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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>MELAS - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="MELAS">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2018/11/29">
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<meta name="citation_author" content="Ayman W El-Hattab">
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<meta name="citation_author" content="Mohammed Almannai">
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<meta name="citation_author" content="Fernando Scaglia">
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<meta name="citation_pmid" content="20301411">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1233/">
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<meta name="citation_keywords" content="Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes">
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<meta name="citation_keywords" content="MELAS, MT-ND6-Related">
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<meta name="citation_keywords" content="MELAS, MT-ND1-Related">
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<meta name="citation_keywords" content="MELAS, MT-TK-Related">
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<meta name="citation_keywords" content="MELAS, MT-TH-Related">
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<meta name="citation_keywords" content="Cytochrome b">
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<meta name="citation_keywords" content="Cytochrome c oxidase subunit 2">
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<meta name="citation_keywords" content="Cytochrome c oxidase subunit 3">
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<meta name="citation_keywords" content="MELAS">
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<meta name="DC.Title" content="MELAS">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Ayman W El-Hattab">
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<meta name="DC.Contributor" content="Mohammed Almannai">
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<meta name="DC.Contributor" content="Fernando Scaglia">
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<meta name="DC.Date" content="2018/11/29">
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<meta name="description" content='MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Common clinical manifestations include stroke-like episodes, encephalopathy with seizures and/or dementia, muscle weakness and exercise intolerance, normal early psychomotor development, recurrent headaches, recurrent vomiting, hearing impairment, peripheral neuropathy, learning disability, and short stature. During the stroke-like episodes neuroimaging shows increased T2-weighted signal areas that do not correspond to the classic vascular distribution (hence the term "stroke-like"). Lactic acidemia is very common and muscle biopsies typically show ragged red fibers.'>
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<meta name="og:title" content="MELAS">
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<meta name="og:description" content='MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Common clinical manifestations include stroke-like episodes, encephalopathy with seizures and/or dementia, muscle weakness and exercise intolerance, normal early psychomotor development, recurrent headaches, recurrent vomiting, hearing impairment, peripheral neuropathy, learning disability, and short stature. During the stroke-like episodes neuroimaging shows increased T2-weighted signal areas that do not correspond to the classic vascular distribution (hence the term "stroke-like"). Lactic acidemia is very common and muscle biopsies typically show ragged red fibers.'>
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class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1233_"><span class="title" itemprop="name">MELAS</span></h1><p class="contribs">El-Hattab AW, Almannai M, Scaglia F.</p><p class="fm-aai"><a href="#_NBK1233_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 33 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="melas.Summary" itemprop="description"><h2 id="_melas_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>MELAS (<i>m</i>itochondrial <i>e</i>ncephalomyopathy, <i>l</i>actic <i>a</i>cidosis, and <i>s</i>troke-like episodes) is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Common clinical manifestations include stroke-like episodes, encephalopathy with seizures and/or dementia, muscle weakness and exercise intolerance, normal early psychomotor development, recurrent headaches, recurrent vomiting, hearing impairment, peripheral neuropathy, learning disability, and short stature. During the stroke-like episodes neuroimaging shows increased T<sub>2</sub>-weighted signal areas that do not correspond to the classic vascular distribution (hence the term "stroke-like"). Lactic acidemia is very common and muscle biopsies typically show ragged red fibers.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of MELAS is based on meeting clinical diagnostic criteria and identifying a pathogenic variant in one of the genes associated with MELAS. The m.3243A>G pathogenic variant in the mitochondrial gene <i>MT-TL1</i> is present in approximately 80% of individuals with MELAS. Pathogenic variants in <i>MT-TL1</i> or other mtDNA genes, particularly <i>MT-ND5</i>, can also cause this disorder.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Treatment for MELAS is generally supportive. During the acute stroke-like episode, a bolus of intravenous arginine (500 mg/kg for children or 10 g/m<sup>2</sup> body surface area for adults) within three hours of symptom onset is recommended followed by the administration of a similar dosage of intravenous arginine as a continuous infusion over 24 hours for the next three to five days. Coenzyme Q<sub>10</sub>, L-carnitine, and creatine have been beneficial in some individuals. Sensorineural hearing loss has been treated with cochlear implantation; seizures respond to traditional anticonvulsant therapy (although valproic acid should be avoided). Ptosis, cardiomyopathy, cardiac conduction defects, nephropathy, and migraine headache are treated in the standard manner. Diabetes mellitus is managed by dietary modification, oral hypoglycemic agents, or insulin therapy. Exercise intolerance and weakness may respond to aerobic exercise.</p><p><i>Prevention of primary manifestations</i>: Once an individual with MELAS has the first stroke-like episode, arginine should be administered prophylactically to reduce the risk of recurrent stroke-like episodes. A daily dose of 150 to 300 mg/kg/day oral arginine in three divided doses is recommended.</p><p><i>Prevention of secondary complications</i>: Because febrile illnesses may trigger acute exacerbations, individuals with MELAS should receive standard childhood vaccinations, flu vaccine, and pneumococcal vaccine.</p><p><i>Surveillance:</i> Affected individuals and their at-risk relatives should be followed at regular intervals to monitor progression and the appearance of new symptoms. Annual ophthalmologic, audiology, and cardiologic (electrocardiogram and echocardiogram) evaluations are recommended. Annual urinalysis and fasting blood glucose level are also recommended.</p><p><i>Agents/circumstances to avoid:</i> Mitochondrial toxins, including aminoglycoside antibiotics, linezolid, cigarettes, and alcohol; valproic acid for seizure treatment; metformin because of its propensity to cause lactic acidosis; dichloroacetate (DCA) because of increased risk for peripheral neuropathy.</p><p><i>Pregnancy management:</i> Affected or at-risk pregnant women should be monitored for diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions</p></div><div><h4 class="inline">Genetic counseling.</h4><p>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 a mtDNA pathogenic variant cannot transmit the variant to any of his offspring. A woman with a mtDNA pathogenic variant (whether symptomatic or asymptomatic) transmits the variant to all of her offspring. Prenatal testing and preimplantation genetic testing 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.</p></div></div><div id="melas.Diagnosis"><h2 id="_melas_Diagnosis_">Diagnosis</h2><p>Clinical diagnostic criteria for MELAS (<i>m</i>itochondrial <i>e</i>ncephalomyopathy, <i>l</i>actic <i>a</i>cidosis, and <i>s</i>troke-like episodes) have been published [<a class="bibr" href="#melas.REF.hirano.1992.125" rid="melas.REF.hirano.1992.125">Hirano et al 1992</a>, <a class="bibr" href="#melas.REF.yatsuga.2012.619" rid="melas.REF.yatsuga.2012.619">Yatsuga et al 2012</a>] (see <a href="#melas.Establishing_the_Diagnosis">Establishing the Diagnosis</a>).</p><div id="melas.Suggestive_Findings"><h3>Suggestive Findings</h3><p>MELAS (<i>m</i>itochondrial <i>e</i>ncephalomyopathy, <i>l</i>actic <i>a</i>cidosis, and <i>s</i>troke-like episodes) <b>should be suspected</b> in individuals with the following features.</p><div id="melas.Clinical_Features"><h4>Clinical Features</h4><ul><li class="half_rhythm"><div>Stroke-like episodes before the age of 40 years</div></li><li class="half_rhythm"><div>Acquired encephalopathy with seizures and/or dementia</div></li><li class="half_rhythm"><div>Recurrent headaches</div></li><li class="half_rhythm"><div>Muscle weakness and exercise intolerance</div></li><li class="half_rhythm"><div>Cortical vision loss</div></li><li class="half_rhythm"><div>Hemiparesis</div></li><li class="half_rhythm"><div>Recurrent vomiting</div></li><li class="half_rhythm"><div>Short stature</div></li><li class="half_rhythm"><div>Hearing impairment</div></li><li class="half_rhythm"><div>Normal early psychomotor development</div></li><li class="half_rhythm"><div>Peripheral neuropathy</div></li><li class="half_rhythm"><div>Learning disability</div></li></ul></div><div id="melas.Brain_Imaging"><h4>Brain Imaging</h4><p>
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<b>Brain MRI</b>
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</p><ul><li class="half_rhythm"><div>During the stroke-like episodes, the affected areas:</div><ul><li class="half_rhythm"><div>Have increased T<sub>2</sub> signal;</div></li><li class="half_rhythm"><div>Do not correspond to the classic vascular distribution (hence the term "stroke-like");</div></li><li class="half_rhythm"><div>Are asymmetric;</div></li><li class="half_rhythm"><div>Typically involve predominantly the posterior cerebrum (temporal, parietal, and occipital lobes);</div></li><li class="half_rhythm"><div>Can be restricted to cortical areas or involve subcortical white matter [<a class="bibr" href="#melas.REF.hirano.1992.125" rid="melas.REF.hirano.1992.125">Hirano et al1992</a>, <a class="bibr" href="#melas.REF.sproule.2008.133" rid="melas.REF.sproule.2008.133">Sproule & Kaufmann 2008</a>].</div></li></ul></li><li class="half_rhythm"><div>Slow spreading of the stroke-like lesions occurs in the weeks following the first symptoms, typically documented by T<sub>2</sub>-weighted MRI [<a class="bibr" href="#melas.REF.iizuka.2003.1238" rid="melas.REF.iizuka.2003.1238">Iizuka et al 2003</a>].</div></li><li class="half_rhythm"><div>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 [<a class="bibr" href="#melas.REF.kolb.2003.11" rid="melas.REF.kolb.2003.11">Kolb et al 2003</a>].</div></li><li class="half_rhythm"><div>MR angiography is usually normal and MR spectroscopy shows decreased N-acetylaspartate signals and accumulation of lactate [<a class="bibr" href="#melas.REF.sproule.2008.133" rid="melas.REF.sproule.2008.133">Sproule & Kaufmann 2008</a>].</div></li></ul><p><b>Head CT.</b> Basal ganglia calcifications are occasionally seen.</p></div><div id="melas.Electromyography_and_Nerve_Conduct"><h4>Electromyography and Nerve Conduction Studies</h4><p>Findings are consistent with a myopathic process, but neuropathy may coexist. Neuropathy can be axonal or mixed axonal and demyelinating [<a class="bibr" href="#melas.REF.k_rpp_.2003.216" rid="melas.REF.k_rpp_.2003.216">Kärppä et al 2003</a>, <a class="bibr" href="#melas.REF.kaufmann.2006b.746" rid="melas.REF.kaufmann.2006b.746">Kaufmann et al 2006b</a>].</p></div><div id="melas.Suggestive_Laboratory_Findings"><h4>Suggestive Laboratory Findings</h4><p><b>Lactic acidosis both in blood and CSF.</b> Lactic acidemia is very common. CSF lactate is also elevated in most affected individuals.</p><p>Lactic acidemia is not specific for MELAS syndrome as it can occur in other mitochondrial diseases, metabolic diseases, and systemic illness. Other situations (unrelated to the diagnosis of MELAS) in which lactate can be elevated are acute neurologic events such as seizure or stroke. On the other hand, lactate level can be normal in a minority of individuals with MELAS syndrome [<a class="bibr" href="#melas.REF.hirano.1994.4" rid="melas.REF.hirano.1994.4">Hirano & Pavlakis 1994</a>].</p><p><b>Elevated CSF protein</b> rarely surpasses 100 mg/dL.</p><p>
