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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>MERRF - 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="MERRF">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2021/01/07">
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<meta name="citation_author" content="Frances Velez-Bartolomei">
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<meta name="citation_author" content="Chung Lee">
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<meta name="citation_author" content="Gregory Enns">
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<meta name="citation_keywords" content="Myoclonic Epilepsy Associated with Ragged Red Fibers">
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<meta name="citation_keywords" content="Myoclonic Epilepsy Associated with Ragged-Red Fibers">
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<meta name="citation_keywords" content="MERRF">
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<meta name="DC.Title" content="MERRF">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Frances Velez-Bartolomei">
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<meta name="DC.Contributor" content="Chung Lee">
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<meta name="DC.Contributor" content="Gregory Enns">
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<meta name="description" content="MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, exercise intolerance, and dementia. Onset can occur from childhood to adulthood, occurring after normal early development. Common findings are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac dysrhythmias such as Wolff-Parkinson-White syndrome, and peripheral neuropathy. Pigmentary retinopathy, optic neuropathy, diabetes mellitus, and lipomatosis have been observed.">
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<meta name="og:description" content="MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, exercise intolerance, and dementia. Onset can occur from childhood to adulthood, occurring after normal early development. Common findings are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac dysrhythmias such as Wolff-Parkinson-White syndrome, and peripheral neuropathy. Pigmentary retinopathy, optic neuropathy, diabetes mellitus, and lipomatosis have been observed.">
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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="_NBK1520_"><span class="title" itemprop="name">MERRF</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: Myoclonic Epilepsy Associated with Ragged Red Fibers</div><p class="contribs">Velez-Bartolomei F, Lee C, Enns G.</p><p class="fm-aai"><a href="#_NBK1520_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 21 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="merrf.Summary" itemprop="description"><h2 id="_merrf_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>MERRF (<i>m</i>yoclonic <i>e</i>pilepsy with <i>r</i>agged <i>r</i>ed <i>f</i>ibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, exercise intolerance, and dementia. Onset can occur from childhood to adulthood, occurring after normal early development. Common findings are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac dysrhythmias such as Wolff-Parkinson-White syndrome, and peripheral neuropathy. Pigmentary retinopathy, optic neuropathy, diabetes mellitus, and lipomatosis have been observed.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>A clinical diagnosis of MERRF can be established in a proband with the following four "canonic" features: myoclonus, generalized epilepsy, ataxia, and ragged red fibers (RRF) in the muscle biopsy. A molecular diagnosis is established in a proband with suggestive findings and a pathogenic variant in one of the genes associated with MERRF. The m.8344A>G pathogenic variant in the mitochondrial gene <i>MT-TK</i> is present in more than 80% of affected individuals with typical findings. Pathogenic variants in <i>MT-TF</i>, <i>MT-TH</i>, <i>MT-TI</i>, <i>MT-TL1</i>, <i>MT-TP</i>, <i>MT-TS1</i>, and <i>MT-TS2</i> have also been described in a subset of individuals with MERRF.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Ubiquinol, carnitine, alpha lipoic acid, vitamin E, vitamin B complex, and creatine may be of benefit to some individuals; traditional anticonvulsant therapy per neurologist for seizures; levetiracetam or clonazepam for myoclonus; physical therapy to improve any impaired motor function; aerobic exercise; standard pharmacologic therapy for cardiac symptoms; hearing aids or cochlear implants for hearing loss; diabetes mellitus treatment per endocrinologist.</p><p><i>Prevention of primary manifestations:</i> Coenzyme Q<sub>10</sub> (50-200 mg 2-3x/day), L-carnitine (1000 mg 2-3x/day), alpha lipoic acid, vitamin E, vitamin B supplements, and creatine, often used to improve mitochondrial function, have been of modest benefit in some individuals. Doses for children should be adjusted appropriately.</p><p><i>Surveillance:</i> Routine evaluations every six to 12 months initially; annual neurologic, ophthalmologic, cardiology (electrocardiogram and echocardiogram), and endocrinologic evaluations (fasting blood sugar and TSH); audiology evaluations every two to three years.</p><p><i>Agents/circumstances to avoid:</i> Mitochondrial toxins (e.g., aminoglycoside antibiotics, linezolid, cigarettes, alcohol); valproic acid should be avoided in the treatment of seizures.</p><p><i>Pregnancy management:</i> During pregnancy, affected or at-risk 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>MERRF 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 male with a mtDNA pathogenic variant cannot transmit the pathogenic variant to any of his offspring. A female with a mtDNA pathogenic variant (whether symptomatic or asymptomatic) transmits the pathogenic variant to all of her offspring. Prenatal testing and preimplantation genetic testing for MERRF are 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 is not possible.</p></div></div><div id="merrf.Diagnosis"><h2 id="_merrf_Diagnosis_">Diagnosis</h2><p>Clinical diagnostic criteria for MERRF (<i>m</i>yoclonic <i>e</i>pilepsy with <i>r</i>agged <i>r</i>ed <i>f</i>ibers) have been published [<a class="bibr" href="#merrf.REF.finsterer.2018.8" rid="merrf.REF.finsterer.2018.8">Finsterer et al 2018</a>] (see <a href="#merrf.Establishing_the_Diagnosis">Establishing the Diagnosis</a>).</p><div id="merrf.Suggestive_Findings"><h3>Suggestive Findings</h3><p>MERRF (<i>m</i>yoclonic <i>e</i>pilepsy with <i>r</i>agged <i>r</i>ed <i>f</i>ibers) <b>should be suspected</b> in individuals with the following features.</p><p>
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<b>Clinical features</b>
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</p><ul><li class="half_rhythm"><div>Myoclonus</div></li><li class="half_rhythm"><div>Generalized epilepsy</div></li><li class="half_rhythm"><div>Ataxia</div></li><li class="half_rhythm"><div>Myopathy</div></li><li class="half_rhythm"><div>Exercise intolerance</div></li><li class="half_rhythm"><div>Dementia</div></li><li class="half_rhythm"><div>Ptosis</div></li><li class="half_rhythm"><div>Sensorineural hearing loss</div></li><li class="half_rhythm"><div>Short stature</div></li><li class="half_rhythm"><div>Optic atrophy</div></li><li class="half_rhythm"><div>Peripheral neuropathy</div></li></ul><p>Less common clinical signs (seen in <50% of affected individuals) include the following:</p><ul><li class="half_rhythm"><div>Cardiomyopathy</div></li><li class="half_rhythm"><div>Pigmentary retinopathy</div></li><li class="half_rhythm"><div>Pyramidal signs</div></li><li class="half_rhythm"><div>Ophthalmoparesis</div></li><li class="half_rhythm"><div>Multiple lipomas</div></li></ul><p>
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<b>Laboratory features</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Lactic acidosis both in blood and in the CSF.</b> In individuals with MERRF, the concentrations of lactate and pyruvate are commonly elevated at rest and increase excessively after moderate activity.</div><div class="half_rhythm">Note: Other situations (unrelated to the diagnosis of MERRF or other mitochondrial diseases) in which lactate and pyruvate can be elevated are acute neurologic events such as seizure or stroke.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Elevated CSF protein concentration.</b> The concentration of CSF protein may be increased but rarely surpasses 100 mg/dL.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Respiratory chain studies.</b> Biochemical analysis of respiratory chain enzymes in muscle extracts usually shows decreased activity of respiratory chain complexes containing mtDNA-encoded subunits, especially COX deficiency. However, biochemical studies may also be normal.</div></li></ul><p><b>Histopathologic features on muscle biopsy.</b> Ragged red fibers (RRF) are seen with the modified Gomori trichrome stain and hyperactive fibers with the succinate dehydrogenase stain. Both RRF and some non-RRF fail to stain with the histochemical reaction for cytochrome <i>c</i> oxidase. Occasionally, RRF may not be observed [<a class="bibr" href="#merrf.REF.mancuso.2007.1058" rid="merrf.REF.mancuso.2007.1058">Mancuso et al 2007</a>].</p><p>
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<b>Electrophysiologic features</b>
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</p><ul><li class="half_rhythm"><div><b>Electroencephalogram</b> usually shows generalized spike and wave discharges with background slowing, but focal epileptiform discharges may also be seen.</div></li><li class="half_rhythm"><div><b>Electrocardiogram</b> often shows pre-excitation; heart block has not been described.</div></li><li class="half_rhythm"><div><b>Electromyogram</b> and <b>nerve conduction velocity</b> studies are consistent with a myopathy, but neuropathy may coexist.</div></li></ul><p><b>Brain imaging.</b> Brain MRI often shows brain atrophy and basal ganglia lesions. Bilateral putaminal necrosis and atrophy of the brain stem and cerebellum have been reported [<a class="bibr" href="#merrf.REF.orcesi.2006.79" rid="merrf.REF.orcesi.2006.79">Orcesi et al 2006</a>, <a class="bibr" href="#merrf.REF.ito.2008.392" rid="merrf.REF.ito.2008.392">Ito et al 2008</a>].</p></div><div id="merrf.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The clinical diagnosis of MERRF (<i>m</i>yoclonic <i>e</i>pilepsy with <i>r</i>agged <i>r</i>ed <i>f</i>ibers) <b>can be</b>
