MELAS Syndrome Medication

For individuals with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome and for those with other oxidative phosphorylation (OXPHOS) disorders, metabolic therapies are administered to increase the production of adenosine triphosphate (ATP) and to slow or arrest the deterioration of this condition and other mitochondrial encephalomyopathies. Metabolic therapies used for the management of MELAS syndrome include carnitine, CoQ10, phylloquinone, menadione, ascorbate (ie, ascorbic acid), riboflavin, nicotinamide, creatine monohydrate, idebenone, succinate, and dichloroacetate. However, assessment of the efficacy of these compounds is far from complete, and efficacy is believed to be limited to individual cases.

Treatment with CoQ10 has been helpful in some patients with MELAS syndrome. No adverse effects have been reported from its administration. Menadione (vitamin K-3), phylloquinone (vitamin K-1), and ascorbate have been used to donate electrons to cytochrome c. Idebenone has also been used to treat this condition, and improvements in clinical and metabolic abnormalities have been reported. Riboflavin has been reported to improve the function of a patient with complex I deficiency and the m.3250 T → C mutation. Nicotinamide has been used because complex I accepts electrons from nicotinamide adenine dinucleotide (NADH) and ultimately transfers electrons to Q10. Dichloroacetate is another compound used with these agents, because levels of lactate are lowered in plasma and cerebrospinal fluid (CSF). Patients reportedly may respond in a favorable manner.

A patient with MELAS syndrome reportedly had fewer strokelike episodes with the use of sodium succinate; however, sodium succinate is not the standard of care, and further investigation is necessary. An increase in muscle strength in high-intensity anaerobic and aerobic activities has been reported with the administration of creatine monohydrate.

Arginine administration during the acute and interictal periods of the strokelike episodes of the MELAS syndrome may represent a potential new therapy to reduce brain damage due to mitochondrial dysfunction, and is one of the most promising therapies to date. Based on the hypothesis that the strokelike episodes in MELAS syndrome are triggered by impaired vasodilation in the intracerebral arteries due to decreased levels of circulating NO, elevation of arginine and NO levels may ameliorate this effect. In addition, L-arginine may modulate excitation by neurotransmitters at nerve endings and such effects might contribute to alleviation of strokelike symptoms in MELAS syndrome. Patients with MELAS may have less chance of having strokelike episodes by improving their endothelial function with oral supplementation of L-arginine.

Class Summary

Vitamins are organic substances the body requires in small amounts for various metabolic processes. Vitamins may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. Some case reports using dietary supplements have reported an improvement in patient symptoms.

Arginine (R-Gene)

May be beneficial for treatment/prevention of strokelike episodes in MELAS syndrome. The strokelike episodes in MELAS syndrome may be triggered by impaired vasodilation in the intracerebral arteries due to decreased levels of circulating NO; therefore, elevation of arginine and increased NO synthesis may ameliorate this effect.

Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and argininosuccinate. Provides 1 mol of urea plus 1 mol ornithine per mol of arginine when cleaved by arginase.

L-carnitine (Carnitor)

An amino acid derivative, synthesized from methionine and lysine, required in energy metabolism. Can promote excretion of excess fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies that cause acyl CoA esters to bioaccumulate.

In secondary carnitine deficiency associated with MELAS syndrome, carnitine may restore generation of free CoA and avoid carnitine depletion. If MELAS syndrome occurs associated with LCFAO defect, use of carnitine is debatable because it may enhance formation of long-chain acylcarnitines, which may cause ventricular arrhythmogenesis.

Ubidecarenone (CoQ-10, Coenzyme Q-10, Ubiquinone)

A fat-soluble quinone, whose function is transfer of electrons from complex I to complex III. Appears to stabilize OXPHOS complexes located in mitochondrial inner membrane; may also act as potent antioxidant for free radicals. Amelioration of muscle weakness and decreased serum lactate has been observed.

Idebenone (Avan)

Data are limited; however, it is believed to enhance cerebral metabolism and improve electron-transfer system function of brain mitochondria. It also inhibits lipid peroxidation of the mitochondrial membrane, thus, increasing mitochondrial respiratory activity.

Has been used to treat patients with MELAS syndrome based on proposed physiologic effects as antioxidant, putative effect on impairments of short-term and long-term memory, and structural similarity to CoQ10. Not approved for patient use in United States; however, has been used in Japan. Improvement in clinical and metabolic abnormalities is observed in patients with MELAS syndrome. No known adverse effects.

Riboflavin (Vitamin B2)

After conversion to flavin monophosphate and flavin adenine dinucleotide, functions as cofactor for electron transport in complex I, complex II, and electron transfer flavoprotein. Reportedly of benefit in cases of complex I deficiency and MELAS.

Ascorbic acid (Vita-C, Dull-C)

May be useful in individual patients as antioxidant.

Menadione (vitamin K-3)

Has been reported anecdotally to improve cellular phosphate metabolism; enhances rate of fumarate reduction by permitting electron transfer to S3 iron sulfur cluster of complex II; appears to improve electron transfer after complex I inhibition by rotenone. Although passage through placenta is poor, administer with caution to pregnant patients with MELAS syndrome close to term because hemolysis and hyperbilirubinemia reportedly have affected newborns.

Creatine monohydrate

May have beneficial effect in patients with MELAS and other mitochondrial disorders; effect may be related to increased intracellular creatine and/or phosphocreatine content, which may be involved in maintaining cellular ATP and in stabilizing permeability transition pore with subsequent neuronal death due to apoptosis. Creatine supplementation may increase muscle power in patients with MELAS syndrome (observed in one patient with MELAS syndrome enrolled in a study). Potential cytotoxic effect from long-term administration.

Sodium dichloroacetate (Ceresine)

Currently an orphan drug in United States. A compound believed to activate the pyruvate dehydrogenase complex by inhibiting the inactivating kinase. This decreases lactate production and promotes pyruvate oxidation. Used to lower levels of lactate in both plasma and CSF. Currently available only under research protocols. Primary effect is to stimulate function of PDH by inhibiting kinase that inactivates PDH. Also may stimulate glycolytic enzyme phosphofructokinase by suppressing allosteric inhibitor (citrate) and increasing levels of activator (fructose 2,6 biphosphate) to enhance oxidation of lactate in liver.