75例儿童肝豆状核变性的临床及基因变异特征

Clinical and gene variation characteristic of 75 cases of hepatolenticular degeneration in children

目的了解儿童肝豆状核变性的起病临床特点,明确基因诊断在儿童肝豆状核变性患者中的意义。方法选取2011年至2018年就诊于北京协和医院儿科门诊的75例肝豆状核变性患儿进行回顾性研究;进行铜离子转运ATP酶β肽(ATP7B)基因测序、多重连接探针扩增技术(MLPA)分析;对其起病时临床表现及基因检测结果进行总结。结果75例儿童肝豆状核变性患者中,男女比例为1.27∶1,年龄为(6.5±4.0)岁(1.3~17.5岁)。55例以无症状肝酶升高起病,所有患者铜蓝蛋白均<0.2 g/L,72例患者24小时尿铜>40μg,其中29例患者24小时尿铜在40~100μg之间,16例患儿K-F环阳性,可以临床确诊的共有16例(21%),有15例年龄均>7岁。75例进行了ATP7B基因检测,共检出48种致病变异。最常见的致病变异为c.2333G>T、p.R778L、c.2621C>L、p.A874V、c.2975C>T、p.P992L,其等位基因频率分别为30.49%、14.89%、9.92%。结论对于儿童患者,多表现为无症状肝酶升高,K-F环阳性率较低,临床确诊难度大。本研究临床确诊率为21.33%,基因检测对于该病的早期诊断和治疗具有重要意义。

Objective To investigate the clinical characteristics of the hepatolenticular degeneration in children,and to clarify the significance of gene diagnosis in children with hepatolenticular degeneration.Methods A total of 75 patients with hepatolenticular degeneration were enrolled in the Department of Pediatrics,Peking Union Medical College Hospital from 2011 to 2018.All of them carried out a generation of gene sequencing for ATPase Cu^(2+)trans⁃porting beta polypeptide(ATP7B)gene and multiplex ligation⁃dependent probe amplification(MLPA)analysis.Results Among the 75 pediatric patients,55 patients were asymptomatic and had elevated aminotransferases as the incidental findings.All the pediatric patients had decreased ceruloplasmin.Seventy⁃two of pediatric patients had 24⁃hour urinary copper>40μg/d.There were 16 cases that had Kayser⁃Fleischer(K⁃F)rings.Sixteen six out of 75(2133%)cases were diagnosed clinically and 15 cases were>7 years old.All the remaining patients needed genetic diagnosis.Sixty⁃six patients had two mutations and 9 patients had only one mutation,1 had no mutation.Forty eight different mutations were found to be localized in ATP7B gene.These mutations included 32 missense mutations,6 splice mutations,5 deletion mutations,2 repeated mutations,2 insert mutations and 1 nonsense muta⁃tions.The most frequently three mutations were c2333G>T,pR778L,c2621C>T,pA874V,c2975C>T,pP992L,whose allele frequencies were 3049%,1489%,992%.Conclusions The research showed that in young aged patients,the nervous system symptoms are not obvious and the positive rate of laboratory tests are lower than adults so is a challenge to clinical diagnosis.So Genetic testing is of great significance for the early diagnosis and early treatment of disease in pediatric patients.