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<b>established</b> in a proband based on clinical diagnostic criteria [<a class="bibr" href="#merrf.REF.finsterer.2018.8" rid="merrf.REF.finsterer.2018.8">Finsterer et al 2018</a>] or the molecular diagnosis can be established in a proband with <a href="#merrf.Suggestive_Findings">suggestive findings</a> and a pathogenic variant in one of the genes listed in <a href="/books/NBK1520/table/merrf.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobmerrfTmoleculargenetictestingusedi">Table 1</a>, identified by molecular genetic testing.</p><p><b>Clinical diagnosis.</b> The clinical diagnosis is based on the following four "canonic" features:</p><ul><li class="half_rhythm"><div>Myoclonus</div></li><li class="half_rhythm"><div>Generalized epilepsy</div></li><li class="half_rhythm"><div>Ataxia</div></li><li class="half_rhythm"><div>Ragged red fibers (RRF) in the muscle biopsy</div></li></ul><p><b>Molecular diagnosis.</b> The diagnosis of MERRF <b>is established</b> in a proband with <a href="#merrf.Suggestive_Findings">suggestive findings</a> and a pathogenic variant in one of the genes listed in <a href="/books/NBK1520/table/merrf.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobmerrfTmoleculargenetictestingusedi">Table 1</a>.</p><p>Note: Pathogenic variants can usually be detected in mtDNA from leukocytes in individuals with typical MERRF; 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 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="#merrf.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#merrf.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="#merrf.Option_2">Option 2</a>).</p><div id="merrf.Option_1"><h4>Option 1</h4><p><b>Serial single-gene</b>
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<b>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><p><b>Targeted analysis.</b> Typically, blood leukocyte DNA is initially screened for pathogenic variants in <i>MT-TK</i> using targeted analysis for the <a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">m.8344A>G</a> pathogenic variant, which is present in more than 80% of individuals with typical clinical findings. Note: If no pathogenic variant is found, consider targeted analysis for this pathogenic variant on DNA from buccal mucosa, muscle, or urine sediment.</p><p><b>Entire mitochondrial</b>
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<b>genome sequencing</b> that includes the genes in <a href="/books/NBK1520/table/merrf.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobmerrfTmoleculargenetictestingusedi">Table 1</a> and other mtDNA genes of interest (<a href="#merrf.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype.</p><p><b>A</b>
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<b>multigene panel</b> that includes the genes in <a href="/books/NBK1520/table/merrf.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobmerrfTmoleculargenetictestingusedi">Table 1</a> and other genes of interest (see <a href="#merrf.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 at the most reasonable cost 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>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="merrf.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</b>
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<b>testing</b>, which does not require the clinician to determine which gene is 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="figmerrfTmoleculargenetictestingusedi"><a href="/books/NBK1520/table/merrf.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobmerrfTmoleculargenetictestingusedi"><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="merrf.T.molecular_genetic_testing_used_i"><a href="/books/NBK1520/table/merrf.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobmerrfTmoleculargenetictestingusedi">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in MERRF </p></div></div></div></div></div><div id="merrf.Clinical_Characteristics"><h2 id="_merrf_Clinical_Characteristics_">Clinical Characteristics</h2><div id="merrf.Clinical_Description"><h3>Clinical Description</h3><p>MERRF (<i>m</i>yoclonic <i>e</i>pilepsy with <i>r</i>agged <i>r</i>ed <i>f</i>ibers) is a multisystem disorder characterized by myoclonus, which is often the first symptom, followed by generalized epilepsy, ataxia, weakness, exercise intolerance, and dementia. Onset can occur from childhood to adulthood, after normal early development. <a href="/books/NBK1520/table/merrf.T.merrf_frequency_of_select_featur/?report=objectonly" target="object" rid-ob="figobmerrfTmerrffrequencyofselectfeatur">Table 2</a> lists the most frequent signs and symptoms reported [<a class="bibr" href="#merrf.REF.hirano.1996" rid="merrf.REF.hirano.1996">Hirano & DiMauro 1996</a>, <a class="bibr" href="#merrf.REF.mancuso.2013.2049" rid="merrf.REF.mancuso.2013.2049">Mancuso et al 2013</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmerrfTmerrffrequencyofselectfeatur"><a href="/books/NBK1520/table/merrf.T.merrf_frequency_of_select_featur/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobmerrfTmerrffrequencyofselectfeatur"><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="merrf.T.merrf_frequency_of_select_featur"><a href="/books/NBK1520/table/merrf.T.merrf_frequency_of_select_featur/?report=objectonly" target="object" rid-ob="figobmerrfTmerrffrequencyofselectfeatur">Table 2. </a></h4><p class="float-caption no_bottom_margin">MERRF: Frequency of Select Features </p></div></div><p>
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<b>Neurologic manifestations</b>
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</p><ul><li class="half_rhythm"><div><b>Myopathy.</b> The most common features are exercise intolerance, muscle weakness, and elevated blood creatine kinase level.</div></li><li class="half_rhythm"><div><b>Epilepsy.</b> Generalized myoclonic seizures are the most frequent seizure type in individuals with MERRF. Other reported types of seizures include focal myoclonic, focal atonic, focal clonic, generalized tonic-clonic, generalized atonic, generalized myoclonic-atonic, typical absences, myoclonic absences, or tonic-clonic seizures of unknown onset [<a class="bibr" href="#merrf.REF.finsterer.2017.166" rid="merrf.REF.finsterer.2017.166">Finsterer & Zarrouk-Mahjoubb 2017</a>].</div></li><li class="half_rhythm"><div><b>Migrainous headaches</b>. Migraines are common in individuals with MERRF and can be present at the onset of symptoms. <a class="bibr" href="#merrf.REF.vollono.2018.1093" rid="merrf.REF.vollono.2018.1093">Vollono et al [2018]</a> reported seven individuals with MERRF and migraines and found that migraines can present with or without aura. The frequency of migraine episodes in most individuals was every two months.</div></li><li class="half_rhythm"><div><b>Hearing impairment</b>. Hearing loss is typically sensorineural and occurs in 35%-91% of individuals.</div></li><li class="half_rhythm"><div><b>Peripheral neuropathy</b>. It has been reported that either sensory axonal neuropathy or sensory motor axonal neuropathy can be present.</div></li><li class="half_rhythm"><div><b>Early psychomotor development</b>. Early development is typically normal in individuals with MERRF.</div></li><li class="half_rhythm"><div><b>Psychiatric illnesses.</b> Although psychiatric illness is not a prominent feature in this disorder, several individuals with depressive mood disorders have been reported.</div></li></ul><p><b>Cardiac involvement.</b> Cardiomyopathy can be observed. Both hypertrophic and dilated cardiomyopathy have been described. Arrhythmias are common in individuals with MERRF and can accompany the cardiomyopathy or be an isolated cardiac finding.</p><p><b>Lipomatosis</b> can be seen in adulthood in individuals with MERRF, with an average age of onset of 45.2 years [<a class="bibr" href="#merrf.REF.chong.2003.1" rid="merrf.REF.chong.2003.1">Chong et al 2003</a>]. Lipomas can be infiltrative, progressive, and massive in size [<a class="bibr" href="#merrf.REF.gilson.2018.822" rid="merrf.REF.gilson.2018.822">Gilson & Osswald 2018</a>]. The most common location of lipomas is the cervical region.</p></div><div id="merrf.Phenotype_Correlations_by_Gene"><h3>Phenotype Correlations by Gene</h3><p>No phenotype correlations by gene have been identified.</p></div><div id="merrf.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No genotype-phenotype correlations have been identified.</p><p>For all mtDNA pathogenic variants, clinical expression depends on three factors:</p><ul><li class="half_rhythm"><div><b>Heteroplasmy.</b> The relative abundance of mutated mtDNAs</div></li><li class="half_rhythm"><div><b>Tissue distribution</b> of mutated mtDNAs</div></li><li class="half_rhythm"><div><b>Threshold effect.</b> The vulnerability of each tissue to impaired oxidative metabolism</div></li></ul><p>The tissue vulnerability threshold probably does not vary substantially among individuals, but variable mutational load and tissue distribution may account for the clinical diversity of individuals with MERRF.</p></div><div id="merrf.Penetrance"><h3>Penetrance</h3><p>See <a href="#merrf.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>.</p></div><div id="merrf.Nomenclature"><h3>Nomenclature</h3><p>Ramsay <a class="bibr" href="#merrf.REF.hunt.1921.490" rid="merrf.REF.hunt.1921.490">Hunt [1921]</a> described six individuals with a disorder characterized by ataxia, myoclonus, and epilepsy, which he called "dyssynergia cerebellaris myoclonica." Individuals with the diagnosis of Ramsay Hunt syndrome should be investigated for MERRF.</p></div><div id="merrf.Prevalence"><h3>Prevalence</h3><p>Four epidemiologic studies of mtDNA-related diseases in northern Europe gave concordantly low estimates for the prevalence of the <a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">m.8344A>G</a> pathogenic variant:</p><ul><li class="half_rhythm"><div>0-1.5:100,000 in the adult population of northern Finland [<a class="bibr" href="#merrf.REF.remes.2005.976" rid="merrf.REF.remes.2005.976">Remes et al 2005</a>]</div></li><li class="half_rhythm"><div>0.39:100,000 in the adult population of northern England [<a class="bibr" href="#merrf.REF.schaefer.2008.35" rid="merrf.REF.schaefer.2008.35">Schaefer et al 2008</a>]</div></li><li class="half_rhythm"><div>0-0.25:100,000 in a pediatric population of western Sweden [<a class="bibr" href="#merrf.REF.darin.2001.377" rid="merrf.REF.darin.2001.377">Darin et al 2001</a>]</div></li><li class="half_rhythm"><div>0.7:100,000 in a large population-based study in northeast England [<a class="bibr" href="#merrf.REF.gorman.2015.753" rid="merrf.REF.gorman.2015.753">Gorman et al 2015</a>]</div></li></ul><p>See <a href="/books/n/gene/mt-overview/?report=reader">Mitochondrial Disorders Overview</a> for general prevalence information.