AUTHOR INFORMATION

Section 1 of 11

Authored by Fernando Scaglia, MD, Assistant Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital

Fernando Scaglia, MD, is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, Juvenile Diabetes Foundation, and Society for Inherited Metabolic Disorders

Edited by Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Fernando Scaglia, MD
Editor's Email:	Edward Kaye, MD

eMedicine Journal, October 25 2006, VOLUME 7, Number 10

INTRODUCTION

Section 2 of 11

Background: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) 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, short stature, and exercise intolerance are clearly part of the disorder.

Pathophysiology: Strokelike episodes and mitochondrial myopathy characterize MELAS. Multisystemic organ involvement is seen, including the central nervous system (CNS), skeletal muscle, eye, cardiac muscle, and, more rarely, the GI and renal systems.

Approximately 80% of patients with the clinical characteristics of MELAS 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). However, other mitochondrial DNA (mtDNA) mutations are observed, including the 3244 G®A, 3258 T®C, 3271 T®C, and 3291 T®C in the mitochondrial tRNA^Leu(UUR) gene.

The pathogenesis of the strokelike episodes in MELAS 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 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.

Mutations in this disorders 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 may have complex I or complex I + IV deficiency. A close relationship appears to exist 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).

Frequency:

• In the US: 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 African Americans.

• Internationally: The first assessment of the epidemiology of mitochondrial disorders found a prevalence of more than 10.2 per 100,000 for the 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. 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 and conduction abnormalities, such as atrioventricular blocks or Wolff-Parkinson-White syndrome. 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 hypothalamic pituitary dysfunction.

Race: No predilection for a particular ethnic group exists.

Sex: No sexual predilection exists.

Age: In many patients with MELAS, 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

Section 3 of 11

History:

• Onset of the disorder may be myopathic with weakness, easy fatigability, and exercise intolerance.



• MELAS 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.



• Failure to thrive may be the presenting feature in some patients with MELAS.



• 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 also may reflect the strokelike episodes. Pedigrees of patients with classic MELAS 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.



• Polydipsia and polyuria may be the presenting signs of diabetes; diabetes appears to be the most common manifestation of MELAS. Usually, type II diabetes is described in individuals with MELAS, although type I (formerly termed insulin-dependent diabetes) may also be observed.



• Palpitations and shortness of breath may be present in some patients with MELAS 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 3243 A®G mutation. Dementia has been another clinical manifestation.



• Some patients may develop apnea and an ataxic gait in association with neuroradiologic features of MELAS syndrome.



• Oliguria can be associated with MELAS and may indicate the onset of nephrotic syndrome.

Physical:

• On physical examination, 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.



• Cardiomyopathy with signs of congestive heart failure (CHF) may also be observed on physical examination.



• Skin manifestations of cutaneous purpura, hirsutism, and a scaly, pruritic, diffuse erythema with reticular pigmentation may be observed in patients with MELAS.



• Short stature may be the first manifestation of MELAS in many patients.

Causes: MELAS has been associated with at least 6 different point mutations, 4 of which are located in the same gene, the tRNA^{Leu (UUR)} gene in MELAS. The most common mutation, found in 80% of individuals with MELAS, is an A-to-G transition at nucleotide (nt) 3243 in the tRNA^{Leu (UUR)} gene. An additional 7.5% have a heteroplasmic T-to-C point mutation at bp 3271 in the terminal nucleotide pair of the anticodon stem of the tRNA^{Leu (UUR)} gene.

These mutations are heteroplasmic, which reflects the different percentages of mutated mtDNA present in different tissues. Variable heteroplasmy among individuals affected with MELAS 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 disorder 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 3243 mutation. Cybrids with more than 95% of mutant DNA had decreased rates of synthesis of mitochondrial proteins, leading to respiratory chain defects.

