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

线粒体肌病是一种多系统的母系遗传性疾病，以人类线粒体DNA的异常、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（mitochondrial myopathy，encephalopathy，lactic acidosis and stroke-like episodes）是一种母系遗传的线粒体多系统疾病，以20岁以前的脑卒中为特征。许多MELAS患者报告了线粒体血管病，表现为肌内小动脉和小动脉内皮细胞中异常线粒体增加的退行性变化。然而，年轻MELAS卒中样发作的主要原因，线粒体细胞病或血管病，或两者兼而有之仍有争议。由于异常的线粒体产生超氧阴离子，我们假设MELAS的血管并发症可能与线粒体内的超氧阴离子有关。 ...更多信息 与氧化应激引起的内皮功能障碍有关。9例经临床、肌肉病理或遗传学诊断为MELAS，其中6例存在线粒体tRNALeu（UUR）基因A3243 G突变，1例存在T3271 C突变，2例未发现遗传异常。在这项研究中，我们研究了血流介导的血管舒张，作为一种非侵入性的测量内皮功能，和抗氧化剂，维生素 *n MELAS患者的影响。我们分析了点突变的数量之间的相关性在内皮细胞和内皮功能的单细胞PCR分析。我们还研究了药理作用的临床过程中，和生化参数后，管理L-精氨酸的患者在急性期中风的三个不同的场合，并在功能方面的脑血流动力学使用单光子发射计算机断层扫描（SPECT）。MELAS患者的血流介导的血管舒张显著较少（年龄匹配对照组的10%）。硝酸甘油诱导的内皮依赖性血管舒张也受损。维生素C管理显着恢复流量介导的扩张和甘油三硝酸酯诱导的血管舒张接近正常水平的MELAS，但没有影响他们在控制。给予L-精氨酸后，患者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（左颞叶）的颅内血流动力学也得到改善，但脑干（丘脑）无变化。点突变的数量与内皮细胞的内皮依赖性血管舒张功能之间存在明显的负相关关系。我们的数据表明，MELAS中所见的血管病变涉及内皮系统血管舒张能力的异常，这可能在导致这种疾病的卒中样发作中发挥重要作用。少

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。

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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。