维生素B_(12)依赖型甲基丙二酸血症一家系临床表型和基因突变分析及疗效评价

目的探讨维生素B_(12)依赖型甲基丙二酸血症家系临床特点、基因突变和维生素B_(12)治疗效果。方法采集一维生素B_(12)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B_(12)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.482GA(p.Arg161Gln)和c.609GA(p.Trp203X),其父携带MMACHC基因错义突变c.482GA(p.Arg161Gln),其母携带MMACHC基因无义突变c.609GA(p.Trp203X)。经维生素B_(12)治疗后均症状好转。结论晚发型维生素B_(12)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B_(12)治疗反应良好,早期诊断、及时治疗对患者预后意义重大。

Analysis of clinical phenotype and genetic mutation with outcome evaluation in one family of vitamin B12-dependent methylmalonic aciduria

Objective To explore the clinical features,genetic mutation and vitamin B12 therapeutive effectiveness in vitamin B12-dependent methylmalonic acidemia (MMA).Methods Clinical data in a pedigree of 4 members with vitamin B12-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.