</p></div></div><div id="merrf.Genetically_Related_Allelic_Disord"><h2 id="_merrf_Genetically_Related_Allelic_Disord_">Genetically Related (Allelic) Disorders</h2><p>Other phenotypes associated with germline pathogenic variants in <i>MT-TF</i>, <i>MT-TH</i>, <i>MT-TI</i>, <i>MT-TK</i>, and <i>MT-TL1</i> are summarized in <a href="/books/NBK1520/table/merrf.T.selected_allelic_disorders/?report=objectonly" target="object" rid-ob="figobmerrfTselectedallelicdisorders">Table 3</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmerrfTselectedallelicdisorders"><a href="/books/NBK1520/table/merrf.T.selected_allelic_disorders/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobmerrfTselectedallelicdisorders"><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="merrf.T.selected_allelic_disorders"><a href="/books/NBK1520/table/merrf.T.selected_allelic_disorders/?report=objectonly" target="object" rid-ob="figobmerrfTselectedallelicdisorders">Table 3. </a></h4><p class="float-caption no_bottom_margin">Selected Allelic Disorders </p></div></div><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with pathogenic variants in <i>MT-TP</i>.</p></div><div id="merrf.Differential_Diagnosis"><h2 id="_merrf_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Neurologic findings.</b> The differential diagnosis includes other mitochondrial disorders (see <a href="/books/n/gene/mt-overview/?report=reader">Mitochondrial Disorders Overview</a>), syndromes characterized by ataxia (see <a href="/books/n/gene/ataxias/?report=reader">Hereditary Ataxia Overview</a>) and myoclonus epilepsy (e.g., <a href="/books/n/gene/epm1/?report=reader">Unverricht-Lundborg disease</a>, <a href="/books/n/gene/lafora/?report=reader">Lafora type progressive myoclonus epilepsy</a>, neuronal ceroid lipofuscinosis, and sialidosis [<a class="bibr" href="#merrf.REF.k_lvi_inen.2015.293" rid="merrf.REF.k_lvi_inen.2015.293">Kälviäinen 2015</a>]), and the disorders summarized in <a href="/books/NBK1520/table/merrf.T.genes_of_interest_in_the_differe/?report=objectonly" target="object" rid-ob="figobmerrfTgenesofinterestinthediffere">Table 4</a>.</p><p>The multisystem involvement, lactic acidosis, evidence of maternal inheritance, and muscle biopsy with RRF (ragged red fibers) distinguish MERRF (<i>m</i>yoclonic <i>e</i>pilepsy with <i>r</i>agged <i>r</i>ed <i>f</i>ibers) from other conditions.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmerrfTgenesofinterestinthediffere"><a href="/books/NBK1520/table/merrf.T.genes_of_interest_in_the_differe/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobmerrfTgenesofinterestinthediffere"><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="merrf.T.genes_of_interest_in_the_differe"><a href="/books/NBK1520/table/merrf.T.genes_of_interest_in_the_differe/?report=objectonly" target="object" rid-ob="figobmerrfTgenesofinterestinthediffere">Table 4. </a></h4><p class="float-caption no_bottom_margin">Genes of Interest in the Differential Diagnosis of MERRF </p></div></div><p><b>Lipomas.</b> Other syndromes that cause multiple lipomas (e.g., multiple symmetric lipomatosis [OMIM <a href="http://omim.org/entry/151800" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">151800</a>]) need to be considered.</p></div><div id="merrf.Management"><h2 id="_merrf_Management_">Management</h2><div id="merrf.Evaluations_Following_Initial_Diag"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with MERRF (<i>m</i>yoclonic <i>e</i>pilepsy with <i>r</i>agged <i>r</i>ed <i>f</i>ibers), the evaluations summarized in <a href="/books/NBK1520/table/merrf.T.recommended_evaluations_followin/?report=objectonly" target="object" rid-ob="figobmerrfTrecommendedevaluationsfollowin">Table 5</a> (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="figmerrfTrecommendedevaluationsfollowin"><a href="/books/NBK1520/table/merrf.T.recommended_evaluations_followin/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobmerrfTrecommendedevaluationsfollowin"><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="merrf.T.recommended_evaluations_followin"><a href="/books/NBK1520/table/merrf.T.recommended_evaluations_followin/?report=objectonly" target="object" rid-ob="figobmerrfTrecommendedevaluationsfollowin">Table 5. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with MERRF </p></div></div></div><div id="merrf.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmerrfTtreatmentofmanifestationsini"><a href="/books/NBK1520/table/merrf.T.treatment_of_manifestations_in_i/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobmerrfTtreatmentofmanifestationsini"><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="merrf.T.treatment_of_manifestations_in_i"><a href="/books/NBK1520/table/merrf.T.treatment_of_manifestations_in_i/?report=objectonly" target="object" rid-ob="figobmerrfTtreatmentofmanifestationsini">Table 6. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with MERRF </p></div></div></div><div id="merrf.Prevention_of_Primary_Manifestatio"><h3>Prevention of Primary Manifestations</h3><p>The administration of coenzyme Q<sub>10</sub> (CoQ<sub>10</sub>) (50-200 mg 2-3x/day) and L-carnitine (1000 mg 2-3x/day) has been of some benefit to some individuals. In a small randomized double-blind placebo-controlled study of affected individuals with heterogeneous mitochondrial diseases, CoQ<sub>10</sub> combined with creatine and lipoic acid produced modest benefits including slowing progression of ankle weakness and lower resting plasma lactate concentration [<a class="bibr" href="#merrf.REF.rodriguez.2007.235" rid="merrf.REF.rodriguez.2007.235">Rodriguez et al 2007</a>].</p><p>The Mitochondrial Medicine Society published a consensus statement which recommends that CoQ<sub>10</sub>, alpha lipoic acid, and riboflavin should be offered to individuals with mitochondrial disease. Folinic acid should be considered in those with central nervous system involvement. L-carnitine should be supplemented in those with documented deficiency and levels should continue to be monitored [<a class="bibr" href="#merrf.REF.parikh.2015.689" rid="merrf.REF.parikh.2015.689">Parikh et al 2015</a>]. Despite the empiric rationale to administer these vitamins and supplements, there is limited clinical trial evidence supporting their use [<a class="bibr" href="#merrf.REF.rodriguez.2007.235" rid="merrf.REF.rodriguez.2007.235">Rodriguez et al 2007</a>].</p></div><div id="merrf.Surveillance"><h3>Surveillance</h3><p>Affected individuals and their at-risk relatives should be followed at regular intervals (e.g., every 6-12 months initially) to monitor progression of disease and the appearance of new symptoms.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmerrfTrecommendedsurveillanceforind"><a href="/books/NBK1520/table/merrf.T.recommended_surveillance_for_ind/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobmerrfTrecommendedsurveillanceforind"><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="merrf.T.recommended_surveillance_for_ind"><a href="/books/NBK1520/table/merrf.T.recommended_surveillance_for_ind/?report=objectonly" target="object" rid-ob="figobmerrfTrecommendedsurveillanceforind">Table 7. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with MERRF </p></div></div></div><div id="merrf.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Individuals with MERRF should avoid mitochondrial toxins such as aminoglycoside antibiotics, linezolid, cigarettes, and alcohol. Valproic acid should be avoided in the treatment of seizures.</p></div><div id="merrf.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. Evaluations can include:</p><ul><li class="half_rhythm"><div>Molecular genetic testing if the pathogenic variant in the family is known;</div></li><li class="half_rhythm"><div>Complete neurologic evaluation, ophthalmologic and audiology evaluations, EKG, echocardiogram, and blood lactate if the pathogenic variant in the family is not known.</div></li></ul><p>See <a href="#merrf.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="merrf.Pregnancy_Management"><h3>Pregnancy Management</h3><p>During pregnancy, affected or at-risk women should be monitored for diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions.</p></div><div id="merrf.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Mitochondrial replacement therapy (MRT) – replacement of a woman's abnormal mitochondrial DNA with healthy mitochondrial DNA from a donor [<a class="bibr" href="#merrf.REF.sharma.2020.e04643" rid="merrf.REF.sharma.2020.e04643">Sharma et al 2020</a>] – has been under investigation as a way to prevent these disorders from continuing in a family. MRT includes three types of techniques: spindle transfer, pronuclear transfer, and polar body transfer. MRT was successfully approved by the United Kingdom Parliament and a clinical trial is underway. To date, these techniques are not approved in the United States.</p><p>Genetic therapy through the delivery of mitochondrially targeted zinc finger nucleases delivered by an adeno-associated virus has been studied in mouse models with mitochondrial disorders. The mutational load decreased by 20% in treated animals, and biochemical phenotypes were reversed [<a class="bibr" href="#merrf.REF.gammage.2018.1691" rid="merrf.REF.gammage.2018.1691">Gammage et al 2018</a>].</p><p>Search <a href="http://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="http://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="merrf.Genetic_Counseling"><h2 id="_merrf_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="merrf.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>MERRF (<i>m</i>yoclonic <i>e</i>pilepsy with <i>r</i>agged <i>r</i>ed <i>f</i>ibers) is caused by pathogenic variants in mitochondrial DNA (mtDNA) and transmitted by maternal inheritance.</p></div><div id="merrf.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 is not at risk of having 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 clinical manifestations of the disorder. 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>Some individuals diagnosed with MERRF have no known family history of the disorder. The explanation for apparently simplex cases may be the absence of a comprehensive and/or reliable family history or, in rare cases, a <i>de novo</i> mtDNA pathogenic variant in the proband.