10例儿童肝豆状核变性患者临床分析和基因检测

发布时间：2018-04-03 00:01

  本文选题：肝豆状核变性　切入点：儿童　出处：《青岛大学》2017年硕士论文

【摘要】：目的对肝豆状核变性(hepatolenticular degeneration,HLD)患者的临床资料进行总结分析,了解HLD患者的基因突变类型及治疗方法,进一步丰富HLD患者临床资料,提高诊断率,总结有效的治疗方法,以期对临床医生有指导作用。方法回顾性分析我院近3年收治的10例肝豆状核变性患者的临床资料、实验室检查结果、治疗及随访,并对患者及其父母应用DNA一代测序检测ATP7B基因(21个外显子编码区及内含子—外显子交界处),进行基因诊断。结果本研究共有10例患者,其中男4例,女6例,无阳性家族史。对其首发症状进行统计:肝功能异常为主者5例,神经系统症状为主者2例,血液系统疾病为主者2例,肝功能异常合并神经系统症状为1例。10例患者24h尿铜指标均高于正常值,铜蓝蛋白含量均低于0.08g/L;10例HLD患者检查角膜K-F环,7例出现阳性;对10例HLD患者的肝、脾、肾等器官进行超声检查,发现10例患者中6例患者出现肝肿大,1例患者出现肝硬化,5例患者出现脾肿大,1例患者出现肾脏错构瘤;尿液分析检查2例患者出现蛋白尿,2例患者出现血尿。颅脑MRI检查10例患者,发现1例患者脑部存在异常,表现为双侧豆状核、尾状核、脑桥多发异常信号。本研究对10例患者及父母的ATP7B基因全外显子的编码区进行DNA一代测序,10例确诊为HLD的患者中均发现ATP7B基因存在突变,共发现9种基因突变,包括1种剪接突变、1种无义突变(p.Arg1319*)和7种错义突变(p.Arg778Leu、p.Ala874Val、p.Pro992Leu、p.Asn1270Ser、p.Pro840Leu、p.Thr935Met、p.Asp1047Val)。本研究中检出的基因突变均为杂合突变,5例患者均存在8号外显子p.Arg778Leu突变;3例患者均存在13号外显子p.Pro992Leu突变,基因突变频率分别为25%、15%。根据本研究可以认为,本地区ATP7B基因的高频突变位点是8号外显子第778密码子(R778L),其次为第13号外显子第992密码子(P992L)。针对10例患者的不同情况,采用二巯丙磺酸钠注射液、硫酸锌、青霉胺进行驱铜治疗及保肝治疗,结合肝功能检查、24小时尿铜等随访指标,10例患者的病情的得到控制并趋于平稳。结论1、不明原因的肝病和(或)神经系统异常、脾肿大、黄疸、溶血性贫血、肾脏损害,需考虑本病的可能。综合患者铜蓝蛋白、角膜K-F环、24小时尿铜,并结合临床表现及肝、脑等影像学检查,可以做出临床确诊。2、本地区HLD患者ATP7B基因的高频突变位点是8号外显子第778密码子(R778L),其次为第13号外显子第992密码子(P992L)。3、该研究表明对HLD患者采取驱铜及保肝治疗是行之有效的。
[Abstract]:Objective to summarize and analyze the clinical data of patients with hepatolenticular degenerationHLD (hepatolenticular degenerationHLD), to understand the type of gene mutation and the treatment methods in HLD patients, to enrich the clinical data of HLD patients, to improve the diagnostic rate, and to summarize the effective treatment methods.With a view to clinical doctors have a guiding role.Methods the clinical data, laboratory findings, treatment and follow-up of 10 patients with hepatolenticular degeneration were retrospectively analyzed.DNA generation sequencing was used to detect the ATP7B gene (21 exon coding regions and intron-exon junction) in patients and their parents for gene diagnosis.Results A total of 10 patients, including 4 males and 6 females, had no positive family history.The initial symptoms were as follows: 5 cases with abnormal liver function, 2 cases with nervous system symptoms, 2 cases with hematological diseases, 5 cases with abnormal liver function, 2 cases with nervous system symptoms and 2 cases with hematological diseases.The urine copper index of 10 patients with abnormal liver function and nervous system symptom was higher than normal value, the content of ceruloplasmin was lower than 0.08g / L in 10 patients with HLD, 7 patients were positive for K-F loop of cornea, 10 patients with HLD had liver, spleen, liver, spleen, liver, spleen, liver, spleen, liver, spleen, liver, spleen, liver, spleen, liver, spleen, liver and spleen.Ultrasound examination of kidney and other organs showed that 6 out of 10 patients had hepatomegaly and 1 patient had cirrhosis and 5 patients had splenomegaly and 1 patient had renal hamartoma.Urine analysis was performed in 2 patients with proteinuria and 2 patients with hematuria.Brain MRI examination in 10 cases showed that 1 patient had abnormal brain signals, including bilateral lentiform nucleus, caudate nucleus and pontine multiple abnormal signals.In this study, 10 patients and their parents' ATP7B gene were sequenced by DNA generation sequencing. In 10 patients with HLD, 9 mutations were found in ATP7B gene.鍖呮嫭1绉嶅壀鎺ョ獊鍙，

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