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This syndrome, most commonly caused by an A\u2010to\u2010G transition mutation at position 3243 of the mitochondrial genome, is typified by characteristic neurological manifestations including seizures, encephalopathy, and strokelike episodes, as well as other frequent secondary manifestations including short stature, cognitive impairment, migraines, depression, cardiomyopathy, cardiac conduction defects, and diabetes mellitus. In this review, we discuss the history, pathogenesis, clinical features, and diagnostic and management strategies of mitochondrial disease in general and of MELAS in particular. We explore features of mitochondrial genetics, including the concepts of heteroplasmy, mitotic segregation, and threshold effect, as a basis for understanding the variability and complicated inheritance patterns seen with this group of diseases. We also describe systemic manifestations of MELAS\u2010associated mutations, including cardiac, renal, endocrine, gastrointestinal, and endothelial abnormalities and pathology, as well as the hypothetical role of derangements to COX enzymatic function in driving the unique pathology and clinical manifestations of MELAS. Although therapeutic options for MELAS and other mitochondrial diseases remain limited, and recent trials have been disappointing, we also consider current and potential therapeutic modalities.<\/jats:p>","DOI":"10.1196\/annals.1444.011","type":"journal-article","created":{"date-parts":[[2009,8,11]],"date-time":"2009-08-11T08:07:53Z","timestamp":1249978073000},"page":"133-158","source":"Crossref","is-referenced-by-count":311,"title":["Mitochondrial Encephalopathy, Lactic Acidosis, and Strokelike Episodes"],"prefix":"10.1196","volume":"1142","author":[{"given":"Douglas M.","family":"Sproule","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Kaufmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,10,23]]},"reference":[{"key":"e_1_2_26_2_2","first-page":"652","article-title":"Circular dimer and catenate forms of mitochondrial DNA in human leukaemic leucocytes","volume":"35","author":"Clayton D.A.","year":"1967","journal-title":"J. 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