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MELAS

Synonyms: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes; Myopathy, Mitochondrial-Encephalopathy-Lactic Acidosis-Stroke

, MD and , MD.

Author Information
, MD
Department of Neurology
Columbia University
New York, New York
, MD
Department of Neurology
Columbia University
New York, New York

Initial Posting: ; Last Update: November 21, 2013.

Summary

Disease characteristics. MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with onset typically in childhood. Early psychomotor development is usually normal, but short stature is common. Onset of symptoms is frequently between the ages of two and ten years. The most common initial symptoms are generalized tonic-clonic seizures, recurrent headaches, anorexia, and recurrent vomiting. Exercise intolerance or proximal limb weakness can be the initial manifestation. Seizures are often associated with stroke-like episodes of transient hemiparesis or cortical blindness. These stroke-like episodes may be associated with altered consciousness and may be recurrent. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and mentation, often by adolescence or young adulthood. Sensorineural hearing loss is common.

Diagnosis/testing. The diagnosis of MELAS is based on a combination of clinical findings and molecular genetic testing. Mutations in the mitochondrial DNA (mtDNA) gene MT-TL1 encoding tRNALeu(UUA/UUG) are causative. The most common mutation, present in about 80% of individuals with typical clinical findings, is an A-to-G transition at nucleotide 3243 (m.3243A>G). Mutations in MT-TL1 or other mtDNA genes, particularly MT-ND5, can also cause this disorder. Mutations can usually be detected in mtDNA from leukocytes in individuals with typical MELAS; however, the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, the pathogenic mutation may be undetectable in mtDNA from leukocytes and may be detected only in other tissues, such as cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.

Management. Treatment of manifestations: No specific treatment for MELAS exists. Sensorineural hearing loss has been treated with cochlear implantation; seizures respond to traditional anticonvulsant therapy. Diabetes mellitus is managed by dietary modification, oral hypoglycemic agents, or insulin therapy. L-arginine showed promise in treating stroke-like episodes. Migraine headaches and cardiac manifestations are treated in the usual manner.

Prevention of primary manifestations: Coenzyme Q10 and its analog, idebenone, have been beneficial in some individuals.

Prevention of secondary complications: Because febrile illnesses may trigger acute exacerbations, individuals with MELAS should receive standard childhood vaccinations, flu vaccine, and pneumococcal vaccine.

Surveillance: Affected individuals and their at-risk relatives should be followed at regular intervals to monitor progression and the appearance of new symptoms. Annual ophthalmologic, cardiologic (electrocardiogram and echocardiogram), and endocrinologic (fasting blood sugar and TSH) evaluations are recommended.

Agents/circumstances to avoid: Mitochondrial toxins, including aminoglycoside antibiotics, linezolid, cigarettes, and alcohol; valproic acid for seizure treatment; dichloroacetate (DCA) because of increased risk for peripheral neuropathy.

Pregnancy management: Affected or at-risk pregnant women should be monitored for diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions

Genetic counseling. MELAS is caused by mutations in mtDNA and is transmitted by maternal inheritance. The father of a proband is not at risk of having the disease-causing mtDNA mutation. The mother of a proband usually has the mtDNA mutation and may or may not have symptoms. A man with an mtDNA mutation cannot transmit the mutation to any of his offspring. A woman (affected or unaffected) transmits the mutation to all of her offspring. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for MELAS is possible if a mtDNA mutation has been detected in the mother. However, because the mutational load in embryonic and fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of all fetal tissues, and because the mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation, prediction of the phenotype from prenatal studies cannot be made with certainty.

Diagnosis

Clinical Diagnosis

The clinical diagnosis of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is based on the following features:

  • Stroke-like episodes, typically before age 40 years
  • Encephalopathy with seizures and/or dementia
  • Mitochondrial myopathy, evidenced by lactic acidosis and/or ragged red fibers (RRF) on muscle biopsy

To confirm the diagnosis, two of the following are also required [Hirano et al 1992]:

  • Normal early psychomotor development
  • Recurrent headache
  • Recurrent vomiting

Testing

Lactic acidosis both in blood and in the CSF. In individuals with MELAS, lactate concentrations are commonly elevated at rest and increase excessively after moderate exercise.

Note: Other situations (unrelated to the diagnosis of MELAS) in which lactate and pyruvate can be elevated are acute neurologic events such as seizure or stroke.

Elevated CSF protein. The concentration of CSF protein may be elevated but rarely surpasses 100 mg/dL.

