eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

MELAS Syndrome

Fernando Scaglia, MD, FACMG, Associate Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital

Updated: Jul 23, 2009

Introduction

Background

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome is a progressive neurodegenerative disorder. Patients may present sporadically or as members of maternal pedigrees with a wide variety of clinical presentations. The typical presentation of patients with MELAS syndrome includes features that comprise the name of the disorder, such as mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. Other features, such as seizures, diabetes mellitus, hearing loss, cardiac disease, short stature, endocrinopathies, exercise intolerance, and neuropsychiatric dysfunction are clearly part of the disorder.

Pathophysiology

Strokelike episodes and mitochondrial myopathy characterize MELAS syndrome. Multisystemic organ involvement is seen, including the CNS, skeletal muscle, eye, cardiac muscle, and, more rarely, the GI and renal systems.

Approximately 80% of patients with the clinical characteristics of MELAS syndrome have a heteroplasmic A-to-G point mutation in the dihydrouridine loop of the transfer RNA (tRNA)^{Leu (UUR)} gene at base pair (bp) 3243 (ie, 3243 A → G mutation).¹ However, other mitochondrial DNA (mtDNA) mutations are observed, including the m.3244 G → A, m.3258 T → C, m.3271 T → C, and m.3291 T → C in the mitochondrial tRNA^Leu(UUR) gene.

The pathogenesis of the strokelike episodes in MELAS syndrome has not been completely elucidated. These metabolic strokelike episodes may be nonvascular and due to transient oxidative phosphorylation (OXPHOS) dysfunction within the brain parenchyma. A mitochondrial angiopathy of small vessel is responsible for contrast enhancement of affected regions and mitochondrial abnormalities of endothelial cells and smooth muscle cells of blood vessels. The multisystem dysfunction in patients with MELAS syndrome may be due to both parenchymal and vascular OXPHOS defects. Increased production of free radicals in association with an OXPHOS defect leading to vasoconstriction may offset the effect of potent vasodilators (eg, nitric oxide).

The unusual strokelike episodes and higher morbidity observed in MELAS syndrome may be secondary to alterations in nitric oxide homeostasis that cause microvascular damage. Nitric oxide can bind the cytochrome c oxidase–positive sites in the blood vessels present in the CNS, displacing heme-bound oxygen and resulting in decreased oxygen availability in the surrounding tissue and decreased free nitric oxide. Furthermore, coupling of the vascular mitochondrial dysfunction with cortical spreading depression might underlie the selective distribution of ischemic lesions in the posterior cortex in these subjects.   

Mutations in this disorder affect mitochondrial tRNA function, leading to the disruption of the global process of intramitochondrial protein synthesis. Measurements of respiratory enzyme activities in intact mitochondria have revealed that more than one half of the patients with MELAS syndrome may have complex I or complex I + IV deficiency. A close relationship is apparent between MELAS and complex I deficiency. The decreased protein synthesis may ultimately lead to the observed decrease in respiratory chain activity by reduced translation of UUG-rich genes such as ND6 (component of complex I).²

In addition, studies revealed that the 3243 A → G mutation produces a severe combined respiratory chain defect in myoblasts, with almost complete lack of assembly of complex I, IV, and V, and a slight decrease of assembled complex III. This assembly defect occurs despite a modest reduction in the overall rate of mitochondrial protein synthesis. Translation of some polypeptides is decreased, and evidence of amino acid misincorporation is noted in others.

Frequency

United States

No estimates concerning the prevalence of the common MELAS mutation are available for the North American population; however, the syndrome has been observed to be less frequent in blacks.

International

The first assessment of the epidemiology of mitochondrial disorders found a prevalence of more than 10.2 per 100,000 for the m.3243A → G mutation in the adult Finnish population. If the assumption is made that all first-degree maternal relatives of a verified mutation carrier also harbor the mutation, prevalence increases to more than 16.3 per 100,000. This high prevalence suggests that mitochondrial disorders may constitute one of the largest diagnostic categories of neurogenetic diseases among adults. In Northern England, the prevalence of this mutation in the adult population has been determined to be approximately 1 per 13,000.

