Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Symptoms

Introduction:

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a condition that affects many of the body’s systems such as the brain and nervous system (encephalo-) and muscles (myopathy). In 1984 MELAS was defined as a distinctive syndrome that can be differentiated from other clinical disorders that can be associated with mitochondrial myopathy and cerebral (of the brain) disease. Defining features of this disease include the appearance of ragged red fibers in skeletal muscle, short stature, seizures, and hemiparesis (partial weakness on one side of the body), hemianopia (blindness in half the field of vision), or blindness (Pavlakis et al. 1984)

Etiology:

MELAS is a mitochondrial genetic disorder. Many different transfer RNA (tRNA) mutations in mitochondrial genetic information can cause MELAS. The most common mutation is in the MTTL1 mitochondrial gene. A single base pair mutation, m.3243A>G, is found in 80% patients, and a second common mutation, m.3271T>C, is found in 10% (El-Hattab et al. 2015).

Epidemiology:

MELAS is one of the most common mitochondrial diseases, with an estimated incidence of 1 in 4000. About 90% of cases present in early childhood or before the age of 40 (El-Hattab et al. 2015)

Physiology:

MELAS syndrome targets organ systems with high metabolic activity, including the nervous and cardiovascular systems, and clinical onset typically occurs in early adulthood after a seemingly normal childhood with development attributable to cumulative effects of chronic lactic acidosis. Ragged red muscle fibers suggest an abnormality of the electron transport system. Ragged red fibers get their name from the appearance of the degenerating granular fibers following staining with a modified Gomori trichrome stain. The presence of ragged red fibers suggests an abnormality of the electron transport system and these findings are regularly seen in documented biochemical deficiencies that involve the respiratory chain (Pavlakis et al. 1984).

A3243G mutation results in impaired synthesis of mitochondrial proteins, thus compromising the function of the electron transport chain. The lack of adequate energy production leads to the production of lactate from cellular metabolism which generates ATP but at a much slower rate. Lactic acidosis may account for symptoms such as nausea, vomiting, and exercise intolerance observed in these patients. Cerebral levels of lactate are correlated with the characteristic neurological impairment and degeneration. 

Treatment:

Symptomatic treatment of seizures with anti-epileptic medications. Vitamins such as coenzyme Q10 or L-carnitine can help increase energy production by mitochondria and may slow the effects of the disease. There are ongoing MELAS phase I and II trials of Idebenone, a synthetic coenzyme Q10, which has been shown to improve neurological function in other mitochondrial disorders (Scaglia, ClinicalTrials.gov Identifier: NCT00887562) L-arginine has been shown to reduce the severity of symptoms during acute attacks and may decrease the frequency of episodes. L-citrulline is liekly beneficial in recovery and reduction of stroke risk. The roles of L-arginine and L-citrulline are likely to due to the correction of nitric oxide deficiency in MELAS patients since arginine and citrulline are precursors to nitric oxide production (El-Hattab et al. 2015).