与 MMACHC c.609G>A 同源突变相关的可变表型和结局：大型病例队列的长期随访。
Variable phenotypes and outcomes associated with the MMACHC c.609G>A homologous mutation: long term follow-up in a large cohort of cases.
机构信息
Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China.
Research Center for Translational Medicine, Medical Innovation Research Division of Chinese PLA General Hospital, Beijing, 100853, China.
出版信息
Orphanet J Rare Dis. 2020 Aug 3;15(1):200. doi: 10.1186/s13023-020-01485-7.
BACKGROUND
Cobalamin C deficiency (cblC) caused by the MMACHC mutations is the most common type of the disorders of intracellular cobalamin metabolism. While the c.609G > A mutation is most frequent in Chinese cblC patients, its correlation with phenotype has not been delineated. Here we aim to investigate the factors affecting variable phenotypes and outcomes associated with the MMACHC c.609G > A homologous mutation in 149 Chinese cases to have implications for treatment and prevention.
METHODS
We assessed 149 cblC patients caused by MMACHC c.609G > A homozygous mutation. The clinical manifestations, complications, treatment, and outcomes were evaluated; 120 patients were followed-up till December 2019.
RESULTS
Two patients (1.3%) were prenatally diagnosed, treated after birth and consequently showed normal development. In 15 patients (10.1%) detected by newborn screening, 10 were treated at the age of 2 weeks and showed normal development, while the other 5 were treated after onset and showed neurologic disorders. All 132 clinically diagnosed patients (88.6%) developed symptoms at age from few minutes after birth to 72 months. Among them, 101 (76.5%) had early-onset (before the age of 12 months) and 31 (23.5%) had late-onset (after the age of 12 months). Totally 5 patients died and 24 were lost to follow-up. Of the 132 clinical diagnosed patients, 92 (69.7%) presented with developmental delay, 65 (49.2%) had seizures, 37 (28.0%) had anemia, 24 (18.2%) had feeding difficulty, 23 (17.4%) had ocular problems, and 22 (16.7%) had hydrocephalus. Compared with the non-developmental delay group, the onset age, the age at treatment initiation and the time from onset to treatment initiation were later in the developmental delay group. Seizure group showed significantly higher urinary methylmalonic acid concentration. During long-term follow-up, plasma total homocysteine (tHcy) levels were significantly higher in patients in the uncontrolled group than those in the seizure-free group.
CONCLUSIONS
Most cblC patients caused by MMACHC c.609G > A homozygous mutation showed early-onset. The clinically diagnosed patients usually showed the presence of irreversible brain disorders. Patients treated from the pre-symptomatic stage showed favorable outcomes. Therefore, newborn screening, prenatal diagnosis and early treatment are crucial and the c.609G > A mutant allele should be listed in the pre-pregnancy carrier screening panel in China.
背景
由 MMACHC 基因突变引起的钴胺素 C 缺乏症（cblC）是细胞内钴胺素代谢紊乱中最常见的类型。虽然 c.609G>A 突变在中国 cblC 患者中最为常见，但尚未阐明其与表型的相关性。在此，我们旨在研究影响与 MMACHC c.609G>A 同源突变相关的 149 例中国患者可变表型和结局的因素，为治疗和预防提供依据。
方法
我们评估了 149 例由 MMACHC c.609G>A 纯合突变引起的 cblC 患者。评估了临床表现、并发症、治疗和结局；120 例患者随访至 2019 年 12 月。
结果
2 例（1.3%）为产前诊断，出生后进行治疗，随后发育正常。在 15 例（10.1%）通过新生儿筛查检测到的患者中，有 10 例在 2 周龄时进行治疗，发育正常，而其余 5 例在发病后进行治疗，出现神经功能障碍。所有 132 例临床诊断的患者（88.6%）在出生后数分钟至 72 个月时出现症状。其中，101 例（76.5%）为早发型（12 月龄前），31 例（23.5%）为晚发型（12 月龄后）。共有 5 例死亡，24 例失访。在 132 例临床诊断的患者中，92 例（69.7%）出现发育迟缓，65 例（49.2%）出现癫痫发作，37 例（28.0%）出现贫血，24 例（18.2%）出现喂养困难，23 例（17.4%）出现眼部问题，22 例（16.7%）出现脑积水。与非发育迟缓组相比，发育迟缓组的发病年龄、开始治疗的年龄以及从发病到开始治疗的时间均较晚。癫痫发作组的尿甲基丙二酸浓度明显升高。在长期随访中，未控制组的血浆总同型半胱氨酸（tHcy）水平明显高于无癫痫发作组。
结论
由 MMACHC c.609G>A 纯合突变引起的 cblC 患者多为早发型。临床上诊断的患者通常存在不可逆转的脑损伤。从症状前阶段开始治疗的患者预后良好。因此，新生儿筛查、产前诊断和早期治疗至关重要，中国应将 c.609G>A 突变等位基因列入孕前携带者筛查。
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