CAJ | 학술논문

目的分析并确定佩梅样病(Pelizaeus-Merzbacher-like disease,PMLD)3个家系的临床及分子遗传学特点,为PMLD患者家庭提供准确的遗传咨询及产前检查打基础.方法 2010年5月至2013年3月北京大学第一医院儿科收集3个家系4例(P1-4) PMLD男性患儿及其家系成员临床资料,其中P1与P2为表型相似的同胞兄弟,进行临床特点分析:包括病史、体征、辅助检查特点;应用聚合酶链反应和DNA直接测序方法进行缝隙连接蛋白gamma-2基因(GJC2)与蛋白脂蛋白1基因(PLP1)突变检测,采用多重连接依赖的探针扩增技术(MLPA)检测PLP1重复突变,明确基因突变类型,进行分子遗传学特点分析.结果 1.临床特点:4例患儿均具有共济失调以及头颅磁共振成像(MRI)脑白质髓鞘化不良特点,P1-3主要于婴儿期发病,以眼球震颤为首发症状,均表现为精神运动发育落后、肌张力低下.P4于8岁7个月以手抖、听力下降发病,根据临床特征及头颅MRI表现P1-4均符合临床诊断PMLD.2.遗传学特点点:4例PMLD患儿共发现GJC2 5种核苷酸改变:c.579delC(p.Gly193fsX17)、c.1296_1297insG(p.Gly433fsX59)、c.735C＞A(p.Cvs245X)、c.689delG(p.Gly230AlafsX241)与c.1199C＞ A(p.Ala400Glu),均为国际上未报道的新突变. P1-3均为复合杂合突变致病,分别遗传自表型正常的父母;P4发现GJC2 c.1199C ＞A(p.Ala400Glu)纯合突变,表型正常P4之父为本位点的杂合改变,母亲在本位点为野生型.结论本研究3个家系4例PMLD患儿临床表现均符合PMLD的特点,PMLD临床诊断成立.GJC2分析发现了5种突变均为国际上尚未报道的新突变,扩展了GJC2的突变谱.明确了PMLD 3个家系临床与分子遗传学特征,为准确的遗传咨询和进一步的产前诊断打下了基础.
목적 분석병학정패매양병(Pelizaeus-Merzbacher-like disease,PMLD)3개가계적림상급분자유전학특점,위PMLD환자가정제공준학적유전자순급산전검사타기출.방법 2010년5월지2013년3월북경대학제일의원인과수집3개가계4례(P1-4) PMLD남성환인급기가계성원림상자료,기중P1여P2위표형상사적동포형제,진행림상특점분석:포괄병사、체정、보조검사특점;응용취합매련반응화DNA직접측서방법진행봉극련접단백gamma-2기인(GJC2)여단백지단백1기인(PLP1)돌변검측,채용다중련접의뢰적탐침확증기술(MLPA)검측PLP1중복돌변,명학기인돌변류형,진행분자유전학특점분석.결과 1.림상특점:4례환인균구유공제실조이급두로자공진성상(MRI)뇌백질수초화불량특점,P1-3주요우영인기발병,이안구진전위수발증상,균표현위정신운동발육락후、기장력저하.P4우8세7개월이수두、은력하강발병,근거림상특정급두로MRI표현P1-4균부합림상진단PMLD.2.유전학특점점:4례PMLD환인공발현GJC2 5충핵감산개변:c.579delC(p.Gly193fsX17)、c.1296_1297insG(p.Gly433fsX59)、c.735C＞A(p.Cvs245X)、c.689delG(p.Gly230AlafsX241)여c.1199C＞ A(p.Ala400Glu),균위국제상미보도적신돌변. P1-3균위복합잡합돌변치병,분별유전자표형정상적부모;P4발현GJC2 c.1199C ＞A(p.Ala400Glu)순합돌변,표형정상P4지부위본위점적잡합개변,모친재본위점위야생형.결론 본연구3개가계4례PMLD환인림상표현균부합PMLD적특점,PMLD림상진단성립.GJC2분석발현료5충돌변균위국제상상미보도적신돌변,확전료GJC2적돌변보.명학료PMLD 3개가계림상여분자유전학특정,위준학적유전자순화진일보적산전진단타하료기출.
Objective To analyze the clinical and molecular genetic features in 3 pedigrees with PelizaeusMerzbacher-like disease (PMLD),thus providing a better genetic counseling and correct prenatal diagnosis for those families with PMLD.Methods Clinical data of 4 male pediatric patients (P1-4) and their family members in 3 pedigrees with PMLD were collected from May,2010 to Mar.2013 in Department of Pediatrics,Peking University First Hospital,including medical history,physical signs,and auxiliary examinations.For 4 pediatric patients,P1 and P2 were siblings with similar clinical manifestations.Polymerase chain reaction and sequence analysis of DNA were performed to determine the gene mutation of gap junction protein gamma-2 (GJC2) and proteolipid protein 1(PLP1),and multiplex ligation-dependent probe amplification was utilized to detect PLP1 duplication.With these detection methods,the gene mutations were confirmed,and then genetic features were analyzed.Results 1.Clinical features:Four patients with PMLD showed ataxia and hypomyelination abnormalities from brain nuclear magnetic resonance imaging(MRI).Ages of onset were mainly in infants for P1-3,and 8 vears old and 7 months for P4.Nystagmus was the first symptom for P1-3 while hands shaking and hearing loss for P4.Psychomotor development delay and hypotonia were observed in all of P1-3.The clinical data and brain MRI of 4 patients were all in conformity with the clinical diagnosis standards of PMLD.2.Genetic Features:five novel GJC2 mutations,including c.579delC (p.Glv193fsX17),c..1296_ 1297insG (p.Gly433fsX59),c.735C ＞ A (p.Cys245X),c.689delG (p.Glv230AlafsX241),and c.1199C ＞ A (p.Ala400Glu)were found in 4 patients,which had never been reported home and abroad.P1-3 showed a compound hete-rozygous mutation,which were inherited from their parents with normal phenotype.And c.1199C ＞ A (p.Ala400Glu) homozygous mutation in GJC2 was detected from P4,and their fathers and mothers,heterozygous variation and wild type were found in the corresponding locus,respectively.Conclusions Four patients from 3 pedigrees were diagnosed as PMLD clinically based on their clinical data.Five novel GJC2 mutations were found in this study.Therefore,the spectrum of GJC2 mutations will be expanded.In addition,this study elucidated the clinical and genetic characteristies of 3 pedigrees with PMLD,which would lay a solid foundation for the correct genetic counseling and prenatal diagnosis for those pedigrees.