Brain imaging. During stroke-like episodes, brain MRI shows areas of increased T2 signal, typically involving the posterior cerebrum and not conforming to the distribution of major arteries. Slow spreading of the stroke-like lesions in the weeks following the first symptoms can be documented by T2-weighted MRI [Iizuka et al 2003]. In addition, diffusion-weighted MRI shows increased apparent diffusion coefficient (ADC) in the stroke-like lesions of MELAS, in contrast to the decreased ADC seen in ischemic strokes [Kolb et al 2003].

Basal ganglia calcifications are also sometimes seen on CT.

Electrocardiogram (ECG) may show evidence of cardiomyopathy, pre-excitation, or incomplete heart block.

Electromyography and nerve conduction studies are consistent with a myopathic process, but neuropathy may coexist. Neuropathy is relatively common (22% in a study of 32 individuals) and is predominantly axonal and sensory [Karppa et al 2003, Kaufmann et al 2006b].

Muscle biopsy typically shows ragged red fibers (RRF) with the modified Gomori trichrome stain or "ragged blue fibers" resulting from the hyperintense reaction with the histochemical stain for succinate dehydrogenase (SDH). Most RRFs stain positively for cytochrome c oxidase (COX) activity [DiMauro & Bonilla 1997], unlike in other mtDNA-related disorders such as Kearns-Sayre syndrome (KSS) and MERRF (myoclonic epilepsy ragged red fibers), in which RRFs do not react with the cytochrome c oxidase (COX) histochemical stain [Filosto et al 2007]. An additional morphologic feature that is characteristic (though not pathognomonic) of MELAS is the overabundance of mitochondria in smooth muscle and endothelial cells of intramuscular blood vessels, best revealed with the SDH stain ("strongly succinate dehydrogenase-reactive blood vessels," or SSVs) [Hasegawa et al 1991].

Respiratory chain studies. Biochemical analysis of respiratory chain enzymes in muscle extracts usually shows multiple partial defects, especially involving complex I and/or complex IV. However, biochemical results can also be normal.

Molecular Genetic Testing

Genes

  • MT-TL1. The mitochondrial DNA (mtDNA) gene MT-TL1 encoding tRNA leucine 1, tRNALeu(UUA/UUG), is the gene in which mutations are known to cause approximately 80% of cases of MELAS.
  • MT-ND5. Mutations in MT-ND5 encoding the NADH-ubiquinone oxidoreductase subunit 5 have been reported with increasing frequency in individuals with isolated MELAS or with overlap syndromes [DiMauro & Davidzon 2005].

Other mtDNA genes. Mutations known to cause MELAS have been identified in other mtDNA tRNA genes including MT-TC, MT-TK, MT-TV, MT-TF, MT-TQ, MT-TS1, MT-TS2, and MT-TW, and in the protein-encoding genes MT-CO1, MT-CO2, MT-CO3, MT-CYB, MT-ND1, MT-ND3, and MT-ND6 (see Table 1 and Molecular Genetics).

Clinical testing

  • MT-TL1
    • Targeted mutation analysis. The most common mutation in MELAS, present in more than 80% of individuals with typical clinical findings, is m.3243A>G in MT-TL1, first described by Goto et al [1990]. Mutations included in targeted mutation analysis testing panels vary across laboratories and may include the MT-TL1 mutations m.3243A>G, m.3271T>C, and m.3252A>G as well as additional rare mutations (Table 5).

      Note: (1) Mutations are usually present in all tissues and can be detected in mtDNA from blood leukocytes in individuals with typical MELAS; however, the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, in individuals having one or only a few symptoms consistent with MELAS or asymptomatic maternal relatives, the pathogenic mutation may be undetectable in mtDNA from leukocytes and may only be detected in other tissues (e.g., cultured skin fibroblasts, hair follicles, urinary sediment, or, most reliably, skeletal muscle). Among readily accessible tissues, urinary sediment has proven the most useful for detecting the m.3243A>G mutation [McDonnell et al 2004, Shanske et al 2004]. (2) A muscle biopsy is recommended in the rare instance in which the MT-TL1 m.3243A>G mutation cannot be detected by standard techniques in mtDNA from leukocytes or urinary sediment from an individual with classic MELAS.
    • Sequence analysis/mutation scanning. Sequence analysis/mutation scanning of MT-TL1 may be an option for individuals in whom a mutation is not detected through targeted mutation analysis.
  • MT-ND5
  • MT-TF, MT-TH, MT-TK, MT-TQ, MT-TS1, MT-TS2, MT-ND1, MT-ND6
    • Sequence analysis
  • Other mtDNA genes. Complete sequencing of the mitochondrial genome can be used to detect rare mutations in all genes known to cause MELAS, if clinically indicated.

