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.
The diagnosis of MELAS is based on a combination of clinical findings and molecular genetic testing. Pathogenic variants in the mitochondrial DNA (mtDNA) gene MT-TL1 encoding tRNALeu(UUA/UUG) are causative. The most common pathogenic variant, present in about 80% of individuals with typical clinical findings, is an A-to-G transition at nucleotide 3243 (m.3243A>G). Pathogenic variants in MT-TL1 or other mtDNA genes, particularly MT-ND5, can also cause this disorder. Pathogenic variants 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 variant 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.
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
MELAS is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance. The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. A man with an mtDNA pathogenic variant cannot transmit the variant to any of his offspring. A woman (affected or unaffected) transmits the variant to all of her offspring. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for MELAS is possible if a mtDNA pathogenic variant 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.
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
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 [Kärppä 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
- MT-TL1. The mitochondrial DNA (mtDNA) gene MT-TL1 encoding tRNA leucine 1, tRNALeu(UUA/UUG), is the gene in which pathogenic variants are known to cause approximately 80% of cases of MELAS.
- MT-ND5. Pathogenic variants 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. Pathogenic variants 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).
- Targeted analysis for pathogenic variants. The most common pathogenic variant 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 . Pathogenic variants included in targeted analysis testing panels vary across laboratories and may include the MT-TL1 pathogenic variants m.3243A>G, m.3271T>C, and m.3252A>G as well as additional rare pathogenic variants (Table 5).
Note: (1) Pathogenic variants 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 variant 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 variant [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 variant cannot be detected by standard techniques in mtDNA from leukocytes or urinary sediment from an individual with classic MELAS.
- Sequence analysis/scanning for pathogenic variants. Sequence analysis / scanning of MT-TL1 may be an option for individuals in whom a pathogenic variant is not detected through targeted analysis.
- Targeted analysis for the most common MT-ND5 pathogenic variant, m.13513G>A
- Sequence analysis of 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 pathogenic variants in all genes known to cause MELAS, if clinically indicated.
To confirm/establish the diagnosis in a proband
- 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 uncertain clinical significance (see Molecular Genetics, Pathogenic allelic variants).
As alternatives to blood leukocytes, buccal mucosa, muscle, or urine sediment can be tested for mtDNA pathogenic variants.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.
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.
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.
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].
No clear genotype-phenotype correlations have been identified.
For all mtDNA pathogenic variants, 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 pathogenic variant, m.3243A>G. This may be the result of the higher abundance of the pathogenic variant 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 pathogenic variants [Moraes et al 1993].
In mtDNA-related disorders, penetrance typically depends on mutational load and tissue distribution, which show random variation within families (see Genotype-Phenotype Correlations).
No evidence of anticipation has been found. Knowledge of the molecular defect may favor earlier diagnosis in subsequent generations.
An epidemiologic study from northern Finland estimated the prevalence of the m.3243A>G pathogenic variant 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 prevalence of 236:100,000 for m.3243A>G, frequently associated with hearing loss [Manwaring et al 2007].
Genetically Related (Allelic) Disorders
The m.3243A>G pathogenic variant of MT-TL1 can also be associated with a variety of mitochondrial disorders including progressive external ophthalmoplegia (PEO), maternally inherited diabetes mellitus with or without deafness, cardiomyopathy, or deafness [Nesbitt et al 2013]. See Mitochondrial Disorders Overview.
POLG. One individual with MELAS had compound heterozygous pathogenic variants 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:
- Myasthenia gravis (fluctuating weakness, electrophysiologic tests, increased levels of anti-acetylcholine receptor antibodies, lack of family history). It is usually possible to distinguish myasthenia gravis from PEO at the bedside by examining saccadic velocity and performing an edrophonium test.
- Oculopharyngeal muscular dystrophy (late onset, autosomal dominant inheritance, ptosis, mild ophthalmoparesis, dysphagia, limb weakness muscle biopsy showing rimmed vacuoles, molecular genetic testing of PABPN1)
- Myotonic dystrophy type 1 (myotonia, facial weakness, distal muscle atrophy, autosomal dominant inheritance, molecular genetic testing of DMPK)
- PEO with ragged red fibers. If muscle biopsy shows RRF, the mitochondrial DNA deletion syndromes with PEO as well as MERRF need to be considered. Simplex cases (affected individuals with no known family history of PEO) usually have large-scale single deletions of mtDNA demonstrable by Southern blot analysis of muscle mtDNA, but could have an autosomal dominant or autosomal recessive disorder caused by primary pathogenic variants in nuclear genes [DiMauro & Hirano 2005]. Maternally inherited PEO in most cases is caused by MT-TL1 pathogenic variant m.3243A>G [Moraes et al 1993]. However, a small number of additional mtDNA pathogenic variants have been associated with PEO.
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.
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease. When gastrointestinal dysmotility, cachexia, and neuropathy are prominent, MNGIE needs to be considered [Hirano et al 2004].
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
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.
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 mutational 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.
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 [Díaz-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 pathogenic variant 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 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 pathogenic variants 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 mtDNA pathogenic variant.
- The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. In some mothers, the pathogenic variant 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 pathogenic variant.