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<b>Muscle biopsy</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm">Ragged red fibers (RRFs) with the modified Gomori trichrome stain, which represent mitochondrial proliferation below the plasma membrane of the muscular fibers causing the contour of the muscle fiber to become irregular. These proliferated mitochondria also stain strongly with the succinate dehydrogenase (SDH) stain giving the appearance of ragged blue fibers.</div><div class="half_rhythm">Although RRFs are present in many other mitochondrial diseases e.g., MERRF (myoclonic epilepsy with ragged red fibers), most of the RRFs in MELAS stain positively with the cytochrome <i>c</i> oxidase (COX) histochemical stain, unlike other mitochondrial diseases where RRFs do not react with COX.</div></li><li class="half_rhythm"><div class="half_rhythm">An 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)</div></li><li class="half_rhythm"><div class="half_rhythm">Respiratory chain studies on muscle tissue: typically multiple partial defects, especially involving complex I and/or complex IV. However, biochemical results can also be normal.</div></li></ul><p>Note: Muscle biopsy is not required to make this diagnosis; molecular genetic testing is frequently used in lieu of muscle biopsy to <a href="#melas.Establishing_the_Diagnosis">establish the diagnosis</a>.</p></div></div><div id="melas.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>Two sets of clinical diagnostic criteria for MELAS (<i>m</i>itochondrial <i>e</i>ncephalomyopathy, <i>l</i>actic <i>a</i>cidosis, and <i>s</i>troke-like episodes) have been published:</p><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>I.</dt><dd><p class="no_top_margin">A clinical diagnosis of MELAS can be made if the following three criteria are met [<a class="bibr" href="#melas.REF.hirano.1992.125" rid="melas.REF.hirano.1992.125">Hirano et al 1992</a>]:</p><ul><li class="half_rhythm"><div>Stroke-like episodes before age 40 years</div></li><li class="half_rhythm"><div>Encephalopathy characterized by seizures and/or dementia</div></li><li class="half_rhythm"><div>Mitochondrial myopathy is evident by the presence of lactic acidosis and/or ragged-red fibers (RRFs) on muscle biopsy.</div></li></ul><p><b>AND</b> at least two of the following criteria are present:</p><ul><li class="half_rhythm"><div>Normal early psychomotor development</div></li><li class="half_rhythm"><div>Recurrent headaches</div></li><li class="half_rhythm"><div>Recurrent vomiting episodes</div></li></ul></dd></dl><dl class="bkr_refwrap"><dt>II.</dt><dd><p class="no_top_margin">A clinical diagnosis of MELAS can also be made in an individual with at least two category A <b>AND</b> two category B criteria [<a class="bibr" href="#melas.REF.yatsuga.2012.619" rid="melas.REF.yatsuga.2012.619">Yatsuga et al 2012</a>]:</p><p>
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<b>Category A criteria</b>
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</p><ul><li class="half_rhythm"><div>Headaches with vomiting</div></li><li class="half_rhythm"><div>Seizures</div></li><li class="half_rhythm"><div>Hemiplegia</div></li><li class="half_rhythm"><div>Cortical blindness</div></li><li class="half_rhythm"><div>Acute focal lesions on neuroimaging (See Suggestive Findings, <a href="#melas.Brain_Imaging">Brain Imaging</a>.)</div></li></ul><p>
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<b>Category B criteria</b>
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</p><ul><li class="half_rhythm"><div>High plasma or cerebrospinal fluid (CSF) lactate</div></li><li class="half_rhythm"><div>Mitochondrial abnormalities on muscle biopsy (See Suggestive Findings, <a href="#melas.Suggestive_Laboratory_Findings">Suggestive Laboratory Findings</a>.)</div></li><li class="half_rhythm"><div>A MELAS-related pathogenic variant (See <a href="/books/NBK1233/table/melas.T.genetic_causes_of_melas/?report=objectonly" target="object" rid-ob="figobmelasTgeneticcausesofmelas">Table 1</a>.)</div></li></ul></dd></dl></dl><p>The diagnosis of MELAS <b>is established</b> in a proband who meets the clinical diagnostic criteria discussed above and who has a pathogenic (or likely pathogenic) variant in one of the genes listed in <a href="/books/NBK1233/table/melas.T.genetic_causes_of_melas/?report=objectonly" target="object" rid-ob="figobmelasTgeneticcausesofmelas">Table 1</a> identified by molecular genetic testing.</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bibr" href="#melas.REF.richards.2015.405" rid="melas.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include any likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in one of the genes listed in <a href="/books/NBK1233/table/melas.T.genetic_causes_of_melas/?report=objectonly" target="object" rid-ob="figobmelasTgeneticcausesofmelas">Table 1</a> does not establish or rule out a diagnosis. (3) 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 buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing, concurrent or serial single-gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, exome array, genome sequencing) depending on the phenotype.</p><p>Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in <a href="#melas.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#melas.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other inherited disorders with seizures and weakness are more likely to be diagnosed using genomic testing (see <a href="#melas.Option_2">Option 2</a>).</p><div id="melas.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of MELAS, molecular genetic testing approaches can include <b>serial single-gene testing</b> or use of a <b>multigene panel</b>.</p><p><b>Serial single-gene testing</b> can be considered if (1) mutation of a particular gene accounts for a large proportion of the condition <b>or</b> (2) clinical findings, laboratory findings, ancestry, or other factors indicate that mutation of a particular gene is most likely.</p><ul><li class="half_rhythm"><div>Typically, blood leukocyte DNA is initially tested for the <a href="/books/NBK1233/table/melas.T.pathogenic_variants_in_mitochond/?report=objectonly" target="object" rid-ob="figobmelasTpathogenicvariantsinmitochond">m.3243A>G</a> pathogenic variant in <i>MT-TL1</i>, which is present in approximately 80% of individuals with typical clinical findings.</div></li><li class="half_rhythm"><div>If this is normal, targeted testing for the pathogenic variants <a href="/books/NBK1233/table/melas.T.pathogenic_variants_in_mitochond/?report=objectonly" target="object" rid-ob="figobmelasTpathogenicvariantsinmitochond">m.3271T>C</a> and <a href="/books/NBK1233/table/melas.T.pathogenic_variants_in_mitochond/?report=objectonly" target="object" rid-ob="figobmelasTpathogenicvariantsinmitochond">m.3252A>G</a> in <i>MT-TL1</i> and <a href="/books/NBK1233/table/melas.T.pathogenic_variants_in_mitochond/?report=objectonly" target="object" rid-ob="figobmelasTpathogenicvariantsinmitochond">m.13513G>A</a> in <i>MT-ND5</i> is considered next.</div></li></ul><p><b>A multigene panel</b> that includes <i>MT-TL1, MT-ND5</i>, and other mtDNA genes of interest (see <a href="/books/NBK1233/table/melas.T.genetic_causes_of_melas/?report=objectonly" target="object" rid-ob="figobmelasTgeneticcausesofmelas">Table 1</a> and <a href="#melas.Differential_Diagnosis">Differential Diagnosis</a>) may also be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</p><p><b>Entire mitochondrial genome sequencing</b> that includes <i>MT-TL1, MT-ND5</i>, and other mtDNA genes of interest (see <a href="/books/NBK1233/table/melas.T.genetic_causes_of_melas/?report=objectonly" target="object" rid-ob="figobmelasTgeneticcausesofmelas">Table 1</a> and <a href="#melas.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="melas.Option_2"><h4>Option 2</h4><p>When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and weakness, <b>comprehensive</b>
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<b>genomic testing</b> (which does not require the clinician to determine which gene[s] are likely involved) is the best option. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible. Many laboratories require that the clinician specify if the mitochondrial genome should be included as part of the comprehensive genomic testing.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmelasTgeneticcausesofmelas"><a href="/books/NBK1233/table/melas.T.genetic_causes_of_melas/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobmelasTgeneticcausesofmelas"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="melas.T.genetic_causes_of_melas"><a href="/books/NBK1233/table/melas.T.genetic_causes_of_melas/?report=objectonly" target="object" rid-ob="figobmelasTgeneticcausesofmelas">Table 1. </a></h4><p class="float-caption no_bottom_margin">Genetic Causes of MELAS </p></div></div></div></div></div><div id="melas.Clinical_Characteristics"><h2 id="_melas_Clinical_Characteristics_">Clinical Characteristics</h2><div id="melas.Clinical_Description"><h3>Clinical Description</h3><p>MELAS is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Childhood is the typical age of onset with 65%-76% of affected individuals presenting at or before age 20 years. Onset of symptoms before age two years or after age 40 years is uncommon (age<2 years: 5%-8% of individuals; age >40 years: 1%-6% of individuals).</p><p>Individuals with MELAS frequently present with more than one initial clinical manifestation. The most common initial symptoms are seizures, recurrent headaches, stroke-like episodes, cortical vision loss, muscle weakness, recurrent vomiting, and short stature (<a href="/books/NBK1233/table/melas.T.melas_initial_clinical_manifesta/?report=objectonly" target="object" rid-ob="figobmelasTmelasinitialclinicalmanifesta">Table 2</a>). <a href="/books/NBK1233/table/melas.T.melas_additional_clinical_manife/?report=objectonly" target="object" rid-ob="figobmelasTmelasadditionalclinicalmanife">Table 3</a> summarizes the clinical manifestations of MELAS organized according to their prevalence [<a class="bibr" href="#melas.REF.hirano.1994.4" rid="melas.REF.hirano.1994.4">Hirano & Pavlakis 1994</a>, <a class="bibr" href="#melas.REF.sproule.2008.133" rid="melas.REF.sproule.2008.133">Sproule & Kaufmann 2008</a>, <a class="bibr" href="#melas.REF.yatsuga.2012.619" rid="melas.REF.yatsuga.2012.619">Yatsuga et al 2012</a>, <a class="bibr" href="#melas.REF.elhattab.2015.4" rid="melas.REF.elhattab.2015.4">El-Hattab et al 2015</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmelasTmelasinitialclinicalmanifesta"><a href="/books/NBK1233/table/melas.T.melas_initial_clinical_manifesta/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobmelasTmelasinitialclinicalmanifesta"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="melas.T.melas_initial_clinical_manifesta"><a href="/books/NBK1233/table/melas.T.melas_initial_clinical_manifesta/?report=objectonly" target="object" rid-ob="figobmelasTmelasinitialclinicalmanifesta">Table 2. </a></h4><p class="float-caption no_bottom_margin">MELAS: Initial Clinical Manifestations </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmelasTmelasadditionalclinicalmanife"><a href="/books/NBK1233/table/melas.T.melas_additional_clinical_manife/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobmelasTmelasadditionalclinicalmanife"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="melas.T.melas_additional_clinical_manife"><a href="/books/NBK1233/table/melas.T.melas_additional_clinical_manife/?report=objectonly" target="object" rid-ob="figobmelasTmelasadditionalclinicalmanife">Table 3. </a></h4><p class="float-caption no_bottom_margin">MELAS: Additional Clinical Manifestations </p></div></div><p>
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<b>Neurologic manifestations</b>
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</p><ul><li class="half_rhythm"><div><b>Stroke-like episodes</b> present clinically with partially reversible aphasia, cortical vision loss, motor weakness, headaches, altered mental status, and seizures with the eventual progressive accumulation of neurologic deficits.</div></li><li class="half_rhythm"><div><b>Dementia</b> affects intelligence, language, perception, attention, and memory function.</div><ul><li class="half_rhythm"><div>Both the underlying neurologic dysfunction and the accumulating cortical injuries due to stroke-like episodes contribute to dementia.</div></li><li class="half_rhythm"><div>Executive function deficits have been observed despite the relative sparing of the frontal lobe on neuroimaging, indicating an additional diffuse neurodegenerative process in addition to the damage caused by the stroke-like episodes [<a class="bibr" href="#melas.REF.sproule.2008.133" rid="melas.REF.sproule.2008.133">Sproule & Kaufmann 2008</a>].</div></li></ul></li><li class="half_rhythm"><div>
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<b>Epilepsy</b>