Mortality/Morbidity

The progressive disorder has a high morbidity and mortality. The encephalomyopathy, associated with strokelike episodes followed by hemiplegia and hemianopia, is severe. Focal and general convulsions may occur in association with these episodes.

Other abnormalities that may be observed are ventricular dilatation, cortical atrophy, and basal ganglia calcification. Mental deterioration usually progresses after repeated episodic attacks. Psychiatric abnormalities and cognitive decline (eg, altered mental status, schizophrenia) may accompany the strokelike episodes. Bipolar disorder is another psychiatric abnormality observed in MELAS syndrome. Autism spectrum disorders (ASDs) with or without additional neurological features can be early presentations of the m.3243 A → G mutation. Myopathy may be debilitating. The encephalopathy may progress to dementia; eventually, the clinical course rapidly declines, leading to severe disability and premature death.

Another cause of high mortality is the less common feature of cardiac involvement, which can include hypertrophic cardiomyopathy, hypertension, and conduction abnormalities, such as atrioventricular blocks, long QT syndrome, or Wolff-Parkinson-White syndrome. Subjects with MELAS syndrome were found to have increased ascending aortic stiffness and enlarged aortic dimensions suggesting vascular remodeling. Aortic root dissection was found in one patient with MELAS syndrome.³ Some patients may develop Leigh syndrome (ie, subacute necrotizing encephalopathy). Patients may develop renal failure due to focal segmental glomerulosclerosis.

More rarely, these patients may exhibit severe GI dysmotility and endocrine dysfunction, including hypothyroidism and hyperthyroidism.

Race

No predilection for a particular ethnic group is noted.

Sex

No sexual predilection is present.

Age

In many patients with MELAS syndrome, presentation occurs with the first strokelike episode, usually when an individual is aged 4-15 years. Less often, onset of disease may occur in infancy with delayed developmental milestones and learning disability. One presentation of the disorder was reported in a 4-month-old infant.

Clinical

History

• Onset of the disorder may be myopathic with weakness, easy fatigability, and exercise intolerance.
• Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome onset may occur early in infancy with a history of developmental delay and learning disabilities. Developmental delay, learning disability, or attention deficit disorder is primarily found in patients prior to the development of the first stroke. An encephalopathic picture that is progressive and leads to dementia may be present. Patients may be apathetic. The level of cognitive functioning worsens over time by Karnofsky score in fully symptomatic patients.
• Failure to thrive may be the presenting feature in some patients with MELAS syndrome.
• Strokelike episodes are the hallmark feature of this disorder. Initially, episodes may manifest with vomiting and headache that may last several days. These patients may also experience episodes of seizures and visual abnormalities followed by hemiplegia. Seizure types may be tonic-clonic or myoclonic.
• Migraine or migrainelike headaches observed in these patients may also reflect the strokelike episodes. Pedigrees of patients with classic MELAS syndrome identify many members whose only manifestations are migraine headaches.
• Patients may have visual complaints due to ophthalmoplegia, and they may experience blindness because of optic atrophy and difficulties with night vision due to pigmentary retinopathy.
• Some patients may experience hearing loss, which may accompany diabetes. It may be observed in association with the classic disorder of MELAS syndrome.
• Polydipsia and polyuria may be the presenting signs of diabetes; diabetes appears to be the most common manifestation of MELAS syndrome. Usually, type 2 diabetes is described in individuals with MELAS syndrome, although type 1 (formerly termed insulin-dependent diabetes) may also be observed. Guidelines for diagnosis and management of type 2 diabetes have been established.⁴
• Palpitations and shortness of breath may be present in some patients with MELAS syndrome secondary to cardiac conduction abnormalities, such as Wolff-Parkinson-White syndrome. Patients may experience shortness of breath secondary to cardiomyopathy, which is usually of the hypertrophic type; however, dilated cardiomyopathy has also been described.
• Acute onset of GI manifestations (eg, acute onset of abdominal pain) may reflect pancreatitis, ischemic colitis, and intestinal obstruction.
• Numbness, tingling sensation, and pain in the extremities can be manifestations of peripheral neuropathy.
• Psychiatric disorders (eg, depression, bipolar disorder) have been associated with the m.3243 A → G mutation. Dementia has been another clinical manifestation. Moreover, autism spectrum disorders (ASD) have been associated with the 3243 A → G mutation.
• Patients may develop features of hypothyroidism and hyperthyroidism
• Some patients may develop apnea and an ataxic gait in association with neuroradiologic features of MELAS syndrome.
• Oliguria can be associated with MELAS syndrome and may indicate the onset of nephrotic syndrome.
• Patients with MELAS syndrome may have functional vascular involvement. Aortic root dissection has been reported in one patient with MELAS syndrome.

