线粒体神经胃肠脑肌病一家系临床及TYMP基因突变分析

发布时间：2018-06-24 02:39

本文选题：线粒体神经胃肠脑肌病 + 胃肠蠕动障碍　；参考：《山西医科大学》2014年硕士论文

【摘要】：研究背景：线粒体神经胃肠脑肌病（mitochondrial neurogastrointestinal encephalomy-opathy, MNGIE）是一种罕见的多系统受累的常染色体隐性遗传的线粒体疾病，其致病基因为TYMP。该基因突变可引起胸苷磷酸化酶（thymidine phosphorylase,TP)活性受损，导致核苷在血浆中和组织中蓄积以及线粒体功能障碍。临床以神经系统和胃肠系统受累为主要表现。主要通过检测白细胞中TP活性和TYMP基因突变分析来明确诊断。目的：分析一个中国MNGIE家系的临床、肌肉病理及遗传学特征，并对患者及其家系成员行TYMP基因检测，以明确致病突变位点。方法：对山西医科大学第一医院神经内科临床拟诊为MNGIE的患者，进行详尽的家系分析研究，收集先证者以及该家系成员详尽的临床资料和外周血标本，对先证者的临床特点、影像学资料、肌肉活检结果进行分析，并采用聚合酶链式反应进行TYMP基因突变分析。结果： 1.先证者为45岁男性，20岁起病，以反复腹泻为特征，后期表现为进行性的体重下降，查体可见先证者体型消瘦，眼睑下垂及眼外肌麻痹，眼球各方向活动障碍，听力下降及周围神经损害；头颅MRI提示广泛的脑白质病变，，但基底节区和胼胝体区未受累。先证者父母为近亲结婚。家系中其他成员无类似临床表现。 2.先证者肌肉病理示：HE染色示肌纤维大小不一，可见数个紫红色边缘嗜碱性肌纤维，MGT染色可见多个破碎红纤维，COX染色可见酶活性缺失纤维，SDH染色可见酶活性增强纤维。 3.先证者TYMP基因分析发现一个新的纯合重复突变，即c.1193_1216dupGGGCGCTGCCGCTGGCGCTGGTGC，p.(Arg398_Val405dup)；该家系成员中III:1、III:3、IV:1、IV:6、V:2、V:3、V:4、V:5、V:7均为c.1193_1216dup的杂合突变。结论： 1.先证者的临床特点、血生化、影像学检查及肌肉活检结果，均符合典型MNGIE的表现。 2.先证者为c.1193_1216dup纯合突变，该家系成员中有9例（III:1、III:3、IV:1、IV:6、V:2、V:3、V:4、V:5、V:7）均为c.1193_1216dup杂合突变，结合临床表型及辅助检查结果，该突变为本家系致病突变。 3.先证者c.1193_1216dup纯合突变所致MNGIE为国内外首次报道。
[Abstract]:Background: mitochondrial neurogastroenteric encephalomyopathy (MNGIE) is a rare multisystem involving autosomal recessive mitochondrial disease. The mutation of this gene can damage the activity of thymidine phosphorylase TP, lead to the accumulation of nucleoside in plasma and tissue and the dysfunction of mitochondria function. The main clinical manifestations were nervous system and gastrointestinal system involvement. The diagnosis was determined by detecting TP activity and TYMP gene mutation in leukocytes. Objective: to analyze the clinical, muscular pathological and genetic characteristics of a Chinese MNGIE family, and to detect the TYMP gene of the patients and their family members in order to identify the pathogenicity mutation sites. Methods: the patients of Department of Neurology, the first Hospital of Shanxi Medical University, who were clinically diagnosed as MNGIE, were analyzed and studied in detail, and the clinical data and peripheral blood samples of the proband and the members of the family were collected. The clinical features, imaging data, muscle biopsy results and TYMP gene mutation were analyzed by polymerase chain reaction (PCR). Results: 1. The proband was a 45-year-old male who had been sick since the age of 20, characterized by repeated diarrhea, with progressive weight loss in the later stage. The body examination showed that the proband was thin, the eyelid drooping and the extraocular muscle paralysis, and the movement of the eyeball in all directions. Hearing loss and peripheral nerve damage, cranial MRI showed extensive white matter lesions, but the basal ganglia and corpus callosum were not involved. The proband's parents were married for their close relatives. Other members of the family have no similar clinical manifestations. 2. The muscle pathology of the proband showed that the size of muscle fiber was different with the staining of% HE. MGT staining of several purplish red edge basophilic muscle fibers can be seen in several broken red fibers Cox staining can be seen enzyme activity missing fiber SDH staining can be seen enzyme activity enhancement fiber. 3. A new homozygous repeat mutation was found in proband TYMP gene analysis, I. e., c.119316pGGCGCTGCCGCTGCTGCTGCTGGTGCCf. (Arg398Val405dup). Conclusion: 1. The clinical features, blood biochemistry, imaging findings and muscle biopsy results of the proband were in accordance with the typical MNGIE findings. 2. The proband was a homozygous mutation of c.1193_1216dup. Nine of the members (III: 1 / III: 3IV: 1: 1) were c.1193_1216dup heterozygosity mutations. Combined with the clinical phenotypic and auxiliary examination results, the mutation was a pathogenic mutation of this family. MNGIE caused by homozygous mutation of proband c.1193_1216dup was first reported at home and abroad.
【学位授予单位】：山西医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R741

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