Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S435-42. doi: 10.1007/s10545-010-9217-0. Epub 2010 Oct 6.
The most common inborn error of cobalamin (cbl) metabolism in China is the cblC type characterized by combined methylmalonic acidemia and hyperhomocysteinemia. The clinical presentation is relatively nonspecific, such as feeding difficulty, recurrent vomiting, hypotonia, lethargy, seizures, progressive developmental delay, and mental retardation, together with anemia and metabolic acidosis. More specific biochemical findings include high levels of propionylcarnitine (C3), free carnitine (C3/C0), and acetylcarnitine (C3/C2) measured by tandem mass spectrometry (MS/MS), elevation of methylmalonic acid (MMA) measured by gas chromatography-mass spectrometry (GC-MS), and increased total homocysteine with normal or decreased methionine. We report on 50 Chinese patients with combined methylmalonic acidemia and hyperhomocysteinemia. Forty-six belonged to the cblC complementation group. Mutation analysis of the MMACHC gene was performed to characterize the mutational spectrum of cblC deficiency, and 17 different mutations were found. Most were clustered in exons 3 and 4, accounting for 91.3% of all mutant alleles. Two mutations were novel, namely, c.315 C>G (p.Y105X) and c.470 G>C(p.W157S). In terms of genotype-phenotype correlation, the c.609 G>A mutation was associated with early-onset disease when homozygous. Unlike previous reports from other populations, c.609 G>A (p.W203X) was the most frequent cblC mutation detected in our study of Chinese patients, affecting 51 of 92 MMACHC alleles (55.4%). The high prevalence of this nonsense mutation could have potential therapeutic significance for Chinese cblC patients. Besides traditional approaches consisting of hydroxocobalamin injections, carnitine, betaine, and protein restriction, novel drugs that target premature termination codons may have a role in the future.
在中国，钴胺素（cbl）代谢中最常见的先天缺陷是 cblC 型，其特征是甲基丙二酸血症和高同型半胱氨酸血症合并。临床表现相对非特异性，如喂养困难、反复呕吐、张力减退、嗜睡、癫痫发作、进行性发育迟缓、智力低下，同时伴有贫血和代谢性酸中毒。更具体的生化发现包括串联质谱（MS/MS）测定的丙酰肉碱（C3）、游离肉碱（C3/C0）和乙酰肉碱（C3/C2）水平升高，气相色谱-质谱（GC-MS）测定的甲基丙二酸（MMA）升高，以及同型半胱氨酸总量升高，蛋氨酸正常或降低。我们报告了 50 例合并甲基丙二酸血症和高同型半胱氨酸血症的中国患者。其中 46 例属于 cblC 互补组。对 MMACHC 基因进行突变分析，以确定 cblC 缺陷的突变谱，发现了 17 种不同的突变。大多数突变集中在 3 号和 4 号外显子，占所有突变等位基因的 91.3%。有 2 种突变是新发现的，即 c.315C>G(p.Y105X)和 c.470G>C(p.W157S)。关于基因型-表型相关性，c.609G>A 突变纯合时与早发性疾病相关。与来自其他人群的先前报道不同，c.609G>A(p.W203X)是我们对中国患者研究中检测到的最常见的 cblC 突变，影响了 92 个 MMACHC 等位基因中的 51 个（55.4%）。这种无意义突变的高发生率可能对中国 cblC 患者具有潜在的治疗意义。除了包括羟钴胺素注射、肉碱、甜菜碱和蛋白质限制在内的传统方法外，针对提前终止密码子的新型药物可能在未来具有一定作用。
