15例甲基丙二酸血症患儿临床特征和基因突变分析  

Clinical features and gene mutations in 15 children with methylmalonic acidemia

作　　者：董昭樱[1] 王朝 黄金月[2] 舒剑波[2] 蔡春泉[2] 李东[3] DONG Zhao-ying;WANG Chao;HUANG Jin-yue;SHU Jian-bo;CAI Chun-quan;LI Dong(Department of Neurology,Tianjin People's Hospital,Tianjin 300121,China;Tianjin Pediatric Research Institute,Tianjin Key Laboratory of Birth Defects for Prevention and Treatment,Tianjin Children's Hospital,Children's Hospital of Tianjin University,Tianjin 300074,China;Department of Neurology,Tianjin Children's Hospital,Children's Hospital of Tianjin University,Tianjin 300074,China)

机构地区：[1]天津市人民医院神经内科,天津300121 [2]天津市儿童医院·天津大学儿童医院天津市儿科研究所天津市儿童出生缺陷防治重点实验室,天津300074 [3]天津市儿童医院·天津大学儿童医院神经内科,天津300074

出　　处：《生物医学工程与临床》2021年第5期611-616,共6页Biomedical Engineering and Clinical Medicine

基　　金：国家自然科学基金资助项目(81771589);天津市重大疾病防治科技重大专项基金资助项目(18ZXDBSY00170);天津市卫生健康科技项目(ZC20120);天津市卫生健康科技项目(KJ20039)。

摘　　要：目的分析15例甲基丙二酸血症(MMA)患儿临床特征和基因突变,为家系遗传咨询、产前诊断和新生儿筛查提供依据。方法选择15例先证者MMA患儿,其中男性7例,女性8例;年龄63 h~11岁,中位年龄2岁;cblC型12例(1个月~11岁,中位年龄1岁6个月),mut型3例(年龄63 h、3 d和3岁)。分析其临床资料。应用液相色谱和串联质谱技术对患儿尿液和血液代谢物进行筛查,应用Sanger测序方法结合高通量测序对患儿家系进行相关基因检测和分析。结果15例MMA患儿临床表现各异,累及全身多系统,常见临床表型主要为癫痫、水电解质紊乱、贫血、粒细胞缺乏和呼吸性/代谢性酸中毒等。在12例cblC型患儿钴胺素代谢相关C基因(MMACHC)中共检测出8种基因突变,包括7种错义突变和1种缺失突变,其中最常见的为c.658-660delAAG、c.609G>A和c.80A>G,分别占25%(6/24)、20.83%(5/24)和20.83%(5/24)。在3例mut型患儿甲基丙二酰辅酶A变位酶基因(MUT)中共检测出5种基因突变,包括3种错义突变、2种剪接位点突变。结论MMA亚型cblC型与表型存在一定相关性,mut型临床表现比cblC型更为严重。该研究结果丰富了MMA相关基因突变谱,为遗传咨询、产前诊断和新生儿筛查提供了依据。Objective To analyze the clinical features and genetic mutation of children with methylmalonic academia(MMA),and provide evidence for family genetic counseling,prenatal diagnosis and neonatal screening.Methods A total of 15 cases of children with MMA were enrolled,which included 7 males and 8 females,aged 63 hours-11 years old with median age of2 years old.There were 12 cases of cblC type(1 month to 11 years old with median age of 1 year and 6 months)and 3 cases of mut type(63 hours,3 days and 3 years old).The clinical data was analyzed,the liquid chromatography and tandem mass spectrometry were used to screen metabolites in urine and blood.Sanger sequencing combined with next-generation sequencing was used to detect and analyze the related genes in pedigree.Results The clinical manifestations of the 15 children with MMA were different,which involved multiple systems,and including epilepsy,electrolyte disorders,anemia,agranulocytosis and respiratory/metabolic acidosis.Eight kinds of gene mutations were detected in metabolism of cobalamin associated C gene(MMACHC)of 12 cases with cblC type,which included 7 missense mutations and 1 deletion mutation.The most common mutations were c.658-660 delAAG,c.609 G>A and c.80 A>G,accounted for 25%(6/24),20.83%(5/24)and 20.83%(5/24),respectively.Five kinds of gene mutations were detected in methylmalonyl-CoA mutase gene(MUT)of 3 cases with mut,which included 3 missense mutations and 2 splicesite mutations.Conclusion It is demonstrated that there is a certain correlation between MMA subtype cblC type and phenotype.The clinical manifestation of mut type is more serious than that of cblC type,which enriches MMArelated gene mutation spectrum and provides the basis for genetic counseling,prenatal diagnosis and newborn screening.

关 键 词：甲基丙二酸血症(MMA) 钴胺素代谢相关C基因(MMACHC) 甲基丙二酰辅酶A变位酶基因(MUT) cblC型 mut型 基因表型 基因型 儿童 

分 类 号：R725.8[医药卫生—儿科] Q344[医药卫生—临床医学]