Table 1. Summary of Molecular Genetic Testing Used in MELAS

Gene 1Proportion of MELAS Attributed to Mutations in This GeneTest MethodMutations Detected 2
MT-TL1~80%Targeted mutation analysis 3m.3243A>G
~7.5%m.3271T>C
<5%m.3252A>G
<10%Sequence analysis 4 / mutation scanning 5Sequence variants
MT-ND5<15%Targeted mutation analysis 3Only targeted variants 3 m.13513G>A
<5%Sequence analysis 4 / mutation scanning 5Sequence variants
MT-TFRareSequence analysis 4Sequence variants
MT-THRareSequence analysis 4 / mutation scanning 5Sequence variants
MT-TKRareSequence analysisSequence variants
MT-TQRareTargeted mutation analysis 3Only targeted variants 3 m.4332G>A
Sequence analysis 4 / mutation scanning 5Sequence variants
MT-TS1RareSequence analysis 4Sequence variants
MT-TS2RareSequence analysis 4Sequence variants
MT-ND1RareSequence analysis 4Sequence variants
MT-ND6RareSequence analysis 4Sequence variants

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Mutations detected may vary among laboratories.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Typically, blood leukocyte DNA is initially tested for the m.3243A>G mutation, followed by testing for m.13513G>A, m.3271T>C, and m.3252A>G.
  • Alternatively, multi-gene panels that include some/all of the genes of interest may be used.
  • Sequence analysis of the mitochondrial genome is also possible but increases the detection of variants of unknown clinical significance (see Molecular Genetics, Pathogenic allelic variants).

As alternatives to blood leukocytes, buccal mucosa, muscle, or urine sediment can be tested for mtDNA mutations.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

MELAS is a multisystem disorder with protean manifestations. In typical cases, onset is in childhood. Early psychomotor development is usually normal, but short stature is common. First onset of symptoms is frequently between ages two and ten years, with some persons having delayed onset between ages ten and 40 years. Onset of symptoms before age two years or after age 40 years is uncommon. The most common initial symptoms are seizures, recurrent headaches, anorexia, and recurrent vomiting. Exercise intolerance or proximal limb weakness can be the initial manifestation, followed by generalized tonic-clonic seizures.

Table 2. MELAS: Age of Onset

Age of Onset (87 individuals)Number of IndividualsPercent (%)
<2 years78
2-5 years1720
6-10 years2731
11-20 years1517
21-40 years2023
>40 years11

Table 3. MELAS: Initial Clinical Manifestation

Initial Symptom(s) or Sign(s) in 60 Individuals 1 Number of IndividualsPercent (%)
Seizures1728
Recurrent headaches1728
Gastrointestinal symptoms (recurrent vomiting, anorexia)1525
Limb weakness1118
Short stature/stopped growth1118
Stroke1017
Altered consciousness712
Impaired mentation712
Hearing loss610
Exercise intolerance610
Visual symptom58
Developmental delay35
Fever35
Drop attacks11
Impaired gait11

1. Affected individuals frequently presented with more than one manifestation.

Seizures are often associated with stroke-like episodes of transient hemiparesis or cortical blindness that may produce altered consciousness and may recur. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and mentation, often by adolescence or young adulthood. Sensorineural hearing loss adds to the progressive decline of these individuals.

Migrainous headaches occur in the majority of affected individuals and are often severe during the acute phase of the stroke.

Individuals with this condition may also have psychiatric manifestations. A review of the psychiatric manifestations of mitochondrial disorders included 26 individuals with MELAS syndrome with one or more of the following symptoms: major depressive disorder (n=5), cognitive impairment (n=11), psychotic disorder (n=15), anxiety disorder (n=6), frontal lobe syndrome (n=3) or personality change (n=2) [Anglin et al 2012].

Less common symptoms include myoclonus, ataxia [Petruzzella et al 2004], episodic coma, optic atrophy, cardiomyopathy [Menotti et al 2004, Wortmann et al 2007], pigmentary retinopathy, ophthalmoplegia, diabetes mellitus, hirsutism, gastrointestinal dysmotility [Garcia-Velasco et al 2003, Chang et al 2004], and nephropathy.

Table 4. Clinical Features of 110 Individuals with MELAS

ManifestationsSign/SymptomPresent 1 Recorded 2 Percent (%)
Cardinal Exercise intolerance3232100
Onset <age 40 years 798099
Stroke10610799
Seizures9710296
Ragged red fibers929895
Lactic acidosis9410194
Frequent Normal early development566290
Dementia546090
Limb weakness586589
Hemiparesis576983
Short stature587182
Hemianopsia425379
Headache415377
Nausea, vomiting496477
Onset <age 20 years 618076
Hearing loss466175
Learning disability284760
CSF protein >45 mg/dL173652
Other Basal ganglia calcification245345
Family history378444
Myoclonus277238
Cerebellar signs237033
Episodic coma94420
Optic atrophy84120
Congestive heart failure95118
Pigmentary retinopathy106416
Wolff-Parkinson-White64314
Progressive external ophthalmoplegia96813
Cardiac conduction block3476
Diabetes mellitus2275
Nephropathy2??

