Inborn errors of vitamin B(12) (cobalamin) metabolism are characterized by decreased production of active cobalamin cofactors and subsequent deficiencies in the activities of methionine synthase and methylmalonyl-CoA mutase. With the recent discovery of the cblJ defect in two patients with phenotypes mimicking the cblF defect, there are nine genes known to be involved in cobalamin metabolism. The new defect is caused by mutations in the ABCD4 gene, encoding an ABC transporter. At the moment, there is no clear distinction between the cblJ and cblF defects either clinically or biochemically, and both defects result in blocks in the transport of cobalamin from the lysosome to the cytoplasm. A patient was diagnosed with hyperhomocysteinemia and methylmalonic aciduria at the age of 8 years. Incorporations of both [(14)C]propionate and [(14)C]methyltetrahydrofolate in cultured fibroblasts were within reference ranges and thus too high to allow for complementation analysis. We observed decreased synthesis of both adenosylcobalamin and methylcobalamin and accumulation of unmetabolized cyanocobalamin. Exome sequencing was performed to identify causative mutation(s) and Sanger re-sequencing was performed to validate segregation of mutation in the family. By this approach, a homozygous mutation, c.423C>G, in the ABCD4 gene was identified. Here, we report the successful application of exome sequencing for diagnosis of a rare inborn error of vitamin B(12) metabolism in a patient whose unusual presentation precluded diagnosis using standard biochemical and genetic approaches. The patient represents only the third known patient with the cblJ disorder.

译文

:维生素B(12)(钴胺素)代谢的先天性错误的特征在于活性钴胺素辅因子的产生减少以及蛋氨酸合酶和甲基丙二酰辅酶A突变酶的活性随后不足。随着最近在两名模仿cblF缺陷的表型患者中发现cblJ缺陷,已知有9个基因与钴胺素代谢有关。新的缺陷是由编码ABC转运蛋白的ABCD4基因突变引起的。目前,在临床或生化方面,cblJ和cblF缺陷之间尚无明确区分,并且两种缺陷均导致钴胺素从溶酶体到细胞质的转运受阻。一名患者在8岁时被诊断出患有高同型半胱氨酸血症和甲基丙二酸尿症。 [(14)C]丙酸酯和[(14)C]甲基四氢叶酸在培养的成纤维细胞中的掺入均在参考范围内,因此含量过高,无法进行互补分析。我们观察到腺苷钴胺素和甲基钴胺素的合成减少以及未代谢的氰钴胺素的积累。进行了外显子组测序以鉴定致病突变,并进行了桑格重测序以验证家族中突变的分离。通过这种方法,鉴定出ABCD4基因中的纯合突变,即c.423C> G。在这里,我们报告外显子组测序在维生素B(12)代谢的罕见先天性错误的诊断中成功应用,该患者的异常表现排除了使用标准生化和遗传方法进行诊断的可能性。该患者仅代表第三位已知的cblJ疾病患者。

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