MELAS Syndrome Treatment & Management

Updated: Dec 12, 2017
  • Author: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Treatment

Approach Considerations

Acute decompensation: Because nitric oxide (NO) deficiency can play a major role in the pathogenesis of MELAS syndrome complications, supplementation of NO precursors, arginine and citrulline, can result in increased NO availability and so may have therapeutic effects on NO deficiency–related manifestations of MELAS syndrome.

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Medical Care

Evaluation for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome may be performed on an outpatient basis if the patient is stable. Evaluation may consist of determining levels of serum lactate and serum pyruvate, mtDNA mutation studies on blood, and brain imaging studies (eg, head CT scan, brain MRI, brain proton magnetic resonance spectroscopy [1 H-MRS]). EEG should be performed for nonconvulsive status epilepticus. Muscle biopsy for mitochondrial enzymes and DNA mutation analysis can be performed as an elective procedure for which the patient is admitted to the hospital.

In incidents of acute decompensation, perform inpatient studies in the acute phase and following stabilization of the patient.

Various supportive measures are available, although no controlled trial has proven efficacy. Long-term benefits of dietary manipulations are unknown. Improvements in some patients may be related to improved nutritional status and hydration.

The following medications have been used:

  • Patients with known MELAS who present with any symptoms suggestive of a metabolic stroke should receive a loading dose of intravenous arginine hydrochloride to reduce brain damage due to impaired vasodilation in intracerebral arteries caused by nitric oxide depletion. Although the optimal dose has not been defined, a bolus of 0.5 g/kg given within 3 hours of symptom onset is recommended. After the initial arginine bolus, an additional 0.5 g/kg should be administered as a continuous infusion for 24 hours for the following 3-5 days. Although there is no clinical evidence on how long to continue the maintenance dose of arginine, most mitochondrial specialists recommend continuing treatment for at least 3 days.
  • Citrulline acts as a nitric oxide precursor, and hypocitrullinemia has been observed in patients with MELAS. Short-term citrulline supplementation increases nitric oxide production to more than arginine because of the significant increase in de novo arginine synthesis associated with citrulline supplementation. Therefore, in addition to arginine, administration of citrulline has the potential for therapeutic use in MELAS. Controlled studies that assessed the effects of citrulline supplementation on clinical aspects of MELAS are needed to support its use as a therapeutic modality.
  • Treatment with coenzyme 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 CoQ10.
  • Dichloroacetate is another compound used with these agents since levels of lactate are lowered in plasma and cerebrospinal fluid (CSF); patients reportedly may respond in a favorable manner. Sensory neuropathy may result after extended use of this drug.
  • Sodium succinate has been used, and a patient with MELAS syndrome reportedly had fewer strokelike episodes with its use; however, sodium succinate is not the standard of care. Further investigation is necessary.
  • Creatine monohydrate has also been used, and an increase in muscle strength in high-intensity anaerobic and aerobic activities has been reported.
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Consultations

The following consultations may be indicated:

  • Geneticist
  • Neurologist (to evaluate patient for strokelike episodes or seizures, both convulsive and nonconvulsive)
  • Cardiologist (for evaluation of cardiomyopathy, arrhythmias and hypertension)
  • Nephrologist (to evaluate for the onset of nephrotic syndrome)
  • Ophthalmologist (to evaluate for pigmentary retinopathy)
  • Endocrinologist (to evaluate for endocrine dysfunctions such as diabetes mellitus, hypothyroidism, hyperthyroidism and hypoparathyroidism)
  • Psychiatrist (to evaluate for affective disorders)
  • Neuropsychologist (to evaluate for autism spectrum disorder [ASD])
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Diet

The effect of dietary manipulation is not completely known, and the efficacy of dietary supplements is unproven. Dicarboxylic aciduria and secondary impairment of long-chain fatty acid oxidation (LCFAO) may occur in mitochondrial disorders. Improvement observed in many patients is probably related to improved nutrition.

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Activity

In patients with mitochondrial myopathies, moderate treadmill training may result in improvement of aerobic capacity and a drop in resting lactate and postexercise lactate levels. Concentric exercise training may also play an important role because after a short period of concentric exercise training a remarkable increase reportedly occurs in the ratio of wild type–to–mutant mtDNAs and in the proportion of muscle fibers with normal respiratory chain activity.

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Prevention

If conditions such as cardiomyopathy are present, restrict exercise. Although the long-term effects of dietary manipulations are unknown, ensure good nutritional status, good hydration, and avoidance of fasting as part of a supportive plan. A mild degree of aerobic activity may lead to an improvement of aerobic capacity. Restrict strenuous exercise because of the possible complication of rhabdomyolysis.

