He Ruxuan, Mo Ruo, Zhang Yao, Shen Ming, Kang Lulu, Chen Zhehui, Liu Yi, Song Jinqing, Zhang Hongwu, Yao Hongxin, Liu Yupeng, Dong Hui, Jin Ying, Li Mengqiu, Qin Jiong, Zheng Hong, Chen Yongxing, Wei Haiyan, Li Dongxiao, Li Xiyuan, Zheng Rongxiu, Zhang Huifeng, Huang Min, Zhang Chunyan, Jiang Yuwu, Liang Desheng, Tian Yaping, Yang Yanling
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Jun 10;39(6):565-570. doi: 10.3760/cma.j.cn511374-20210211-00130.
To investigate the factors affecting phenotypes in the patients of methylmalonic acidemia combined with homocysteinemia cblC type with MMACHC c.609G>A homologous variant.
A retrospective study on the clinical manifestations, complications, treatment, and outcome in 164 patients of cblC type with MMACHC c.609G>A homologous variant was conducted. The patients were diagnosed by biochemical and genetic analysis from January 1998 to December 2020.
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 from the 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).
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.
探讨影响伴有MMACHC基因c.609G>A同源变异的甲基丙二酸血症合并高同型半胱氨酸血症cblC型患者表型的因素。
对164例伴有MMACHC基因c.609G>A同源变异的cblC型患者的临床表现、并发症、治疗及预后进行回顾性研究。这些患者于1998年1月至2020年12月通过生化和基因分析确诊。
164例患者中，2例为产前诊断，出生后开始治疗，年龄分别为3岁和12岁，身心发育正常。21例通过新生儿筛查确诊，其中15例发育正常，于无症状期2周龄开始治疗；6例于发病后1至3个月开始治疗，发育延迟。141例为临床诊断，发病年龄从出生后几分钟至6岁不等。110例为早发型（78.0%），31例为晚发型（22.0%），其中5例死亡，24例失访。141例临床诊断患者中，130例（92.2%）有精神运动发育迟缓，69例（48.9%）有癫痫，39例（27.7%）有贫血，30例（21.3%）有视力障碍，27例（19.1%）有脑积水，26例（18.4%）有喂养困难，7例（5.0%）有肝损害，5例（3.5%）有代谢综合征。早发型组脑积水和癫痫的发生率显著更高。癫痫患者尿甲基丙二酸显著升高。长期随访中，癫痫未控制组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）。
大多数伴有MMACHC基因c.609G>A纯合变异的患者发病早，死亡率和致残率高。若不及时治疗，会导致神经损伤，引发癫痫、智力发育迟缓、脑积水及多器官损害。症状前诊断和治疗对于预防不可逆神经损伤至关重要。新生儿筛查和产前诊断对改善患者预后具有重要意义。