Physical

• Patients with MELAS syndrome may exhibit hypertension.
• Myopathy presents with hypotonia and weakness. Proximal muscles tend to be more involved than distal muscles. Musculature is thin, and patients may present with a myopathic face.
• Strokelike episodes may present with convulsions, visual abnormalities, numbness, hemiplegia, and aphasia. Episodes may be followed by transient hemiplegia or hemianopia, which lasts a few hours to several weeks.
• Additional features on neurologic examination may include ataxia, tremor, myoclonus, dystonia, visual disturbances, and cortical blindness. Some patients may present with ophthalmoplegia and ptosis.
• On ophthalmologic examination, patients have presented with pigmentary retinopathy.
• Sensorineural deafness has been reported as part of the disorder in approximately 25% of patients with MELAS syndrome.
• Cardiomyopathy with signs of congestive heart failure (CHF) may also be observed upon physical examination.
• Skin manifestations of cutaneous purpura, hirsutism, and a scaly, pruritic, diffuse erythema with reticular pigmentation may be observed in patients with MELAS syndrome.
• Short stature may be the first manifestation of MELAS syndrome in many patients.

Causes

• MELAS syndrome has been associated with at least 6 different point mutations, 4 of which are located in the same gene, the tRNA^{Leu (UUR)} gene. The most common mutation, found in 80% of individuals with MELAS syndrome, is an A → G transition at nucleotide (nt) 3243 in the tRNA^{Leu (UUR)} gene. An additional 7.5% have a heteroplasmic T → C point mutation at bp 3271 in the terminal nucleotide pair of the anticodon stem of the tRNA^{Leu (UUR)} gene. Moreover, a MELAS phenotype has been observed associated with an m.13513G → A mutation in the ND5 gene and in POLG deficiency.   
• These mutations are heteroplasmic, which reflects the different percentages of mutated mtDNA present in different tissues. Variable heteroplasmy among individuals affected with MELAS syndrome reflects variable segregation in the ovum. Mutations in tRNA^Lys may be expected to have an important effect on translation and protein synthesis in mitochondria. The MELAS disorder–associated human mitochondrial tRNA^{Leu (UUR)} mutation causes aminoacylation deficiency and a concomitant defect in translation initiation.
• Abnormal calcium homeostasis resulting in neuronal injury has been suggested as another mechanism contributing to the CNS involvement observed in MELAS syndrome.
• Patients with MELAS syndrome have been found to have a marked decrease in the activity of complex I. The major effects observed secondary to nt 3243 and nt 3271 mutations have been a reduction in protein synthesis and the activity of complex I. These effects have been demonstrated through studying cybrids in which human cell lines without mtDNA are fused with exogenous mitochondria containing 0-100% of the common m.3243 mutation. Cybrids with more than 95% of mutant DNA had decreased rates of synthesis of mitochondrial proteins, leading to respiratory chain defects.

Differential Diagnoses

Other Problems to Be Considered

Sensorineural hearing loss
Peripheral neuropathy
Rhabdomyolysis
Intestinal pseudoobstruction
Myoclonic epilepsy and ragged red fiber disease
Neurodegeneration, ataxia, and retinitis pigmentosa
Primary mtDNA depletion syndrome
Disorders of pyruvate metabolism

Workup

Laboratory Studies

• Serum lactic acid, serum pyruvic acid, cerebrospinal fluid (CSF) lactic acid, and CSF pyruvic acid  
  • Lactic acidosis is an important feature of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome.
    
