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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2018/07/26" /><meta name="citation_author" content="Julia Wang" /><meta name="citation_author" content="Ayman W El-Hattab" /><meta name="citation_author" content="Lee-Jun C Wong" /><meta name="citation_pmid" content="23230576" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK114628/" /><meta name="citation_keywords" content="Mitochondrial DNA Depletion Syndrome 2 (MTDPS2), Myopathic Type" /><meta name="citation_keywords" content="TK2 Deficiency" /><meta name="citation_keywords" content="TK2 Deficiency" /><meta name="citation_keywords" content="Mitochondrial DNA Depletion Syndrome 2 (MTDPS2), Myopathic Type" /><meta name="citation_keywords" content="Thymidine kinase 2, mitochondrial" /><meta name="citation_keywords" content="TK2" /><meta name="citation_keywords" content="TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Julia Wang" /><meta name="DC.Contributor" content="Ayman W El-Hattab" /><meta name="DC.Contributor" content="Lee-Jun C Wong" /><meta name="DC.Date" content="2018/07/26" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK114628/" /><meta name="description" content="TK2-related mitochondrial DNA (mtDNA) maintenance defect is a phenotypic continuum that ranges from severe to mild. To date, approximately 107 individuals with a molecularly confirmed diagnosis have been reported." /><meta name="og:title" content="TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form" /><meta name="og:type" content="book" /><meta name="og:description" content="TK2-related mitochondrial DNA (mtDNA) maintenance defect is a phenotypic continuum that ranges from severe to mild. To date, approximately 107 individuals with a molecularly confirmed diagnosis have been reported." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK114628/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/gene/tk2-mtddepl/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK114628/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.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><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK114628_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK114628_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/thoc6-id/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/traps/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK114628_"><span class="title" itemprop="name"><i>TK2</i>-Related Mitochondrial DNA Maintenance Defect, Myopathic Form</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Mitochondrial DNA Depletion Syndrome 2 (MTDPS2), Myopathic Type; TK2 Deficiency</div><p class="contrib-group"><span itemprop="author">Julia Wang</span>, BS, <span itemprop="author">Ayman W El-Hattab</span>, MD, FAAP, FACMG, and <span itemprop="author">Lee-Jun C Wong</span>, PhD, FACMG.</p><a data-jig="ncbitoggler" href="#__NBK114628_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK114628_ai__"><div class="contrib half_rhythm"><span itemprop="author">Julia Wang</span>, BS<div class="affiliation small">Baylor College of Medicine<br />Houston, Texas<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.mcb@gnaw.ailuj" class="oemail">ude.mcb@gnaw.ailuj</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Ayman W El-Hattab</span>, MD, FAAP, FACMG<div class="affiliation small">Associate Professor, Department of Clinical Sciences<br />College of Medicine<br />University of Sharjah<br />Sharjah, United Arab Emirates<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.oohay@wabattahle" class="oemail">moc.oohay@wabattahle</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Lee-Jun C Wong</span>, PhD, FACMG<div class="affiliation small">Baylor College of Medicine<br />Houston, Texas<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.mcb@gnowjl" class="oemail">ude.mcb@gnowjl</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">December 6, 2012</span>; Last Update: <span itemprop="dateModified">July 26, 2018</span>.</p><p><em>Estimated reading time: 18 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="tk2-mtddepl.Summary" itemprop="description"><h2 id="_tk2-mtddepl_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>TK2</i>-related mitochondrial DNA (mtDNA) maintenance defect is a phenotypic continuum that ranges from severe to mild. To date, approximately 107 individuals with a molecularly confirmed diagnosis have been reported.</p><p>Three main subtypes of presentation have been described:</p><ul><li class="half_rhythm"><div>Infantile-onset myopathy with neurologic involvement and rapid progression to early death. Affected individuals experience progressive muscle weakness leading to respiratory failure. Some individuals develop dysarthria, dysphagia, and/or hearing loss. Cognitive function is typically spared.</div></li><li class="half_rhythm"><div>Juvenile/childhood onset with generalized proximal weakness and survival to at least 13 years</div></li><li class="half_rhythm"><div>Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions. Some affected individuals develop respiratory insufficiency, chronic progressive external ophthalmoplegia, dysphagia, and dysarthria.</div></li></ul></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>TK2</i>-related mtDNA maintenance defect is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with infantile onset of disease with severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle. The diagnosis of <i>TK2</i>-related mtDNA maintenance defect is established in a proband older than age two years with reduced mtDNA content or multiple mtDNA deletions, ragged red fibers and/or COX-deficient fibers in skeletal muscle. The diagnosis is confirmed by the identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>TK2</i> by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Management should involve a multidisciplinary team. Feeding difficulties should be managed aggressively, including use of a nasogastric tube or gastrostomy tube when the risk for aspiration is high. Physical therapy can help maintain muscle function; a physical medicine and rehabilitation (PM&R) specialist can help those who have difficulty walking. A pulmonologist can oversee chest physiotherapy to improve pulmonary function, reduce the risk of pulmonary infection, and manage respiratory insufficiency, if present. Hearing loss and seizures are managed in a standard manner.