eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
MELAS Syndrome: Treatment & Medication
Updated: Jul 23, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
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, brain1 H-MRS).
- 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.
- 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.
- The administration of L-arginine during the acute and interictal periods may represent a potential new therapy for this syndrome to reduce brain damage due to impaired vasodilation in intracerebral arteries owing to nitric oxide depletion.
Consultations
- Geneticist
- Neurologist (to evaluate patient for strokelike episodes)
- 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])
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.
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.
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.Vitamins and dietary supplements
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.
Adult
Acute episodes: 10 g/m2/d IV continuous infusion over 24 h
Interictal periods: 10 g/m2/d PO
Pediatric
Acute episodes: 0.5 g/kg/d IV continuous infusion over 24 h
Interictal periods: 0.5 g/kg/d PO
Increased toxicity of estrogen-progesterone combinations due to growth hormone response and glucagon and insulin effects; spironolactone may cause potentially fatal hyperkalemia
Documented hypersensitivity; renal or hepatic failure
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
IV administration may cause mild-to-moderate metabolic acidosis; may cause nausea, vomiting, headache, hyperkalemia, hypotension, hyperglycemia, or venous irritation during IV administration
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.
Adult
1 g/dose PO/IV tid, not to exceed 3 g/d
Pediatric
100-200 mg/kg/d PO divided tid, not to exceed 3 g/d
None reported
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Presence of secondary defect in LCFAO
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.
Adult
4.3 mg/kg PO qd
Pediatric
4.3 mg/kg/d PO divided bid
Decreases warfarin effect
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Because of complexities of absorption, monitoring blood levels can be helpful; if patients are unable to swallow compound, it can be dissolved in vegetable oil, which can be added to food to make it more palatable
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.
Adult
90 mg PO qd
Pediatric
Limited data available; administer as in adults
None reported
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause GI complaints, headache, anxiety, drowsiness, or tachycardia
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.
Adult
50-200 mg PO qd
Pediatric
Administer as in adults
None reported
Documented hypersensitivity
Pregnancy
A - Fetal risk not revealed in controlled studies in humans
Precautions
Pregnancy category C with doses exceeding RDA; GI adverse effects (eg, abdominal pain, nausea, vomiting)
Ascorbic acid (Vita-C, Dull-C)
May be useful in individual patients as antioxidant.
Adult
1 g PO tid
Pediatric
57 mg/kg/d PO
Decreases effects of warfarin and fluphenazine; increases aspirin levels
Documented hypersensitivity; can be contraindicated with history of nephrolithiasis
Pregnancy
A - Fetal risk not revealed in controlled studies in humans
Precautions
Prolonged high doses may cause renal calculi, especially in patients with diabetes
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.
Adult
25-35 mg PO tid
Pediatric
1.1-1.5 mg/kg/d PO divided tid
Antagonizes action of warfarin b
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
May produce hemolytic anemia, hyperbilirubinemia, and kernicterus in newborns; reactions resembling hypersensitivity have occurred after IV administration
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.
Adult
0.1-0.2 g/kg/d PO divided bid/tid for 3 mo; no data on long-term administration
Pediatric
Administer as in adults
None reported
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Long-term administration may lead to cytotoxic effects; creatine is metabolized to methylamine, which is converted eventually to formaldehyde; formaldehyde is well known to cross-link proteins and DNA and can lead to pathologic conditions (eg, vascular damage, diabetic complications, nephropathy); caution in dehydration or renal impairment
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.
Adult
35-50 mg/kg/d PO/IV
Pediatric
15-200 mg/kg/d PO/IV
Limited data exist; inhibits glucose synthesis, caution with coadministration of hypoglycemic agents
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Effect on morbidity and mortality of patients with MELAS syndrome has not been determined, and more trials are required to determine these issues; long-term administration of dichloroacetate has been associated with sensory neuropathy
Urinary oxalate crystal formation has been reported and is a dose-related phenomenon; monitor for metabolic acidosis and hypoglycemia
More on MELAS Syndrome |
| Overview: MELAS Syndrome |
| Differential Diagnoses & Workup: MELAS Syndrome |
 Treatment & Medication: MELAS Syndrome |
| Follow-up: MELAS Syndrome |
| Multimedia: MELAS Syndrome |
| References |
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References
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Further Reading
Keywords
MELAS syndrome, mitochondrial encephalomyopathy, lactic acidosis, stroke, oxidative phosphorylation, OXPHOS disorder, strokelike episode, seizures, diabetes mellitus, hearing loss, cardiac disease, short stature, endocrinopathies, exercise intolerance, neuropsychiatric dysfunction, hemiplegia, hemianopia, schizophrenia, bipolar disorder, autism spectrum disorders, ASD, hypertrophic cardiomyopathy, hypertension, atrioventricular blocks, long QT syndrome, Wolff-Parkinson-White syndrome, Leigh syndrome, subacute necrotizing encephalopathy, hypothyroidism, hyperthyroidism, developmental delay, learning disability, attention deficit disorder, polydipsia, polyuria, nephrotic syndrome, treatment, diagnosis
