目的:探讨钴胺(cbl)X型甲基丙二酸血症(MMA)患儿的临床和遗传特点。
方法:收集2016-2020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确诊的5例cblX型MMA患儿的临床资料。通过串联质谱检测血液中的酰基肉碱,通过气相色谱-质谱法检测尿中有机酸的水平,通过全外显子基因测序检测致病基因,并通过生物信息学分析预测新的致病突变对蛋白质三维结构的影响。
结果:诊断出5名cblX型婴儿,包括4名男性和1名女性,发病年龄0~6个月。4例男性主要临床表现为顽固性癫痫,智力和运动迟钝,代谢异常呈现血同型半胱氨酸水平轻度升高.其中,3例患者伴有尿甲基丙二酸轻度升高,1例伴有丙酰肉碱(C3)和C3/乙酰肉碱(C2)的增加。基因检测发现2例携带相同的半合子突变c.344C>T(p。HCFC1基因的A115V),这是报道最多的突变,另外2例携带新的致病突变,c.92G>A(p。R31Q)和c.166G>C(p。V56L)。这3个基因突变位于HCFC1蛋白的Kelch域。一名女婴携带c.3731G>T的良性突变(p。R1244L)。她的临床症状很轻微,只有尿甲基丙二酸略有增加。
结论:cblX型MMA患儿的临床表现为难治性癫痫,智力和运动迟钝,和其他严重的神经症状。他们的代谢异常表现出血高半胱氨酸与甲基丙二酸(尿甲基丙二酸或/和血液C3,C3/C2)的增加。临床和生化表型分离,因此诊断应与基因检测结果相结合。
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 gas-chromatography 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.