</p><p><i>Prevention of secondary complications</i>: Chest physiotherapy can help reduce the risk of pulmonary infection; physical therapy can help prevent joint contractures.</p><p><i>Surveillance:</i> No clinical guidelines are available. Treating physicians should consider: routine evaluation of growth and weight, pulmonary function tests with consideration of blood gases, neurodevelopmental assessments at each visit, and at least annual audiology evaluations in those with infantile-onset disease.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>TK2</i>-related mtDNA maintenance defect is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk are possible if the pathogenic variants in the family have been identified.</p></div></div><div id="tk2-mtddepl.Diagnosis"><h2 id="_tk2-mtddepl_Diagnosis_">Diagnosis</h2><p><i>TK2</i>-related mitochondrial DNA (mtDNA) maintenance defect comprises a phenotypic continuum ranging from severe to mild. Three main subtypes of presentation have been described:</p><ul><li class="half_rhythm"><div>Infantile-onset myopathy with neurologic involvement and rapid progression to early death</div></li><li class="half_rhythm"><div>Juvenile/childhood onset with generalized proximal weakness and survival to adolescence or adulthood</div></li><li class="half_rhythm"><div>Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions</div></li></ul><div id="tk2-mtddepl.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>TK2</i>-related mtDNA maintenance defect <b>should be suspected</b> in individuals with the following clinical features (by age), supportive laboratory findings, electromyography results, skeletal muscle pathology, mtDNA content (copy number) analysis, and electron transport chain activity in skeletal muscle.</p><div id="tk2-mtddepl.Clinical_Features"><h4>Clinical Features</h4><p>
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<b>Infantile onset (<2 years)</b>
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</p><ul><li class="half_rhythm"><div>Generalized hypotonia</div></li><li class="half_rhythm"><div>Rapidly progressive proximal muscle weakness</div></li><li class="half_rhythm"><div>Loss of previously acquired motor skills</div></li><li class="half_rhythm"><div>Poor feeding</div></li><li class="half_rhythm"><div>Respiratory difficulties</div></li><li class="half_rhythm"><div>Encephalopathy</div></li><li class="half_rhythm"><div>Epilepsy</div></li><li class="half_rhythm"><div>Sensorineural hearing loss</div></li></ul><p><b>Juvenile/childhood onset (>2 years but <18 years).</b> Progressive generalized or proximal muscle weakness</p><p>
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<b>Adult/late onset (>18 years)</b>
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</p><ul><li class="half_rhythm"><div>Chronic progressive external ophthalmoplegia</div></li><li class="half_rhythm"><div>Mild proximal limb muscle weakness and progressive myopathy</div></li><li class="half_rhythm"><div>Slow progression to respiratory insufficiency</div></li><li class="half_rhythm"><div>Facial weakness including ptosis, dysphagia, and dysarthria</div></li></ul></div><div id="tk2-mtddepl.Supportive_Laboratory_Findin"><h4>Supportive Laboratory Findings</h4><p>Liver enzymes are elevated.</p><p>Serum creatine phosphokinase (CK) concentration is five to ten times the upper limit of normal.</p><p>Note: Serum CK concentration can be normal in affected individuals with severe muscle wasting.</p></div><div id="tk2-mtddepl.Electromyography"><h4>Electromyography</h4><p>Findings are nonspecific but suggestive of a myopathy.</p></div><div id="tk2-mtddepl.Skeletal_Muscle_Pathology"><h4>Skeletal Muscle Pathology</h4><p>Histopathologic findings include prominent variance in fiber size, sarcoplasmic vacuoles, and increased connective tissue.</p><p>Ragged red fibers are invariably present.</p><p>Succinate dehydrogenase (SDH) activity is increased and cytochrome <i>c</i> oxidase (COX) activity is low to absent.</p><p>Electron microscopy shows abnormal mitochondria with circular cristae [<a class="bk_pop" href="#tk2-mtddepl.REF.lesko.2010.198">Lesko et al 2010</a>].</p></div><div id="tk2-mtddepl.Mitochondrial_DNA_Content_co"><h4>Mitochondrial DNA Content (copy number) Analysis in Skeletal Muscle</h4><p>Content is severely reduced, usually from 5% to 30% of tissue- and age-matched controls.</p><p>Note: Mitochondrial DNA content ranging from 60% to normal has been reported in rare instances, especially in those with later-onset disease [<a class="bk_pop" href="#tk2-mtddepl.REF.vil_.2003.1203">Vilà et al 2003</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.leshinskysilver.2008.309">Leshinsky-Silver et al 2008</a>].</p><p>In addition to severe mtDNA depletion, multiple mtDNA deletions may be observed, particularly in those with the adult-onset form.</p></div><div id="tk2-mtddepl.Electron_Transport_Chain_Act"><h4>Electron Transport Chain Activity in Skeletal Muscle</h4><p>Activity of multiple complexes is decreased; complexes I, I+III, and IV are the most affected.</p></div></div><div id="tk2-mtddepl.