</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. If the mother has the mtDNA pathogenic variant, all the sibs of a proband will inherit the mtDNA pathogenic variant. Women with higher levels of mutated mtDNA in their blood may have a greater likelihood of having affected offspring [<a class="bibr" href="#merrf.REF.chinnery.1998.1889" rid="merrf.REF.chinnery.1998.1889">Chinnery et al 1998</a>].</div></li><li class="half_rhythm"><div>Clinical expression in sibs depends on the percentage of mutated mitochondria (mutational load) and the organs and tissues in which they are found (tissue distribution and threshold effect). Sibs often inherit different percentages of mutated mtDNA and have a wide range of clinical manifestations (see <a href="#merrf.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</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 pathogenic variant.</div></li><li class="half_rhythm"><div>Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic 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 the mother has a mtDNA pathogenic variant, her sibs and mother are also at risk.</p></div><div id="merrf.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#merrf.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p><b>Phenotypic variability.</b> The phenotype of an individual with a mtDNA pathogenic variant results from a combination of factors including the percentage of mutated mitochondria (mutational load) and the organs and tissues in which they are found (tissue distribution). Family members can have a wide range of clinical symptoms.</p><p><b>Interpretation of testing results of asymptomatic at-risk family members</b> is extremely difficult. Prediction of phenotype based on test results is not possible. Furthermore, absence of the mtDNA pathogenic variant in one tissue (e.g., blood) does not guarantee its absence in other tissues.</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 general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.</div></li></ul><p><b>DNA banking</b> is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.</p></div><div id="merrf.Prenatal_Testing_and_Preimplantati"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the mtDNA pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MERRF are technically possible. However, prenatal testing for mtDNA pathogenic variants causing MERRF is of uncertain utility 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><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="merrf.Resources"><h2 id="_merrf_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>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>MitoAction</b>
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</div><div><b>Phone:</b> 888-648-6228</div><div><b>Email:</b> support@mitoaction.org</div><div>
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<a href="http://www.mitoaction.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">mitoaction.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Mitochondrial Disease: A Guide for the Newly Diagnosed</b>
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</div><div>Mitochondrial Care Network</div><div>
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<a href="http://www.mitonetwork.org/patient-guide" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.mitonetwork.org/patient-guide</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="merrf.Molecular_Genetics"><h2 id="_merrf_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="figmerrfmolgenTA"><a href="/books/NBK1520/table/merrf.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobmerrfmolgenTA"><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="merrf.molgen.TA"><a href="/books/NBK1520/table/merrf.molgen.TA/?report=objectonly" target="object" rid-ob="figobmerrfmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">MERRF: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmerrfmolgenTB"><a href="/books/NBK1520/table/merrf.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobmerrfmolgenTB"><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="merrf.molgen.TB"><a href="/books/NBK1520/table/merrf.molgen.TB/?report=objectonly" target="object" rid-ob="figobmerrfmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for MERRF (View All in OMIM) </p></div></div><div id="merrf.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>The origin of mtDNA pathogenic variants is uncertain. It is also unclear how the mtDNA single-nucleotide variants cause MERRF. Using rho<sup>0</sup> cell lines (permanent human cell lines emptied of their mtDNA by exposure to ethidium bromide) repopulated with mitochondria harboring the m.8344A>G pathogenic variant, <a class="bibr" href="#merrf.REF.chomyn.1991.2236" rid="merrf.REF.chomyn.1991.2236">Chomyn et al [1991]</a> found that high mutational loads correlated with decreased protein synthesis, decreased oxygen consumption, and cytochrome <i>c</i> oxidase deficiency. The polypeptides containing higher numbers of lysine residues were more severely affected by the pathogenic variant, suggesting that the <i>MT-TK</i> pathogenic variant directly inhibits protein synthesis. Similarly, cultured myotubes containing more than 85% mutated mtDNA showed decreased translation, especially of proteins containing large numbers of lysine residues. Cells harboring the <a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">m.8344A>G</a> pathogenic variant contained decreased levels of tRNA<sup>Lys</sup> and aminoacylated tRNA<sup>Lys</sup>. The variant appears to be functionally recessive because only about 15% wild-type mtDNA restores translation and cytochrome <i>c</i> oxidase activity to near-normal levels.</p><p><a class="bibr" href="#merrf.REF.masucci.1995.2872" rid="merrf.REF.masucci.1995.2872">Masucci et al [1995]</a> confirmed that protein synthesis and oxygen consumption were decreased in rho<sup>0</sup> cells repopulated with mtDNA harboring either the <a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">m.8344A>G</a> or the <a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">m.8356T>C</a> pathogenic variant, and identified aberrant mitochondrial protein in both cell lines, which they attributed to ribosomal frameshifting. Studies of engineered in vitro transcribed tRNA<sup>Lys</sup> mutants showed that the pathogenic variants associated with MERRF had no effect on lysylation efficiency, whereas the two pathogenic variants associated with encephalomyopathies without typical MERRF features (m.8313G>A and m.8328G>A in <i>MT-TK</i>) severely impaired lysylation [<a class="bibr" href="#merrf.REF.sissler.2004.841" rid="merrf.REF.sissler.2004.841">Sissler et al 2004</a>].</p><p><b>Mechanism of disease causation.</b> Unknown</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmerrfTmerrfnotablemttkpathogenicva"><a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" title="Table 8. " class="img_link icnblk_img" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva"><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="merrf.T.merrf_notable_mttk_pathogenic_va"><a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">Table 8. </a></h4><p class="float-caption no_bottom_margin">MERRF: Notable <i>MT-TK</i> Pathogenic Variants </p></div></div></div></div><div id="merrf.Chapter_Notes"><h2 id="_merrf_Chapter_Notes_">Chapter Notes</h2><div id="merrf.Author_History"><h3>Author History</h3><p>Salvatore DiMauro, MD; Columbia University Medical Center (2003-2021)<br />Gregory Enns, MB, ChB (2021-present)<br />Michio Hirano, MD; Columbia University Medical Center (2003-2021)<br />Chung Lee, MD (2021-present)<br />Frances Velez-Bartolomei, MD (2021-present)</p></div><div id="merrf.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>7 January 2021 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>29 January 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>18 August 2009 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>27 September 2005 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>3 June 2003 (ca) Review posted live</div></li><li class="half_rhythm"><div>8 May 2003 (sdm) Original submission</div></li></ul></div></div><div id="merrf.References"><h2 id="_merrf_References_">References</h2><div id="merrf.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="merrf.REF.chinnery.1998.1889">Chinnery PF, Howell N, Lightowlers RN, Turnbull DM. 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Multiple symmetric lipomatosis (Madelung disease) in a large Canadian family with the mitochondrial MTTK c.8344A>G Variant. <span><span class="ref-journal">J Investig Med High Impact Case Rep. </span>2018:6.</span> [<a href="/pmc/articles/PMC6166310/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6166310</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30283804" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30283804</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="merrf.REF.remes.2005.976">Remes AM, Majamaa-Voltti K, Karppa M, Moilanen JS, Uimonen S, Helander H, Rusanen H, Salmela PI, Sorri M, Hassinen IE, Majamaa K. Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population. <span><span class="ref-journal">Neurology. </span>2005;<span class="ref-vol">64</span>:976–81.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15781811" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15781811</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="merrf.REF.rodriguez.2007.235">Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. <span><span class="ref-journal">Muscle Nerve. </span>2007;<span class="ref-vol">35</span>:235–42.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17080429" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17080429</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="merrf.REF.schaefer.2008.35">Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, Chinnery PF, Turnbull DM. Prevalence of mitochondrial DNA disease in adults. <span><span class="ref-journal">Ann Neurol. </span>2008;<span class="ref-vol">63</span>:35–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17886296" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17886296</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="merrf.REF.sharma.2020.e04643">Sharma H, Singh D, Mahant A, Sohal SK, Kesavan AK. Samiksha. Development of mitochondrial replacement therapy: a review. <span><span class="ref-journal">Heliyon. </span>2020;<span class="ref-vol">6</span>:e04643. </span> [<a href="/pmc/articles/PMC7492815/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7492815</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32984570" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32984570</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="merrf.REF.sissler.2004.841">Sissler M, Helm M, Frugier M, Giege R, Florentz C. Aminoacylation properties of pathology-related human mitochondrial tRNA(Lys) variants. <span><span class="ref-journal">RNA. </span>2004;<span class="ref-vol">10</span>:841–53.