Adapted from Hirano & Pavlakis [1994]

1. Present = number of individuals demonstrating a clinical feature

2. Recorded = number of individuals evaluated for each clinical feature

Some individuals have one presentation – e.g., progressive external ophthalmoplegia (PEO), diabetes mellitus (DM), cardiomyopathy, or deafness – almost exclusively [Hirano & Pavlakis 1994].

The disease progresses over years with episodic deterioration related to stroke-like events. The course varies from individual to individual. In a cohort of 33 adults with the m.3243A>G MELAS mutation who were followed for three years, deterioration of sensorineural function, cardiac left ventricular hypertrophy, EEG abnormalities, and overall severity were observed [Majamaa-Voltti et al 2006]. In a natural history study of 31 individuals with MELAS and 54 symptomatic and asymptomatic carrier relatives over a follow-up period of up to 10.6 years, neurologic examination, neuropsychological testing, and daily living scores significantly declined in all affected individuals with MELAS, whereas no significant deterioration occurred in carrier relatives. The death rate was more than 17-fold higher in fully symptomatic individuals compared to carrier relatives. The average observed age at death in the affected MELAS group was 34.5±19 years (range 10.2-81.8 years). Of the deaths, 22% occurred in those younger than 18 years. The estimated overall median survival time based on fully symptomatic individuals was 16.9 years from onset of focal neurologic disease [Kaufmann et al 2011]. A Japanese prospective cohort study of 96 individuals with MELAS confirmed a rapidly progressive course within a five-year interval, with 20.8% of affected individuals dying within a median time of 7.3 years from diagnosis [Yatsuga et al 2012].

Neuropathology. Spongiform encephalopathy, predominantly in the cerebral cortex, has been observed [Sparaco et al 1993]. Vascular abnormalities have been found in neuropathologic studies of the brain [Betts et al 2006].

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations have been identified.

For all mtDNA mutations, clinical expression depends on three factors:

  • Heteroplasmy. The presence of a mixture of mutant and normal mtDNAs
  • Tissue distribution of mutant mtDNAs
  • Threshold effect. The vulnerability of each tissue to impaired oxidative metabolism

While the tissue vulnerability threshold probably does not vary substantially among individuals, mutational load and tissue distribution do vary and may account for the clinical diversity seen in individuals with MELAS. Correlations between the frequency of the more common clinical features and the level of mutant mtDNA in muscle, but not in leukocytes, have been observed [Chinnery et al 1997, Jeppesen et al 2006]. Diverse clinical presentations (i.e., progressive external ophthalmoplegia, diabetes mellitus, cardiomyopathy, deafness) can be associated with the same MT-TL1 mutation, m.3243A>G. This may be the result of the higher abundance of the mutation in muscle in individuals with progressive external ophthalmoplegia (PEO) than in those with typical MELAS, which may in turn explain why ragged red fibers in individuals with PEO are COX negative rather than COX positive [Petruzzella et al 1994].

As-yet-undefined nuclear DNA factors may also modify the phenotypic expression of mtDNA mutations [Moraes et al 1993].

Penetrance

In mtDNA-related disorders, penetrance typically depends on mutation load and tissue distribution, which show random variation within families (see Genotype-Phenotype Correlations).

Anticipation

No evidence of anticipation has been found. Knowledge of the molecular defect may favor earlier diagnosis in subsequent generations.

Prevalence

An epidemiologic study from northern Finland estimated the prevalence of the m.3243A>G mutation to be greater than or equal to 16.3:100,000 (95% confidence interval 11.3-21.4:100,000) [Majamaa et al 1997]. According to a more recent Finnish study, this estimate may be high [Uusimaa et al 2004]. However, an Australian study found a mutation prevalence of 236:100,000, frequently associated with hearing loss [Manwaring et al 2007].

Differential Diagnosis

See Mitochondrial Disorders Overview.

POLG. One individual with MELAS had compound heterozygous mutations in the nuclear DNA gene POLG, encoding the catalytic subunit of polymerase gamma. See POLG-related disorders.

