Stroke-like episodes in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)

Abstract

The syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a disease marked by a clinical triad of (1) stroke-like episode (SLE) before age 40 years, (2) encephalopathy characterized by seizures and dementia, and (3) lactic acidosis and ragged red fibers. The development of SLEs, acute neurological deterioration marked by radiographic evidence of strokes that do not adhere to vascular territories, is a pathognomonic clinical feature of this disease. A wide array of other systemic features, including short stature, Wolff-Parkinson-White syndrome, and diabetes mellitus, and neurological symptoms, such as sensorineural hearing loss, depression, and migraines, are also frequent manifestations of the disorder. MELAS is caused by a mutation affecting the mitochondrial genome; more than 30 specific mutations have been recognized, although greater than 80% of cases result from a single adenine-to-guanine transition mutation affecting the mitochondrial tRNA(Leu) gene (m.3243A>G). In this review, we will discuss the mechanisms of mitochondrial inheritance, including concepts such as heteroplasmy and mitotic segregation that underlay the complex genetics of this disease. Clinical and radiographic features of SLEs will be discussed at length, as will hypotheses that attempt to explain the pathogenesis of these events. While current treatment is limited to cofactor supplementation, ongoing research into potential therapies such as idebenone and l-arginine will also be discussed.