</span> [<a href="/pmc/articles/PMC1370574/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1370574</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15100439" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15100439</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="merrf.REF.taivassalo.2004.221">Taivassalo T, Haller RG. Implications of exercise training in mtDNA defects--use it or lose it? <span><span class="ref-journal">Biochim Biophys Acta. </span>2004;<span class="ref-vol">1659</span>:221–31.</span> [<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="merrf.REF.vollono.2018.1093">Vollono C, Primiano G, Della Marca G, Losurdo A, Servidei S. Migraine in mitochondrial disorders: Prevalence and characteristics. <span><span class="ref-journal">Cephalalgia. </span>2018;<span class="ref-vol">38</span>:1093–106.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28762753" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28762753</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="merrf.REF.yoon.1993.433">Yoon KL, Ernst SG, Rasmussen C, Dooling EC, Aprille JR. Mitochondrial disorder associated with newborn cardiopulmonary arrest. <span><span class="ref-journal">Pediatr Res. </span>1993;<span class="ref-vol">33</span>:433–40.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8511015" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8511015</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="merrf.REF.yorns.2012.398">Yorns WR Jr, Valencia I, Jayaraman A, Sheth S, Legido A, Goldenthal MJ. Buccal swab analysis of mitochondrial enzyme deficiency and DNA defects in a child with suspected myoclonic epilepsy and ragged red fibers (MERRF). <span><span class="ref-journal">J Child Neurol. </span>2012;<span class="ref-vol">27</span>:398–401.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22114216" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22114216</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1520_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Frances Velez-Bartolomei</span>, MD<div class="affiliation small">Stanford University<br />Stanford, California<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.drofnats@zelevf" class="oemail">ude.drofnats@zelevf</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Chung Lee</span>, MD<div class="affiliation small">Stanford University<br />Stanford, California<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.drofnats@eelgnuhc" class="oemail">ude.drofnats@eelgnuhc</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Gregory Enns</span>, MB, ChB<div class="affiliation small">Stanford University<br />Stanford, California<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.drofnats@snneg" class="oemail">ude.drofnats@snneg</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">June 3, 2003</span>; Last Update: <span itemprop="dateModified">January 7, 2021</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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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>Velez-Bartolomei F, Lee C, Enns G. MERRF. 2003 Jun 3 [Updated 2021 Jan 7]. 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/melas/?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/cmt2a/?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="figobmerrfTmoleculargenetictestingusedi"><div id="merrf.T.molecular_genetic_testing_used_i" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in MERRF</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1520/table/merrf.T.molecular_genetic_testing_used_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__merrf.T.molecular_genetic_testing_used_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_merrf.T.molecular_genetic_testing_used_i_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_merrf.T.molecular_genetic_testing_used_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of MERRF Attributed to Pathogenic Variants in Gene</th><th id="hd_h_merrf.T.molecular_genetic_testing_used_i_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_merrf.T.molecular_genetic_testing_used_i_1_1_1_1" scope="row" rowspan="1" 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_merrf.T.molecular_genetic_testing_used_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>90% <sup>5</sup></td><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td></tr><tr><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_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_merrf.T.molecular_genetic_testing_used_i_1_1_1_2" rowspan="7" colspan="1" style="text-align:left;vertical-align:middle;"><5%</td><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="7" colspan="1" style="text-align:left;vertical-align:middle;">100%</td></tr><tr><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TH</i>
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</td></tr><tr><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TI</i>
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</td></tr><tr><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TL1</i>
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</td></tr><tr><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TP</i>
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</td></tr><tr><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TS1</i>
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</td></tr><tr><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TS2</i>
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</td></tr><tr><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>6</sup></td><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NA</td><td headers="hd_h_merrf.T.molecular_genetic_testing_used_i_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>1. </dt><dd><div id="merrf.TF.1.1"><p class="no_margin">Genes are listed from most frequent to least frequent genetic cause of MERRF.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="merrf.TF.1.2"><p class="no_margin">See <a href="/books/NBK1520/?report=reader#merrf.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="merrf.TF.1.3"><p class="no_margin">See <a href="#merrf.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="merrf.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 small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene 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 class="bkr_refwrap"><dt>5. </dt><dd><div id="merrf.TF.1.5"><p class="no_margin">Four <i>MT-TK</i> pathogenic variants (<a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">m.8344A>G</a>, <a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">m.8356T>C</a>, <a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">m.8363G>A</a>, and <a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">m.8361G>A</a>) account for approximately 90% of pathogenic variants in individuals with MERRF.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="merrf.TF.1.6"><p class="no_margin">One child with MERRF was found to have two mtDNA deletions in a buccal swab, suggesting an autosomal disorder with multiple mtDNA deletions; however, the causative nuclear gene was not identified [<a class="bibr" href="#merrf.REF.yorns.2012.398" rid="merrf.REF.yorns.2012.398">Yorns et al 2012</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmerrfTmerrffrequencyofselectfeatur"><div id="merrf.T.merrf_frequency_of_select_featur" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>MERRF: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1520/table/merrf.T.merrf_frequency_of_select_featur/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__merrf.T.merrf_frequency_of_select_featur_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of 62 Persons w/Feature <sup>1</sup></th><th id="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of 34 Persons w/Feature <sup>2</sup></th><th id="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of 321 Persons w/Feature <sup>3</sup></th></tr></thead><tbody><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Myoclonus</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">24%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">61%</td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Epilepsy</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">35%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">43%</td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal early development</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ragged red fibers</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">92%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">96%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing loss</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">91%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">35%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">39%</td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lactic acidosis</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">83%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">65%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Family history of MERRF</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">81%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Exercise intolerance</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">80%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">44%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dementia</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">75%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">25%</td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropathy</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">63%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">24%</td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Short stature</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">57%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Impaired sensation</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">50%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Optic atrophy</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">39%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">33%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Arrhythmia</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">22%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">18%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pigmentary retinopathy</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pyramidal signs</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">13%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmoparesis</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">11%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6%</td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lipomatosis</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">32%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8%</td></tr><tr><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Diabetes mellitus</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12%</td><td headers="hd_h_merrf.T.merrf_frequency_of_select_featur_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3%</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="merrf.TF.2.1"><p class="no_margin">
