78例丙酸血症患者的基因型和表型分析

Phenotypes and genotypes of 78 patients with propionic acidemia

目的丙酸血症是由于丙酰辅酶A羧化酶(propionyl CoA carboxylase, PCC)缺乏导致的罕见遗传代谢病, 本研究拟分析我国丙酸血症患者的临床特点和基因突变类型, 并初步探讨临床表型与基因型的关系。方法单中心的回顾性、观察性研究, 来自我国20个省自治区直辖市的78例丙酸血症患者, 男46例, 女32例, 于2007年1月至2022年4月就诊, 初诊年龄7 d至15岁, 就其临床表现、生化代谢异常、基因变异、诊断、治疗及转归进行研究, 采用χ2检验或Mann-WhitneyU检验进行统计学分析。结果 78例患者中, 6例(7.7%)为新生儿筛查发现, 于无症状时开始治疗。72例(92.3%)为发病后临床诊断, 发病年龄为2 h至15岁, 确诊年龄7 d至15岁, 其中早发型32例, 晚发型40例。患者的首发临床表现包括嗜睡、肌张力低下、呕吐、喂养困难、发育落后、惊厥及昏迷等。74例接受基因分析的患者中, 35例(47.3%)有PCCA基因变异, 39例(52.7%)有PCCB基因变异。PCCA最常见的变异为c.2002G>A和c.229C>T, 等位基因频率分别为11.4%和10.0%;PCCB最常见的变异是c.838dupC和c.1087T>C, 等位基因频率分别为14.1%和10.3%。PCCB c.1228C>T和c.1283C>T可能与早发型丙酸血症相关, PCCA c.2002G>A及PCCB c.838dupC、c.1127G>T和c.1316A>G可能与晚发型丙酸血症相关。新生儿筛查发现的6例患儿于无症状时开始治疗, 发育基本正常。发病后临床诊断的72例有不同程度的合并症, 其中10例(12.8%)死亡, 62例经左卡尼汀及饮食等代谢干预后好转。6例患儿仍有频繁代谢危象发作, 进行了肝移植, 术后临床症状改善。结论丙酸血症的临床表现复杂, 缺乏特异性, 多数患者预后不良。新生儿筛查和临床高危筛查有助于早期治疗和改善预后。丙酸血症基因型与表型的关系尚不明确, 但某些基因变异可能与早发型或晚发型丙酸血症有关。

Objective Propionic acidemia is a rare inherited metabolic disorder caused by propionyl CoA carboxylase(PCC)deficiency.This study aims to analyze the clinical characteristics and gene variations of Chinese patients with propionic acidemia,and to explore the correlation between clinical phenotypes and genotypes.Methods Single-center,retrospective and observational study.Seventy-eight patients of propionic acidemia(46 males and 32 females)from 20 provinces and autonomous regions were admitted from January 2007 to April 2022.Their age of initial diagnosis ranged from 7 days to 15 years.The clinical manifestations,biochemical and metabolic abnormalities,genetic variations,diagnosis,treatment and outcome were studied.Chi-Square test or Mann-Whitney U test were used for statistical analysis.Results Among 78 cases,6(7.7%)were identified by newborn screening;72(92.3%)were clinically diagnosed after onset,and the age of onset was 2 hours after birth to 15 years old;32 cases had early-onset disease and 40 cases had late-onset disease.The initial manifestations included lethargy,hypotonia,vomiting,feeding difficulties,developmental delay,epilepsy,and coma.Among the 74 cases who accepted gene analysis,35(47.3%)had PCCA variants and 39(52.7%)had PCCB variants.A total of 39 PCCA variants and 32 PCCB variants were detected,among which c.2002G>A and c.229C>T in PCCA and c.838dupC and c.1087T>C in PCCB were the most common variants in this cohort.The variants c.1228C>T and c.1283C>T in PCCB may be related to early-onset type.The variants c.838dupC,c.1127G>T and c.1316A>G in PCCB,and c.2002G>A in PCCA may be related to late-onset disease.Six patients detected by newborn screening and treated at asymptomatic stage developed normal.The clinically diagnosed 72 cases had varied complications.10(12.8%)cases of them died.62 patients improved after metabolic therapy by L-carnitine and diet.Six patients received liver transplantation because of recurrent metabolic crisis.Their clinical symptoms were markedly improved.Conclusion The clinical manifestations of propionic acidemia are complex and lack of specificity.Newborn screening and high-risk screening are keys for early treatment and better outcome.The correlation between the genotype and phenotype of propionic acidemia is unclear,but certain variants may be associated with early-onset or late-onset propionic acidemia.