五例cblX型甲基丙二酸血症患儿的临床特征及基因型分析

Clinical characteristics and genotype analysis of five infants with cblX type of methylmalonic acidemia

目的:探讨钴胺素(cbl)X型甲基丙二酸血症(MMA)患儿的临床表型及基因型特点。方法:收集2016至2020年在上海交通大学医学院附属新华医院和上海市儿童医院就诊的5例cblX型MMA患儿的临床资料。采用串联质谱法检测血酰基肉碱水平,气相色谱-质谱法检测尿有机酸,全外显子基因测序法检测致病基因,并利用生物信息学分析方法预测新突变对三维蛋白质结构的影响。结果:5例cblX型MMA确诊患儿,男性4例,女性1例,发病年龄为出生后0~6个月。4例男性患儿的主要临床表现为顽固性癫痫、智力运动发育落后,代谢异常均表现为轻度血同型半胱氨酸水平增高,其中伴尿甲基丙二酸轻度升高3例,伴血丙酰基肉碱(C3)、C3/乙酰基肉碱(C2)升高1例;基因检测发现2例携带宿主细胞因子C1(HCFC1)已知基因突变c.344C>T(p.A115V),另外2例携带新的致病基因突变,分别为c.92G>A(p.R31Q)和c.166G>C(p.V56L)。这三种基因突变均位于HCFC1蛋白的Kelch结构域中。1例女性患儿携带c.3731G>T(p.R1244L)突变,临床症状较轻,仅尿甲基丙二酸轻度升高。结论:cblX型MMA患儿的临床表现多为顽固性癫痫、智力运动发育落后等严重的神经症状,代谢异常表现为血同型半胱氨酸伴甲基丙二酸(尿甲基丙二酸或/和血C3、C3/C2)升高,临床和生化表型呈分离现象,需要结合基因检测结果诊断。

Objective:To investigate the clinical and genetic characteristics of infants with cobalamin(cbl)X type of methylmalonic acidemia(MMA).Methods:The clinical data of 5 infants with cblX type of MMA diagnosed in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and Shanghai Children’s Hospital from the year 2016 to 2020 were collected.The levels of blood acylcarnitines were detected by tandem mass spectrometry,the levels of urinary organic acids were detected by gaschromatography mass spectrometry,the pathogenic genes were detected by whole exon gene sequencing,and the effect of new pathogenic mutations on three-dimensional protein structure was predicted by bioinformatics analysis.Results:Five infants with cblX type were diagnosed,including 4 males and 1 female,and the onset age was 0-6 months.The main clinical manifestations of 4 males were intractable epilepsy,mental and motor retardation,metabolic abnormalities presented mild increase of blood homocysteine level.Among them,3 cases were accompanied by slight increase of urinary methylmalonic acid,and 1 case was accompanied by increase of blood propionylcarnitine(C3)and C3/acetylcarnitine(C2).Gene detection found that 2 cases carried a same hemizygous mutation c.344C>T(p.A115V)of HCFC1 gene,which was the most reported mutation,and the other 2 cases carried novel pathogenic mutations,c.92G>A(p.R31Q)and c.166G>C(p.V56L).These 3 gene mutations located in the Kelch domain of HCFC1 protein.One female infant carried a benign mutation of c.3731G>T(p.R1244L).Her clinical symptoms were mild,and only the urinary methylmalonic acid was slightly increased.Conclusions:The clinical manifestations of children with cblX type of MMA are intractable epilepsy,mental and motor retardation,and other serious neurological symptoms.Their metabolic abnormalities present the increase of blood homocysteine with methylmalonic acid(urinary methylmalonic acid or/and blood C3,C3/C2).The clinical and biochemical phenotypes are separated,so the diagnosis should be in combination with the results of gene testing.