MMA were retrospectively analyzed.Paired sample t-test was applied for statistical analysis.Results MMA was eventually diagnosed in 12 patients,among which three were isolated MMA and nine were complicated by homocysteinemia.The three isolated MMA cases failed to response to vitamin B12 treatment without any symptoms on diagnosis.However,vitamin B12 was effective for the other nine patients,among which four had no clinical symptoms on diagnosis and five had manifestations such as slow response,recurrent vomiting,poor feeding,dyspnea,anemia and jaundice.Abnormal results of cranial MRI included bilateral basal ganglia damage,enlarged extracranial space,ventriculomegaly and changes in white matter.All patients underwent genetic analysis and three were found with MUT gene mutations and nine with MMACHC gene mutations.MUT gene mutations were classified into five types,including c.I106G〉A,c.1880A〉G,c.441T〉A,c.581C〉T and c.1741C〉T.Eight types of MMACHC gene mutations were identified,including c.609G〉A,c.658_660delAAG,c.482G〉A,c.1A〉G,c.567dupT,c.80A〉G,c.276＋1G〉A and c.228_23 l delTGAC.Two mutations,c.276＋lG〉A and c.228 23 ldelTGAC,were novel mutations.The most common mut

关 键 词：氨基酸代谢障碍 先天性 载体蛋白质类 甲基丙二酸单酰CoA变位酶 突变 色谱法 液相 串联质谱法 

分 类 号：R722.1[医药卫生—儿科]