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>TK2</i>-related mitochondrial DNA maintenance defect <b>is established</b> in:</p><ul><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with infantile onset of disease with:</div><ul><li class="half_rhythm"><div>Severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle; AND/OR</div></li><li class="half_rhythm"><div>Biallelic pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variants in <i>TK2</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK114628/table/tk2-mtddepl.T.molecular_genetic_testing/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTmoleculargenetictesting">Table 1</a>).</div></li></ul></li><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> older than age two years with:</div><ul><li class="half_rhythm"><div>Reduced mtDNA content or multiple mtDNA deletions, ragged red fibers, and/or COX-deficient fibers in skeletal muscle; AND/OR</div></li><li class="half_rhythm"><div>Biallelic pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variants in <i>TK2</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK114628/table/tk2-mtddepl.T.molecular_genetic_testing/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTmoleculargenetictesting">Table 1</a>).</div></li></ul></li></ul><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bk_pop" href="#tk2-mtddepl.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>TK2</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> (or of one known <i>TK2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and one <i>TK2</i> variant of uncertain significance) does not establish or rule out a diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (single-gene testing, concurrent or serial single-gene testing, <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/chromosomal-microarray/">chromosomal microarray</a> analysis, <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Because the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of <i>TK2</i>-related mitochondrial DNA maintenance defect is broad, individuals with the distinctive findings described in <a href="#tk2-mtddepl.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#tk2-mtddepl.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other mitochondrial myopathies are more likely to be diagnosed using genomic testing (see <a href="#tk2-mtddepl.Option_2">Option 2</a>).</p><div id="tk2-mtddepl.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of <i>TK2</i>-related mitochondrial DNA maintenance defect <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> or use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>TK2</i> detects small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-gene deletions/duplications are not detected. Perform <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> first. If only one or no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found perform gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect intragenic deletions or duplications.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>TK2</i> and other genes of interest (see <a href="#tk2-mtddepl.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> 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>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="tk2-mtddepl.Option_2"><h4>Option 2</h4><p>When the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> is indistinguishable from many other inherited disorders characterized by myopathy, <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (which does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>[s] are likely involved) is the best option. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="tk2-mtddepl.T.molecular_genetic_testing" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>TK2</i>-Related Mitochondrial DNA Maintenance Defect, Myopathic Form</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK114628/table/tk2-mtddepl.T.molecular_genetic_testing/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tk2-mtddepl.T.molecular_genetic_testing_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_tk2-mtddepl.T.molecular_genetic_testing_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_tk2-mtddepl.T.molecular_genetic_testing_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_tk2-mtddepl.T.molecular_genetic_testing_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_tk2-mtddepl.T.molecular_genetic_testing_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TK2</i>
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</td><td headers="hd_h_tk2-mtddepl.T.molecular_genetic_testing_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_tk2-mtddepl.T.molecular_genetic_testing_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>99%</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.molecular_genetic_testing_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>4</sup></td><td headers="hd_h_tk2-mtddepl.T.molecular_genetic_testing_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><1% <sup>5</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="tk2-mtddepl.TF.1.1"><p class="no_margin">See <a href="/books/NBK114628/#tk2-mtddepl.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="tk2-mtddepl.TF.1.2"><p class="no_margin">See <a href="#tk2-mtddepl.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="tk2-mtddepl.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="tk2-mtddepl.TF.1.4"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>5. </dt><dd><div id="tk2-mtddepl.TF.1.5"><p class="no_margin">One of approximately 107 affected individuals reported to date had a 5.8-kb <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> in <i>TK2</i> by using custom oligonucleotide-based array CGH [<a class="bk_pop" href="#tk2-mtddepl.REF.zhang.2010.53">Zhang et al 2010</a>]. The deletion extended from the 5' UTR to <a class="def" href="/books/n/gene/glossary/def-item/intron/">intron</a> 2 of <i>TK2</i>.