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</div><ul><li class="half_rhythm"><div>Focal and primary generalized seizures can occur.</div></li><li class="half_rhythm"><div>Primary generalized seizures in MELAS can occur in the context of normal neuroimaging or be accompanied by neuroimaging abnormalities including stroke-like episodes, white matter lesions, cortical atrophy, and corpus callosum agenesis or hypogenesis (see Suggestive Findings, <a href="#melas.Brain_Imaging">Brain Imaging</a>).</div></li><li class="half_rhythm"><div>Seizures can occur in MELAS as a manifestation of a stroke-like episode or independently, and may even induce a stroke-like episode [<a class="bibr" href="#melas.REF.finsterer.2015.1553" rid="melas.REF.finsterer.2015.1553">Finsterer & Zarrouk-Mahjoub 2015</a>].</div></li></ul></li><li class="half_rhythm"><div><b>Migrainous headaches</b> in the form of recurrent attacks of severe pulsatile headaches with frequent vomiting are typical in individuals with MELAS and can precipitate stroke-like episodes. These headache episodes are often more severe during the stroke-like episodes [<a class="bibr" href="#melas.REF.ohno.1997.781" rid="melas.REF.ohno.1997.781">Ohno et al 1997</a>].</div></li><li class="half_rhythm"><div><b>Hearing impairment</b> due to sensorineural hearing loss is usually mild, insidiously progressive, and often an early clinical manifestation [<a class="bibr" href="#melas.REF.sproule.2008.133" rid="melas.REF.sproule.2008.133">Sproule & Kaufmann 2008</a>].</div></li><li class="half_rhythm"><div><b>Peripheral neuropathy</b> is usually a chronic and progressive, sensorimotor, and distal polyneuropathy. Nerve conduction studies typically show an axonal or mixed axonal and demyelinating neuropathy [<a class="bibr" href="#melas.REF.kaufmann.2006b.746" rid="melas.REF.kaufmann.2006b.746">Kaufmann et al 2006b</a>].</div></li><li class="half_rhythm"><div><b>Early psychomotor development</b> is usually normal, although developmental delay can occasionally occur.</div></li><li class="half_rhythm"><div><b>Psychiatric illnesses</b> including depression, bipolar disorder, anxiety, psychosis, and personality changes can occur in MELAS [<a class="bibr" href="#melas.REF.anglin.2012.506" rid="melas.REF.anglin.2012.506">Anglin et al 2012</a>].</div></li></ul><p><b>Myopathy</b> presents clinically as muscle weakness and exercise intolerance.</p><p>
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<b>Cardiac manifestations</b>
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</p><ul><li class="half_rhythm"><div>Both dilated and hypertrophic cardiomyopathy have been observed, however, the more typical is a non-obstructive concentric hypertrophy [<a class="bibr" href="#melas.REF.sproule.2008.133" rid="melas.REF.sproule.2008.133">Sproule & Kaufmann 2008</a>].</div></li><li class="half_rhythm"><div>Cardiac conduction abnormalities including Wolff-Parkinson-White syndrome has been reported occasionally [<a class="bibr" href="#melas.REF.sproule.2007.1625" rid="melas.REF.sproule.2007.1625">Sproule et al 2007</a>].</div></li></ul><p><b>Gastrointestinal manifestations.</b> Recurrent or cyclic vomiting is common. Other manifestations include diarrhea, constipation, gastric dysmotility, intestinal pseudo-obstruction, recurrent pancreatitis, and failure to thrive [<a class="bibr" href="#melas.REF.fujii.2004.1126" rid="melas.REF.fujii.2004.1126">Fujii et al 2004</a>].</p><p>
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<b>Endocrine manifestations</b>
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</p><ul><li class="half_rhythm"><div><b>Diabetes</b> mellitus occurs occasionally, with an average age of onset of 38 years. Diabetes can be type 1 or type 2. Individuals with type 2 diabetes can initially be treated with diet or sulfonylurea, although significant insulinopenia can develop and affected individuals may require insulin therapy (see <a href="#melas.Management">Management</a>) [<a class="bibr" href="#melas.REF.maassen.2004.s103" rid="melas.REF.maassen.2004.s103">Maassen et al 2004</a>].</div></li><li class="half_rhythm"><div><b>Short stature.</b> Individuals with MELAS syndrome are typically shorter than their unaffected family members. Growth hormone deficiency has occasionally been reported [<a class="bibr" href="#melas.REF.yorifuji.1996.621" rid="melas.REF.yorifuji.1996.621">Yorifuji et al 1996</a>].</div></li><li class="half_rhythm"><div><b>Hypothyroidism, hypogonadotropic hypogonadism, and hypoparathyroidism</b> are infrequent manifestations [<a class="bibr" href="#melas.REF.elhattab.2015.4" rid="melas.REF.elhattab.2015.4">El-Hattab et al 2015</a>].</div></li></ul><p>
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<b>Other manifestations</b>
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</p><ul><li class="half_rhythm"><div><b>Renal manifestations</b> that may include Fanconi proximal tubulopathy, proteinuria, and focal segmental glomerulosclerosis [<a class="bibr" href="#melas.REF.hotta.2001.1236" rid="melas.REF.hotta.2001.1236">Hotta et al 2001</a>]</div></li><li class="half_rhythm"><div><b>Pulmonary hypertension</b> [<a class="bibr" href="#melas.REF.sproule.2008.497" rid="melas.REF.sproule.2008.497">Sproule et al 2008</a>]</div></li><li class="half_rhythm"><div><b>Dermatologic manifestations</b> that may include vitiligo, diffuse erythema with reticular pigmentation, and hypertrichosis [<a class="bibr" href="#melas.REF.kubota.1999.469" rid="melas.REF.kubota.1999.469">Kubota et al 1999</a>]</div></li><li class="half_rhythm"><div><b>Chronic anemia</b> [<a class="bibr" href="#melas.REF.finsterer.2011.100" rid="melas.REF.finsterer.2011.100">Finsterer 2011</a>]</div></li></ul><p><b>Natural history and life expectancy.</b> The disease progresses over years with episodic deterioration related to stroke-like events. The course varies from individual to individual.</p><ul><li class="half_rhythm"><div>In a cohort of 33 adults with the pathogenic m.3243A>G variant in <i>MT-TL1</i> who were followed for three years, deterioration of sensorineural function, cardiac left-ventricular hypertrophy, EEG abnormalities, and overall severity were observed [<a class="bibr" href="#melas.REF.majamaavoltti.2006.1470" rid="melas.REF.majamaavoltti.2006.1470">Majamaa-Voltti et al 2006</a>].</div></li><li class="half_rhythm"><div>In a natural history study of 31 individuals with MELAS and 54 symptomatic and asymptomatic obligate 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.</div></li><li class="half_rhythm"><div>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.</div></li><li class="half_rhythm"><div>The estimated overall median survival time based on fully symptomatic individuals was 16.9 years from onset of focal neurologic disease [<a class="bibr" href="#melas.REF.kaufmann.2011.1965" rid="melas.REF.kaufmann.2011.1965">Kaufmann et al 2011</a>].</div></li><li class="half_rhythm"><div>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 [<a class="bibr" href="#melas.REF.yatsuga.2012.619" rid="melas.REF.yatsuga.2012.619">Yatsuga et al 2012</a>].</div></li></ul></div><div id="melas.Causes_of_Phenotypic_Variability"><h3>Causes of Phenotypic Variability</h3><p>For all mtDNA pathogenic variants, clinical expression depends on three factors:</p><ul><li class="half_rhythm"><div><b>Heteroplasmy.</b> The presence of a mixture of mutated and normal mtDNA</div></li><li class="half_rhythm"><div><b>Tissue distribution</b> of mutated mtDNA</div></li><li class="half_rhythm"><div><b>Threshold effect.</b> The vulnerability of each tissue to impaired oxidative metabolism</div></li></ul><p>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 mutated mtDNA in muscle, but not in leukocytes, have been observed [<a class="bibr" href="#melas.REF.chinnery.1997.1713" rid="melas.REF.chinnery.1997.1713">Chinnery et al 1997</a>, <a class="bibr" href="#melas.REF.jeppesen.2006.1701" rid="melas.REF.jeppesen.2006.1701">Jeppesen et al 2006</a>]. As-yet-undefined nuclear DNA factors may also modify the phenotypic expression of mtDNA pathogenic variants [<a class="bibr" href="#melas.REF.moraes.1993.43" rid="melas.REF.moraes.1993.43">Moraes et al 1993</a>].</p><p>The m.3243A>G pathogenic variant, the most frequent variant associated with MELAS, is associated with diverse clinical manifestations (i.e., progressive external ophthalmoplegia, diabetes mellitus, cardiomyopathy, deafness) that collectively constitute a wide spectrum ranging from MELAS at the severe end to asymptomatic carrier status. More severe phenotypes may be the result of a higher abundance of the pathogenic variant in affected organs [<a class="bibr" href="#melas.REF.elhattab.2015.4" rid="melas.REF.elhattab.2015.4">El-Hattab et al 2015</a>].</p></div><div id="melas.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No clear genotype-phenotype correlations have been identified (see <a href="#melas.Causes_of_Phenotypic_Variability">Causes of Phenotypic Variability</a>).</p></div><div id="melas.Penetrance"><h3>Penetrance</h3><p>In mtDNA-related disorders, penetrance typically depends on mutational load and tissue distribution, which show random variation within families (see <a href="#melas.Causes_of_Phenotypic_Variability">Causes of Phenotypic Variability</a>).</p></div><div id="melas.Nomenclature"><h3>Nomenclature</h3><p>Typically designated by the acronym MELAS, this disorder may also be referred to as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.</p></div><div id="melas.Prevalence"><h3>Prevalence</h3><p>The prevalence of MELAS has been estimated to be 0.2:100,000 in Japan [<a class="bibr" href="#melas.REF.yatsuga.2012.619" rid="melas.REF.yatsuga.2012.619">Yatsuga et al 2012</a>]. The prevalence of the <a href="/books/NBK1233/table/melas.T.pathogenic_variants_in_mitochond/?report=objectonly" target="object" rid-ob="figobmelasTpathogenicvariantsinmitochond">m.3243A>G</a> pathogenic variant was estimated to be 16:100,000–18:100,000 in Finland [<a class="bibr" href="#melas.REF.majamaa.1998.447" rid="melas.REF.majamaa.1998.447">Majamaa et al 1998</a>, <a class="bibr" href="#melas.REF.uusimaa.2007.278" rid="melas.REF.uusimaa.2007.278">Uusimaa et al 2007</a>]. An Australian study found a higher prevalence of the m.3243A>G pathogenic variant: 236:100,000 [<a class="bibr" href="#melas.REF.manwaring.2007.230" rid="melas.REF.manwaring.2007.230">Manwaring et al 2007</a>].</p></div></div><div id="melas.Genetically_Related_Allelic_Disord"><h2 id="_melas_Genetically_Related_Allelic_Disord_">Genetically Related (Allelic) Disorders</h2><p>Pathogenic variants in mtDNA genes known to be associated with MELAS can also be associated with a variety of other mitochondrial disorders. See <a href="/books/n/gene/mt-overview/?report=reader">Mitochondrial Disorders Overview</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmelasTselectedallelicdisorders"><a href="/books/NBK1233/table/melas.T.selected_allelic_disorders/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobmelasTselectedallelicdisorders"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="melas.T.selected_allelic_disorders"><a href="/books/NBK1233/table/melas.T.selected_allelic_disorders/?report=objectonly" target="object" rid-ob="figobmelasTselectedallelicdisorders">Table 4. </a></h4><p class="float-caption no_bottom_margin">Selected Allelic Disorders </p></div></div></div><div id="melas.Differential_Diagnosis"><h2 id="_melas_Differential_Diagnosis_">Differential Diagnosis</h2><p>Clinical manifestations of MELAS can be seen in a wide variety of mitochondrial diseases (see <a href="/books/n/gene/mt-overview/?report=reader">Mitochondrial Disorders Overview</a>).</p><p>The differential diagnosis of acute stroke includes other causes of stroke in a young person: heart disease, carotid or vertebral diseases, <a href="/books/n/gene/sickle/?report=reader">sickle cell disease</a>, vasculopathies, lipoprotein dyscrasias, venous thrombosis, moyamoya disease, complicated migraine (see <a href="/books/n/gene/fhm/?report=reader">Familial Hemiplegic Migraine</a>), <a href="/books/n/gene/fabry/?report=reader">Fabry disease</a>, and <a href="/books/n/gene/homocystinuria/?report=reader">homocystinuria caused by cystathionine beta-synthase deficiency</a> [<a class="bibr" href="#melas.REF.meschia.2004.420" rid="melas.REF.meschia.2004.420">Meschia & Worrall 2004</a>, <a class="bibr" href="#melas.REF.meschia.2005.122" rid="melas.REF.meschia.2005.122">Meschia et al 2005</a>]. Besides appropriate specific tests, a maternal history of other problems suggesting mitochondrial dysfunction (short stature, migraine, hearing loss, diabetes mellitus) can help orient the clinician toward the correct diagnosis.</p><p>A MELAS-like phenotype with defects in nuclear genes including <i>MRM2</i> [<a class="bibr" href="#melas.REF.garone.2017.4257" rid="melas.REF.garone.2017.4257">Garone et al 2017</a>], <i>FASTKD2</i> [<a class="bibr" href="#melas.REF.yoo.2017.54" rid="melas.REF.yoo.2017.54">Yoo et al 2017</a>], and <i>POLG</i> [<a class="bibr" href="#melas.REF.cheldi.2013.8" rid="melas.REF.cheldi.2013.8">Cheldi et al 2013</a>] has been reported.</p></div><div id="melas.Management"><h2 id="_melas_Management_">Management</h2><div id="melas.Evaluations_Following_Initial_Diag"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with MELAS, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmelasTrecommendedevaluationsfollowin"><a href="/books/NBK1233/table/melas.T.recommended_evaluations_followin/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobmelasTrecommendedevaluationsfollowin"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="melas.T.recommended_evaluations_followin"><a href="/books/NBK1233/table/melas.T.recommended_evaluations_followin/?report=objectonly" target="object" rid-ob="figobmelasTrecommendedevaluationsfollowin">Table 5. