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The Power of a Name – Comment HERE

The Power of a Name – Comment HERE

As the acronym MELAS suggests, this disease is characterized by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms. At the first Child Neurological Society meeting, mitochondrial encephalomyopathy was introduced as “a group of neuromuscular disorders with defects in the oxidative pathways of energy production.” Mitochondrial encephalomyopathies are divided into three distinct clinical subgroups: (1) mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS); (2) myoclonus epilepsy associated with ragged-red fibers (MERRF); and (3) chronic progressive external ophthalmoplegia. An A-to-G transition mutation at nucleotide pair 3,243 in the dihydrouridine loop of mitochondrial tRNALeu(UUR) that is specific to patients with MELAS (Goto, Nonaka, and Horai 1990).

MELAS is defined as a distinctive syndrome that can be differentiated from two other clinical disorders that are also associated with mitochondrial myopathy and cerebral disease. The other defining feature of this disease includes ragged red fibers in skeletal muscle, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness (Pavlakis et al. 1984). Like other mitochondrial defects, this syndrome targets organ systems with high metabolic activity, including the nervous and cardiovascular systems, and clinical onset typically occurs in early adulthood (before the age of 40) and symptoms can appear after a seemingly normal childhood with development attributable to cumulative effects of chronic lactic acidosis

MELAS is one of the most common mitochondrial diseases, with an estimated incidence of 1 in 4000.(El-Hattab et al. 2015) The clinical constellation of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome was first characterized in a report on two patients with the clinical presentations described in the name. In other patients reported in the literature, ragged red muscle fibers suggested an abnormality of the electron transport system, but at this time, the precise biochemical disorders in these three clinical syndromes remained to be elucidated.

The ragged red fibers derive their name from the appearance of the degenerating granular fibers after they have been stained with the modified Gomori trichrome stain. The red staining represents growing mitochondrial elements, and the presence of these ragged red fibers suggests an abnormality of the electron transport system since these findings are regularly seen in documented biochemical deficiencies involving the respiratory chain (Pavlakis et al. 1984)

MELAS is a mitochondrial inherited genetic disorder, although it may result from a sporadic mutation with no family history. Mitochondrial genetic disorders are the result of mutations causing impaired mitochondrial function, including oxidative phosphorylation and energy production. In MELAS, mutations in tRNA are believed to cause impairment of protein assembly into respiratory chain complexes. Many different transfer RNA (tRNA) mutations 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).

Although the clinical features are relatively distinctive, the biochemical abnormalities reported so far have not been uniform across cases, therefore implying a syndrome. Most of the current diagnostic criteria on the mitochondrial disease was developed prior to the identification of molecular genetic knowledge. Muscle biopsy was the gold standard for obtaining an accurate diagnosis of mitochondrial diseases. Now, the diagnosis of MELAS is often confirmed by the presence of RRF on succinate dehydrogenase histochemical stain, as a result of diseased mitochondrial aggregates in the subsarcolemmal areas of muscle fibers.

The research indicates that when the mitochondria cause defects in OXPHOS, increasing production of reactive oxygen species (ROS), this triggers the activation of the cell death pathway. Autophagy inpatient-specific induced pluripotent stem (iPS) from fibroblasts of patients with MELAS had well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. An increase in autophagy was observed when compared with its normal counterpart, whereas mitophagy is very scarce contributing to decreased cellular viability.

There is currently no cure for MELAS. Symptoms of seizures are combatted with anti-epileptic medications. Vitamins such as coenzyme Q10 or L-carnitine are thought to 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 attenuate the severity of symptoms when used in acute attacks and decrease the frequency of episodes. L-citrulline is also believed to be beneficial in recovery reduction of stroke risk. This relationship is theorized to be due to the correction of nitric oxide deficiency in MELAS patients, as arginine and citrulline are precursors to nitric oxide production.(El-Hattab et al. 2015)