</p></div></dd></dl></div></div></div></div></div></div><div id="tk2-mtddepl.Clinical_Characteristics"><h2 id="_tk2-mtddepl_Clinical_Characteristics_">Clinical Characteristics</h2><div id="tk2-mtddepl.Clinical_Description"><h3>Clinical Description</h3><p>To date, approximately 107 individuals with molecularly confirmed <i>TK2</i>-related mtDNA maintenance defect have been reported [<a class="bk_pop" href="#tk2-mtddepl.REF.pons.1996.153">Pons et al 1996</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.galbiati.2006.177">Galbiati et al 2006</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.oskoui.2006.1122">Oskoui et al 2006</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.blakely.2008.557">Blakely et al 2008</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.g_tz.2008.2841">Götz et al 2008</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.collins.2009.784">Collins et al 2009</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.lesko.2010.198">Lesko et al 2010</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.mart_.2010.151">Martí et al 2010</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.zhang.2010.53">Zhang et al 2010</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.b_hin.2012.644">Béhin et al 2012</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.garone.2018.515">Garone et al 2018</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.wang.2018.124">Wang et al 2018</a>].</p><p>The clinical presentation of <i>TK2</i>-related mtDNA maintenance defect is variable; as understanding of the disorder increases, the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> continues to broaden (<a href="/books/NBK114628/table/tk2-mtddepl.T.clinical_manifestations_of/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTclinicalmanifestationsof">Table 2</a>).</p><div id="tk2-mtddepl.T.clinical_manifestations_of" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Clinical Manifestations of <i>TK2</i>-Related Mitochondrial DNA Maintenance Defect</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK114628/table/tk2-mtddepl.T.clinical_manifestations_of/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tk2-mtddepl.T.clinical_manifestations_of_lrgtbl__"><table><thead><tr><th id="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Age of Onset</th><th id="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prevalence</th><th id="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation</th><th id="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_1" rowspan="10" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Age <2 years<br />(infantile onset)</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_2" rowspan="10" colspan="1" style="text-align:left;vertical-align:middle;">61/89 (69%)</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypotonia</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">55/57 (96%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Elevated serum CK</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">56/59 (95%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Respiratory difficulties</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">48/53 (91%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Loss of previously acquired motor skills</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">43/49 (88%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">mtDNA depletion</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">33/40 (83%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Hyporeflexia</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">31/39 (79%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Lactic acidemia</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">28/42 (67%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Motor developmental delay</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">18/49 (37%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Seizures</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">11/34 (32%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Cognitive impairment</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4/43 (9%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Age 2-18 years<br />(juvenile/<br />childhood onset)</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_2" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">14/89 (16%)</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Muscle weakness</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8/9 (89%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">mtDNA depletion</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">9/14 (64%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Respiratory failure</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7/12 (58%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Age >18 years<br />(adult onset)</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_2" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">14/89 (16%)</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysphagia</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5/5 (100%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">mtDNA multiple deletions</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4/4 (100%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Muscle weakness</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8/8 (100%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Ptosis</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7/7 (100%)</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Ragged red fibers</td><td headers="hd_h_tk2-mtddepl.T.clinical_manifestations_of_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8/8 (100%)</td></tr></tbody></table></div></div><p><b>Infantile onset (<2 years).</b> The prenatal and perinatal histories are usually unremarkable; onset is typically in the first two years of life.