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Clinical and Molecular Genetical Research for the Treatment of Mitochondrial Encephalomyopathies

线粒体脑肌病治疗的临床和分子遗传学研究

基本信息

批准号：
09670842
负责人：
NAKANO Kazutoshi
金额：
$ 2.18万
依托单位：
TOKYO WOMEN'S MEDICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 2000
项目状态：
已结题

项目摘要

Mitochondrial encephalomyopathy is caused by mitochondrial dysfunction mainly in electron transport system in the inner mitochondrial membrane. The essential treatment has not yet been established, partly because the clinical effect of the treatment has been well evaluated from the point of the serial changes of mitochondrial enzyme activity and mitochondrial (mt) DNA analyses. We developed the methods of mitochondrial enzyme activities and mtDNA analyses in platelet (PLT). We also developed creatine monohydrate (Cr-H_2O) treatment for the mitochondrial encephalomyopathies.Miniaturized assays for isolated PLT were employed for the measurement of protein, complex II+III (II+III), complex IV (IV), and citrate synthase (CS) assays using a microplate reader. We newly developed the miniaturized assay for (IV). A3243G mutation of mtDNA was analyzed with PCR/RFLP methtod for the isolated PLT.We evaluated the stroke-like episode in a patient with MELAS and the efficacy of sodium dichloroacetat … More e (DCA) treatment using PLT mitochondrial enzyme assay. Although her muscle weakness improved with cytochrome c treatment, neurological symptoms including headache, vomiting and visual disturbance developed to intractable headache, which was a mild form of stroke-like episode. The intractable severe headache improved with DCA treatment. PLT (II+III), (IV) and (IV/CS) decreased at the stroke-like episode and DCA treatment improved PLT (II+III), (IV), and (IV/CS). Ratio of A3243G mutation of mtDNA was not changed before and after DCA treatment.Cr-H_2O was orally supplemented (0.2 g/kg/day, divided into two for the first two weeks followed by 0.08-0.12 g/kg/day twice or three times a day for 4-10 months) in two girls with MELAS due to an nt A3243G mtDNA mutation. The brain function was evaluated with frequency analysis of EEG and ^1H MRS.the results demonstrated that Cr-H_2O supplement improved the brain function of MELAS, suggesting the possibility of Cr-H_2O treatment for mitochondrial encephalomyopathy. Less

线粒体脑肌病是由线粒体功能障碍引起的，主要是线粒体内膜电子传递系统的功能障碍。必要的治疗尚未确定，部分原因是从线粒体酶活性和线粒体（mt） DNA分析的一系列变化来看，治疗的临床效果已经得到了很好的评价。我们建立了血小板（PLT）线粒体酶活性和mtDNA分析方法。我们还开发了一水合物肌酸（Cr-H_2O）治疗线粒体脑肌病。使用微孔板读取器对分离PLT进行蛋白质、复合体II+III （II+III）、复合体IV （IV）和柠檬酸合酶（CS）的测定。我们新开发了（IV）的小型化检测方法。采用PCR/RFLP方法对分离的PLT进行mtDNA A3243G突变分析。我们用PLT线粒体酶测定法评估了一例MELAS患者的卒中样发作和二氯乙酸钠（DCA）治疗的疗效。虽然她的肌肉无力在细胞色素c治疗后得到改善，但神经系统症状包括头痛、呕吐和视力障碍发展为顽固性头痛，这是一种轻微的中风样发作。顽固性重度头痛经DCA治疗后得到改善。PLT （II+III）、（IV）和（IV/CS）在卒中样发作时降低，DCA治疗改善PLT （II+III）、（IV）和（IV/CS）。DCA处理前后mtDNA A3243G突变比例无明显变化。在两名因nt A3243G mtDNA突变而患有MELAS的女孩中，口服补充Cr-H_2O （0.2 g/kg/天，前两周分为两次，随后每天两次或三次，每次0.08-0.12 g/kg/天，持续4-10个月）。结果表明，补充Cr-H_2O可改善MELAS的脑功能，提示Cr-H_2O治疗线粒体脑肌病的可能性。少