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<a class="bibr" href="#merrf.REF.hirano.1996" rid="merrf.REF.hirano.1996">Hirano & DiMauro [1996]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="merrf.TF.2.2"><p class="no_margin">
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<a class="bibr" href="#merrf.REF.mancuso.2013.2049" rid="merrf.REF.mancuso.2013.2049">Mancuso et al [2013]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="merrf.TF.2.3"><p class="no_margin">Reviewed from the literature by <a class="bibr" href="#merrf.REF.mancuso.2013.2049" rid="merrf.REF.mancuso.2013.2049">Mancuso et al [2013]</a></p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmerrfTselectedallelicdisorders"><div id="merrf.T.selected_allelic_disorders" class="table"><h3><span class="label">Table 3. </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/NBK1520/table/merrf.T.selected_allelic_disorders/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__merrf.T.selected_allelic_disorders_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_merrf.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_merrf.T.selected_allelic_disorders_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phenotype</th></tr></thead><tbody><tr><td headers="hd_h_merrf.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_merrf.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><a href="/books/n/gene/melas/?report=reader">MELAS</a></div></li></ul>
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</td></tr><tr><td headers="hd_h_merrf.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-TH</i>
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</td><td headers="hd_h_merrf.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><a href="/books/n/gene/melas/?report=reader">MELAS</a></div></li><li class="half_rhythm"><div>Cardiomyopathy (OMIM <a href="https://omim.org/entry/590040" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">590040</a>)</div></li><li class="half_rhythm"><div>Pigmentary retinopathy (OMIM <a href="https://omim.org/entry/590040" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">590040</a>)</div></li><li class="half_rhythm"><div><a href="/books/n/gene/mt-deafness/?report=reader">Deafness</a></div></li></ul>
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</td></tr><tr><td headers="hd_h_merrf.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-TI</i>
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</td><td headers="hd_h_merrf.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><a href="/books/n/gene/narp/?report=reader">Mitochondrial DNA-associated Leigh syndrome</a></div></li><li class="half_rhythm"><div>Neonatal weakness, lactic acidosis, hypoglycemia, cardiopulmonary arrest, & early fatality in one individual <sup>1</sup></div></li></ul>
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</td></tr><tr><td headers="hd_h_merrf.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-TK</i>
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</td><td headers="hd_h_merrf.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Multiple symmetric lipomatosis [<a class="bibr" href="#merrf.REF.perera.2018.6" rid="merrf.REF.perera.2018.6">Perera et al 2018</a>]</div></li><li class="half_rhythm"><div><a href="/books/n/gene/melas/?report=reader">MELAS</a></div></li><li class="half_rhythm"><div>MERRF/<a href="/books/n/gene/melas/?report=reader">MELAS</a> overlap <sup>2, 3</sup> (See also <a href="#merrf.Differential_Diagnosis">Differential Diagnosis</a>.)</div></li><li class="half_rhythm"><div><a href="/books/n/gene/narp/?report=reader">Mitochondrial DNA-associated Leigh syndrome</a></div></li></ul>
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</td></tr><tr><td headers="hd_h_merrf.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-TL1</i>
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</td><td headers="hd_h_merrf.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cardiomyopathy (OMIM <a href="http://omim.org/entry/590050" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">590050</a>)</div></li><li class="half_rhythm"><div>Maternally inherited diabetes mellitus w/ or w/o deafness (OMIM <a href="http://omim.org/entry/590050" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">590050</a>)</div></li><li class="half_rhythm"><div>MERRF/<a href="/books/n/gene/melas/?report=reader">MELAS</a> overlap (See also <a href="#merrf.Differential_Diagnosis">Differential Diagnosis</a>.)</div></li><li class="half_rhythm"><div><a href="/books/n/gene/melas/?report=reader">MELAS</a></div></li><li class="half_rhythm"><div>MERRF/Kearns-Sayre syndrome (See <a href="/books/n/gene/kss/?report=reader">Mitochondrial DNA Deletion Syndromes</a>.) <sup>3, 4</sup></div></li><li class="half_rhythm"><div><a href="/books/n/gene/mt-deafness/?report=reader">Mitochondrial nonsyndromic hearing loss and deafness</a></div></li><li class="half_rhythm"><div>Progressive external ophthalmoplegia (See <a href="/books/n/gene/kss/?report=reader">Mitochondrial DNA Deletion Syndromes</a>.)</div></li></ul>
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</td></tr><tr><td headers="hd_h_merrf.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>
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</td><td headers="hd_h_merrf.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><a href="/books/n/gene/melas/?report=reader">MELAS</a></div></li><li class="half_rhythm"><div><a href="/books/n/gene/mt-deafness/?report=reader">Mitochondrial nonsyndromic hearing impairment</a></div></li></ul>
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</td></tr><tr><td headers="hd_h_merrf.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>
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</td><td headers="hd_h_merrf.T.selected_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><a href="/books/n/gene/melas/?report=reader">MELAS</a></div></li><li class="half_rhythm"><div>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>)</div></li></ul>
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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="merrf.TF.3.1"><p class="no_margin">
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<a class="bibr" href="#merrf.REF.yoon.1993.433" rid="merrf.REF.yoon.1993.433">Yoon et al [1993]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="merrf.TF.3.2"><p class="no_margin">In three families with the <i>MT-TK</i>
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<a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">m.8356T>C</a> pathogenic variant, some affected individuals had typical MERRF but others also had stroke-like episodes and migraine (MERRF/<a href="/books/n/gene/melas/?report=reader">MELAS</a> overlap). See also <a href="#merrf.Differential_Diagnosis">Differential Diagnosis</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="merrf.TF.3.3"><p class="no_margin">One affected individual with MERRF/MELAS overlap syndrome had two pathogenic variants: the <i>MT-TL1</i> variant m.3243A>G (the most frequent cause of MELAS) and the <i>MT-TK</i> variant <a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object" rid-ob="figobmerrfTmerrfnotablemttkpathogenicva">m.8356T>C</a> (a rare cause of MERRF) [<a class="bibr" href="#merrf.REF.nakamura.2010.659" rid="merrf.REF.nakamura.2010.659">Nakamura et al 2010</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="merrf.TF.3.4"><p class="no_margin">A MERRF/Kearns-Sayre syndrome overlap syndrome has been reported to be caused by the pathogenic variant m.3255G>A in <i>MT-TL1</i> (reported in 2 individuals [<a class="bibr" href="#merrf.REF.nishigaki.2003.334" rid="merrf.REF.nishigaki.2003.334">Nishigaki et al 2003</a>, <a class="bibr" href="#merrf.REF.fujioka.2014.13" rid="merrf.REF.fujioka.2014.13">Fujioka et al 2014</a>]) and by the pathogenic variant m.3291T>C in <i>MT-TL1</i> (reported in 1 individual [<a class="bibr" href="#merrf.REF.emmanuele.2011.448" rid="merrf.REF.emmanuele.2011.448">Emmanuele et al 2011</a>]).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmerrfTgenesofinterestinthediffere"><div id="merrf.T.genes_of_interest_in_the_differe" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of MERRF</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1520/table/merrf.T.genes_of_interest_in_the_differe/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__merrf.T.genes_of_interest_in_the_differe_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DiffDx Disorder</th><th id="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Features of DiffDx Disorder</th><th id="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing Features</th></tr></thead><tbody><tr><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CARS2</i>
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</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Combined oxidative phosphorylation deficiency 27 (OMIM <a href="https://omim.org/entry/616672" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616672</a>)</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Juvenile-onset MERRF-like severe myoclonus epilepsy w/ataxia, spastic tetraparesis, vision loss, hearing loss, & cognitive decline</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR inheritance</td></tr><tr><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_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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<br />
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<i>MT-TC</i>
