【作者】 黄丹；

【导师】 邹朝春；

【作者基本信息】 浙江大学 ， 临床医学（专业学位）， 2019， 硕士

【摘要】 目的:血脂代谢紊乱又称血脂异常(dyslipidemia),是一种遗传性或多因素所致的脂质和(或)脂蛋白代谢紊乱为特点的疾病。儿童血脂代谢紊乱是罕见的遗传代谢性疾病,可导致严重的心血管疾病,严重危害着儿童的健康。本文的目的分析10例血脂异常患者临床表型特征,通过二代测序明确儿童血脂代谢紊乱相关致病基因并阐明基因变异致病机制,总结儿童血脂代谢紊乱的诊治近况。方法:回顾性分析浙江大学医学院附属儿童医院内分泌科于2009.06-2017.08门诊及住院收治的10例血脂异常患者的临床资料。对7例先证者及其中2例父母进行二代测序,针对检测到的突变位点,通过分析确定相关致病基因并分析其作用机制。结果:10例先证者临床表型存在差异,4例(P2至P5)带有强致病性基因变异。1.临床表型:(1)10例均来自浙江省,男性5例,女性5例;(2)诊断年龄的中位数是4.7岁;高乳糜微粒血症者发病年龄及出现临床症状时间早,3例(P1、P2、P10)均在1岁以内起病;(3)始发症状及临床表现5例为皮肤黄色瘤,3例(P1、P2、P10)发现血浆外观呈奶油样状;(5)临床表型中5例为高胆固醇血症,4例为混合型高脂血症,1例为高甘油三酯血症。2.分子遗传学结果:7例应用二代测序进行基因检测:1例(P2)中发现LPL基因c.808C>T(Arg270Cys)错义突变;1例(P3)中发现LDLR基因c.2054C>T(Pro685Leu)错义突变;2 例(P4、P5)中均发现 ABCG5 基因突变(1例错义突变、1例无义突变)。P4为复杂型杂合突变,分别为:ABCG5基因存在c.1166 G>A(Arg389His)纯合错义突变,父母亲(表型正常)均为杂合携带者;ABCA1基因存在c.5002G>A(Leu1041Val)及c.3121C>G(Va11668Ile)杂合错义变异,遗传来自父亲。P5中ABCG5基因存在c.751C>T(Gln251*)纯合无义突变。其父母亲(表型正常)均为杂合携带者。P4、P5表型符合谷固醇血症。P1带有意义不明基因变异而其临床表型符合高乳糜微粒血症;以上基因变异均非新发变异。2名(P6、P7)中未发现致病基因变异。3.治疗及预后:均予饮食控制动物固醇摄入量,婴儿予以控制长链脂肪酸摄入量,2例予以药物控制(P3予“辛伐他汀”口服治疗半年,P9予以“阿托伐他汀”口服治疗半年,疗效欠佳);6例血脂水平(P1、P4-P7、P10)可以控制在正常或接近正常上限;谷固醇血症者P4、P5皮肤黄色瘤变大,予同时控制动物和植物固醇摄入,皮肤黄色瘤有改善,未发现先证者出现早发性冠心病。结论:(1)儿童血脂代谢紊乱临床表型多样,不典型,易被漏诊;(2)儿童血脂代谢紊乱具有高遗传异质性,遗传分子诊断可增加临床诊断的准确性,有利于疾病的早诊断、早治疗;(3)谷固醇血症可能是我国高胆固醇血脂的一个重要原因,应建议限制胆固醇和植物甾醇饮食。更多还原

【Abstract】 ObjectiveDyslipidemia is a disease characterized by a genetic or multifactorial disorder of lipid and/or lipoprotein metabolism.Childhood dyslipidemia is a rare genetic metabolic disease that can cause serious cardiovascular disease and seriously endanger children’s health.In order to analyze the clinical phenotypic characteristics of 10 patients with dyslipidemia,we uses second-generation sequencing to identify the related pathogenic genes in children,and elucidate the pathogenesis of gene mutation,and summarize the diagnosis and treatment of dyslipidemia in children.MethodsWe retrospectively analyzed the clinical data of 10 patients with dyslipidemia who were admitted to the Department of Endocrinology,Children’s Hospital of Zhejiang University School of Medicine from June in 2009 to August in 2017.Seven pro bands and two of their parents underwent next generation sequencing.Based on the detected mutation sites,the relevant pathogenic genes were identified by data analysis and their mechanism was analyzed.Result:There were differences in the clinical phenotype of 10 probands,and four probands,P2 to P5,had strong pathogenic mutations.1.Clinical phenotypes:(1)10 cases of proband were from Zhejiang Province,there was 5 males and 5 females;(2)The median age of diagnosis is 4.7 years old;The age of onset and the onset of clinical symptoms in hyperchylomicronemia were early,such as P1,P2 and P10 started within 1 year of age;(3)The symptoms and the clinical manifestations were mostly xanthomas.Three of probands(P1,P2 and P10)were found that the creamy plasma appearance;(5)Among the clinical phenotypes,5 cases were hypercholesterolemia,4 cases were combined hyperlipidemia,and 1 case was hypertriglyceridemia.Two of them were low high density lipoproteinemia.2.Molecular genetic results:Genetic testing was performed in 7 probands by using next generation sequencing:LPL c.808C>T(Arg270Cys)gene missense mutation was found in P2;the mutation c.2054C>T(Pro685Leu)of LDLR gene were found in P3.There were ABCG5 gene mutations in P4 and P5(1 missense mutation and 1 nonsense mutation).There was a complex heterozygous mutation in P4,one is c.1166 G>A(Arg389His),a homozygous missense mutation of ABCG5,and both father and mother were heterozygous carriers.Another is heterozygous missense mutations of c.5002G>A(Leu1041Val)and c.3121C>G(Val1668Ile)of ABCA1.In P5,there was a homozygous nonsense mutation of c.751C>T(Gln251*)in ABCG5.Both parents(normal phenotype)were heterozygous carriers.P1 with an unknown mutation and its clinical phenotype is consistent with hyperchylomicronemia.None of the above gene mutations were new mutations,and no pathogenic gene was found in P6 and P7.3.Treatment and prognosis:They were all given dietary control of cholesterol intake,infants were controlled long-chain fatty acid intake.2 probands were given drug control(P3 was given with "simvastatin" orally,and P9 with"Atorvastatin" orally for 6 months,but the efficacy was not good).6 cases(PI、P4-P7、P10)can control the blood lipid level at normal or near the upper limit levels;xanthoma of 2 cases,sitosterolemia(P4 and P5)became larger.But after controlling animal cholesterol and phytosterol intake simultaneously,the xanthoma has improved.No early-onset coronary heart disease has been found in these probands.Conclusion(1)Children with dyslipidemia have diverse clinical phenotype and symptoms are not typical.It is easy to be missed;(2)Children with dyslipidemia have high genetic heterogeneity.Genetic test can increase the accuracy of clinical diagnosis and contribute to early diagnosis and treatment of diseases.(3)Sitosterolemia may be an important cause of hypercholesterolemia in China.The restriction of cholesterol and phytosterol intake should be suggested for sitosterolemia.更多还原