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with MELAS </p></div></div></div><div id="melas.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment for MELAS is primarily supportive.</p><p><b>Arginine therapy.</b> Recommendations for the management of stroke-like episodes in MELAS with arginine have been published. During the acute stroke-like episode, it is recommended to give a bolus of intravenous arginine (500 mg/kg for children or 10 g/m<sup>2</sup> body surface area for adults) within three hours of symptom onset followed by the administration of a similar dosage of intravenous arginine as a continuous infusion over 24 hours for the next three to five days. Once an individual with MELAS has the first stroke-like episode, arginine should be administered prophylactically to reduce the risk of recurrent stroke-like episodes (see <a href="#melas.Prevention_of_Primary_Manifestatio">Prevention of Primary Manifestations</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmelasTtreatmentofmanifestationsini"><a href="/books/NBK1233/table/melas.T.treatment_of_manifestations_in_i/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobmelasTtreatmentofmanifestationsini"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="melas.T.treatment_of_manifestations_in_i"><a href="/books/NBK1233/table/melas.T.treatment_of_manifestations_in_i/?report=objectonly" target="object" rid-ob="figobmelasTtreatmentofmanifestationsini">Table 6. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with MELAS </p></div></div></div><div id="melas.Prevention_of_Primary_Manifestatio"><h3>Prevention of Primary Manifestations</h3><p>Once an individual with MELAS has the first stroke-like episode, arginine should be administered prophylactically to reduce the risk of recurrent stroke-like episodes. A daily dose of 150 to 300 mg/kg/day oral arginine in three divided doses is recommended [<a class="bibr" href="#melas.REF.koenig.2016.591" rid="melas.REF.koenig.2016.591">Koenig et al 2016</a>, <a class="bibr" href="#melas.REF.elhattab.2017" rid="melas.REF.elhattab.2017">El-Hattab et al 2017</a>].</p></div><div id="melas.Prevention_of_Secondary_Complicati"><h3>Prevention of Secondary Complications</h3><p>Because febrile illnesses may trigger acute exacerbations, individuals with MELAS should receive standard childhood vaccinations, flu vaccine, and pneumococcal vaccine.</p></div><div id="melas.Surveillance"><h3>Surveillance</h3><p>Affected individuals and their at-risk relatives should be followed at regular intervals to monitor progression and the appearance of new symptoms.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmelasTrecommendedannualsurveillance"><a href="/books/NBK1233/table/melas.T.recommended_annual_surveillance/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobmelasTrecommendedannualsurveillance"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="melas.T.recommended_annual_surveillance"><a href="/books/NBK1233/table/melas.T.recommended_annual_surveillance/?report=objectonly" target="object" rid-ob="figobmelasTrecommendedannualsurveillance">Table 7. </a></h4><p class="float-caption no_bottom_margin">Recommended Annual Surveillance for Individuals with MELAS </p></div></div></div><div id="melas.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>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 [<a class="bibr" href="#melas.REF.lin.2007.105" rid="melas.REF.lin.2007.105">Lin & Thajeb 2007</a>].</p><p>Metformin should also be avoided because of its propensity to cause lactic acidosis [<a class="bibr" href="#melas.REF.sproule.2008.133" rid="melas.REF.sproule.2008.133">Sproule & Kaufmann 2008</a>].</p><p>Dichloroacetate, which reduces lactate by activating the pyruvate dehydrogenase enzyme, should be avoided in MELAS syndrome. A study evaluating the effect of dichloroacetate in individuals with MELAS syndrome was terminated because of onset or worsening of peripheral neuropathy, indicating that dichloroacetate can be associated with peripheral nerve toxicity [<a class="bibr" href="#melas.REF.kaufmann.2006a.324" rid="melas.REF.kaufmann.2006a.324">Kaufmann et al 2006a</a>].</p></div><div id="melas.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>Molecular genetic testing of at-risk maternal relatives may reveal individuals who have high mutational loads and are thus at risk of developing symptoms. No proven disease-modifying intervention exists at present. However, asymptomatic individuals can undergo regular surveillance for early detection of complications.</p><p>See <a href="#melas.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="melas.Pregnancy_Management"><h3>Pregnancy Management</h3><p>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 the development of diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions [<a class="bibr" href="#melas.REF.d_azlobato.2005.654" rid="melas.REF.d_azlobato.2005.654">Díaz-Lobato et al 2005</a>].</p></div><div id="melas.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>The transfer of nuclear DNA from fertilized oocytes or zygotes containing a mtDNA pathogenic variant to an enucleated recipient cell could theoretically prevent transmission of mtDNA diseases; proof of this concept has been demonstrated in pronuclear transfers from abnormally fertilized zygotes [<a class="bibr" href="#melas.REF.craven.2010.82" rid="melas.REF.craven.2010.82">Craven et al 2010</a>].</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="melas.Genetic_Counseling"><h2 id="_melas_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="melas.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>MELAS is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance.</p></div><div id="melas.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>The father of a proband does not have the mtDNA pathogenic variant.</div></li><li class="half_rhythm"><div>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 buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.</div></li><li class="half_rhythm"><div>Alternatively, the proband may have a <i>de novo</i> somatic mitochondrial pathogenic variant.</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>The risk to the sibs depends on the genetic status of the mother.</div></li><li class="half_rhythm"><div>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. Women with higher levels of mutated mtDNA in their blood may have a greater likelihood of having affected offspring [<a class="bibr" href="#melas.REF.chinnery.1998.1889" rid="melas.REF.chinnery.1998.1889">Chinnery et al 1998</a>].</div></li></ul><p>
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<b>Offspring of a proband</b>
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</p><ul><li class="half_rhythm"><div>All offspring of females with a mtDNA pathogenic variant will inherit the variant.</div></li><li class="half_rhythm"><div>Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the variant.</div></li></ul><p><b>Other family members.</b> 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.</p></div><div id="melas.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p><b>Interpretation of test results of asymptomatic at-risk family members</b> is extremely difficult. Prediction of phenotype based on test results is not possible.</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>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.</div></li></ul></div><div id="melas.Prenatal_Testing_and_Preimplantati"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the specific mtDNA pathogenic variant in the mother has been identified, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing (PGT) for MELAS are possible. However, prenatal testing for mtDNA pathogenic variants causing MELAS is of uncertain utility.</p><p>Changes in mutational load during pregnancy were evaluated in a small study of nine pregnancies in five women from families with the <a href="/books/NBK1233/table/melas.T.pathogenic_variants_in_mitochond/?report=objectonly" target="object" rid-ob="figobmelasTpathogenicvariantsinmitochond">m.3243A>G</a> 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 [<a class="bibr" href="#melas.REF.bouchet.2006.788" rid="melas.REF.bouchet.2006.788">Bouchet et al 2006</a>]. Eleven pregnancies with fetal mutation levels 35% or lower (assessed with prenatal testing or PGT) 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 [<a class="bibr" href="#melas.REF.monnot.2011.116" rid="melas.REF.monnot.2011.116">Monnot et al 2011</a>, <a class="bibr" href="#melas.REF.treff.2012.1236" rid="melas.REF.treff.2012.1236">Treff et al 2012</a>].</p><p>Interpretation of prenatal testing results is complex for the following reasons:</p><ul><li class="half_rhythm"><div>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.</div></li><li class="half_rhythm"><div>The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.</div></li><li class="half_rhythm"><div>Prediction of phenotype, age of onset, severity, or rate of progression is not possible.</div></li></ul></div></div><div id="melas.Resources"><h2 id="_melas_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>National Library of Medicine Genetics Home Reference</b>
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</div><div>
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<a href="https://ghr.nlm.nih.gov/condition/mitochondrialencephalomyopathylacticacidosisandstrokelikeepisodes" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes</a>
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</div></li><li class="half_rhythm"><div>
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<b>United Mitochondrial Disease Foundation</b>
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</div><div><b>Phone:</b> 888-317-UMDF (8633)</div><div><b>Email:</b> info@umdf.org</div><div>
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<a href="https://www.umdf.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.umdf.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>International Mito Patients</b>
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</div><div>
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<a href="https://www.mitopatients.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.mitopatients.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Mito Foundation</b>
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</div><div>Australia</div><div><b>Phone:</b> 61-1-300-977-180</div><div><b>Email:</b> info@mito.org.au</div><div>
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<a href="https://www.mito.org.au/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.mito.org.au</a>
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</div></li><li class="half_rhythm"><div>
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<b>Muscular Dystrophy Association (MDA) - USA</b>
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</div><div><b>Phone:</b> 833-275-6321</div><div><b>Email:</b> ResourceCenter@mdausa.org</div><div>
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<a href="http://www.mda.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">mda.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>The Lily Foundation</b>
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</div><div>United Kingdom</div><div><b>Email:</b> liz@thelilyfoundation.org.uk</div><div>
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<a href="https://www.thelilyfoundation.org.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.thelilyfoundation.org.uk</a>
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</div></li><li class="half_rhythm"><div>
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<b>RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium</b>
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</div><div>
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<a href="https://www.rarediseasesnetwork.org/cms/namdc" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Patient Contact Registry</a>
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</div></li></ul>
