Scaglia Fernando, Northrop Jennifer L
Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030, USA.
CNS Drugs. 2006;20(6):443-64. doi: 10.2165/00023210-200620060-00002.
Mitochondrial encephalomyopathies are a multisystemic group of disorders that are characterised by a wide range of biochemical and genetic mitochondrial defects and variable modes of inheritance. Among this group of disorders, the mitochondrial myopathy, encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome is one of the most frequently occurring, maternally inherited mitochondrial disorders. As the name implies, stroke-like episodes are the defining feature of the MELAS syndrome, often occurring before the age of 15 years. The clinical course of this disorder is highly variable, ranging from asymptomatic, with normal early development, to progressive muscle weakness, lactic acidosis, cognitive dysfunction, seizures, stroke-like episodes, encephalopathy and premature death. This syndrome is associated with a number of point mutations in the mitochondrial DNA, with over 80% of the mutations occurring in the dihydrouridine loop of the mitochondrial transfer RNA(Leu(UUR)) [tRNA(Leu)((UUR))] gene. The pathophysiology of the disease is not completely understood; however, several different mechanisms are proposed to contribute to this disease. These include decreased aminoacylation of mitochondrial tRNA, resulting in decreased mitochondrial protein synthesis; changes in calcium homeostasis; and alterations in nitric oxide metabolism. Currently, no consensus criteria exist for treating the MELAS syndrome or mitochondrial dysfunction in other diseases. Many of the therapeutic strategies used have been adopted as the result of isolated case reports or limited clinical studies that have included a heterogeneous population of patients with the MELAS syndrome, other defects in oxidative phosphorylation or lactic acidosis due to disorders of pyruvate metabolism. Current approaches to the treatment of the MELAS syndrome are based on the use of antioxidants, respiratory chain substrates and cofactors in the form of vitamins; however, no consistent benefits have been observed with these treatments.
线粒体脑肌病是一组多系统疾病，其特征是存在广泛的生化和遗传性线粒体缺陷以及多种遗传方式。在这组疾病中，线粒体肌病、脑病、伴有卒中样发作的乳酸性酸中毒（MELAS）综合征是最常见的母系遗传线粒体疾病之一。顾名思义，卒中样发作是MELAS综合征的典型特征，通常发生在15岁之前。这种疾病的临床病程差异很大，从早期发育正常且无症状，到进行性肌无力、乳酸性酸中毒、认知功能障碍、癫痫发作、卒中样发作、脑病和过早死亡。该综合征与线粒体DNA中的一些点突变有关，超过80%的突变发生在线粒体转移RNA（亮氨酸（UUR））[tRNA（Leu）（（UUR））]基因的二氢尿苷环中。该疾病的病理生理学尚未完全了解；然而，提出了几种不同的机制来解释这种疾病。这些机制包括线粒体tRNA的氨酰化减少，导致线粒体蛋白质合成减少；钙稳态变化；以及一氧化氮代谢改变。目前，对于治疗MELAS综合征或其他疾病中的线粒体功能障碍，尚无共识标准。许多治疗策略是由于个别病例报告或有限的临床研究而采用的，这些研究纳入了患有MELAS综合征、氧化磷酸化其他缺陷或丙酮酸代谢紊乱导致乳酸性酸中毒的异质性患者群体。目前治疗MELAS综合征的方法基于使用抗氧化剂、呼吸链底物和维生素形式的辅助因子；然而，这些治疗并未观察到一致的益处。
