迟发型多种酰基辅酶A脱氢酶缺乏症3例患儿的临床及遗传学分析  

Analysis of clinical features and genetic variants in three children with late-onset Multiple acyl-Coenzyme A dehydrogenase deficiency

作　　者：王梦琴 王曦 马昂 谷裕 赵小桐 张耀东 李东晓 陈永兴 卫海燕[2] Wang Mengqin;Wang Xi;Ma Ang;Gu Yu;Zhao Xiaotong;Zhang Yaodong;Li Dongxiao;Chen Yongxing;Wei Haiyan(Henan Key Laboratory of Genetic and Metabolic Diseases,Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center,Children′s Hospital Affiliated to Zhengzhou University,Zhengzhou,Henan 450018,China;Department of Endocrinology and Genetics and Metabolism,Children′s Hospital Affiliated to Zhengzhou University,Henan Children′s Hospital,Zhengzhou Children′s Hospital,Zhengzhou,Henan 450018,China)

机构地区：[1]郑州大学附属儿童医院,河南省遗传代谢性疾病重点实验室,河南省儿童神经发育工程研究中心,郑州450018 [2]郑州大学附属儿童医院,河南省儿童医院,郑州儿童医院东区内分泌遗传代谢科,郑州450018

出　　处：《中华医学遗传学杂志》2024年第7期790-796,共7页Chinese Journal of Medical Genetics

基　　金：河南省医学科技攻关计划(LHGJ20200613);郑州市科技惠民计划(2022KJHMOOO5)。

摘　　要：目的探讨3例迟发型(Ⅲ型)多种酰基辅酶A脱氢酶缺乏症(MADD)患儿的临床特征和基因变异特点。方法回顾分析2020年3月至2022年3月就诊于郑州大学附属儿童医院的3例迟发型MADD患儿的临床资料。患儿进行全外显子组测序,针对候选变异进行Sanger测序家系验证。对3例患儿进行改善代谢治疗并追踪随访1~3年。结果3例患儿中男2例、女1例,就诊年龄为出生2个月~11岁7个月,例1及例2分别表现为间断呕吐、下肢肌无力,例3为新生儿筛查异常但未发病。3例患儿血串联质谱结果均提示短中长链多种酰基肉碱升高,例1及例2尿气相色谱质谱分析示戊二酸及多种双羧酸升高。3例患儿均检出ETFDH基因复合杂合变异。其中例1携带父源c.1211T>C(p.M404T)变异及母源c.488-22T>G变异,例2携带父源c.1717C>T(p.Q573X)变异及母源c.250G>A(p.A84T)变异,例3携带父源c.1285+1G>A变异及母源c.629A>G(p.S210N)变异。3例患儿均被给予大剂量维生素B2、左卡尼汀及辅酶Q10等改善代谢,辅以低脂、低蛋白及高碳水化合物饮食。随访患儿均病情稳定,生长发育正常。结论ETFDH基因的复合杂合变异可能是Ⅲ型MADD患儿存在反复肌无力、呕吐,短中长链多种酰基肉碱升高,戊二酸及多种双羧酸升高的遗传学病因。Objective To explore the clinical characteristics and genetic variants in three children with late-onset Multiple acyl-Coenzyme A dehydrogenase deficiency(MADD typeⅢ).Methods Clinical data of three children diagnosed with late-onset MADD at the Children′s Hospital Affiliated to Zhengzhou University between March 2020 and March 2022 were retrospectively analyzed.All children were subjected to whole exome sequencing(WES),and candidate variants were verified by Sanger sequencing.All children had received improved metabolic therapy and followed up for 1~3 years.Results The children had included 2 males and 1 female,and aged from 2 months to 11 years and 7 months.Child 1 had intermittent vomiting,child 2 had weakness in lower limbs,while child 3 had no symptom except abnormal neonatal screening.Tandem mass spectrometry of the three children showed elevation of multiple acylcarnitines with short,medium and long chains.Children 1 and 2 showed increased glutaric acid and multiple dicarboxylic acids by urine Gas chromatography-mass spectrometry(GC-MS)analysis.All children were found to harbor compound heterozygous variants of the ETFDH gene,including a paternal c.1211T>C(p.M404T)and a maternal c.488-22T>G variant in child 1,a paternal c.1717C>T(p.Q573X)and a maternal c.250G>A(p.A84T)variant in child 2,and a paternal c.1285+1G>A and maternal c.629A>G(p.S210N)variant in child 3.As for the treatment,high-dose vitamin B2,levocarnitine and coenzyme Q10 were given to improve the metabolism,in addition with a low fat,hypoproteinic and high carbohydrate diet.All children showed a stable condition with normal growth and development during the follow-up.Conclusion The compound heterozygous variants of the ETFDH gene probably underlay the muscle weakness,remittent vomiting,elevated short,medium,and long chain acylcarnitine,as well as elevated glutaric acid and various dicarboxylic acids in the three children with typeⅢMADD.

关 键 词：遗传性疾病 迟发型多种酰基辅酶A脱氢酶缺乏症 ETFDH基因 血串联质谱 尿气相色谱质谱 基因变异 

分 类 号：R725.9[医药卫生—儿科]