Molecular complementation study of mitochondrial myopathy and their therapeutic trial.

线粒体肌病是一种多系统、母系遗传性疾病，以人类线粒体DNA异常、点突变、缺失或重复为特征。其中，线粒体tRNALeu （UUR）基因的点突变是患者中最常见的遗传异常。MELAS（线粒体肌病、脑病、乳酸酸中毒和卒中样发作）是一种母亲遗传的线粒体多系统疾病，以20岁前卒中为特征。线粒体血管病变表现为退行性改变，肌内小动脉和小动脉内皮细胞异常线粒体增加，已在许多MELAS患者中报道。然而，年轻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，还是两者兼而有之，仍然存在争议。由于线粒体异常产生超氧阴离子，我们推测MELAS的血管并发症可能与氧化应激引起的内皮功能障碍有关。9例患者经临床、肌肉病理学或遗传学诊断为MELAS。6例患者有A3243G突变，1例患者线粒体tRNALeu （UUR）基因有T3271C突变，2例患者未发现其遗传异常。在这项研究中，我们检查了血流介导的血管舒张，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分析内皮细胞中点突变的数量与内皮功能的相关性。我们还研究了l -精氨酸对中风急性期患者的临床病程和生化参数的药理学影响，以及使用单光子发射计算机断层扫描（SPECT）对脑血流动力学的功能方面的影响。MELAS患者血流介导的血管舒张明显减少（占年龄匹配对照组的10%）。三硝酸甘油诱导的内皮依赖性血管舒张也受到损害。在MELAS患者中，给予维生素C显著地将血流介导的扩张和三硝酸甘油诱导的血管扩张恢复到接近正常水平，但在对照组中没有影响它们。给予l -精氨酸后，提示卒中样发作的所有症状均得到临床改善。在使用ECD的SPECT上，缺血区域（左颞叶）的颅内血流动力学也有所改善，但脑干（丘脑）的血流动力学不变。在内皮细胞中，点突变的数量与内皮依赖性血管舒张能力之间存在明显的负相关关系。我们的数据表明，MELAS患者的血管病变涉及内皮系统血管舒张能力的异常，这可能在该疾病中引起卒中样发作中起重要作用。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