</p><ul><li class="half_rhythm"><div>Initial development is normal, followed by gradual onset of hypotonia:</div><ul><li class="half_rhythm"><div class="half_rhythm">A subset of affected individuals have early severe muscle weakness with encephalopathy and intractable epilepsy.</div></li><li class="half_rhythm"><div class="half_rhythm">Some affected individuals have elevated serum concentrations of aminotransferases and CK in the first year of life.</div><div class="half_rhythm">Note: The observed elevation in serum transaminases may reflect skeletal muscle involvement [<a class="bk_pop" href="#tk2-mtddepl.REF.zhang.2010.53">Zhang et al 2010</a>].</div></li></ul></li><li class="half_rhythm"><div>Subsequently generalized fatigue, decreased physical stamina, proximal muscle weakness (manifest as difficulty getting to standing or walking), and feeding difficulties develop.</div></li><li class="half_rhythm"><div>Muscle atrophy becomes evident [<a class="bk_pop" href="#tk2-mtddepl.REF.mart_.2010.151">Martí et al 2010</a>].</div></li><li class="half_rhythm"><div>Some children develop bulbar weakness including dysarthria and dysphagia. Previously acquired motor skills are lost.</div></li><li class="half_rhythm"><div>Sensorineural hearing loss develops.</div></li><li class="half_rhythm"><div>Cognitive function is typically spared.</div></li></ul><p>Muscle weakness rapidly progresses leading to respiratory failure and death within a few years after onset. Most children succumb to complications of respiratory muscle weakness; several are ventilator dependent before age six years. The most common cause of death is pulmonary infection.</p><p><b>Juvenile-/childhood-onset (ages 2-18 years)</b> disease is characterized by distinct disease progression:</p><ul><li class="half_rhythm"><div>Moderate-to-severe progression of generalized weakness</div><ul><li class="half_rhythm"><div>The severity of muscle weakness can vary widely among affected individuals.</div></li><li class="half_rhythm"><div>In its mildest form, affected individuals may report myalgia and muscle weakness; in severe cases muscle weakness can progress to the point that ventilator assistance is required.</div></li></ul></li><li class="half_rhythm"><div>Survival to at least age 13 years, with respiratory failure as the primary cause of death</div></li></ul><p><b>Adult-onset (>18 years)</b> disease is characterized by:</p><ul><li class="half_rhythm"><div>Mild proximal limb muscle weakness due to progressive mitochondrial myopathy;</div></li><li class="half_rhythm"><div>Slow progression to respiratory failure in some affected individuals;</div></li><li class="half_rhythm"><div>Involvement of the facial and extraocular muscles with manifestations including chronic progressive external ophthalmoplegia, ptosis, dysphagia, and dysarthria.</div></li></ul></div><div id="tk2-mtddepl.GenotypePhenotype_Correlatio"><h3>Genotype-Phenotype Correlations</h3><p>It is possible that the range of phenotypes observed may be explained by the variability in the amount of residual activity of mutated enzymes [<a class="bk_pop" href="#tk2-mtddepl.REF.poulton.2009.1109">Poulton et al 2009</a>].</p><p>The small number of individuals reported to date precludes identification of <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a>; however, the following have been observed:</p><ul><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTtk2pathogenicvariantsdi">p.Arg130Trp</a> appears to be associated with the most severe <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>, with CNS involvement (i.e., seizures and loss of previously acquired motor skills) during the first months of life [<a class="bk_pop" href="#tk2-mtddepl.REF.lesko.2010.198">Lesko et al 2010</a>].</div></li><li class="half_rhythm"><div>Homozygosity for <a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTtk2pathogenicvariantsdi">p.Arg183Trp</a> is associated with myopathy and severe mtDNA depletion restricted to skeletal muscle [<a class="bk_pop" href="#tk2-mtddepl.REF.g_tz.2008.2841">Götz et al 2008</a>].</div></li><li class="half_rhythm"><div>Homozygosity for <a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTtk2pathogenicvariantsdi">p.Lys202del</a> has only been found in individuals with adult-onset <i>TK2</i>-related mtDNA maintenance defect [<a class="bk_pop" href="#tk2-mtddepl.REF.wang.2018.124">Wang et al 2018</a>].</div></li><li class="half_rhythm"><div>When the <a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTtk2pathogenicvariantsdi">p.Arg192Lys</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found <i>in trans</i> with other variants (<a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTtk2pathogenicvariantsdi">p.Thr108Met</a> and <a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTtk2pathogenicvariantsdi">p.Lys202del</a>), childhood onset of symptoms with prolonged survival is typical [<a class="bk_pop" href="#tk2-mtddepl.REF.wang.2018.124">Wang et al 2018</a>].</div></li></ul></div><div id="tk2-mtddepl.Prevalence"><h3>Prevalence</h3><p>The prevalence of <i>TK2</i>-related mtDNA maintenance defect is unknown; the disorder appears to be rare, with only approximately 107 affected individuals reported to date.</p></div></div><div id="tk2-mtddepl.Genetically_Related_Allelic"><h2 id="_tk2-mtddepl_Genetically_Related_Allelic_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>TK2</i>.</p></div><div id="tk2-mtddepl.Differential_Diagnosis"><h2 id="_tk2-mtddepl_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Myopathic form</b> of <i>TK2</i>-related mtDNA maintenance defect needs to be differentiated from other mtDNA maintenance defects that present with myopathy (summarized in <a href="/books/NBK114628/table/tk2-mtddepl.T.mitochondrial_dna_maintena/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTmitochondrialdnamaintena">Table 3</a>). Myopathic mtDNA maintenance defects include a group of diseases that vary in their age of onset. Skeletal muscles are the main system involved in all of them. Cardiomyopathy can occur in some of these disorders (see <a href="/books/n/gene/mtdna-md-ov/">Mitochondrial DNA Maintenance Defects Overview</a>).