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</div><div id="melas.Molecular_Genetics"><h2 id="_melas_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmelasmolgenTA"><a href="/books/NBK1233/table/melas.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobmelasmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="melas.molgen.TA"><a href="/books/NBK1233/table/melas.molgen.TA/?report=objectonly" target="object" rid-ob="figobmelasmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">MELAS: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmelasmolgenTB"><a href="/books/NBK1233/table/melas.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobmelasmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="melas.molgen.TB"><a href="/books/NBK1233/table/melas.molgen.TB/?report=objectonly" target="object" rid-ob="figobmelasmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for MELAS (View All in OMIM) </p></div></div><div id="melas.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>The pathogenesis of MELAS syndrome, which is not fully understood, is likely explained by several interacting mechanisms including impaired mitochondrial energy production, microvasculature angiopathy, and nitric oxide (NO) deficiency. The MELAS-associated variants typically result in impaired mitochondrial translation leading to decreased mitochondrial protein synthesis, which affects the electron transport chain (ETC) complex subunits. Decreased synthesis of ETC complexes results in impaired mitochondrial energy production. The inability of dysfunctional mitochondria to generate sufficient energy to meet the energy needs of various organs results in the multiorgan dysfunction observed in MELAS syndrome. Energy deficiency can also stimulate mitochondrial proliferation. Angiopathy due to mitochondrial proliferation in smooth muscle and endothelial cells of small blood vessels leads to impaired blood perfusion in microvasculature, contributing to the complications observed in MELAS – particularly stroke-like episodes. In addition, growing evidence suggests that NO deficiency occurs in MELAS and can contribute significantly to its complications [<a class="bibr" href="#melas.REF.elhattab.2015.4" rid="melas.REF.elhattab.2015.4">El-Hattab et al 2015</a>].</p><p><b>Genes.</b> See <b>Normal gene product</b> and <a href="/books/NBK1233/?report=reader#melas.molgen.TB">Table B</a>. Details of these genes are at <a href="https://www.mitomap.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.mitomap.org</a>.</p><p><b>Benign variants.</b> Benign polymorphisms are especially frequent in mtDNA and are listed at <a href="https://www.mitomap.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.mitomap.org</a>.</p><p><b>Pathogenic variants.</b> See <a href="/books/NBK1233/table/melas.T.pathogenic_variants_in_mitochond/?report=objectonly" target="object" rid-ob="figobmelasTpathogenicvariantsinmitochond">Table 8</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmelasTpathogenicvariantsinmitochond"><a href="/books/NBK1233/table/melas.T.pathogenic_variants_in_mitochond/?report=objectonly" target="object" title="Table 8. " class="img_link icnblk_img" rid-ob="figobmelasTpathogenicvariantsinmitochond"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="melas.T.pathogenic_variants_in_mitochond"><a href="/books/NBK1233/table/melas.T.pathogenic_variants_in_mitochond/?report=objectonly" target="object" rid-ob="figobmelasTpathogenicvariantsinmitochond">Table 8. </a></h4><p class="float-caption no_bottom_margin">Pathogenic Variants in Mitochondrial DNA Associated with MELAS </p></div></div><p><b>Normal gene product.</b> The mtDNA encodes 22 tRNAs that are essential for mitochondrial protein synthesis, specifically for the incorporation of amino acids into nascent proteins. Eleven of the genes involved in MELAS are tRNA genes: <i>MT-TL1</i>, <i>MT-TL2</i>, <i>MT-TC</i>, <i>MT-TF</i>, <i>MT-TV</i>, <i>MT-TQ</i>, <i>MT-TW</i>, <i>MT-TS1</i>, <i>MT-TS2</i>, <i>MT-TH</i>, and <i>MT-TK</i>.</p><p>Six protein-encoding genes are also involved in MELAS. <i>MT-CO2</i>, cytochrome <i>c</i> oxidase subunit II (227 amino acids) and <i>MT-CO3</i>, cytochrome <i>c</i> oxidase subunit III (261 amino acids) are catalytic subunits of mitochondrial complex IV, which is the terminal electron acceptor of the respiratory chain. <i>MT-CYB</i>, cytochrome <i>b</i> (112 amino acids) is an essential subunit of mitochondrial respiratory chain complex III. <i>MT-ND1</i>, NADH dehydrogenase subunit 1 (318 amino acids); <i>MT-ND5</i>, NADH dehydrogenase subunit 5 (603 amino acids); and <i>MT-ND6</i>, NADH dehydrogenase subunit 6 (174 amino acids) are critical components of mitochondrial respiratory chain complex I. See <a href="/books/NBK1233/?report=reader#melas.molgen.TB">Table B</a>.</p><p><b>Abnormal gene product.</b> Pathogenic variants in mitochondrial tRNA genes result in impaired mitochondrial protein synthesis. Pathogenic variants in ETC structural subunits result in impaired ATP synthesis via oxidative phosphorylation.</p></div></div><div id="melas.Chapter_Notes"><h2 id="_melas_Chapter_Notes_">Chapter Notes</h2><div id="melas.Author_History"><h3>Author History</h3><p>Mohammed Almannai, MD (2018-present)<br />Salvatore DiMauro, MD; Columbia University (2001-2018)<br />Ayman El-Hattab, MD (2018-present)<br />Michio Hirano, MD; Columbia University (2001-2018)<br />Fernando Scaglia, MD (2018-present)</p></div><div id="melas.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>29 November 2018 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>21 November 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>14 October 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>13 October 2005 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>18 June 2003 (ca) Comprehensive update posted live</div></li><li class="half_rhythm"><div>27 February 2001 (me) Review posted live</div></li><li class="half_rhythm"><div>September 2000 (sdm) Original submission</div></li></ul></div></div><div id="melas.References"><h2 id="_melas_References_">References</h2><div id="melas.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.abuamero.2009.77">Abu-Amero
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KK, Al-Dhalaan
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H, Bohlega
|
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S, Hellani
|
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A, Taylor
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RW. A patient with typical clinical features of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) but without an obvious genetic cause: a case report.
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J Med Case Rep.
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2009;3:77.
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[<a href="/pmc/articles/PMC2783076/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2783076</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19946553" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19946553</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.anglin.2012.506">Anglin
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RE, Garside
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SL, Tarnopolsky
|
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MA, Mazurek
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MF, Rosebush
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PI. The psychiatric manifestations of mitochondrial disorders: a case and review of the literature.
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J Clin Psychiatry.
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2012;73:506–12.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/22579150" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22579150</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.bataillard.2001.405">Bataillard
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M, Chatzoglou
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E, Rumbach
|
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L, Sternberg
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D, Tournade
|
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A, Laforet
|
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P, Jardel
|
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C, Maisonobe
|
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T, Lombes
|
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A.
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Atypical MELAS syndrome associated with a new mitochondrial tRNA glutamine point mutation.
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Neurology
|
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2001;56:405-7
|
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[<a href="https://pubmed.ncbi.nlm.nih.gov/11171912" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11171912</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.bhati.2005.2286">Bhati
|
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RS, Sheridan
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BC, Mill
|
|
MR, Selzman
|
|
CH. Heart transplantation for progressive cardiomyopathy as a manifestation of MELAS syndrome.
|
|
J Heart Lung Transplant.
|
|
2005;24:2286–89.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/16364883" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16364883</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.bouchet.2006.788">Bouchet
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C, Steffann
|
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J, Corcos
|
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J, Monnot
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S, Paquis
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V, Rötig
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A, Lebon
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S, Levy
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P, Royer
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G, Giurgea
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I, Gigarel
|
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N, Benachi
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A, Dumez
|
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Y, Munnich
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A, Bonnefont
|
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JP. Prenatal diagnosis of myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome: contribution to understanding mitochondrial DNA segregation during human embryofetal development.
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J Med Genet.
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2006;43:788-92.
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[<a href="/pmc/articles/PMC2563165/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2563165</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16690729" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16690729</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.calvaruso.2011.778">Calvaruso
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MA, Willemsen
|
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MA, Rodenburg
|
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RJ, van den Brand
|
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M, Smeitink
|
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JA, Nijtmans
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L. New mitochondrial tRNA HIS mutation in a family with lactic acidosis and stroke-like episodes (MELAS).
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Mitochondrion.
|
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2011;11:778-82.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/21704194" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21704194</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.campos.2000.493">Campos
|
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Y, Lorenzo
|
|
G, Martin
|
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MA, Torregrosa
|
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A, del Hoyo
|
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P, Rubio
|
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JC, Garcia
|
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A, Arenas
|
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J. A mitochondrial tRNA(Lys) gene mutation (T8316C) in a patient with mitochondrial myopathy, lactic acidosis, and stroke-like episodes.
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Neuromuscul Disord.
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2000;10:493-6.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/10996780" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10996780</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.cheldi.2013.8">Cheldi
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A, Ronchi
|
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D, Bordoni
|
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A, Bordo
|
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B, Lanfranconi
|
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S, Bellotti
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MG, Corti
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S, Lucchini
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V, Sciacco
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M, Moggio
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M, Baron
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P, Comi
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G.P, Colombo
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A, Bersano
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A, et al.
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POLG1 mutations and stroke like episodes: a distinct clinical entity rather than an atypical MELAS syndrome.
|
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BMC Neurol.
|
|
2013;13:8.
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|
[<a href="/pmc/articles/PMC3570393/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3570393</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23324391" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23324391</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.chinnery.1998.1889">Chinnery
|
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PF, Howell
|
|
N, Lightowlers
|
|
RN, Turnbull
|
|
DM. MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring.
|
|
Brain.