DIFFERENTIALS

Section 4 of 11

Antiphospholipid Antibody Syndrome
Antithrombin III Deficiency
Atrioventricular Block, Second Degree
Atrioventricular Block, Third Degree, Acquired
Cardiomyopathy, Dilated
Cardiomyopathy, Hypertrophic
Carnitine Deficiency
Diabetic Ketoacidosis
Failure to Thrive
Hypoparathyroidism
Kearns-Sayre Syndrome
Long QT Syndrome
Long-Chain Acyl CoA Dehydrogenase Deficiency
Medium-Chain Acyl-CoA Dehydrogenase Deficiency
Mood Disorder: Bipolar Disorder
Mood Disorder: Depression
Nephrotic Syndrome
Oliguria
Pancreatitis and Pancreatic Pseudocyst
Pearson Syndrome
Supraventricular Tachycardia, Wolff-Parkinson-White Syndrome
Thromboembolism
Ulcerative Colitis

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

Section 5 of 11

Lab Studies:

• Serum lactic acid, serum pyruvic acid, cerebrospinal fluid (CSF) lactic acid, and CSF pyruvic acid


• • Lactic acidosis is an important feature of this disorder.
  
  
  
  • 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, 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.
  
  
  
  • 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 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 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 3243 A®G mutation may segregate to extremely low levels, making genetic diagnosis from blood difficult.
  
  
  
  • Urinary sediment, followed by skin fibroblasts and buccal mucosa, are the accessible tissues of choice since 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 who have a presentation similar to Leigh syndrome may have calcifications in the basal ganglia.
  
  
  
• Positron emission tomography studies


• • Positron emission tomography (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 computed tomography studies


• • Single-photon emission computed tomography (SPECT) studies can ascertain strokes in individuals with MELAS 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 (¹H-MRS) 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.



• Echocardiogram is useful to evaluate a cardiomyopathy; However, cardiomyopathy is not a common feature in individuals with MELAS.

Other Tests:

• Electroencephalogram


• • EEG findings are usually abnormal.
  
  
  
  • Epileptiform spike discharges are usually present.
  
  
  
• Electrocardiogram


• • ECG is used to look for conduction abnormalities with ventricular arrhythmias.
  
  
  
  • ECG can identify preexcitation syndromes and cardiac conduction block.
  
  
  

Procedures:

• Muscle biopsy


• • Consider performing a muscle biopsy if MELAS 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.
  
  
  

TREATMENT

Section 6 of 11

Medical Care:

• Evaluation for MELAS 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 ¹H-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.
  
  
  
• A variety of 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. 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 3250 T®C mutation.

  • Nicotinamide has been used because complex I accepts electrons from NADH and ultimately transfers electrons to CoQ10.

  • Dichloroacetate is another compound used with these agents since levels of lactate are lowered in plasma and 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 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, a less common presentation)



• 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 and hypoparathyroidism)

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, since, 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

Section 7 of 11

For individuals with MELAS and for those with other 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 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. 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 3250 T®C mutation. Nicotinamide has been used because complex I accepts electrons from NADH and ultimately transfers electrons to Q10. Dichloroacetate is another compound used with these agents, since levels of lactate are lowered in plasma and CSF. Patients reportedly may respond in a favorable manner.

A patient with MELAS 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.

Drug Category: 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.

Drug Name	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, carnitine may restore generation of free CoA and avoid carnitine depletion. If MELAS 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 Dose	1 g/dose PO/IV tid, not to exceed 3 g/d
Pediatric Dose	100-200 mg/kg/d PO divided tid, not to exceed 3 g/d
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Presence of secondary defect in LCFAO

Drug Name	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; also may act as potent antioxidant for free radicals. Amelioration of muscle weakness and decreased serum lactate has been observed.
Adult Dose	4.3 mg/kg PO qd
Pediatric Dose	4.3 mg/kg/d PO divided bid
Contraindications	Documented hypersensitivity
Interactions	Decreases warfarin effect
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Name	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 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. No known adverse effects.
Adult Dose	90 mg PO qd
Pediatric Dose	Limited data exist; administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause GI complaints, headache, anxiety, drowsiness, or tachycardia

Drug Name	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 Dose	50-200 mg PO qd
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	A - Safe in pregnancy
Precautions	Pregnancy category C with doses exceeding RDA; GI adverse effects (eg, abdominal pain, nausea, vomiting)