Sibs of a proband
- The risk to the sibs depends on the genetic status of the mother.
- If the mother has the mtDNA pathogenic variant, all the sibs of a proband will inherit the mtDNA pathogenic variant 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 pathogenic variant will inherit the variant.
- Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the variant.
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 pathogenic variant, her sibs and mother are also at risk.
Related Genetic Counseling Issues
Phenotypic variability. Family members with the MT-TL1 pathogenic variant 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 pathogenic variant results from a combination of factors including the severity of the pathogenic variant, the percentage of mutated 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.
- 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
Although prenatal testing for mtDNA pathogenic variants causing MELAS is of uncertain utility, it may be available from a clinical laboratory that offers either testing of the relevant gene or custom prenatal testing. The specific mtDNA pathogenic variant in the mother must be identified before prenatal testing can be performed.
Changes in mutational load during pregnancy were evaluated in a small study of nine pregnancies in five women from families with the m.3243A>G mtDNA pathogenic variant. Mutational 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.
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 pathogenic variants have been identified.
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.
- My46 Trait Profile
- National Library of Medicine Genetics Home Reference
- United Mitochondrial Disease Foundation (UMDF)8085 Saltsburg RoadSuite 201Pittsburg PA 15239Phone: 888-317-8633 (toll-free); 412-793-8077Fax: 412-793-6477Email: firstname.lastname@example.org
- Australian Mitochondrial Disease Foundation (AMDF)Suite 4, Level 6, 9-13 Young StreetSydneyAustraliaPhone: 1-300-977-180Fax: 02-9999-3474Email: email@example.com
- Muscular Dystrophy Association - USA (MDA)222 South Riverside PlazaSuite 1500Chicago IL 60606Phone: 800-572-1717Email: firstname.lastname@example.org
- The Lily Foundation31 Warren ParkSurrey CR6 9LDUnited KingdomPhone: 07947 257247Fax: 01883 623799Email: email@example.com
- eyeGENEÂ® - National Ophthalmic Disease Genotyping Network RegistryPhone: 301-435-3032Email: eyeGENEinfo@nei.nih.gov
- RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
|MT-CO1||Mitochondria||Cytochrome c oxidase subunit 1|
|MT-CO2||Mitochondria||Cytochrome c oxidase subunit 2|
|MT-CO3||Mitochondria||Cytochrome c oxidase subunit 3|
|MT-ND1||Mitochondria||NADH-ubiquinone oxidoreductase chain 1|
|MT-ND5||Mitochondria||NADH-ubiquinone oxidoreductase chain 5|
|MT-ND6||Mitochondria||NADH-ubiquinone oxidoreductase chain 6|
|516000||COMPLEX I, SUBUNIT ND1; MTND1|
|516005||COMPLEX I, SUBUNIT ND5; MTND5|
|516006||COMPLEX I, SUBUNIT ND6; MTND6|
|516020||CYTOCHROME b OF COMPLEX III; MTCYB|
|516030||COMPLEX IV, CYTOCHROME c OXIDASE SUBUNIT I; MTCO1|
|516040||COMPLEX IV, CYTOCHROME c OXIDASE SUBUNIT II; MTCO2|
|516050||CYTOCHROME c OXIDASE III; MTCO3|
|540000||MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC ACIDOSIS, AND STROKE-LIKE EPISODES; MELAS|
|590020||TRANSFER RNA, MITOCHONDRIAL, CYSTEINE; MTTC|
|590030||TRANSFER RNA, MITOCHONDRIAL, GLUTAMINE; MTTQ|
|590040||TRANSFER RNA, MITOCHONDRIAL, HISTIDINE; MTTH|
|590050||TRANSFER RNA, MITOCHONDRIAL, LEUCINE, 1; MTTL1|
|590060||TRANSFER RNA, MITOCHONDRIAL, LYSINE; MTTK|
|590070||TRANSFER RNA, MITOCHONDRIAL, PHENYLALANINE; MTTF|
|590080||TRANSFER RNA, MITOCHONDRIAL, SERINE, 1; MTTS1|
|590085||TRANSFER RNA, MITOCHONDRIAL, SERINE, 2; MTTS2|
|590095||TRANSFER RNA, MITOCHONDRIAL, TRYPTOPHAN; MTTW|
|590105||TRANSFER 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 variants [King & Attardi 1989]. The cybrid cell-line studies showed that high proportions of the MT-TL1 m.3243A>G pathogenic variant 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, Börner et al 2000, Chomyn et al 2000]. An alternative theory, also based on cybrid work, attributes the pathogenesis of the variant 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 single-nucleotide variants and one 4-bp deletion in MT-CYB have been associated with the MELAS syndrome (Table 5).
Sequence analysis of the mitochondrial genome can be performed to screen for pathogenic variants. As with other sequence-based testing, this approach detects known mtDNA pathogenic variants, 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 variants, while 167 (22.4%) carried “putative” pathogenic variants [Bannwarth et al 2013]. Interpretation of such “putative pathogenic variants” 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. Pathogenic variants 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.
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DiMauro S, Hirano M. MELAS. 2001 Feb 27 [Updated 2013 Nov 21]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.