Acute stroke. The differential diagnosis includes other causes of stroke in a young person: heart disease, carotid or vertebral diseases, sickle cell disease, vasculopathies, lipoprotein dyscrasias, venous thrombosis, Moyamoya disease, complicated migraine (see Familial Hemiplegic Migraine), Fabry disease, and homocystinuria caused by cystathionine beta-synthase deficiency [Meschia & Worrall 2004, Meschia et al 2005]. Besides appropriate specific tests, a maternal history of other problems suggesting mitochondrial dysfunction (short stature, migraine, hearing loss, DM) can help orient the clinician toward the correct diagnosis.

Progressive external ophthalmoplegia (PEO). The differential diagnosis includes other forms of ophthalmoparesis:

Diabetes mellitus. Individuals with MELAS who have diabetes mellitus are typically thin, with mid-adult onset. Although individuals initially respond to diet, then to oral hypoglycemic agents, they rapidly develop insulin dependence. MELAS should be considered in individuals with diabetes mellitus who are deaf or have a family history suggesting maternal inheritance.

Deafness. See Hereditary Hearing Loss and Deafness Overview and Mitochondrial Nonsyndromic Hearing Loss.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease. When gastrointestinal dysmotility, cachexia, and neuropathy are prominent, MNGIE needs to be considered [Hirano et al 2004].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MELAS, the following evaluations are recommended:

  • Measurement of height and weight to assess growth
  • Audiologic evaluation
  • Ophthalmologic evaluation
  • Assessment of cognitive abilities
  • Physical therapy assessment
  • Neurologic evaluation, MRI, MRS [Kaufmann et al 2004], and, if seizures are suspected, EEG
  • Cardiac evaluation
  • Screening for diabetes mellitus by fasting serum glucose concentration and glucose tolerance test
  • Medical genetics consultation

Treatment of Manifestations

Sensorineural hearing loss has been successfully treated with cochlear implantation [Sue et al 1998, Scarpelli et al 2012].

Ptosis can benefit from eyelid "crutches," blepharoplasty, or frontalis muscle-eyelid sling placement.

No therapy is available for PEO or retinopathy.

Aerobic exercise is helpful in MELAS and other mitochondrial diseases [Taivassalo & Haller 2004]. Physical therapy should be implemented in individuals after strokes.

Seizures respond to traditional anticonvulsant therapy.

Standard analgesics can be used for migraine headaches.

Cardiac manifestations can benefit from standard pharmacologic therapy.

Diabetes mellitus can be managed by dietary modification only, especially in thin individuals, or with oral hypoglycemic agents, but often requires insulin therapy.

L-arginine showed promise in treating stroke-like episodes in MELAS [Koga et al 2010].

Prevention of Primary Manifestations

No specific treatment for MELAS exists.

The administration of coenzyme Q10 (CoQ10) (50-100 mg 3x/day) and L-carnitine (1000 mg 3x/day) has been of some benefit to some individuals. In a small randomized double-blind placebo-controlled study, CoQ10 combined with creatine and lipoic acid produced modest benefits including slowing progression of ankle weakness and lower resting plasma lactate concentration [Rodriguez et al 2007].

Idebenone, an analog of CoQ10 that crosses the blood-brain barrier more efficiently, has also been reported as beneficial in anecdotal reports [Napolitano et al 2000]. A clinical trial of idebenone for MELAS is in progress [Author, personal observation].

Prevention of Secondary Complications

Because febrile illnesses may trigger acute exacerbations, individuals with MELAS should receive standard childhood vaccinations, flu vaccine, and pneumococcal vaccine.

Surveillance

Affected individuals and their at-risk relatives should be followed at regular intervals to monitor progression and the appearance of new symptoms. Annual ophthalmologic, cardiologic (electrocardiogram and echocardiogram), and endocrinologic evaluations (fasting blood sugar and TSH) are recommended.

Agents/Circumstances to Avoid

Individuals with MELAS should avoid mitochondrial toxins such as: aminoglycoside antibiotics, linezolid, cigarettes, and alcohol. Valproic acid should be avoided in the treatment of seizures [Lin & Thajeb 2007].

Dichloroacetate (DCA) reduces blood lactate by activating the pyruvate dehydrogenase complex. Anecdotal reports of effectiveness have not been substantiated by a double-blind, placebo-controlled trial, which in fact documented a toxic effect of DCA on peripheral nerves and concluded that individuals with MELAS (who are already at increased risk for peripheral neuropathies) should avoid DCA [Kaufmann et al 2006a].

Evaluation of Relatives at Risk

Molecular genetic testing of at-risk maternal relatives may reveal individuals who have high mutation loads and are thus at risk of developing symptoms. However, no proven disease-modifying intervention exists at present.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Infertility may preclude pregnancy in some affected individuals. Women with MELAS should receive genetic counseling prior to pregnancy. During pregnancy, affected or at-risk women should be monitored for diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions [Diaz-Lobato et al 2005].