    

    

    Pathophysiologic classification of lactic acidosis.

    
    
  • In general, lactic acidosis does not lead to systemic metabolic acidosis, and it may be absent in patients with impressive CNS involvement.
  • In some individuals with MELAS syndrome, lactic acid levels may be normal in blood but elevated in CSF.
  • In respiratory chain defects, the ratio between lactate and pyruvate is high.
• Serum creatine kinase levels
  • The levels of serum creatine kinase are mildly to moderately increased in some patients with MELAS syndrome.
  • Levels tend to increase during and immediately after episodes.
• Respiratory chain enzyme activities in skeletal muscle  
  • If a muscle biopsy is performed to pursue a diagnostic evaluation, then test respiratory chain enzyme activities.
  • Patients with MELAS syndrome have been found to have marked deficiency in complex I activity of the respiratory chain.
  • Some patients with the disorder have a combined deficiency of complex I and complex IV.
• Mitochondrial DNA mutation analysis on blood, skeletal muscle, hair follicles, buccal mucosa, and urinary sediment
  • Individuals with more severe clinical manifestations of MELAS syndrome generally have greater than 80% mutant mtDNA in stable tissues such as muscle.
  • In rapidly dividing cells, such as the components of the hematopoietic lineages, the m.3243 A → G mutation may segregate to extremely low levels, making genetic diagnosis from blood difficult. The percentage of the mutation decreases progressively in DNA isolated from blood. The mutant load isolated from blood is neither useful for prognosis nor for functional assessment.
  • Urinary sediment, followed by skin fibroblasts and buccal mucosa, are the accessible tissues of choice because they are easy to access and the mutation load is higher than that found in blood.
  • If the diagnosis is still suspected after normal mtDNA mutation analysis results in these tissues, a skeletal muscle biopsy is required to confirm or rule out the presence of the mutation.

Imaging Studies

• CT scan or MRI of the brain
  • CT scan or MRI of the brain following a strokelike episode reveals a lucency that is consistent with infarction.
  • Later, cerebral atrophy and calcifications may be observed on brain imaging studies.
  • Patients with MELAS syndrome who have a presentation similar to Leigh syndrome may have calcifications in the basal ganglia.
• Positron emission tomography (PET) studies
  • PET studies may reveal a reduced cerebral metabolic rate for oxygen.
  • Increased cerebral blood flow in cortical regions may be observed.
  • PET may demonstrate preservation of the cerebral metabolic rate for glucose.
• Single-photon emission CT studies
  • Single-photon emission computed tomography (SPECT) studies can ascertain strokes in individuals with MELAS syndrome using a tracer, N -isopropyl-p-[123-I]-iodoamphetamine.
  • The tracer accumulates in the parietooccipital region, and it can delineate the extent of the lesion. SPECT studies are used to monitor the evolution of the disease.
• Proton magnetic resonance spectroscopy (¹ H-MRS): This is used to identify metabolic abnormalities, including the lactate-to-creatine ratio in either muscle or brain and the decreased CNS N -acetylaspartate–to–creatine ratio in regions of stroke. With this technique, elevated regions of lactate have been detected while serum levels are normal.
• Echocardiography: This is useful to evaluate for hypertrophic and dilated cardiomyopathy and aortic root dimensions; however, cardiomyopathy is not a common feature in individuals with MELAS syndrome.

Other Tests

• EEG
  • EEG findings are usually abnormal.
  • Epileptiform spike discharges are usually present.
• ECG
  • ECG is used to look for conduction abnormalities with ventricular arrhythmias.
  • ECG can identify presymptomatic cardiac involvement, preexcitation syndromes, and cardiac conduction block.

Procedures

• Consider performing a muscle biopsy if MELAS syndrome is suspected and if the mtDNA mutation analysis in blood and other accessible tissues provides unremarkable results.
• In rapidly dividing cell lines, the mutations may segregate to low levels, making genetic diagnosis from blood difficult.