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</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MERRF/<a href="/books/n/gene/melas/?report=reader">MELAS</a> overlap syndrome</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mat</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May initially resemble MERRF <sup>1</sup></td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Stroke-like episodes</td></tr><tr><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_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>
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</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>MT-TL2</i> disorder</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mat</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Features of MERRF & NARP in 1 person <sup>2</sup></td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Retinitis pigmentosa</td></tr><tr><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>POLG</i>
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</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/alpers/?report=reader"><i>POLG</i>-related disorders</a>
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</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Myoclonus, epilepsy, ataxia, peripheral neuropathy</td><td headers="hd_h_merrf.T.genes_of_interest_in_the_differe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absence of RRF in <i>POLG</i> phenotype</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">AR = autosomal recessive; DiffDx = differential diagnosis; Mat = maternal; MOI = mode of inheritance; NARP = neuropathy-ataxia-retinitis pigmentosa; RRF = ragged red fibers</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="merrf.TF.4.1"><p class="no_margin"><a class="bibr" href="#merrf.REF.crimi.2003.1857" rid="merrf.REF.crimi.2003.1857">Crimi et al [2003]</a>, <a class="bibr" href="#merrf.REF.dimauro.2005.222" rid="merrf.REF.dimauro.2005.222">DiMauro & Davidzon [2005]</a>, <a class="bibr" href="#merrf.REF.naini.2005.473" rid="merrf.REF.naini.2005.473">Naini et al [2005]</a>, <a class="bibr" href="#merrf.REF.herreromart_n.2010.471" rid="merrf.REF.herreromart_n.2010.471">Herrero-Martín et al [2010]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="merrf.TF.4.2"><p class="no_margin">
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<a class="bibr" href="#merrf.REF.mart_njim_nez.2012.288" rid="merrf.REF.mart_njim_nez.2012.288">Martín-Jiménez et al [2012]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmerrfTrecommendedevaluationsfollowin"><div id="merrf.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 MERRF</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1520/table/merrf.T.recommended_evaluations_followin/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__merrf.T.recommended_evaluations_followin_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_merrf.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_merrf.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_merrf.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_merrf.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_merrf.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_merrf.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for short stature</td></tr><tr><td headers="hd_h_merrf.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>
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</td><td headers="hd_h_merrf.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_merrf.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for neurologic deficits</td></tr><tr><td headers="hd_h_merrf.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_merrf.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_merrf.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_merrf.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_merrf.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_merrf.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess cognitive abilities & evidence of dementia</td></tr><tr><td headers="hd_h_merrf.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>
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</td><td headers="hd_h_merrf.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic eval</td><td headers="hd_h_merrf.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_merrf.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_merrf.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval</td><td headers="hd_h_merrf.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_merrf.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>
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</td><td headers="hd_h_merrf.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_merrf.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For persons w/neurologic deficits</td></tr><tr><td headers="hd_h_merrf.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>
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</td><td headers="hd_h_merrf.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiac eval incl echocardiogram</td><td headers="hd_h_merrf.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for cardiomyopathy & cardiac defects</td></tr><tr><td headers="hd_h_merrf.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_merrf.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To screen for conduction abnormalities</td></tr><tr><td headers="hd_h_merrf.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>Endocrinologic</b>
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</td><td headers="hd_h_merrf.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Fasting serum glucose</div></li><li class="half_rhythm"><div>Glucose tolerance test</div></li></ul>
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</td><td headers="hd_h_merrf.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To screen for diabetes mellitus</td></tr><tr><td headers="hd_h_merrf.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>Genetic</b>
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<br />
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<b>counseling</b>
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</td><td headers="hd_h_merrf.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_merrf.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform patients & their families re nature, MOI, & implications of MERRF to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_merrf.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>Family support/</b>
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<br />
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<b>resources</b>
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</td><td headers="hd_h_merrf.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess:
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<ul><li class="half_rhythm"><div>Use of community or <a href="#merrf.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Need for social work involvement for parental support;</div></li><li class="half_rhythm"><div>Need for home nursing referral.</div></li></ul>
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</td><td headers="hd_h_merrf.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">MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="merrf.TF.5.1"><p class="no_margin">Medical geneticist, certified genetic counselor, or certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmerrfTtreatmentofmanifestationsini"><div id="merrf.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 MERRF</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1520/table/merrf.T.treatment_of_manifestations_in_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__merrf.T.treatment_of_manifestations_in_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_merrf.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_merrf.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_merrf.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_merrf.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>Overall disease process</b>
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</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ubiquinol, carnitine, alpha lipoic acid, vitamin E, vitamin B complex, creatine</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be of benefit to some persons</td></tr><tr><td headers="hd_h_merrf.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>Seizures</b>
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</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Traditional anticonvulsant therapy per neurologist</td><td headers="hd_h_merrf.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="#merrf.AgentsCircumstances_to_Avoid">Agents/Circumstances to Avoid</a>).</td></tr><tr><td headers="hd_h_merrf.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>Myoclonus</b>
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</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Levetiracetam or clonazepam</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a class="bibr" href="#merrf.REF.crest.2004.640" rid="merrf.REF.crest.2004.640">Crest et al [2004]</a>, <a class="bibr" href="#merrf.REF.mancuso.2007.1058" rid="merrf.REF.mancuso.2007.1058">Mancuso et al [2007]</a></td></tr><tr><td headers="hd_h_merrf.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>Impaired motor abilities</b>
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</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>PT</div></li><li class="half_rhythm"><div>Aerobic exercise</div></li></ul>
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</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#merrf.REF.taivassalo.2004.221" rid="merrf.REF.taivassalo.2004.221">Taivassalo & Haller [2004]</a>
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</td></tr><tr><td headers="hd_h_merrf.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>Cardiomyopathy</b>
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</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Standard pharmacologic therapy per cardiologist</td><td headers="hd_h_merrf.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_merrf.T.treatment_of_manifestations_in_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cardiac conduction defects</b>
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</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_3" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_merrf.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>Hearing loss</b>
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</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing aids, cochlear implants</td><td headers="hd_h_merrf.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_merrf.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>Diabetes mellitus</b>
