摘要：

目的 探讨维生素B12 依赖型甲基丙二酸血症家系临床特点、基因突变和维生素B₁₂ 治疗效果。 方法 采集一维生素B₁₂ 依赖型甲基丙二酸血症家系共4 名成员临床资料，抽取外周静脉血行血浆氨基酸和酰基肉碱谱分析及基因检测，评价维生素B12 治疗效果。 结果 家系中先证者12 岁发病，以学习成绩下降、性格改变为首发症状，病程中出现幻觉、双下肢无力；先证者之弟主要表现为易怒、学习成绩较差。经血浆氨基酸和酰基肉碱谱分析，先证者及其弟血浆丙酰肉碱、丙酰肉碱/乙酰肉碱比值升高，尿液甲基丙二酸水平升高。基因检测显示，先证者及其弟均存在MMACHC 基因复合杂合突变c.482G > A（p.Arg161Gln）和c.609G > A（p.Trp203X），其父携带MMACHC 基因错义突变c.482G > A（p.Arg161Gln），其母携带MMACHC 基因无义突变c.609G > A（p.Trp203X）。经维生素B₁₂ 治疗后均症状好转。 结论 晚发型维生素B₁₂ 依赖型甲基丙二酸血症系MMACHC 基因复合杂合突变所致，维生素B₁₂ 治疗反应良好，早期诊断、及时治疗对患者预后意义重大。

关键词: 甲基丙二酸, 代谢缺陷, 先天性, 维生素B₁₂, 表型, 基因, 突变, 系谱

Abstract:

Objective  To explore the clinical features, genetic mutation and vitamin B₁₂ therapeutive effectiveness in vitamin B_12-dependent methylmalonic acidemia (MMA). Methods  Clinical data in a pedigree of 4 members with vitamin B_12-dependent MMA was collected. Peripheral blood samples were collected for plasma amino acids and acylcarnitines and gene muatation analysis. The therapeutic efficacy of vitamin B₁₂ was evaluated.  Results  The initial presentations of the proband were underachievement and personality changes in 12-year old, and accompanied by visual hallucinations and weakness of lower limbs during the course of disease. The younger brother of the proband presented with bad-temper and lower acheivement. The analysis of plasma amino acid and acylcarnitine showed that proband and his younger brother's plasma propionylcarnitine and propionylcarnitine/acetylcarnitine ratio, and the level of methylmalonic acid in urine were increased significantly. Compound heterozygeous mutation of c.482G > A (p.Arg161Gln) and c.609G > A (p.Trp203X) in MMACHC gene were seen in the proband and her younger brother. Her father carried MMACHC gene missense mutation c.482G > A (p.Arg161Gln), while her mother carried MMACHC gene nonsense mutation c.609G > A (p.Trp203X). Symptoms of the proband were improved after vitamin B12 therapy.   Conclusions   The late - onset vitamin B₁₂ -dependent MMA is caused by compound heterozygote mutation of MMACHC gene. It had good responsive to vitamin B12 therapy. Early diagnosis and timely treatment may play a critical role for the outcomes of patients with this disease.

Key words: Methylmalonic acid, Metabolism, inborn errors, Vitamin B₁₂, Phenotype, Genes, Mutation, Pedigree