Therapies Under Investigation

Oral administration of L-arginine seems to attenuate the severity of strokes when administered in the acute phase [Koga et al 2005] and to reduce the frequency of strokes when given interictally [Koga et al 2005, Koga et al 2010]; double-blind studies are needed to confirm these data.

Beneficial effects of oral succinate were reported in one individual [Oguro et al 2004].

The role of heart transplantation for progressive cardiomyopathy has been reviewed [Bhati et al 2005].

The transfer of nuclear DNA from fertilized oocytes or zygotes harboring a mtDNA mutation to a recipient enucleated recipient cells could theoretically prevent transmission of mtDNA diseases and proof of this concept has been demonstrated in pronuclear transfers from abnormally fertilized zygotes that were allowed to under several replications in vitro [Craven et al 2010].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MELAS is caused by mutations in mtDNA and is transmitted by maternal inheritance.

Risk to Family Members

Parents of a proband

  • The father of a proband does not have the disease-causing mtDNA mutation.
  • The mother of a proband usually has the mtDNA mutation and may or may not have symptoms. In some mothers, the disease-causing mutation may be undetectable in mtDNA from leukocytes and may be detected in other tissues, such as cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
  • Alternatively, the proband may have a de novo somatic mitochondrial mutation.

Sibs of a proband

  • The risk to the sibs depends on the genetic status of the mother.
  • If the mother has the mtDNA mutation, all the sibs of a proband will inherit the disease-causing mtDNA mutation and may or may not have symptoms. One group has reported that women with higher levels of mutant mtDNA in their blood have a greater likelihood of having affected offspring [Chinnery et al 1998].

Offspring of a proband

  • All offspring of females with a mtDNA mutation will inherit the mutation.
  • Offspring of males with a mtDNA mutation are not at risk of inheriting the mutation.

Other family members of a proband

  • The risk to other family members depends on the genetic status of the proband's mother.
  • If she has a mtDNA mutation, her sibs and mother are also at risk.

Related Genetic Counseling Issues

Phenotypic variability. Family members with the MT-TL1 mutation m.3243A>G are more likely to have non-MELAS manifestations (i.e., diabetes mellitus, hearing loss).

The phenotype of an individual with a mtDNA mutation results from a combination of factors including the severity of the mutation, the percentage of mutant mitochondria (mutational load), and the organs and tissues in which they are found (tissue distribution). Different family members often inherit different percentages of mutant mtDNA and therefore can have a wide range of clinical symptoms.

Interpretation of test results of asymptomatic at-risk family members is extremely difficult. Prediction of phenotype based on test results is not possible.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Although prenatal testing for mtDNA mutations causing MELAS is of uncertain utility, it is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The specific mtDNA mutation in the mother must be identified before prenatal testing can be performed.

Changes in mutation load during pregnancy were evaluated in a small study of nine pregnancies in five women from families with the m.3243A>G mtDNA mutation. Mutation loads in chorionic villi (which were analyzed once) and in amniocytes (analyzed once or twice during pregnancy) were found to be stable [Bouchet et al 2006]. Eleven pregnancies with fetal mutation levels 35% or lower (assessed with prenatal diagnosis or PGD) resulted in healthy children who have been followed for one month to five years; one pregnancy, with 63% mutation level in the fetus, was terminated [Monnot et al 2011, Treff et al 2012]. Additional studies are necessary to establish the value of prenatal testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Interpretation of prenatal diagnostic results is complex for the following reasons:

  • The mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues.
  • The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.

Prediction of phenotype, age of onset, severity, or rate of progression is not possible.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. MELAS: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for MELAS (View All in OMIM)

516000COMPLEX I, SUBUNIT ND1; MTND1
516005COMPLEX I, SUBUNIT ND5; MTND5
516006COMPLEX I, SUBUNIT ND6; MTND6
516020CYTOCHROME b OF COMPLEX III; MTCYB
516030COMPLEX IV, CYTOCHROME c OXIDASE SUBUNIT I; MTCO1
516040COMPLEX IV, CYTOCHROME c OXIDASE SUBUNIT II; MTCO2
516050CYTOCHROME c OXIDASE III; MTCO3
540000MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC ACIDOSIS, AND STROKE-LIKE EPISODES; MELAS
590020TRANSFER RNA, MITOCHONDRIAL, CYSTEINE; MTTC
590030TRANSFER RNA, MITOCHONDRIAL, GLUTAMINE; MTTQ
590040TRANSFER RNA, MITOCHONDRIAL, HISTIDINE; MTTH
590050TRANSFER RNA, MITOCHONDRIAL, LEUCINE, 1; MTTL1
590060TRANSFER RNA, MITOCHONDRIAL, LYSINE; MTTK
590070TRANSFER RNA, MITOCHONDRIAL, PHENYLALANINE; MTTF
590080TRANSFER RNA, MITOCHONDRIAL, SERINE, 1; MTTS1
590085TRANSFER RNA, MITOCHONDRIAL, SERINE, 2; MTTS2
590095TRANSFER RNA, MITOCHONDRIAL, TRYPTOPHAN; MTTW
590105TRANSFER RNA, MITOCHONDRIAL, VALINE; MTTV