Histologic Findings

• In muscle biopsies stained with hematoxylin and eosin, variation is observed in type 1 and type 2 fiber sizes, representing myopathic changes.
• Ragged red fibers are the hallmark of MELAS syndrome. The ragged red fibers stain brilliant red with occasional cytoplasmic bodies with trichrome stain. Ragged red fibers usually stain positive with cytochrome oxydase stain.
• Staining with periodic acid-Schiff, nicotinamide adenine dinucleotide (NADH) dehydrogenase tetrazolium reductase, or for succinic dehydrogenase demonstrates increased subsarcolemmal activity. This mitochondrial proliferation has also been observed in blood vessels and is determined using a stain for succinate dehydrogenase.
• Electron microscopy demonstrates an increase in number and size of mitochondria, some with paracrystalline bodies.

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.

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.

Dosing

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

Interactions

Increased toxicity of estrogen-progesterone combinations due to growth hormone response and glucagon and insulin effects; spironolactone may cause potentially fatal hyperkalemia

Contraindications

Documented hypersensitivity; renal or hepatic failure

Precautions

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.

Dosing

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

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

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.

Dosing

Adult

4.3 mg/kg PO qd

Pediatric

4.3 mg/kg/d PO divided bid

Interactions

Decreases warfarin effect

Contraindications

Documented hypersensitivity

Precautions

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.

Dosing

Adult

90 mg PO qd

Pediatric

Limited data available; administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

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.

Dosing

Adult

50-200 mg PO qd

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

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.

Dosing

Adult

1 g PO tid

Pediatric

57 mg/kg/d PO

Interactions

Decreases effects of warfarin and fluphenazine; increases aspirin levels

Contraindications

Documented hypersensitivity; can be contraindicated with history of nephrolithiasis

Precautions

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.

Dosing

Adult

25-35 mg PO tid

Pediatric

1.1-1.5 mg/kg/d PO divided tid

Interactions

Antagonizes action of warfarin b

Contraindications

Documented hypersensitivity

Precautions

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.

Dosing

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

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

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.

Dosing

Adult

35-50 mg/kg/d PO/IV

Pediatric

15-200 mg/kg/d PO/IV

Interactions

Limited data exist; inhibits glucose synthesis, caution with coadministration of hypoglycemic agents

Contraindications

Documented hypersensitivity

Precautions

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

Follow-up

Further Inpatient Care

• Admit for medical management of strokelike episodes and seizures.
• 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 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.

Further Outpatient Care

• Carefully monitor the progress of the encephalomyopathy and sequelae.
• Neurodevelopmental testing is appropriate because progressive intellectual deterioration follows stroke-like 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.
• 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.

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 stroke-like episodes (eg, L-arginine): 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.

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
  • Stroke-like episodes

Deterrence/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.

Complications

• Failure to thrive and short stature
• Progressive intellectual deterioration and decline that eventually may lead to dementia
• Psychosis with depression, schizophrenia, or bipolar disorder
• Autism spectrum disorders (ASDs)
• Sensorineural hearing loss
• Endocrine dysfunction with hypogonadism, diabetes, hypoparathyroidism, hypothyroidism, and hyperthyroidism
• CHF from cardiomyopathy and sudden death from conduction defects
• Visual difficulties related to pigmentary degeneration of the retina or cortical blindness as one of the sequelae of progressive cortical atrophy and strokelike episodes
• End-stage renal failure as a complication of focal segmental glomerulosclerosis
• Acute renal failure secondary to rhabdomyolysis
• GI dysfunction secondary to intestinal pseudoobstruction or pancreatitis
• Aortic root dissection (reported in one kindred; requires further studies to evaluate the prevalence)

Prognosis

• MELAS syndrome widely varies in presentation; however, patients in general tend to have a poor prognosis and outcome.
• The encephalomyopathy tends to be severe and progressive to dementia. The patient with MELAS syndrome may end up in a state of cachexia.
• Currently, no therapies have proven efficacy.

