1. Department of Endocrinology, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, China.
2. Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2022 Jun 25;51(3):298-305. doi: 10.3724/zdxbyxb-2022-0194.
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 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.
目的：研究钴胺素（cbl）X 型甲基丙二酸血症（MMA）患儿的临床和遗传特征。
方法：收集 2016 年至 2020 年上海交通大学医学院附属新华医院和上海儿童医学中心诊断为 cblX 型 MMA 的 5 例婴儿的临床资料。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水平，全外显子基因测序检测致病基因，生物信息学分析预测新致病突变对三维蛋白结构的影响。
结果：共诊断 5 例 cblX 型 MMA 患儿，男 4 例，女 1 例，发病年龄 0~6 个月。4 例男性的主要临床表现为难治性癫痫、精神运动发育迟缓，代谢异常表现为血同型半胱氨酸水平轻度升高。其中 3 例伴有轻度尿甲基丙二酸升高，1 例伴有血丙酰肉碱（C3）和 C3/乙酰肉碱（C2）升高。基因检测发现 2 例携带同一致病突变 c.344C>T（p.A115V）的基因，为最常见突变，另 2 例携带新的致病突变 c.92G>A（p.R31Q）和 c.166G>C（p.V56L）。这 3 种基因突变位于 HCFC1 蛋白的 Kelch 结构域。1 例女性患儿携带良性突变 c.3731G>T（p.R1244L）。其临床症状较轻，仅尿甲基丙二酸轻度升高。
结论：cblX 型 MMA 患儿的临床表现为难治性癫痫、精神运动发育迟缓等严重神经系统症状，其代谢异常表现为血同型半胱氨酸升高伴甲基丙二酸（尿甲基丙二酸或/和血 C3、C3/C2）升高。临床和生化表型分离，因此诊断应结合基因检测结果。
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