Molecular Genetic Pathogenesis

The pathogenic mechanism is not completely clear, but interesting insights were obtained from studies of cybrid cell lines. Cybrids are mtDNA-less human immortal cell lines (rho0 cells) repopulated with mitochondria from individuals with MELAS harboring the m.3243A>G or other pathogenic mutations [King & Attardi 1989]. The cybrid cell-line studies showed that high proportions of the MT-TL1 m.3243A>G mutation correlated with decreased mitochondrial protein synthesis, decreased oxygen consumption, and increased amounts of an unprocessed RNA fragment containing the mutated gene and designated RNA-19 [King et al 1992]. High levels of RNA-19 were documented in tissues from individuals with MELAS [Kaufmann et al 1996]. Other studies have demonstrated low levels of the mutant tRNA, decreased aminoacylation, and hypomodification of the D-stem – alterations that may contribute to the observed decreased protein synthesis [Helm et al 1999, Borner et al 2000, Chomyn et al 2000]. An alternative theory, also based on cybrid work, attributes the pathogenesis of the mutation to a misreading of leucine codons as phenylalanine codons [Yasukawa et al 2000] because of lack of methyltaurine modification of the anticodon wobble base [Kirino et al 2004].

Benign allelic variants. Benign polymorphisms are especially frequent in mtDNA and are listed at www.mitomap.org. The mtDNA encodes 22 tRNAs that are essential for mitochondrial protein synthesis, specifically for the incorporation of amino acids into nascent proteins. Nine of the genes discussed in this GeneReview are tRNA genes: MT-TL1, MT-TC, MT-TF, MT-TV, MT-TQ, MT-TW, MT-TS1, MT-TS2, and MT-TK. Seven protein-encoding genes are also discussed. See Table B.

Pathogenic allelic variants. See Table 5.

Twenty-nine point mutations and one 4-bp deletion in MT-CYB have been associated with the MELAS syndrome (Table 5).

Table 5. Pathogenic Variants in Mitochondrial DNA Associated with MELAS

% of Affected IndividualsMitochondrial DNA Nucleotide Change
(Alias 1)
GeneProtein Amino Acid ChangeReference Sequences 2References
~80% m.3243A>GMT-TL1 No protein translatedNC_012920​.1Goto et al [1990]
~<10% m.3271T>CGoto et al [1991]
<5% m.3252A>GMorten et al [1993]
Rare m.3291T>CGoto et al [1994]
m.3256C>TSato et al [1994]
m.3260A>GNishino et al [1996]
m.583G>AMT-TFHanna et al [1998]
m.1642G>AMT-TV Taylor et al [1996]
m.1644G>ATanji et al [2008]
m.4332G>AMT-TQBataillard et al [2001]
m.5521G>AMT-TWHerrero-Martin et al [2010]
m.5814A>GMT-TC Manfredi et al [1996]
m.7512T>CMT-TS1Lindberg et al [2008]
m.12146A>GMT-TL2Calvaruso et al [2011]
m.12299A>CAbu-Amero et al [2009]
m.8316T>CMT-TKCampos et al [2000]
m.8296A>GMT-TKSakuta et al [2002]
m.3481G>AMT-ND1p.Gln59LysNC_012920​.1
ACT53096​.1
Malfatti et al [2007]
m.3697G>AMT-ND1p.Gly131SerNC_012920​.1
ACT53096​.1
Kirby et al [2004]
m.3946G>AMT-ND1p.Gln214LysNC_012920​.1
ACT53096​.1
Kirby et al [2004]
m.3949T>CMT-ND1p.Tyr215HisNC_012920​.1
ACT53096​.1
Kirby et al [2004]
m.7023G>AMT-CO2p.Val374MetNC_012920​.1
ACT53096​.1
Tam et al [2008]
m.9957T>CMT-CO3 p.Phe251LeuNC_012920​.1
NP_536849​.1
Manfredi et al [1995]
<10%m.13513G>AMT-ND5 p.Asp393AsnNC_012920​.1
NP_536853​.1
Santorelli et al [1997]
Rarem.12770A>Gp.Glu145GlyLiolitsa et al [2003]
m.13042G>A p.Ala236ThrNaini et al [2005]
m.13084A>T p.Ser250CysCrimi et al [2003]
m.13514A>G p.Asp393GlyCorona et al [2001]
m.13528A>Gp.Thr398AlaMcKenzie et al [2007]
m.14453G>AMT-ND6 p.Ala74ValNC_012920​.1
NP_536854​.1
Ravn et al [2001]
m.14787delTTAA
(4-bp del)
MT-CYB p.Ile14ThrfsNC_012920​.1
NP_536855​.1
De Coo et al [1999]
m.14864T>Cp.Cys40ArgEmmanuele et al [2013]

