Molecular complementation study of mitochondrial myopathy and their therapeutic trial.

线粒体肌病的分子互补研究及其治疗试验。

• 批准号: 11670805
• 负责人: KOGA Yasutoshi
• 金额: $ 2.3万
• 依托单位: Department of Pediatrics and Child Health, Kurume University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670805/
• 关键词: mitochondrial DNA; mitochondrial myopathy; respiratory chain enzyme; mitochondrial tRNA; heteroplasmy; PCR; endothelial function

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

线粒体肌病是一个多系统和主要渗透的疾病，其特征是人线粒体DNA，点突变，缺失或重复。其中，线粒体trnaleu（UUR）基因的点突变是患者最常见的遗传异常。 Melas（线粒体肌病，脑病，乳酸性酸中毒和类似于中风的发作）的特征是在20岁之前中风，是一种主要具有线粒体多系统疾病的疾病。线粒体血管病在许多MELAS患者中据报道，在肌内小动脉和小动脉的内皮细胞中线粒体异常的线粒体异常，表现出了变性。但是，年轻的Melas Strokelike发作的主要原因是线粒体细胞病或血管病，或者两者仍然存在争议。由于线粒体异常会产生超氧化阴离子，因此我们假设Melas中的血管并发症可能是相关的……与由氧化应激引起的内皮功能障碍更加与内皮功能障碍相关。有9例在临床上，肌肉行为学或遗传诊断为MELAS的患者。SIX患者患有A3243G突变，一名患者在线粒体TRNALEU（UUR）基因中患有T3271C突变，两名患者尚未发现其遗传异常。在这项研究中，我们研究了流动介导的血管舒张作用，是对内皮功能的无创测量，以及抗氧化剂，维生素 *N患者MELAS的影响。我们通过单细胞PCR分析了内皮细胞中点突变的相关性。我们还研究了对临床过程的药物效应，并在三个单独的情况下，在中风的急性阶段对患者进行L-精氨酸后，以及使用单个光子血液动力学的功能方面，使用单个光子发射计算机造影（SPECT）。 MELAS患者中流动介导的血管舒张作用明显较小（占年龄匹配对照的10％）。糖基酸酯诱导的三硝酸盐诱导的内皮依赖性血管舒张也受到损害。维生素C给药可显着恢复流动介导的词典和三硝酸盐诱导的血管扩张至MELAS接近正常水平，但在对照中不影响它们。施用L-精氨酸后，患者的所有症状都表明示意性发作症状在临床上得到改善。在使用ECD的SPECT上，颅内血液动力学在缺血区域（在左临时叶中）也得到了改善，但在脑干（thalamus）中没有变化。点突变的量与内皮细胞中内皮依赖性 - 舒张的能力之间存在明显的逆相关性。我们的数据表明，在MELAS中看到的血管病涉及内皮系统血管舒张的异常，这可能在引起这种疾病中引起strokelikelikelikelike的发作中起重要作用。较少的

项目成果

Akita Y, Koga Y, Iwanaga R, Wada N, Tsubone J, Fukuda S, Nakamura Y, Kato H: "Fatal hypertrophic cardiomyopathy associated with an A8296G mutation in the mitochondrial tRNALys gene."Human Mutation. #306 online. 1-7 (2000)

Akita Y、Koga Y、Iwanaga R、Wada N、Tsubone J、Fukuda S、Nakamura Y、Kato H：“与线粒体 tRNALys 基因 A8296G 突变相关的致命肥厚性心肌病。”人类突变。

Yoshino M et al: "Management of acute metabolic decompensation in maple syrup urine disease: A multi-center study."Pediatrics International. 41. 132-137 (1999)

Yoshino M 等人：“枫糖浆尿病急性代谢失代偿的治疗：一项多中心研究。”国际儿科。

Koga Y, Akita Y, Takane N, Sato Y, Kato H: "Heterogeneous presentation in A3243G mutation in the mitochondrial tRNALeu (UUR) gene."Archieves of Disease in Childhood. 82(5). 407-411 (2000)

Koga Y、Akita Y、Takane N、Sato Y、Kato H：“线粒体 tRNALeu (UUR) 基因中 A3243G 突变的异质表现。”儿童疾病档案。

Iwanaga R, Koga Y, Aramaki S, Kato S, Kato H.: "Inter- and/or intra-organ distribution of mitochondrial C3303T or A3243G mutation in mitochondrial cytopathy."Acta Neuropathol (Berl). 101. 179-184 (2001)

Iwanaga R、Koga Y、Aramaki S、Kato S、Kato H.：“线粒体细胞病中线粒体 C3303T 或 A3243G 突变的器官间和/或器官内分布。”Acta Neuropathol (Berl)。

Koga Y.et al.: "Single fiber analysis of mitochondrial A3243G mutation in four different phenotypes."Acta Neuropathologica. 99. 186-190 (2000)

Koga Y.等人：“四种不同表型中线粒体 A3243G 突变的单纤维分析。”神经病理学报。