Drug Name	Ascorbic acid (Vita-C, Dull-C) -- May be useful in individual patients as antioxidant.
Adult Dose	1 g PO tid
Pediatric Dose	57 mg/kg/d PO
Contraindications	Documented hypersensitivity; can be contraindicated with history of nephrolithiasis
Interactions	Decreases effects of warfarin and fluphenazine; increases aspirin levels
Pregnancy	A - Safe in pregnancy
Precautions	Prolonged high doses may cause renal calculi, especially in patients with diabetes

Drug Name	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 close to term, since hemolysis and hyperbilirubinemia reportedly have affected newborns.
Adult Dose	25-35 mg PO tid
Pediatric Dose	1.1-1.5 mg/kg/d PO divided tid
Contraindications	Documented hypersensitivity
Interactions	Antagonizes action of warfarin b
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May produce hemolytic anemia, hyperbilirubinemia, and kernicterus in newborns; reactions resembling hypersensitivity have occurred after IV administration

Drug Name	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 (observed in one patient with MELAS enrolled in a study). Potential cytotoxic effect from long-term administration.
Adult Dose	0.1-0.2 g/kg/d PO divided bid/tid for 3 mo; no data on long-term administration
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Name	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 Dose	35-50 mg/kg/d PO/IV
Pediatric Dose	15-200 mg/kg/d PO/IV
Contraindications	Documented hypersensitivity
Interactions	Limited data exist; inhibits glucose synthesis, caution with coadministration of hypoglycemic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Effect on morbidity and mortality of patients with MELAS 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

Section 8 of 11

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 MELAS.



• Admit for signs of cardiac arrhythmia (Wolff-Parkinson-White syndrome) or 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, since progressive intellectual deterioration follows strokelike episodes of MELAS.



• Monitor growth curves, since mitochondrial disorders such as MELAS 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 for hearing loss with a hearing evaluation, including distortion product otoacoustic emissions and auditory brainstem evoked responses.



• Carefully monitor patients for cardiomyopathy with an echocardiogram. Request an ECG as a baseline study to monitor for conduction defects, even if patients are asymptomatic.



• Carefully monitor patients for the persistence of lactic acidosis.



• ¹H-MRS of the brain may be used to monitor potential therapeutic efficacy if increased permeability of the blood-brain barrier is a concern.

In/Out Patient Meds:

• 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 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 exist of successful treatment in patients with MELAS. 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
  
  
  
  • Strokelike 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



• Sensorineural hearing loss



• Endocrine dysfunction with hypogonadism, diabetes, and hypoparathyroidism



• 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

Prognosis:

• MELAS displays considerable variability 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 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).



• For excellent patient education resources, visit eMedicine’s Stroke Center. Also, see eMedicine’s patient education article Stroke.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Failure to evaluate for or exclude MELAS 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



• 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



• 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
  
  
  
  • Pancreatitis
  
  
  
  • Intestinal pseudoobstruction
  
  
  
  • Peripheral neuropathy
  
  
  
  • Nephrotic syndrome
  
  
  
  • Ischemic colitis
  
  
  
  • Rhabdomyolysis
  
  
  

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following is the inheritance pattern of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) disorder?

A: Maternal
B: Autosomal dominant
C: Autosomal recessive
D: X-linked recessive
E: X-linked dominant

The correct answer is A: MELAS is inherited in a maternal pattern, and the gene is on the mitochondrial genome.

CME Question 2: Which of the following is the most common form of presentation for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) disorder?

A: Nephrotic syndrome with focal segmental glomerulosclerosis
B: Intestinal obstruction
C: Hearing loss
D: Severe progressive encephalomyopathy
E: Hypertrophic cardiomyopathy

The correct answer is D: The typical presentation in the individual with MELAS is a progressive encephalomyopathy following a period of normal development. Cardiomyopathy is less common and may be found in approximately 10% of patients. Other presentations are possible, including nephrotic syndrome associated with focal segmental glomerulosclerosis. Sensorineural hearing loss is a common manifestation that may be observed in patients with the classic presentation of MELAS. Intestinal obstruction is another feature that has been reported in association with MELAS.

Pearl Question 1 (T/F): The most common age of onset of symptoms in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) disorder is in infancy.