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|
1998;121:1889–94.
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|
[<a href="https://pubmed.ncbi.nlm.nih.gov/9798744" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9798744</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.chinnery.1997.1713">Chinnery
|
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PF, Howell
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N, Lightowlers
|
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R.N, Turnbull
|
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DM.
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Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes.
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Brain.
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1997;120:1713–21.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/15576055" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15576055</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.tam.2008.328">Tam
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EW, Feigenbaum
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A, Addis
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JB, Blaser
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S, Mackay
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M, Taylor
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RW, Ackerley
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C, Cameron
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JM, Robinson
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BH. A novel mitochondrial DNA mutation in COX1 leads to strokes, seizures, and lactic acidosis.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/19568996" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19568996</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.tanji.2008.23">Tanji
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K, Kaufmann
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P, Naini
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AB, Lu
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J, Parsons
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TC, Wang
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D, Willey
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JZ, Shanske
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LP. A novel tRNA(Val) mitochondrial DNA mutation causing MELAS.
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RW, Chinnery
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PF, Haldane
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F, Morris
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AA, Bindoff
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LA, Wilson
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J, Turnbull
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DM. MELAS associated with a mutation in the valine transfer RNA gene of mitochondrial DNA.
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Ann Neurol.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/8797538" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8797538</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.treff.2012.1236">Treff
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NR, Campos
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J, Tao
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X, Levy
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B, Ferry
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KM, Scott
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RT. Blastocyst preimplantation genetic diagnosis (PGD) of a mitochondrial DNA disorder.
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Fertil Steril.
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2012;98:1236-40.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/22921075" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22921075</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.uusimaa.2007.278">Uusimaa
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J, Moilanen
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JS, Vainionpää
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L, Tapanainen
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P, Lindholm
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P, Nuutinen
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M, Löppönen
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T, Mäki-Torkko
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E, Rantala
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H, Majamaa
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K. Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children.
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Ann. Neurol.
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2007;62:278-87.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/17823937" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17823937</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.wong.2006.e46">Wong
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L-JC, Yim
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D, Bai
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R-K, Kwon
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H, Vacek
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MM, Zane
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J, Hoppel
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CL, Kerr
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DS. A novel mutation in the mitochondrial tRNA-ser(AGY) gene associated with mitochondrial myopathy, encephalopathy, and complex I deficiency.
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J Med Genet.
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2006;43:e46.
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[<a href="/pmc/articles/PMC2564579/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2564579</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16950817" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16950817</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.yatsuga.2012.619">Yatsuga
|
|
S, Povalko
|
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N, Nishioka
|
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J, Katayama
|
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K, Kakimoto
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N, Matsuishi
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T, Kakuma
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T, Koga
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Y, Matsuoka
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T, et al.
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MELAS: a nationwide prospective cohort study of 96 patients in Japan.
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Biochim Biophys Acta.
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2012;1820:619-24.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/21443929" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21443929</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.yoo.2017.54">Yoo
|
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DH, Choi
|
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Y-C, Nam
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DE, Choi
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SS, Kim
|
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JW, Choi
|
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B-O, Chung
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KW. Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome.
|
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Mitochondrion.
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2017;35:54-8.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/28499982" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28499982</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="melas.REF.yorifuji.1996.621">Yorifuji
|
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T, Kawai
|
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M, Momoi
|
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T, Sasaki
|
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H, Furusho
|
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K, Muroi
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J, Shimizu
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K, Takahashi
|
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Y, Matsumura
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M, Nambu
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M, Okuno
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T. Nephropathy and growth hormone deficiency in a patient with mitochondrial tRNA(Leu(UUR)) mutation.
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J Med Genet.
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1996;33:621–2.
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[<a href="/pmc/articles/PMC1050677/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1050677</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8818955" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8818955</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1233_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Ayman W El-Hattab</span>, MD, FAAP, FACMG<div class="affiliation small">Associate Professor, Department of Clinical Sciences<br />College of Medicine<br />University of Sharjah<br />Sharjah, United Arab Emirates<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.oohay@wabattahle" class="oemail">moc.oohay@wabattahle</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Mohammed Almannai</span>, MD, FAAP, FACMG<div class="affiliation small">Medical Genetics and Metabolic Consultant, Section of Medical Genetics<br />King Fahad Medical City<br />Riyadh, Saudi Arabia<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="as.dem.cmfk@iannamlam" class="oemail">as.dem.cmfk@iannamlam</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Fernando Scaglia</span>, MD, FAAP, FACMG<div class="affiliation small">Department of Molecular and Human Genetics<br />Baylor College of Medicine<br />Houston, Texas</div><div class="affiliation small">Joint BCM-CUHK Center of Medical Genetics<br />Prince of Wales Hospital<br />Sha Tin, New Territories, Hong Kong<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.mcb@ailgacsf" class="oemail">ude.mcb@ailgacsf</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">February 27, 2001</span>; Last Update: <span itemprop="dateModified">November 29, 2018</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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a registered trademark of the University of Washington, Seattle. All rights
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reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
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hereby granted to reproduce, distribute, and translate copies of content materials for
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noncommercial research purposes only, provided that (i) credit for source (<a href="http://www.genereviews.org/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">http://www.genereviews.org/</a>) and copyright (© 1993-2025 University of
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Washington) are included with each copy; (ii) a link to the original material is provided
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>El-Hattab AW, Almannai M, Scaglia F. MELAS. 2001 Feb 27 [Updated 2018 Nov 29]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/mef2c-dis/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/merrf/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobmelasTgeneticcausesofmelas"><div id="melas.T.genetic_causes_of_melas" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Genetic Causes of MELAS</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1233/table/melas.T.genetic_causes_of_melas/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__melas.T.genetic_causes_of_melas_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_melas.T.genetic_causes_of_melas_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1, 2</sup></th><th id="hd_h_melas.T.genetic_causes_of_melas_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of MELAS Attributed to Pathogenic Variants in Gene</th><th id="hd_h_melas.T.genetic_causes_of_melas_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>3</sup> Detectable by Sequence Analysis <sup>4</sup></th></tr></thead><tbody><tr><td headers="hd_h_melas.T.genetic_causes_of_melas_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TL1</i>
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</td><td headers="hd_h_melas.T.genetic_causes_of_melas_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>80%</td><td headers="hd_h_melas.T.genetic_causes_of_melas_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td></tr><tr><td headers="hd_h_melas.T.genetic_causes_of_melas_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-ND5</i>
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</td><td headers="hd_h_melas.T.genetic_causes_of_melas_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><10%</td><td headers="hd_h_melas.T.genetic_causes_of_melas_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td></tr><tr><td headers="hd_h_melas.T.genetic_causes_of_melas_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TC</i>
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<br />
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<i>MT-TF</i>
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<br />
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<i>MT-TH</i>
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<br />
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<i>MT-TK</i>
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<br />
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<i>MT-TL2</i>
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<br />
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<i>MT-TQ</i>
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<br />
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<i>MT-TV</i>
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<br />
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<i>MT-TW</i>
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<br />
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<i>MT-TS1</i>
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<br />
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<i>MT-TS2</i>
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<br />
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<i>MT-ND1</i>
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<br />
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<i>MT-ND6</i>
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<br />
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<i>MT-CO2</i>
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<br />
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<i>MT-CO3</i>
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<br />
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<i>MT-CYB</i>
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</td><td headers="hd_h_melas.T.genetic_causes_of_melas_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_melas.T.genetic_causes_of_melas_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Pathogenic variants of any one of the genes included in this table account for >1% of MELAS.</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="melas.TF.1.1"><p class="no_margin">Genes are listed from most frequent to least frequent genetic cause of MELAS.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="melas.TF.1.2"><p class="no_margin">See <a href="/books/NBK1233/?report=reader#melas.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="melas.TF.1.3"><p class="no_margin">See <a href="#melas.Molecular_Genetics">Molecular Genetics</a> for information on pathogenic allelic variants detected.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="melas.TF.1.4"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmelasTmelasinitialclinicalmanifesta"><div id="melas.T.melas_initial_clinical_manifesta" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>MELAS: Initial Clinical Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1233/table/melas.T.melas_initial_clinical_manifesta/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__melas.T.melas_initial_clinical_manifesta_lrgtbl__"><table><thead><tr><th id="hd_h_melas.T.melas_initial_clinical_manifesta_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th><th id="hd_h_melas.T.melas_initial_clinical_manifesta_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestations</th></tr></thead><tbody><tr><td headers="hd_h_melas.T.melas_initial_clinical_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">≥25%</td><td headers="hd_h_melas.T.melas_initial_clinical_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Seizures</div></li><li class="half_rhythm"><div>Recurrent headaches</div></li><li class="half_rhythm"><div>Stroke-like episodes</div></li><li class="half_rhythm"><div>Cortical vision loss</div></li><li class="half_rhythm"><div>Muscle weakness</div></li><li class="half_rhythm"><div>Recurrent vomiting</div></li><li class="half_rhythm"><div>Short stature</div></li></ul>
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</td></tr><tr><td headers="hd_h_melas.T.melas_initial_clinical_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%-24%</td><td headers="hd_h_melas.T.melas_initial_clinical_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Altered consciousness</div></li><li class="half_rhythm"><div>Impaired mentation</div></li><li class="half_rhythm"><div>Hearing impairment</div></li><li class="half_rhythm"><div>Diabetes mellitus (type 1 or 2)</div></li></ul>
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</td></tr><tr><td headers="hd_h_melas.T.melas_initial_clinical_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><10%</td><td headers="hd_h_melas.T.melas_initial_clinical_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Developmental delay</div></li><li class="half_rhythm"><div>Fever</div></li></ul>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobmelasTmelasadditionalclinicalmanife"><div id="melas.T.melas_additional_clinical_manife" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>MELAS: Additional Clinical Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1233/table/melas.T.melas_additional_clinical_manife/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__melas.T.melas_additional_clinical_manife_lrgtbl__"><table><thead><tr><th id="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th><th id="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestations</th></tr></thead><tbody><tr><td headers="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">≥90%</td><td headers="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Stroke-like episodes</div></li><li class="half_rhythm"><div>Dementia</div></li><li class="half_rhythm"><div>Epilepsy</div></li><li class="half_rhythm"><div>Lactic acidemia</div></li><li class="half_rhythm"><div>Ragged red fibers (RRFs) on muscle biopsy</div></li></ul>
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</td></tr><tr><td headers="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7%-89%</td><td headers="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hemiparesis</div></li><li class="half_rhythm"><div>Cortical vision loss</div></li><li class="half_rhythm"><div>Recurrent headaches</div></li><li class="half_rhythm"><div>Hearing impairment</div></li><li class="half_rhythm"><div>Muscle weakness</div></li></ul>
|
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</td></tr><tr><td headers="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">50%-74%</td><td headers="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Peripheral neuropathy</div></li><li class="half_rhythm"><div>Learning disability</div></li><li class="half_rhythm"><div>Memory impairment</div></li><li class="half_rhythm"><div>Recurrent vomiting</div></li><li class="half_rhythm"><div>Short stature</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">25%-49%</td><td headers="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Basal ganglia calcification</div></li><li class="half_rhythm"><div>Myoclonus</div></li><li class="half_rhythm"><div>Ataxia</div></li><li class="half_rhythm"><div>Episodic altered consciousness</div></li><li class="half_rhythm"><div>Gait disturbance</div></li><li class="half_rhythm"><div>Depression</div></li><li class="half_rhythm"><div>Anxiety</div></li><li class="half_rhythm"><div>Psychotic disorders</div></li><li class="half_rhythm"><div>Diabetes mellitus (type 1 or 2)</div></li></ul>
