Objective: To analyz the current situation of the diagnosis, treatment and prevention of methylmalonic acidemia, the phenotypes, biochemical features and genotypes of the patients in the mainland of China, were investigated. Methods: Tottally 1 003 patients of methylmalonic acidemia from 26 provinces and municipalities of the mainland of China were enrolled. The clinical data, biochemical features and gene mutations were studied. Blood aminoacids and acylcarnitines, urine organic acids, and plasma total homocysteine were determined for the biochemical diagnosis. Gene analyses were performed for the genetic study of 661 patients. The patients were treated with individual intervention and long-term follow up. Prenatal diagnoses were carried out for 165 fetuses of the families. Results: Among 1 003 patients (580 boys and 423 girls), 296 cases (29.5%) had isolated methylmalonic acidemia; 707 cases (70.5%) had combined homocysteinemia; 59 patients (5.9%) were detected by newborn screening; 944 patients (94.1%) had the onset at the ages from several minutes after birth to 25 years and diagnosed at 3 days to 25 years of age. The main clinical presentations were psychomotor retardation and metabolic crisis. Multi-organ damage, including hematological abnormalities, pulmonary hypertension, kidney damage, were found. MMACHC, MUT, MMAA, MMAB, HCFC1, SUCLG1, SUCLA2 mutations were found in 631 patients (96.6%) out of 661 patients who accepted gene analysis. MMACHC mutations were detected in 460 patients (94.7%) out of 486 cases of methylmalonic acidemia combined with homocysteinemia. MUT mutations were found in 158 (90.3%) out of 169 cases of isolated methylmalonic acidemia. The development of 59 patients detected by newborn screening were normal; 918 cases (97.2%) were diagnosed after onset accepted the treatment. Forty-five of them completely recovered with normal development. Twenty-six patients (2.7%) died; 873 (92.5%) patients had mild to severe psychomotor retardation. Methylmalonic acidemia were found in 35 out of 165 fetuses by metabolites assay of amniotic fluid and amniocytes gene analysis. Conclusion: Combined methylmalonic acidemia and homocysteinemia is the common type of methylmalonic acidemia in the mainland of China. CblC defect due to MMACHC mutations is the most common type of methylmalonic acidemia combined with homocysteinemia. MUT gene mutations are frequent in the patients with isolated methylmalonic acidemia. Newborn screening is key for the early diagnosis and the better outcome. Combined diagnosis of biochemical assays and gene analysis are reliable for the prenatal diagnosis of methylmalonic acidemia.
目的： 分析中国甲基丙二酸血症患者的临床表型、生化表型、基因型以及防治情况。 方法： 多中心回顾性研究1998年1月—2017年12月来自我国26个省、市、自治区的1 003例甲基丙二酸血症患者的诊疗经过、生化及基因变异，生化诊断采用血氨基酸及酯酰肉碱谱、尿有机酸及血浆总同型半胱氨酸测定，661例患者接受了基因分析。确诊后进行个体化干预治疗，长期随访，对部分家系进行下一胎产前诊断。 结果： 1 003例甲基丙二酸血症患者中男580例，女423例，其中单纯型296例（29.5%），707例（70.5%）合并同型半胱氨酸血症。仅59例经新生儿筛查发现（5.9%），944例（94.1%）为临床诊断，于生后数分钟~25岁发病，首发的临床表现为神经精神损害：智力运动发育落后（725例，74.3%），286例（29.3%）合并癫痫，76例（7.8%）合并脑积水，部分患者合并血液、心血管、肾脏等多脏器损害。661例患者接受了基因分析，其中631例（96.6%）获得了基因诊断，发现了MUT、MMACHC、MMAA、MMAB、HCFC1、SUCLG1、SUCLA2共7种基因缺陷，获得基因诊断的169例单纯型甲基丙二酸血症患者中158例（90.3%）为MUT基因变异，获基因诊断的462例合并型甲基丙二酸血症患者中460例（94.7%）为MMACHC基因变异。新生儿筛查发现的59例患儿发育较好。经临床诊断的944患者中918例（97.2%）接受了治疗，45例（4.7%）获得康复，智力、运动发育正常，26例（2.7%）死亡，873例（92.5%）患儿遗留轻~极重度智力运动障碍。165例家系接受了下一胎产前诊断，经羊水代谢物及基因联合分析证实35例胎儿患病。 结论： 甲基丙二酸血症合并同型半胱氨酸血症是我国大陆甲基丙二酸血症的主要类型，MMACHC基因变异最常见。MUT基因变异是单纯型甲基丙二酸血症的主要病因。经新生儿筛查及早期治疗的患者生存质量显著改善。再生育指导、产前诊断是减少甲基丙二酸血症患者出生的关键措施。.
Keywords: Homocysteinemia; Inherited metabolic disorders; Methylmalonic acidemia; Neonatal screening; Prenatal diagnosis.