DiagnosisClinical DiagnosisThe 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 TestingLactic 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 TestingGenes MT-TL1. The mitochondrial DNA (mtDNA) gene MT-TL1 encoding tRNA leucine 1, tRNA^Leu(UUA/UUG), is the gene associated with 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 causing 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 over 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, such as 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 Targeted mutation analysis for the most common MT-ND5 mutation, m.13513G>A Sequence analysis of MT-ND5 MT-TF, MT-TH, MT-TK, MT-TQ, MT-TS1, MT-TS2, MT-ND1, MT-ND6Sequence analysisOther 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 MELASView in own windowGene SymbolProportion of MELAS Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityMT-TL1~80%Targeted mutation analysis 2m.3243A>G 100% for the targeted variantClinical~7.5%m.3271T>C 100% for the targeted variantm.3252A>G100% for the targeted variantSequence analysisSequence variants 3 ~100%MT-ND5Targeted mutation analysis 2Only targeted variants 2 m.13513G>A 100% for the targeted variantClinicalSequence analysisSequence variants 3MT-TFRareSequence analysisSequence variants 3~100%ClinicalMT-THRareSequence analysisSequence variants 3~100%MT-TKRareSequence analysisSequence variants 3~100%ClinicalMT-TQRareSequence analysisSequence variants 3~100%ClinicalMT-TS1RareSequence analysisSequence variants 3~100%ClinicalMT-TS2RareSequence analysisSequence variants 3~100%ClinicalMT-ND1RareSequence analysisSequence variants 3~100%ClinicalMT-ND6RareSequence analysisSequence variants 3~100%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutations detected may vary among laboratories.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense and nonsense mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here. Testing StrategyTo confirm/establish the diagnosis in a proband. Typically, blood leukocyte DNA is initially tested for the m.3243A>G mutation followed by testing for the m.13513G>A, m.3271T>C, and m.3252A>G mutations. Alternatively, DNA from buccal mucosa, muscle, or urine sediment can be tested for mtDNA mutations. If MT-TL1 mutations are excluded, mtDNA sequencing can be performed in probands with family histories compatible with maternal inheritance. In simplex cases (i.e., a single occurrence in a family) with myoclonus, epilepsy, and ataxia, muscle biopsy is often useful in detecting signs of mitochondrial dysfunction such as ragged-red fibers, strongly succinate dehydrogenase-reactive blood vessels (SSVs), or biochemical defects of mitochondrial respiratory chain enzymes.Sequence analysis of other mitochondrial genes known to cause MELAS can be performed if clinically indicatedPrenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersThe m.3243A>G mutation of MT-TL1 can also be associated with a variety of mitochondrial disorders including progressive external ophthalmoplegia (PEO), diabetes mellitus, cardiomyopathy, or deafness. See Mitochondrial Disorders Overview.}

Natural HistoryMELAS 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 age two and ten years, with some persons having delayed onset between 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 View in own windowAge of Onset (87 individuals)Number of IndividualsPercent (%)782-5 years17206-10 years273111-20 years151721-40 years2023>40 years11Table 3. MELAS: Initial Clinical ManifestationView in own windowInitial Symptom(s) or Sign(s) in 60 Individuals ¹ Number of IndividualsPercent (%)Seizures1728Recurrent headaches1728Gastrointestinal symptoms (recurrent vomiting, anorexia)1525Limb weakness1118Short stature/stopped growth1118Stroke1017Altered consciousness712Impaired mentation712Hearing loss610Exercise intolerance610Visual symptom58Developmental delay35Fever35Drop attacks11Impaired gait111. 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. 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 View in own windowManifestationsSign/SymptomPresent ¹ Recorded ² Percent (%) Cardinal Exercise intolerance3232100Onset 798099Stroke10610799Seizures9710296Ragged red fibers929895Lactic acidosis9410194Frequent Normal early development566290Dementia546090Limb weakness586589Hemiparesis576983Short stature587182Hemianopsia425379Headache415377Nausea, vomiting496477Onset 618076Hearing loss466175Learning disability284760CSF protein >45 mg/dL173652Other Basal ganglia calcification245345Family history378444Myoclonus277238Cerebellar signs237033Episodic coma94420Optic atrophy84120Congestive heart failure95118Pigmentary retinopathy106416Wolff-Parkinson-White64314Progressive external ophthalmoplegia96813Cardiac conduction block3476Diabetes mellitus2275Nephropathy2??Adapted from Hirano & Pavlakis [1994] 1. Present = number of individuals demonstrating a clinical feature2. Recorded = number of individuals evaluated for each clinical featureSome individuals have one presentation – e.g., progressive external ophthalmoplegia (PEO), diabetes mellitus (DM), cardiomyopathy, or deafness – almost exclusively [Hirano & Pavlakis 1994]. The clinical course of MELAS is characterized by progressive deterioration punctuated by acute neurologic deterioration in the setting of acute stroke-like events. The typical age of death ranges from ten to 35 years, but some individuals live into their sixth decade [Ciafaloni et al 1992, Majamaa-Voltti et al 2006]. Intercurrent infections or intestinal obstruction are often the terminal events [Hirano & Pavlakis 1994]. 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 CorrelationsNo 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 mtDNAsTissue 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].

