浙江地区肝豆状核变性的ATP7B突变特征及特殊表型分析

发布时间：2018-04-24 15:03

本文选题：浙江 + 地区　；参考：《浙江大学》2017年博士论文

【摘要】：肝豆状核变性是一种常染色体隐性遗传的铜代谢障碍病,其特征表现为进行性加重的锥体外系神经症状及肝脏损伤。该病的致病基因为ATP7B基因,编码一种P型ATP酶并参与肝脏的铜代谢。目前ATP7B基因已经有超过800种致病突变被报道,分布于整个基因全长。因此,肝豆状核变性患者的基因型十分复杂,不同人群及地区的基因突变热点均存在差异。本研究纳入了 118个以浙江地区为主的肝豆状核变性家系,包含123名经过基因确诊的患者,其中以神经症状起病的患者59例(48.0%),肝病症状起病的患者15例(12.2%),骨关节症状起病患者6例(4.9%),精神症状起病患者4例(3.3%)及无症状患者39例(31.7%)。我们在118个先证者中检测到64种ATP7B基因突变,前三位频率最高的突变分别是p.R778L(34.15%),p.P992L(15.45%)及 p.A874V(3.66%)。随后,我们比较了不同起病类型和不同基因型患者间临床指标的差异,包括起病年龄、神经症状出现年龄、血清铜蓝蛋白、24小时尿铜、血常规、肝肾功能常规、血脂常规、骨代谢指标及电解质。我们发现含有p.R778L纯合突变的患者血清铜蓝蛋白水平较低,而含有p.V1106I突变的患者起病年龄及神经症状出现的年龄较晚,其血清铜蓝蛋白水平亦较高,高度提示其和晚发的肝豆状核变性疾病相关。除此之外,我们总结和分析了过去十年来接诊的13名以骨关节症状为首发表现的肝豆状核变性患者的临床资料,为特殊类型的肝豆状核变性临床早期诊断提供借鉴和参考。
[Abstract]:Hepatolenticular degeneration is an autosomal recessive copper metabolic disorder characterized by progressive exacerbation of extrapyramidal nervous symptoms and liver injury. The pathogenic gene of the disease is ATP7B gene, which encodes a P type ATP enzyme and participates in copper metabolism in the liver. At present, more than 800 pathogenicity mutations of ATP7B gene have been reported and distributed in the whole length of the gene. Therefore, the genotypes of patients with hepatolenticular degeneration are very complex, and gene mutation hotspots are different in different populations and regions. This study included 118 families with hepatolenticular degeneration in Zhejiang province, including 123 patients with genetic diagnosis. There were 59 patients with neurological symptoms, 15 patients with liver diseases, 6 patients with bone and joint symptoms, 4 patients with mental symptoms, and 39 patients with asymptomatic symptoms. 64 mutations of ATP7B gene were detected in 118 proband patients. The highest frequency mutations in the first three loci were p. R778L / 34.15p. P992L / 15.45and p. A874V / 3.66B, respectively. Then, we compared the difference of clinical indexes among patients with different onset types and genotypes, including onset age, age of onset of neurological symptoms, 24 hours urine copper in serum ceruloplasmin, routine blood routine, routine liver and kidney function, routine blood lipids. Indexes of bone metabolism and electrolytes. We found that patients with homozygous mutation of p.R778L had lower levels of serum ceruloplasmin, while patients with p.V1106I mutation had lower onset age and later onset of neurological symptoms, and higher levels of serum ceruloplasmin. It is highly associated with late onset of hepatolenticular degeneration. In addition, we summarized and analyzed the clinical data of 13 cases of hepatolenticular degeneration with osteoarticular symptoms as the first manifestation in the past ten years, which provided reference and reference for the early clinical diagnosis of special types of hepatolenticular degeneration.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R742.4

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