The correct answer is False: Onset of MELAS most often occurs with the first strokelike episode when individuals are aged 4-15 years. Fewer patients experience onset of their disease in infancy, with developmental delay or with an infantile-onset encephalopathy associated with the MELAS syndrome A→G mutation at base pair 3243.

Pearl Question 2 (T/F): Patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) disorder may present with acute liver failure.

The correct answer is False: The liver does not appear to be involved in MELAS disorder. A variety of organs have been involved in individual patients with manifestations such as nephrotic syndrome, pancreatitis, peripheral neuropathy, and ischemic colitis. Liver involvement is observed in other mitochondrial disorders (eg, mitochondrial deoxyribonucleic acid depletion, Alpers syndrome).

Pearl Question 3 (T/F): Lactic acidosis is an important feature and diagnostic criteria of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) disorder.

The correct answer is True: An important feature of MELAS, lactic acidosis may not necessarily lead to systemic metabolic acidosis. In some incidents, lactic acidosis may be absent in patients with significant involvement of the central nervous system. Lactate levels may be elevated in the cerebrospinal fluid but completely normal in blood.

Pearl Question 4 (T/F): Patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) disorder have been found to have complex I deficiency of the respiratory chain.

The correct answer is True: In mitochondria from muscle, rotenone-sensitive nicotinamide adenine dinucleotide cytochrome reductase activity was found in 0-27% of controls, with immunochemical studies revealing a general decrease in complex I subunits.

BIBLIOGRAPHY

Section 11 of 11

• Borner GV, Zeviani M, Tiranti V, et al: Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. Hum Mol Genet 2000 Mar 1; 9(4): 467-75[Medline].
• Ciafaloni E, Ricci E, Shanske S, et al: MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol 1992 Apr; 31(4): 391-8[Medline].
• Hirano M, Pavlakis SG: Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol 1994 Jan; 9(1): 4-13[Medline].
• Hirano M, Ricci E, Koenigsberger MR, et al: Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord 1992; 2(2): 125-35[Medline].
• Jacobs HT, Holt IJ: The np 3243 MELAS mutation: damned if you aminoacylate, damned if you don't. Hum Mol Genet 2000 Mar 1; 9(4): 463-5[Medline].
• 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 1997 Dec; 44(6): 805-9[Medline].
• Kaufmann P, Engelstad K, Wei Y: Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 2006 Feb 14; 66(3): 329-330[Medline].
• Koga Y, Akita Y, Nishioka J: L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology 2005 Feb 22; 64(4): 710-2[Medline].
• Matsumoto J, Saver JL, Brennan KC, Ringman JM: Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS). Rev Neurol Dis 2005; 2(1): 30-4[Medline].
• Pavlakis SG, Phillips PC, DiMauro S, et al: Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984 Oct; 16(4): 481-8[Medline].
• Scaglia F, Northrop JL: The mitochondrial myopathy encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome: a review of treatment options. CNS Drugs 2006; 20(6): 443-64[Medline].
• Shimotake T, Furukawa T, Inoue K, et al: Familial occurrence of intestinal obstruction in children with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). J Pediatr Surg 1998 Dec; 33(12): 1837-9[Medline].
• Sue CM, Bruno C, Andreu AL, et al: Infantile encephalopathy associated with the MELAS A3243G mutation. J Pediatr 1999 Jun; 134(6): 696-700[Medline].
• Tanahashi C, Nakayama A, Yoshida M, et al: MELAS with the mitochondrial DNA 3243 point mutation: a neuropathological study. Acta Neuropathol (Berl) 2000 Jan; 99(1): 31-8[Medline].
• Thambisetty M, Newman NJ, Glass JD, Frankel MR: A practical approach to the diagnosis and management of MELAS: case report and review. Neurologist 2002 Sep; 8(5): 302-12[Medline].

eMedicine Journals > Pediatrics > Genetics And Metabolic Disease > MELAS Syndrome

Please email us with any comments you have on our new chapter format.

Author Information | Introduction | Clinical | Differentials | Workup | Treatment | Medication | Follow-up | Miscellaneous | Test Questions | Bibliography