Differential DiagnosisSee 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: 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 mutations in nuclear genes [DiMauro & Hirano 2005]. Maternally inherited PEO in most cases is caused by MT-TL1 mutation m.3243A>G [Moraes et al 1993]. However, a small number of additional mtDNA mutations 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. 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].

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease 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 Treatment of ManifestationsSensorineural hearing loss has been successfully treated with cochlear implantation [Sue et al 1998, Sinnathuray et al 2003]. 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 ManifestationsNo 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]. SurveillanceAffected individuals and their at-risk relatives should be followed at regular intervals to monitor progression and the appearance of new symptoms. Annual ophthalmologic, cardiologic, and endocrinologic evaluations are recommended.Agents/Circumstances to AvoidDichloroacetate (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]. Valproic acid should be avoided in the treatment of seizures [Lin & Thajeb 2007].Evaluation of Relatives at RiskMolecular 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. Therapies Under InvestigationOral 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameMT-ND6MitochondriaNADH-ubiquinone oxidoreductase chain 6MT-ND1MitochondriaNADH-ubiquinone oxidoreductase chain 1MT-TKMitochondriaNot applicableMT-TWMitochondriaNot applicableMT-TS1MitochondriaNot applicableMT-ND5MitochondriaNADH-ubiquinone oxidoreductase chain 5MT-TL1MitochondriaNot applicableMT-CYBMitochondriaCytochrome bMT-TVMitochondriaNot applicableMT-CO1MitochondriaCytochrome c oxidase subunit 1MT-CO2MitochondriaCytochrome c oxidase subunit 2MT-CO3MitochondriaCytochrome c oxidase subunit 3MT-TS2MitochondriaNot applicableMT-TCMitochondriaNot applicableMT-TFMitochondriaNot applicableMT-TQMitochondriaNot applicableData 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) View in own window 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 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; MTTVMolecular Genetic PathogenesisThe 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].Normal 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. Pathologic 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. Pathologic Allelic Variants in Mitochondrial DNA Associated with MELASView in own window% of Affected IndividualsMitochondrial DNA Nucleotide Change
(Alias ¹)Gene SymbolProtein 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] 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.12299A>CMT-TL2Abu-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​.1Malfatti et al [2007]m.3697G>AMT-ND1p.Gly131SerNC_012920​.1
ACT53096​.1Kirby et al [2004]m.3946G>AMT-ND1p.Gln214LysNC_012920​.1
ACT53096​.1Kirby et al [2004]m.3949T>CMT-ND1p.Tyr215HisNC_012920​.1
ACT53096​.1Kirby et al [2004]m.7023G>AMT-CO2p.Val374MetNC_012920​.1
ACT53096​.1Tam et al [2008]m.9957T>C
(T9957C) MT-CO3 p.Phe251LeuNC_012920​.1
NP_536849​.1Manfredi et al [1995]m.13513G>AMT-ND5 p.Asp393AsnNC_012920​.1
NP_536853​.1Santorelli 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>A
(G14453GA)MT-ND6 p.Ala74ValNC_012920​.1
NP_536854​.1Ravn et al [2001]m.14787delTTAA
(4-bp del)MT-CYB p.Ile14ThrfsNC_012920​.1
NP_536855​.1De Coo et al [1999]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 conventions2. Numbering based on mitochondrial DNA reference sequence: AC_000021.2 and individual protein reference sequencesFor more information, see Table A and Table B.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.}