Information on the therapeutic efficacy of reported compounds used as nutritional supplements are limited; however, most do not have any serious adverse effects. Nutritional supplements may help to prevent further deterioration in some individuals; however, further research is warranted.

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Long-Term Monitoring

Carefully monitor the progress of the encephalomyopathy and sequelae. Neurodevelopmental testing is appropriate because progressive intellectual deterioration follows strokelike episodes of MELAS syndrome. Neuropsychological evaluation is appropriate for presence of autism spectrum disorder (ASD).

Monitor growth curves because mitochondrial disorders such as MELAS syndrome are associated with short stature or failure to thrive.

Refer the patient to an ophthalmologist to monitor for pigmentary degeneration of the retina, which may be similar to that observed in patients with neuropathy, ataxia, and retinitis pigmentosa syndrome. Closely monitor signs (eg, ophthalmoplegia, ptosis).

Carefully monitor individuals with MELAS syndrome for hearing loss with a hearing evaluation, including distortion product otoacoustic emissions and auditory brainstem evoked responses. Carefully monitor patients for cardiomyopathy and measure Z-score for aortic root diameter with echocardiography. Request an ECG as a baseline study to monitor for conduction defects, even if patients are asymptomatic. Carefully monitor patients for type 2 diabetes, hypothyroidism, hyperthyroidism, and parathyroid dysfunction. Carefully monitor patients for the persistence of lactic acidosis.

Positron magnetic resonance spectroscopy (1 H-MRS) of the brain may be used to monitor potential therapeutic efficacy if increased permeability of the blood-brain barrier is a concern.

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Further Inpatient Care

Admit for metabolic decompensation or signs of diabetic ketoacidosis. Diabetes appears to be the most common manifestation of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome. Admit for medical management of strokelike episodes and seizures. Admit for signs of cardiac arrhythmia (Wolff-Parkinson-White syndrome), hypertension, impending aortic root dissection, or congestive heart failure (CHF) associated with hypertrophic or dilated cardiomyopathy. Admit for signs of nephrotic syndrome that may present in association with focal segmental glomerulosclerosis. Admit if a sign of acute abdomen is present; acute abdomen may be an indication of pancreatitis. [13]

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Inpatient & Outpatient Medications

Medications include the following:

  • Compounds that may increase ATP production or transfer of electrons (eg, ascorbate, riboflavin, CoQ10, vitamins K-1 and K-3, nicotinamide, creatine monohydrate)
  • Compounds that can be used to prevent a possible secondary carnitine deficiency or secondary dysfunction of fatty acid oxidation (eg, carnitine)
  • Compounds that can be used to prevent or ameliorate the progression of strokelike episodes (eg, L-arginine and citrulline): L-arginine could modulate mitochondrial energy metabolism by inhibiting glutamate uptake into mitochondria and decreasing neurotoxicity associated with nitric oxide-mediated mitochondrial dysfunction.
  • Compounds that may be used to treat lactic acidosis (eg, dichloroacetate)
    • Dichloroacetate stimulates pyruvate dehydrogenase function by inhibiting pyruvate dehydrogenase kinase, the enzyme that normally phosphorylates and inactivates pyruvate dehydrogenase. Therefore, in conditions that result in the accumulation of lactate and alanine, activation of pyruvate dehydrogenase decreases the release of these compounds from peripheral tissues and enhances their oxidative metabolism by the liver.
    • This medication has been used to treat lactic acidosis in adult and pediatric patients. Anecdotal reports detail successful treatment in patients with MELAS syndrome. Dichloroacetate has been administered orally at doses of 12.5-100 mg/kg/d. This medication is available only under research protocols in the United States.

If seizures have developed as part of the condition, do not use valproic acid as an anticonvulsant, since incidents of pancreatitis following valproate administration have occurred and valproic acid has been associated with mitochondrial toxicity.

Use phenobarbital with caution, because the drug has demonstrated inhibition of the respiratory chain in vitro.

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Transfer

Transfer to a tertiary care center may be required to better coordinate the diagnostic evaluation to include the following:

  • Muscle biopsy
  • Evaluation for mitochondrial enzyme defects
  • Analysis of mtDNA mutation

If diagnosis is already known and the patient has been stabilized, transfer may be required for better management of complications such as the following:

  • Pancreatitis
  • Cardiac arrhythmias
  • Cardiomyopathy
  • Ketoacidosis
  • Strokelike episodes
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