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|
</td></tr><tr><td headers="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><25%</td><td headers="hd_h_melas.T.melas_additional_clinical_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Optic atrophy</div></li><li class="half_rhythm"><div>Pigmentary retinopathy</div></li><li class="half_rhythm"><div>Progressive external ophthalmoplegia</div></li><li class="half_rhythm"><div>Motor developmental delay</div></li><li class="half_rhythm"><div>Cardiomyopathy</div></li><li class="half_rhythm"><div>Cardiac conduction abnormalities</div></li><li class="half_rhythm"><div>Nephropathy</div></li><li class="half_rhythm"><div>Vitiligo</div></li></ul>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobmelasTselectedallelicdisorders"><div id="melas.T.selected_allelic_disorders" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Selected Allelic Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1233/table/melas.T.selected_allelic_disorders/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__melas.T.selected_allelic_disorders_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phenotype 1</th></tr></thead><tbody><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-CO2</i>
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</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cytochrome <i>c</i> oxidase (COX) deficiency (OMIM <a href="https://omim.org/entry/516040" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">516040</a>)</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-CO3</i>
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|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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|
<a href="/books/n/gene/narp/?report=reader">Mitochondrial DNA-associated Leigh syndrome</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Cytochrome <i>c</i> oxidase (COX) deficiency (OMIM <a href="https://omim.org/entry/516050" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">516050</a>)</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/lhon/?report=reader">Leber hereditary optic neuropathy</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-CYB</i>
|
|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/lhon/?report=reader">Leber hereditary optic neuropathy</a>
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|
</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-ND1</i>
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|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/narp/?report=reader">Mitochondrial DNA-associated Leigh syndrome</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/lhon/?report=reader">Leber hereditary optic neuropathy</a>
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|
</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-ND5</i>
|
|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/narp/?report=reader">Mitochondrial DNA-associated Leigh syndrome</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
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|
<a href="/books/n/gene/lhon/?report=reader">Leber hereditary optic neuropathy</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-ND6</i>
|
|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/narp/?report=reader">Mitochondrial DNA-associated Leigh syndrome</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
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|
<a href="/books/n/gene/lhon/?report=reader">Leber hereditary optic neuropathy</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TC</i>
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|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<a href="/books/n/gene/dystonia-ov/?report=reader">Dystonia</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TF</i>
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</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/merrf/?report=reader">MERRF</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TH</i>
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</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/merrf/?report=reader">MERRF</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy (OMIM <a href="https://omim.org/entry/590040" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">590040</a>)</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Pigmentary retinopathy (OMIM <a href="https://omim.org/entry/590040" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">590040</a>)</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/mt-deafness/?report=reader">Deafness</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TK</i>
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</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/narp/?report=reader">Mitochondrial DNA-associated Leigh syndrome</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/merrf/?report=reader">MERRF</a>
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</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;"><i>MT-TL1</i><br />(<a href="/books/NBK1233/table/melas.T.pathogenic_variants_in_mitochond/?report=objectonly" target="object" rid-ob="figobmelasTpathogenicvariantsinmitochond">m.3243A>G</a>)</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/kss/?report=reader">Progressive external ophthalmoplegia</a> (PEO)</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Maternally inherited diabetes mellitus with or without deafness (OMIM <a href="https://omim.org/entry/590050" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">590050</a>)</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy (OMIM <a href="https://omim.org/entry/590050" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">590050</a>)</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/mt-deafness/?report=reader">Deafness</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
|
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<a href="/books/n/gene/merrf/?report=reader">MERRF</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TL2</i>
|
|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy (OMIM <a href="https://omim.org/entry/590055" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">590055</a>)</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>MT-TQ</i>
|
|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/mt-deafness/?report=reader">Deafness</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>MT-TS1</i>
|
|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/deafness-overview/?report=reader">Mitochondrial nonsyndromic hearing impairment</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>MT-TS2</i>
|
|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar ataxia, cataract, and diabetes mellitus (OMIM <a href="https://omim.org/entry/590085" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">590085</a>)</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>MT-TV</i>
|
|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/narp/?report=reader">Mitochondrial DNA-associated Leigh syndrome</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>MT-TW</i>
|
|
</td><td headers="hd_h_melas.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/narp/?report=reader">Mitochondrial DNA-associated Leigh syndrome</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="melas.TF.4.1"><p class="no_margin">See hyperlinked <i>GeneReview</i>, OMIM phenotype entry, or cited reference for more information.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmelasTrecommendedevaluationsfollowin"><div id="melas.T.recommended_evaluations_followin" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with MELAS</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1233/table/melas.T.recommended_evaluations_followin/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__melas.T.recommended_evaluations_followin_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_melas.T.recommended_evaluations_followin_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Growth</b>
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</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of height & weight</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eyes</b>
|
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</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmology eval</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To screen for ptosis, optic atrophy, pigmentary retinopathy, ophthalmoplegia, vision deficits</td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Ears</b>
|
|
</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiology eval</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To detect hearing loss</td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Cardiovascular</b>
|
|
</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To screen for cardiomyopathy <sup>1</sup></td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Electrocardiogram</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for conduction abnormalities <sup>1</sup></td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Renal</b>
|
|
</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Urinalysis & urine amino acid analysis</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for renal tubulopathy</td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Musculoskeletal</b>
|
|
</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PT/OT assessment</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For individuals w/neurologic deficits</td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Neurologic</b>
|
|
</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for neurologic deficits <sup>2</sup></td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Head MRI w/MRS</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for pathologic changes at baseline</td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">EEG</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If seizures are suspected</td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Neuropsychiatric testing</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess cognitive abilities & for evidence of dementia</td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Endocrinologic</b>
|
|
</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fasting serum glucose</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">To screen for diabetes mellitus <sup>3</sup></td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Glucose tolerance test</td></tr><tr><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Other</b>
|
|
</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_melas.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">OT = occupational therapy; PT = physical therapy</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="melas.TF.5.1"><p class="no_margin">Consider referral to a cardiologist.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="melas.TF.5.2"><p class="no_margin">Consider referral to a neurologist.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="melas.TF.5.3"><p class="no_margin">Consider referral to an endocrinologist.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmelasTtreatmentofmanifestationsini"><div id="melas.T.treatment_of_manifestations_in_i" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with MELAS</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1233/table/melas.T.treatment_of_manifestations_in_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__melas.T.treatment_of_manifestations_in_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Overall disease process</b>
|
|
</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CoQ<sub>10</sub>
|
|
<ul><li class="half_rhythm"><div>Children: 5-10 mg/kg/day</div></li><li class="half_rhythm"><div>Adults: 200–400 mg/day in 3 divided doses</div></li></ul>
|
|
</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">May benefit some individuals <sup>1</sup></td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">L-carnitine
|
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<ul><li class="half_rhythm"><div>Children: 100 mg/kg/day</div></li><li class="half_rhythm"><div>Adults: 3 g/day in 3 divided doses</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Creatine
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<ul><li class="half_rhythm"><div>Children: 100 mg/kg/day</div></li><li class="half_rhythm"><div>Adults: 2-5 g/day in 3 divided doses</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Ptosis</b>
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|
</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard therapy</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eyelid "crutches," blepharoplasty, or frontalis muscle-eyelid implantation could be considered.</td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Sensorineural hearing loss</b>
|
|
</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard therapy</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cochlear implantation successful in some <sup>2</sup></td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Cardiomyopathy</b>
|
|
</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Standard pharmacologic therapy <sup>3</sup></td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Per cardiologist</td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Cardiac conduction defects</b>
|
|
</td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Nephropathy</b>
|
|
</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard therapy</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Exercise intolerance & weakness</b>
|
|
</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Aerobic exercise <sup>4</sup></td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Stroke-like episodes</b>
|
|
</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Arginine therapy (See <a href="#melas.Treatment_of_Manifestations">above</a>.) <sup>5</sup></td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical & occupational therapy after acute phase, as appropriate</td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Seizures</b>
|
|
</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Traditional anticonvulsant therapy</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Avoid valproic acid. (See <a href="#melas.AgentsCircumstances_to_Avoid">Agents/Circumstances to Avoid</a>.)</td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Migraine headaches</b>
|
|
</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard analgesics</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Diabetes mellitus <sup>6</sup></b>
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|
</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dietary modification</td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be particularly successful in thin individuals</td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Oral hypoglycemic agents <sup>7</sup></td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Avoid metformin. (See <a href="#melas.AgentsCircumstances_to_Avoid">Agents/Circumstances to Avoid</a>.)</td></tr><tr><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Insulin therapy <sup>8</sup></td><td headers="hd_h_melas.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per endocrinologist</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">CoQ<sub>10</sub> = coenzyme Q<sub>10</sub></p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="melas.TF.6.1"><p class="no_margin">
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<a class="bibr" href="#melas.REF.elhattab.2015.4" rid="melas.REF.elhattab.2015.4">El-Hattab et al [2015]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="melas.TF.6.2"><p class="no_margin">
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<a class="bibr" href="#melas.REF.scarpelli.2012.287432" rid="melas.REF.scarpelli.2012.287432">Scarpelli et al [2012]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="melas.TF.6.3"><p class="no_margin">Individuals with MELAS can be suitable candidates for cardiac transplantation. Before transplantation, however, careful consideration of the multisystemic nature of the disease is indicated to determine the suitability of candidates [<a class="bibr" href="#melas.REF.bhati.2005.2286" rid="melas.REF.bhati.2005.2286">Bhati et al 2005</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="melas.TF.6.4"><p class="no_margin">
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<a class="bibr" href="#melas.REF.taivassalo.2004.221" rid="melas.REF.taivassalo.2004.221">Taivassalo & Haller [2004]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="melas.TF.6.5"><p class="no_margin"><a class="bibr" href="#melas.REF.koenig.2016.591" rid="melas.REF.koenig.2016.591">Koenig et al [2016]</a>, <a class="bibr" href="#melas.REF.elhattab.2017" rid="melas.REF.elhattab.2017">El-Hattab et al [2017]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="melas.TF.6.6"><p class="no_margin">Diabetes can be type 1 or type 2</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="melas.TF.6.7"><p class="no_margin">Typically sulfonylureas</p></div></dd></dl><dl class="bkr_refwrap"><dt>8. </dt><dd><div id="melas.TF.6.8"><p class="no_margin">
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<a class="bibr" href="#melas.REF.maassen.2004.s103" rid="melas.REF.maassen.2004.s103">Maassen et al [2004]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmelasTrecommendedannualsurveillance"><div id="melas.T.recommended_annual_surveillance" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Recommended Annual Surveillance for Individuals with MELAS</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1233/table/melas.T.recommended_annual_surveillance/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__melas.T.recommended_annual_surveillance_lrgtbl__"><table><thead><tr><th id="hd_h_melas.T.recommended_annual_surveillance_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_melas.T.recommended_annual_surveillance_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annual Evaluation</th></tr></thead><tbody><tr><td headers="hd_h_melas.T.recommended_annual_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eyes</b>
|
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</td><td headers="hd_h_melas.T.recommended_annual_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmology</td></tr><tr><td headers="hd_h_melas.T.recommended_annual_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Ears</b>
|
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</td><td headers="hd_h_melas.T.recommended_annual_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiology</td></tr><tr><td headers="hd_h_melas.T.recommended_annual_surveillance_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cardiovascular</b>
|
|
</td><td headers="hd_h_melas.T.recommended_annual_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Electrocardiogram</td></tr><tr><td headers="hd_h_melas.T.recommended_annual_surveillance_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram</td></tr><tr><td headers="hd_h_melas.T.recommended_annual_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Renal</b>
|
|
</td><td headers="hd_h_melas.T.recommended_annual_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Urinalysis</td></tr><tr><td headers="hd_h_melas.T.recommended_annual_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Endocrinologic</b>
|
|
</td><td headers="hd_h_melas.T.recommended_annual_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fasting blood glucose</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobmelasmolgenTA"><div id="melas.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>MELAS: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1233/table/melas.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__melas.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<i>MT-CO2</i>
|