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

See Quick Reference for an explanation of nomenclature (Note: The mitochondrial genetic code varies from the genomic genetic code given in the Quick Reference. See www​.mitomap.org for genetic code and other features of the mitochondrial genome). Variants named according to current nomenclature guidelines (www​.hgvs.org)

1. Variant designation that does not conform to current naming conventions

2. Numbering based on mitochondrial DNA reference sequence: AC_000021.2 and individual protein reference sequences

For more information, see Table A and Table B.

Sequence analysis of the mitochondrial genome can be performed to screen for mutations. As with other sequence-based testing, this approach detects known mtDNA mutations, however, it has the disadvantage of also detecting variants of uncertain clinical significance [Bannwarth et al 2013, Tang et al 2013]. For example, a study of whole mtDNA sequencing of 743 individuals suspected of having mitochondrial diseases found 65 (7.4%) individuals had known pathogenic mutations, while 167 (22.4%) carried “putative pathogenic mutations” [Bannwarth et al 2013]. Interpretation of such “putative pathogenic mutations” may be complex, requiring additional testing in clinical and/or research laboratories. Interpretation requires application of existing pathogenicity criteria including: assessments of evolutionary conservation, in silico predictions of pathogenicity of the amino acid or nucleotide alterations, mtDNA heteroplasmy vs. homoplasmy, segregation of the variant in the family, correlations with biochemical defects, single-fiber PCR (to measure heteroplasmy in single COX-negative muscle fibers or ragged-red fibers vs. normal fibers), and cybrid cell analyses [DiMauro & Schon 2001, Yarham et al 2011]. Accordingly, in persons with mtDNA sequence variants of uncertain significance, muscle biopsies are particularly useful in assessing pathogenicity of the variants, particularly when heteroplasmic, and therefore amenable to single-fiber analyses.

Normal gene product. MT-CO2, cytochrome c oxidase subunit II (227 amino acids) and MT-CO3, cytochrome c oxidase subunit III (261 amino acids) are catalytic subunits of mitochondrial complex IV, which is the terminal electron acceptor of the respiratory chain.

MT-CYB, cytochrome b (112 amino acids) is an essential subunit of mitochondrial respiratory chain complex III.

MT-ND1, NADH dehydrogenase subunit 1 (318 amino acids); MT-ND5, NADH dehydrogenase subunit 5 (603 amino acids); and MT-ND6, NADH dehydrogenase subunit 6 (174 amino acids) are critical components of mitochondrial respiratory chain complex I.

Abnormal gene product. Mutations in the structural subunits of the mitochondrial respiratory chain complexes impair synthesis of ATP via oxidative phosphorylation and elevate lactic acid levels in blood and cerebrospinal fluid.

References

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Suggested Reading

  1. DiMauro S, Schon EA, Carelli V, Hirano M. The Clinical Maze of Mitochondrial Neurology. Nat Rev Neurol. 2013;9:429–44. [PMC free article: PMC3959773] [PubMed: 23835535]
  2. Klopstock T, Hirano M. MELAS. In: Gilman S, ed-in-chief. Medlink Neurology. San Diego, CA: Medlink Corporation; 2012. Available online (subscription required).
  3. Sproule DM, Kaufmann P. Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome. Ann N Y Acad Sci. 2008;1142:133–58. [PubMed: 18990125]

Chapter Notes

Revision History

  • 21 November 2013 (me) Comprehensive update posted live
  • 14 October 2010 (me) Comprehensive update posted live
  • 13 October 2005 (me) Comprehensive update posted to live Web site
  • 18 June 2003 (ca) Comprehensive update posted to live Web site
  • 27 February 2001 (me) Review posted to live Web site
  • September 2000 (sdm) Original submission
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