Dr. Ciafaloni of the University of Rochester received consulting fees from Biogen and Pfeizer and research grants from Sarepta and Santhera.)
This article includes discussion of MELAS; mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome; mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome; and mitochondrial myopathy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
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. One study has suggested that screening urinary epithelial cells for the m.3243A>G mutation may be the most sensitive non-invasive diagnostic test for MELAS. In this article, the author discusses the clinical manifestations, pathogenesis, and diagnosis of this multisystem disorder. The author puts particular emphasis on recent work on novel biomarkers including (1) nitric oxide production as assessed with a stable isotope tracer infusion technique, (2) intramyocellular lipid accumulation as determined noninvasively by 7T magnetic resonance spectroscopy, and (3) abnormal cortical vein signal in T2/FLAIR MRI sequences. Moreover, preclinical work on newly evolving treatment concepts is reported, including (i) L-citrulline to increase NO production, (ii) L-cysteine to improve mitochondrial protein synthesis, and (iii) ketogenic diet to alleviate mitochondrial dysfunction.
• 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.
• Although 30 different mitochondrial DNA mutations have been associated with MELAS, about 80% of patients harbor an m.3243A>G mutation.
• 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 (Gardner-Medwin et al 1975; Shapira et al 1975; Koenigsberger et al 1976). Seven years later, Rowland and colleagues identified these and 5 additional cases with similar clinical syndromes and ragged-red fibers on muscle biopsy (Rowland et al 1983). 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” (Pavlakis et al 1984). 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)) (Goto et al 1990). Since then, 30 additional point mutations and a 4 base-pair deletion mutation have been reported (Table 1).
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