Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystem disorder characterized by: (1) stroke-like episodes, typically before age 40; (2) encephalopathy, characterized by seizures, dementia, or both; and (3) evidence of a mitochondrial myopathy with lactic acidosis, ragged-red fibers, or both. Although at least 30 distinct mitochondrial DNA mutations have been associated with MELAS, about 80% of patients have the m.3243A> G tRNALeu(UUR) gene mutation. M.3243A>G heteroplasmy levels in blood, urine, and muscle are strongly associated with disease burden and progression. One study suggested that screening urinary epithelial cells for the m.3243A> G mutation may be the most sensitive noninvasive diagnostic test for MELAS. In this article, the authors discuss the clinical manifestations, pathogenesis, and diagnosis of this multisystem disorder, with particular emphasis on recent published works. Moreover, preclinical studies on newly evolving treatment concepts are reported, including (i) L-citrulline and L-arginine to increase NO production, (ii) L-cysteine to improve mitochondrial protein synthesis, (iii) ketogenic diet to alleviate mitochondrial dysfunction, and (iv) taurine supplementation for prevention of stroke-like episodes.
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• The clinical hallmark of MELAS is stroke-like episodes that usually affect young people (typically before age 40) and do not conform to large vessel territories.
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• Although 30 different mitochondrial DNA mutations have been associated with MELAS, about 80% of patients harbor the m.3243A> G mutation.
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• Although MELAS is generally maternally inherited, in most families, only 1 individual has MELAS and others are oligosymptomatic or asymptomatic.
Historical note and terminology
The first cases of MELAS were reported in 1975 by 3 different groups of investigators (34; 125; 70). Seven years later, Rowland and colleagues identified these and 5 additional cases with similar clinical syndromes and ragged-red fibers on muscle biopsy (115). They called this syndrome “mitochondrial myopathy, encephalopathy, and lactic acidosis.” Soon thereafter, Pavlakis identified stroke-like episodes as the distinctive clinical feature and renamed the syndrome “mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes” (108). The acronym MELAS is now widely accepted, although some clinicians prefer the name “mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.” In 1990, Goto and colleagues reported the first mitochondrial point mutation (A-to-G) associated with this syndrome at base pair 3243 (m.3243A> G) in a transfer RNA (tRNALeu(UUR)) (39). Since then, 30 additional point mutations and a 4 base-pair deletion mutation have been reported (Table 1).