Patient Education

• Once the diagnosis is established, refer the patient and family for genetic counseling and evaluation of other family members who may be at risk of being affected.
• Educate the family concerning further deteriorations and complications (eg, cardiomyopathy, nephrotic syndrome, deafness, diabetes, GI difficulties) that may affect the proband. In general, educate the family about maintaining a good nutritional and hydration status, and discuss information concerning current trials (eg, use of dichloroacetate for persistent lactic acidosis in individuals with MELAS syndrome).
• For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.

Miscellaneous

Medicolegal Pitfalls

• Failure to evaluate for or exclude mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome in individuals with strokelike episodes or clinical presentations of encephalomyopathy when other causes have been excluded, unnecessarily delaying diagnosis and counseling
• Failure to recognize that diabetes mellitus, either associated or not associated with deafness, may be a presentation of MELAS syndrome
• Failure to recognize that GI symptoms may be a presentation of MELAS syndrome
• Failure to recognize other less common presentations (eg, nephrotic syndrome, dilated cardiomyopathy, pigmentary retinopathy)
• Failure to investigate other members of the family for possible risk of MELAS syndrome
• Failure to pursue a muscle biopsy to identify the MELAS mutation if the evaluation of blood studies is unremarkable and the condition is still suspected

Special Concerns

• Anticipate less frequent complications, such as the following:
  • Cardiomyopathy
  • Conduction defects
  • Aortic root dissection
  • Pancreatitis
  • Intestinal pseudoobstruction
  • Peripheral neuropathy
  • Nephrotic syndrome
  • Ischemic colitis
  • Rhabdomyolysis
  • Psychiatric (affective disorders) or behavioral abnormalities (autism spectrum disorders [ASDs])
  • Endocrine dysfunction (eg, hyperthyroidism, hypothyroidism)

Multimedia

Media file 1: Pathophysiologic classification of lactic acidosis.

References

1. Mehrazin M, Shanske S, Kaufmann P, Wei Y, Coku J, Engelstad K. Longitudinal changes of mtDNA A3243G mutation load and level of functioning in MELAS. Am J Med Genet A. Feb 15 2009;149A(4):584-7. [Medline].

2. Sasarman F, Antonicka H, Shoubridge EA. The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. Hum Mol Genet. Dec 1 2008;17(23):3697-707. [Medline].

3. Nemes A, Geleijnse ML, Sluiter W, Vydt TC, Soliman OI, van Dalen BM. Aortic distensibility alterations in adults with m.3243A>G MELAS gene mutation. Swiss Med Wkly. Feb 21 2009;139(7-8):117-20. [Medline].

4. [Guideline] International Diabetes Center. Type 2 diabetes practice guidelines. 2003;[Full Text].

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6. Borner GV, Zeviani M, Tiranti V, et al. Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. Hum Mol Genet. Mar 1 2000;9(4):467-75. [Medline].

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12. Joko T, Iwashige K, Hashimoto T, et al. A case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes associated with diabetes mellitus and hypothalamo-pituitary dysfunction. Endocr J. Dec 1997;44(6):805-9. [Medline].

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14. Koga Y, Akita Y, Nishioka J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. Feb 22 2005;64(4):710-2. [Medline].

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19. Shanske S, Coku J, Lu J, Ganesh J, Krishna S, Tanji K. The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome: evidence from 12 cases. Arch Neurol. Mar 2008;65(3):368-72. [Medline].

20. Shimotake T, Furukawa T, Inoue K, Iwai N, Takeuchi Y. Familial occurrence of intestinal obstruction in children with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). J Pediatr Surg. Dec 1998;33(12):1837-9. [Medline].

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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

Contributor Information and Disclosures

Author

Fernando Scaglia, MD, FACMG, Associate Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital
Fernando Scaglia, MD, FACMG is a member of the following medical societies: American College of Medical Genetics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, and Society for the Study of Inborn Errors of Metabolism
Disclosure: Nothing to disclose.

Medical Editor

Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation
Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, American Society of Gene Therapy, American Society of Human Genetics, Child Neurology Society, and Society for Inherited Metabolic Disorders
Disclosure: Genzyme Corporation Salary Management position

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
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Managing Editor

Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Genzyme Grant/research funds PI

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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