</p><div id="tk2-mtddepl.T.mitochondrial_dna_maintena" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Mitochondrial DNA Maintenance Defects Presenting with Myopathy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK114628/table/tk2-mtddepl.T.mitochondrial_dna_maintena/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tk2-mtddepl.T.mitochondrial_dna_maintena_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">mtDNA<br />Maintenance<br />Defect</th><th id="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Usual Age<br />of Onset</th><th id="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_6" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common Clinical Manifestations<br />in Addition to Muscle Weakness</th></tr></thead><tbody><tr><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TK2</i>
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</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>TK2</i>-related mtDNA maintenance defect, myopathic form (this <i>GeneReview</i>)</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Depletion</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infancy or<br />childhood</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Loss of acquired motor skills</div></li></ul>
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</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>AGK</i>
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</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sengers syndrome (OMIM <a href="https://www.omim.org/entry/212350" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">212350</a>)</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Depletion</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neonatal period</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Hypertrophic cardiomyopathy</div></li><li class="half_rhythm"><div>Cataracts</div></li></ul>
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</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>DGUOK</i>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/dguok-mtddepl/">Myopathy</a>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple deletions</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Early or mid-<br />adulthood</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ptosis</div></li><li class="half_rhythm"><div>Ophthalmoplegia</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>DNA2</i>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Myopathy (OMIM <a href="https://omim.org/entry/615156" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615156</a>)</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple deletions</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood or<br />early adulthood</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ptosis</div></li><li class="half_rhythm"><div>Ophthalmoplegia</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>MGME1</i>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Myopathy (OMIM <a href="https://www.omim.org/entry/615084" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615084</a>)</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Depletion & multiple deletions</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood or<br />early adulthood</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ptosis</div></li><li class="half_rhythm"><div>Ophthalmoplegia</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>POLG2</i>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Myopathy (OMIM <a href="https://omim.org/entry/610131" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">610131</a>)</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple deletions</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infancy to<br />adulthood</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ptosis</div></li><li class="half_rhythm"><div>Ophthalmoplegia</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC25A4</i>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy (OMIM <a href="https://omim.org/entry/615418" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615418</a>)</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple deletions</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Exercise intolerance / easy fatigability</div></li><li class="half_rhythm"><div>Hypertrophic cardiomyopathy</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy (OMIM <a href="https://www.omim.org/entry/617184" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">617184</a>)</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Depletion</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Birth</td><td headers="hd_h_tk2-mtddepl.T.mitochondrial_dna_maintena_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Hypertrophic cardiomyopathy</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd></dl></div></div></div><p>In additional to other myopathic mtDNA maintenance defects, the differential diagnosis of <i>TK2</i>-related mtDNA maintenance defect includes the following disorders that cause hypotonia and progressive proximal muscle weakness:</p><ul><li class="half_rhythm"><div><a href="/books/n/gene/pws/"><b>Prader-Willi syndrome</b></a>
|
||
<b>(PWS)</b> is characterized by severe hypotonia and feeding difficulties in early infancy followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. PWS is caused by an absence of expression of <a class="def" href="/books/n/gene/glossary/def-item/imprinted/">imprinted</a> genes in the paternally derived PWS/Angelman syndrome (AS) region of <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 15 by one of several genetic mechanisms.</div></li><li class="half_rhythm"><div><a href="/books/n/gene/sma/"><b>Spinal muscular atrophy</b></a>
