Molecular complementation study of mitochondrial myopathy and their therapeutic trial.

线粒体肌病是一种多系统的母系遗传性疾病，以人类线粒体DNA异常、点突变、缺失或复制为特征。其中，线粒体tRNALeu(UUR)基因点突变是患者最常见的遗传异常。MELAS(线粒体肌病、脑病、乳酸酸中毒和卒中样发作)以20岁前卒中为特征，是一种母系遗传性线粒体多系统疾病。线粒体血管病表现为退行性改变，肌内小动脉和小动脉内皮细胞异常线粒体增多，在许多MELAS患者中已有报道。然而，年轻的MELAS卒中样发作的主要原因，无论是线粒体细胞病变还是血管病变，或者两者兼而有之，仍然存在争议。由于异常线粒体产生超氧阴离子，我们推测MELAS的血管并发症可能与…有关。更多地与氧化应激引起的内皮功能障碍有关。9例患者被临床、肌肉病理或基因诊断为MELAS，6例患者存在A3243G突变，1例患者存在线粒体tRNALeu(UUR)基因T3271C突变，2例患者尚未发现其基因异常。在这项研究中，我们检测了血流介导的血管扩张，作为内皮功能的非侵入性测量，以及抗氧化剂维生素*对MELAS患者的影响。我们通过单细胞PCR分析分析了内皮细胞中点突变的数量与内皮功能的相关性。采用单光子发射计算机断层扫描技术，研究了L精氨酸对中风急性期患者的临床病程、生化指标及脑血流动力学功能方面的影响。在MELAS患者中，血流介导的血管扩张明显较少(年龄匹配对照组的10%)。硝酸甘油诱导的内皮依赖性血管扩张也受到损害。在MELAS患者中，给予维生素C显着将血流介导的血管扩张和硝酸甘油诱导的血管扩张恢复到接近正常的水平，但在对照组中没有影响。经L-精氨酸治疗后，患者所有提示卒中发作的症状均得到改善。在ECD SPECT上，缺血区(左侧颞叶)的颅内血流动力学也有改善，但脑干(丘脑)的血流动力学无明显变化。点突变的数量与内皮细胞的内皮依赖性血管扩张能力之间存在明显的负相关。我们的数据表明，MELAS中的血管病变涉及内皮系统血管扩张能力的异常，这可能在导致这种疾病的卒中样发作中发挥重要作用。较少

Mitochondrial myopathy, which is a multisystem and a maternally inherted disorders, characterized by an abnormality in the human mitochondrial DNA, point mutation, deletion or duplication. Among those, a point mutation in the mitochondrial tRNALeu (UUR) gene is the most frequent genetical abnormality seen in the patient. MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) is characterized by stroke before 20 years old, is a maternally-inherited mitochondrial multisystem disorder. Mitochondrial angiopathy demonstrating degenerative change with increased abnormal mitochondria in the endothelial cells of intramuscular small arteries and arterioles have been reported in many MELAS patients. However, the primary cause of the young MELAS strokelike episodes, either mitochondrial cytopathy or angiopathy, or both is still controversial. Since abnormal mitochondria generates superoxide anion, we hypothesized that vascular complications in MELAS may be associ … More ated with endothelial dysfunction caused by oxidative stress. Nine patients were clinically, muscle-pathologically or genetically diagnosed as MELAS.Six patients have an A3243G mutation, one patient has a T3271C mutation in the mitochondrial tRNALeu (UUR) gene, and two patients have not been found their genetic abnormality. In this study, we examined flow-mediated vasodilatation, as a non-invasive measure of endothelial function, and effects of an antioxidant, vitamin *n patients with MELAS.We analyzed the correlationship between the amount of point mutation in the endothelial cell and the endothelial function by single-cell PCR analysis. We also studied the pharmacological effect on the clinical course, and biochemical parameters after administration of L-arginine to a patient in the acute phase of stroke on three separated occasions and, and on the functional aspects of the cerebral hemodynamics using single photon emission computed tomography (SPECT). Flow-mediated vasodilatation was significantly less (10% of the age-matched controls) in MELAS patients. Endothelium-dependent vasodilatation induced by glyceryl trinitrate was also impaired. Vitamin C administration significantly restored flow-mediated dilation and glyceryl trinitrate-induced vasodilatation to near-normal levels in MELAS but did not affect them in controls. After the administration of L-arginine, all the symptoms of the patient suggesting the strokelike episode were clinically improved. On SPECT using ECD, the intracranial hemodynamics were also improved in the ischemic area (in the left temporal lobe), but unchanged in the brain stem (thalamus). There are clear inverse correlationships between the amount of point mutation and the capacity of endothelial dependent-vasodilatation in the endothelial cells. Our data demonstrated that angiopathy seen in MELAS involved abnormality in the capacity of vasodilatation in the endothelial system, which may play an important role in causing strokelike episodes in this disorder. Less