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</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment per endocrinologist</td><td headers="hd_h_merrf.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Metformin can aggravate lactic acidosis.</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">PT = physical therapy</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmerrfTrecommendedsurveillanceforind"><div id="merrf.T.recommended_surveillance_for_ind" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with MERRF</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1520/table/merrf.T.recommended_surveillance_for_ind/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__merrf.T.recommended_surveillance_for_ind_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic exam</td><td headers="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Annually</div></li><li class="half_rhythm"><div>If normal for 3 yrs, less frequent evals can be considered.</div></li></ul>
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</td></tr><tr><td headers="hd_h_merrf.T.recommended_surveillance_for_ind_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_merrf.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic exam</td></tr><tr><td headers="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cardiovascular</b>
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</td><td headers="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Electrocardiogram</div></li><li class="half_rhythm"><div>Echocardiogram</div></li></ul>
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</td></tr><tr><td headers="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Endocrinologic</b>
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</td><td headers="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Fasting blood sugar</div></li><li class="half_rhythm"><div>TSH</div></li></ul>
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</td></tr><tr><td headers="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hearing</b>
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</td><td headers="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic eval</td><td headers="hd_h_merrf.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 2-3 yrs</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">TSH = thyroid stimulating hormone</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmerrfmolgenTA"><div id="merrf.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>MERRF: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1520/table/merrf.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__merrf.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_merrf.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_merrf.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_merrf.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_merrf.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_merrf.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<i>MT-TF</i>
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</td><td headers="hd_b_merrf.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_merrf.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_merrf.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<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>
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</td></tr><tr><td headers="hd_b_merrf.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<i>MT-TH</i>
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</td><td headers="hd_b_merrf.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_merrf.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_merrf.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<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>
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</td></tr><tr><td headers="hd_b_merrf.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<i>MT-TI</i>
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</td><td headers="hd_b_merrf.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_merrf.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_merrf.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MT-TI[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TI</a>
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</td></tr><tr><td headers="hd_b_merrf.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<i>MT-TK</i>
|
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</td><td headers="hd_b_merrf.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_merrf.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_merrf.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<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>
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</td></tr><tr><td headers="hd_b_merrf.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<i>MT-TL1</i>
|
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</td><td headers="hd_b_merrf.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_merrf.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_merrf.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<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_merrf.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<i>MT-TP</i>
|
|
</td><td headers="hd_b_merrf.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_merrf.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_merrf.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-TP[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MT-TP</a>
|
|
</td></tr><tr><td headers="hd_b_merrf.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<i>MT-TS1</i>
|
|
</td><td headers="hd_b_merrf.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_merrf.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_merrf.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<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_merrf.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<i>MT-TS2</i>
|
|
</td><td headers="hd_b_merrf.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Mitochondrion</td><td headers="hd_b_merrf.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Not applicable</td><td headers="hd_b_merrf.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>
|
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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></dt><dd><div id="merrf.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
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chromosome locus from
|
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
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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="figobmerrfmolgenTB"><div id="merrf.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for MERRF (<a href="/omim/545000,590040,590045,590050,590060,590070,590075,590080,590085" 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/NBK1520/table/merrf.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__merrf.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<a href="/omim/545000" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">545000</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED FIBERS; MERRF</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<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;">
|
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<a href="/omim/590045" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590045</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, ISOLEUCINE; MTTI</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<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;">
|
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<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;">
|
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<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;">
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<a href="/omim/590075" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">590075</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRANSFER RNA, MITOCHONDRIAL, PROLINE; MTTP</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<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;">
|
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<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></tbody></table></div></div></article><article data-type="table-wrap" id="figobmerrfTmerrfnotablemttkpathogenicva"><div id="merrf.T.merrf_notable_mttk_pathogenic_va" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>MERRF: Notable <i>MT-TK</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1520/table/merrf.T.merrf_notable_mttk_pathogenic_va/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__merrf.T.merrf_notable_mttk_pathogenic_va_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mitochondrial DNA Nucleotide Change<br />(Alias <sup>1</sup>)</th><th id="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted<br />Protein Change</th><th id="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequence</th><th id="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">m.8344A>G<br />(A8344G)</td><td headers="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_2" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">No protein translated</td><td headers="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_3" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/nuccore/251831106" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NC_012920<wbr style="display:inline-block"></wbr>​.1</a>
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</td><td headers="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most common pathogenic variant; identified in >80% of persons w/MERRF</td></tr><tr><td headers="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">m.8356T>C<br />(T8356C)</td><td headers="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_4" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Pathogenic variants identified in ~10% of persons w/MERRF</td></tr><tr><td headers="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">m.8363G>A<br />(G8363A)</td></tr><tr><td headers="hd_h_merrf.T.merrf_notable_mttk_pathogenic_va_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">m.8361G>A<br />(G8361A)</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"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="http://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="merrf.TF.8.1"><p class="no_margin">Variant designation that does not conform to current naming conventions</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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