|
||
<b>(SMA)</b> is an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorder characterized by muscle weakness and atrophy resulting from progressive degeneration and loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. Affected individuals typically develop severe and progressive muscle weakness involving respiratory muscles. The age of onset of weakness ranges from before birth to adolescence or young adulthood. The diagnosis of SMA is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with a history of motor difficulties, evidence of motor unit disease on physical examination, and identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>SMN1</i> on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</div></li><li class="half_rhythm"><div><b>Congenital myopathies</b> including central core disease (OMIM <a href="https://omim.org/entry/117000" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">117000</a>), <a href="/books/n/gene/mtm/">centronuclear myopathy</a>, <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> myotubular myopathy (a subtype of <a href="/books/n/gene/mtm/">centronuclear myopathy</a>), and nemaline myopathy (OMIM <a href="https://omim.org/phenotypicSeries/PS161800" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS161800</a>) typically have normal or near-normal serum CK concentration and histologic evidence on muscle biopsy of developmental/structural muscle changes rather than dystrophic changes. The diagnosis is suggested by muscle biopsy and often can be confirmed by the results of <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</div></li><li class="half_rhythm"><div><a href="/books/n/gene/gsd2/"><b>Pompe disease</b></a> is characterized by progressive proximal muscle weakness early in the first few months of life accompanied with hypertrophic cardiomyopathy. The diagnosis is based on complete deficiency of activity of the enzyme lysosomal alpha-glucosidase (GAA) (also called acid maltase) or detection of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>GAA</i> pathogenic variants.</div></li></ul></div><div id="tk2-mtddepl.Management"><h2 id="_tk2-mtddepl_Management_">Management</h2><div id="tk2-mtddepl.Evaluations_Following_Initia"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs of an individual diagnosed with <i>TK2</i>-related mitochondrial DNA maintenance defect, myopathic form, the following evaluations are recommended, if not completed as part of the diagnostic evaluation.</p><div id="tk2-mtddepl.T.recommended_evaluations_fo" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>TK2</i>-Related mtDNA Maintenance Defect</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK114628/table/tk2-mtddepl.T.recommended_evaluations_fo/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tk2-mtddepl.T.recommended_evaluations_fo_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_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_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Growth/feeding</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of chewing & swallowing ability</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to OT / feeding therapist &/or gastroenterologist.</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Ears</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiology eval</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for sensorineural hearing loss</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Pulmonary</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pulmonary function eval</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to pulmonologist.</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic exam</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to neurologist.</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">EEG</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_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_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to PT &/or developmental pediatrician.</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Other</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_tk2-mtddepl.T.recommended_evaluations_fo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">OT = occupational therapist; PT = physical therapist</p></div></dd></dl></div></div></div></div><div id="tk2-mtddepl.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment is primarily supportive; management should involve a multidisciplinary team.</p><div id="tk2-mtddepl.T.treatment_of_manifestation" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with <i>TK2</i>-Related mtDNA Maintenance Defect</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK114628/table/tk2-mtddepl.T.treatment_of_manifestation/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tk2-mtddepl.T.treatment_of_manifestation_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_tk2-mtddepl.T.treatment_of_manifestation_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_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Feeding difficulties</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Placement of nasogastric or gastrostomy tube</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If risk of aspiration is high</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hearing loss</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="/books/n/gene/deafness-overview/">Hereditary Hearing Loss and Deafness Overview</a>.</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Decreased pulmonary function</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Chest physiotherapy <sup>1</sup></td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to pulmonologist.</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory failure</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ventilator assistance may be considered.</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Pulmonary infection</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To prevent deterioration in pulmonary function capacity</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Muscle weakness /</b>