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</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P00403" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Cytochrome c oxidase subunit 2</a>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-CO2[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-CO2</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-CO3</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="http://www.uniprot.org/uniprot/P00414" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Cytochrome c oxidase subunit 3</a>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-CO3[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-CO3</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<i>MT-CYB</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P00156" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Cytochrome b</a>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-CYB[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-CYB</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-ND1</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P03886" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NADH-ubiquinone oxidoreductase chain 1</a>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-ND1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-ND1</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-ND5</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P03915" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NADH-ubiquinone oxidoreductase chain 5</a>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-ND5[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-ND5</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-ND6</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P03923" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NADH-ubiquinone oxidoreductase chain 6</a>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-ND6[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-ND6</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-TC</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TC[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TC</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-TF</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TF[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TF</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-TH</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TH[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TH</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-TK</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TK[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TK</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-TL1</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TL1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TL1</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-TL2</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TL2[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TL2</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-TQ</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TQ[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TQ</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-TS1</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TS1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TS1</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-TS2</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TS2[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TS2</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-TV</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TV[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TV</a>
|
|
</td></tr><tr><td headers="hd_b_melas.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<i>MT-TW</i>
|
|
</td><td headers="hd_b_melas.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_melas.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_melas.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TW[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TW</a>
|
|
</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="melas.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
|
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
|
chromosome locus from
|
|
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
|
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
|
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
|
<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmelasmolgenTB"><div id="melas.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for MELAS (<a href="/omim/516000,516005,516006,516020,516040,516050,540000,590020,590030,590040,590050,590055,590060,590070,590080,590085,590095,590105" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1233/table/melas.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__melas.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/516000" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">516000</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COMPLEX I, SUBUNIT ND1; MTND1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/516005" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">516005</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COMPLEX I, SUBUNIT ND5; MTND5</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/516006" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">516006</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COMPLEX I, SUBUNIT ND6; MTND6</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/516020" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">516020</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CYTOCHROME b OF COMPLEX III; MTCYB</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/516040" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">516040</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COMPLEX IV, CYTOCHROME c OXIDASE SUBUNIT II; MTCO2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/516050" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">516050</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CYTOCHROME c OXIDASE III; MTCO3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/540000" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">540000</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC ACIDOSIS, AND STROKE-LIKE EPISODES; MELAS</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/590020" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590020</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, CYSTEINE; MTTC</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/590030" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590030</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, GLUTAMINE; MTTQ</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/590040" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590040</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, HISTIDINE; MTTH</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/590050" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590050</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, LEUCINE, 1; MTTL1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/590055" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590055</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, LEUCINE, 2; MTTL2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/590060" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590060</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, LYSINE; MTTK</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/590070" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590070</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, PHENYLALANINE; MTTF</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/590080" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590080</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, SERINE, 1; MTTS1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/590085" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590085</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, SERINE, 2; MTTS2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/590095" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590095</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, TRYPTOPHAN; MTTW</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/590105" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590105</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, VALINE; MTTV</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobmelasTpathogenicvariantsinmitochond"><div id="melas.T.pathogenic_variants_in_mitochond" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Pathogenic Variants in Mitochondrial DNA Associated with MELAS</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1233/table/melas.T.pathogenic_variants_in_mitochond/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__melas.T.pathogenic_variants_in_mitochond_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Affected Individuals</th><th id="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mitochondrial DNA Nucleotide Change</th><th id="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences <sup>1</sup></th><th id="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">References</th></tr></thead><tbody><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~80%</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">m.3243A>G</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="6" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-TL1</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" rowspan="19" colspan="1" style="text-align:left;vertical-align:middle;">No protein translated</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_5" rowspan="19" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NC_012920.1?report=graph&log$=seqview" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NC_012920<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.goto.1990.651" rid="melas.REF.goto.1990.651">Goto et al [1990]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><10%</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">m.3271T>C</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.goto.1991.238" rid="melas.REF.goto.1991.238">Goto et al [1991]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><5%</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">m.3252A>G</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.morten.1993.2081" rid="melas.REF.morten.1993.2081">Morten et al [1993]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_1" rowspan="22" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">m.3291T>C</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.goto.1994.1624" rid="melas.REF.goto.1994.1624">Goto et al [1994]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.3256C>T</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.sato.1994.1055" rid="melas.REF.sato.1994.1055">Sato et al [1994]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.3260A>G</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.nishino.1996.1603" rid="melas.REF.nishino.1996.1603">Nishino et al [1996]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.583G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-TF</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.hanna.1998.512" rid="melas.REF.hanna.1998.512">Hanna et al [1998]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.1642G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-TV</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.taylor.1996.459" rid="melas.REF.taylor.1996.459">Taylor et al [1996]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.1644G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.tanji.2008.23" rid="melas.REF.tanji.2008.23">Tanji et al [2008]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.4332G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-TQ</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.bataillard.2001.405" rid="melas.REF.bataillard.2001.405">Bataillard et al [2001]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.5521G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-TW</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.herreromart_n.2010.471" rid="melas.REF.herreromart_n.2010.471">Herrero-Martín et al [2010]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.5814A>G</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-TC</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.manfredi.1996.158" rid="melas.REF.manfredi.1996.158">Manfredi et al [1996]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.7512T>C</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-TS1</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.lindberg.2008.128" rid="melas.REF.lindberg.2008.128">Lindberg et al [2008]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.12207G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-TS2</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.wong.2006.e46" rid="melas.REF.wong.2006.e46">Wong et al [2006]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.12146A>G</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-TL2</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.calvaruso.2011.778" rid="melas.REF.calvaruso.2011.778">Calvaruso et al [2011]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.12299A>C</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.abuamero.2009.77" rid="melas.REF.abuamero.2009.77">Abu-Amero et al [2009]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.8316T>C</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-TK</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.campos.2000.493" rid="melas.REF.campos.2000.493">Campos et al [2000]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.8296A>G</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.sakuta.2002.397" rid="melas.REF.sakuta.2002.397">Sakuta et al [2002]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.12147G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-TH</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.melone.2004.269" rid="melas.REF.melone.2004.269">Melone et al [2004]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.3481G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-ND1</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln59Lys</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_5" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NC_012920.1?report=graph&log$=seqview" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NC_012920<wbr style="display:inline-block"></wbr>​.1</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/254028369" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ACT53096<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.malfatti.2007.1894" rid="melas.REF.malfatti.2007.1894">Malfatti et al [2007]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.3697G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">p.Gly131Ser</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.kirby.2004.784" rid="melas.REF.kirby.2004.784">Kirby et al [2004]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.3946G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">p.Gln214Lys</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.kirby.2004.784" rid="melas.REF.kirby.2004.784">Kirby et al [2004]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.3949T>C</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">p.Tyr215His</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.kirby.2004.784" rid="melas.REF.kirby.2004.784">Kirby et al [2004]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.7023G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-CO2</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val374Met</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.tam.2008.328" rid="melas.REF.tam.2008.328">Tam et al [2008]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.9957T>C</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-CO3</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Phe251Leu</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NC_012920.1?report=graph&log$=seqview" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NC_012920<wbr style="display:inline-block"></wbr>​.1</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_536849.1?report=genpept" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_536849<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.manfredi.1995.391" rid="melas.REF.manfredi.1995.391">Manfredi et al [1995]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><10%</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">m.13513G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="6" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-ND5</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp393Asn</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_5" rowspan="6" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NC_012920.1?report=graph&log$=seqview" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NC_012920<wbr style="display:inline-block"></wbr>​.1</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_536853.1?report=genpept" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_536853<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.santorelli.1997.326" rid="melas.REF.santorelli.1997.326">Santorelli et al [1997]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_1" rowspan="8" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">m.12770A>G</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">p.Glu145Gly</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.liolitsa.2003.128" rid="melas.REF.liolitsa.2003.128">Liolitsa et al [2003]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.13042G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">p.Ala236Thr</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.naini.2005.473" rid="melas.REF.naini.2005.473">Naini et al [2005]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.13084A>T</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">p.Ser250Cys</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.crimi.2003.1857" rid="melas.REF.crimi.2003.1857">Crimi et al [2003]</a>
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|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.13514A>G</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">p.Asp393Gly</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
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<a class="bibr" href="#melas.REF.corona.2001.106" rid="melas.REF.corona.2001.106">Corona et al [2001]</a>
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|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.13528A>G</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">p.Thr398Ala</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
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<a class="bibr" href="#melas.REF.mckenzie.2007.36845" rid="melas.REF.mckenzie.2007.36845">McKenzie et al [2007]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.14453G>A</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>MT-ND6</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ala74Val</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NC_012920.1?report=graph&log$=seqview" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NC_012920<wbr style="display:inline-block"></wbr>​.1</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_536854.1?report=genpept" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_536854<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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|
<a class="bibr" href="#melas.REF.ravn.2001.805" rid="melas.REF.ravn.2001.805">Ravn et al [2001]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.14787delTTAA<br />(4-bp del)</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MT-CYB</i>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ile14Thrfs</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_5" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NC_012920.1?report=graph&log$=seqview" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NC_012920<wbr style="display:inline-block"></wbr>​.1</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_536855.1?report=genpept" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_536855<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.de_coo.1999.130" rid="melas.REF.de_coo.1999.130">De Coo et al [1999]</a>
|
|
</td></tr><tr><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">m.14864T>C</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_4" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">p.Cys40Arg</td><td headers="hd_h_melas.T.pathogenic_variants_in_mitochond_1_1_1_6" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#melas.REF.emmanuele.2013.236" rid="melas.REF.emmanuele.2013.236">Emmanuele et al [2013]</a>
|
|
</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature (Note: The mitochondrial genetic code varies from the genomic genetic code given in the Quick Reference. See <a href="https://www.mitomap.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www<wbr style="display:inline-block"></wbr>​.mitomap.org</a> for genetic code and other features of the mitochondrial genome). Variants named according to current nomenclature guidelines (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>).</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="melas.TF.8.1"><p class="no_margin">Numbering based on mitochondrial DNA reference sequence: AC_000021.2 and individual protein reference sequences</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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