MMACHC c.609G>A纯合变异cblC型甲基丙二酸血症合并同型半胱氨酸尿症患者的表型差异

Factors affecting phenotypes in the patients with MMACHC gene c.609G>A homozygous variant cblC type methylmalonic acidemia combined with homocysteinuria

探讨MMACHC c.609G>A纯合变异cblC型甲基丙二酸血症合并同型半胱氨酸尿症患者的复杂表型差异,分析可能的影响因素。方法回顾性研究1998年1月至2020年12月就诊的164例MMACHC c.609G>A纯合变异cblC型甲基丙二酸血症合并同型半胱氨酸尿症患者,经生化及基因分析确诊,对临床表现、并发症、治疗和预后情况进行分析。结果164例MMACHC c.609G>A纯合变异cblC型患者中,2例为胎儿期诊断,日龄1天时开始治疗,现3岁和12岁,智力运动发育正常。21例经新生儿筛查发现,其中15例于生后2周无症状时开始治疗,发育正常;6例于1~3个月发病后开始治疗,发育落后。141例为发病后临床诊断,于出生后数分钟到6岁发病,其中早发型110例(78.0%),晚发型31例(22.0%)。5例患者死亡,24例失访。在发病后临床诊断的患者中,130例(92.2%)发育迟滞,69例(48.9%)合并癫痫,39例(27.7%)贫血,30例(21.3%)视力损伤,27例(19.1%)合并脑积水,26例(18.4%)喂养困难,7例(5.0%)肝损害,5例(3.5%)合并代谢综合征。早发型中癫痫和脑积水发生率高,晚发型多因发育迟滞就诊。合并癫痫的患者尿甲基丙二酸浓度明显升高。在长期随访中,癫痫未控制组患者的血浆总同型半胱氨酸水平显著高于癫痫控制组,差异有统计学意义(P<0.05)。结论MMACHC c.609G>A纯合变异所致cblC型患者多为早发型,致死及致残率很高。如未能及时获得症状前治疗,多数患者发生神经系统损害,导致癫痫、智力运动落后、脑积水及多脏器损害。早期诊断和及时规范化的治疗是避免脑损害的关键。新生儿筛查和产前诊断是改善预后的关键。

Objective To investigate the factors affecting phenotypes in the patients of methylmalonic acidemia combined with homocysteinemia cblC type with MMACHC c.609G>A homologous variant.Methods A retrospective study on the clinical manifestations,complications,treatment,and outcome in 164patients of cblC type with MMACHC c.609G>A homologous variant was conducted.The patients were diagnosed by biochemical and genetic analysisfrom January 1998 to December 2020.Results Among the 164 patients,2 cases were prenatally diagnosed and began treatment after birth.They are 3 and 12 years old with normal physical and mental development.Twenty-one cases were diagnosed by newborn screening.Among them,15 cases had with normal development.They were treated fromthe age of two weeks at the asymptomatic period.Six cases began treatment aged 1 to 3 months after onset.Their development was delayed.One hundred and forty-one cases were clinically diagnosed.Their onset age ranges from a few minutes after birth to 6 years old.110 cases had early-onset(78.0%).31 cases had late-onset(22.0%).Five of them died.24 patients lost to follow-up.Of the 141 clinically diagnosed patients,130(92.2%)with psychomotor retardation,69(48.9%)with epilepsy,39(27.7%)with anemia,30(21.3%)had visual impairment,27(19.1%)had hydrocephalus,26(18.4%)had feeding difficulties,7(5.0%)with liver damage,and 5(3.5%)with metabolic syndrome.The frequency of hydrocephalus and seizures was significantly higher in the early-onset group.The urinary methylmalonic acid increased significantly in the patients with epilepsy.During the long-term follow-up,the level of plasma total homocysteine in the seizure-uncontrolled group was significantly higher than that in the seizure-controlled group,the difference had a statistical significance(P<0.05).Conclusion Most of the patients with MMACHC c.609G>A homozygous variant had early-onset disease,with a high mortality and disability rate.If not treated in time,it will lead to neurological damage,resulting in epilepsy,mental retardation,hydrocephalus,and multiple organ damage.Pre-symptomatic diagnosis and treatment are crucial to prevent irreversible neurological damage.Neonatal screening and prenatal diagnosis are important to improve the outcome of the patients.