|
||
<br />
|
||
<b>Restricted mobility</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical therapy</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to physical medicine & rehabilitation specialist.</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Wheelchair may be necessary as disease progresses.</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Seizures</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per neurologist</td><td headers="hd_h_tk2-mtddepl.T.treatment_of_manifestation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Education regarding common seizure presentations is appropriate <sup>2</sup>.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="tk2-mtddepl.TF.5.1"><p class="no_margin">Chest physiotherapy may improve pulmonary function and reduce the risk of pulmonary infection.</p></div></dd><dt>2. </dt><dd><div id="tk2-mtddepl.TF.5.2"><p class="no_margin">For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see <a href="https://www.epilepsy.com/tools-resources/forms-resources#Epilepsy-Foundation-Toolbox" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Epilepsy Foundation Toolbox</a>.</p></div></dd></dl></div></div></div><p>The following information represents typical management recommendations for individuals with developmental concerns in the United States; standard recommendations may vary from country to country.</p><div id="tk2-mtddepl.Developmental_Concerns__Educ"><h4>Developmental Concerns / Educational Issues</h4><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.</p><p>
|
||
<b>Ages 5-21 years</b>
|
||
</p><ul><li class="half_rhythm"><div>In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.</div></li><li class="half_rhythm"><div>Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.</div></li></ul><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.</p><p>Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</p><p>In the US:</p><ul><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="tk2-mtddepl.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
|
||
<b>Gross motor dysfunction</b>
|
||
</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility.</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Oral motor dysfunction.</b> Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for affected individuals who have difficulty feeding as a result of poor oral motor control.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="https://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">augmentative and alternative communication</a> [AAC]) for individuals who have significant dysarthria.</p></div></div><div id="tk2-mtddepl.Prevention_of_Secondary_Comp"><h3>Prevention of Secondary Complications</h3><p>Chest physiotherapy can help reduce the risk of pulmonary infection (see <a href="#tk2-mtddepl.Treatment_of_Manifestations">Treatment of Manifestations</a>).</p><p>Physical therapy can help maintain muscle function and prevent joint contractures (see <a href="#tk2-mtddepl.Treatment_of_Manifestations">Treatment of Manifestations</a>).</p></div><div id="tk2-mtddepl.Surveillance"><h3>Surveillance</h3><p>No disease-specific clinical guidelines are available; treating physicians should consider the evaluations included in <a href="/books/NBK114628/table/tk2-mtddepl.T.recommended_surveillance_f/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTrecommendedsurveillancef">Table 6</a>.</p><div id="tk2-mtddepl.T.recommended_surveillance_f" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with <i>TK2</i>-Related mtDNA Maintenance Defect</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK114628/table/tk2-mtddepl.T.recommended_surveillance_f/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tk2-mtddepl.T.recommended_surveillance_f_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_tk2-mtddepl.T.recommended_surveillance_f_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_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Growth/Feeding</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of nutritional status</td><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Routine</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assessment of weight gain & growth parameters</td><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit <sup>1</sup></td></tr><tr><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Ears</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiology evaluation <sup>2</sup></td><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually or if concerns arise</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Pulmonary</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pulmonary function tests <sup>3</sup></td><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Depending on clinical severity</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Assessment of blood gases <sup>4</sup></td></tr><tr><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurodevelopmental assessments <sup>5</sup></td><td headers="hd_h_tk2-mtddepl.T.recommended_surveillance_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="tk2-mtddepl.TF.6.1"><p class="no_margin">Particularly in infancy, childhood, and adolescence; for adults, monitor for persistent weight loss, which may indicate inadequate nutrition.</p></div></dd><dt>2. </dt><dd><div id="tk2-mtddepl.TF.6.2"><p class="no_margin">In those with infantile-onset disease</p></div></dd><dt>3. </dt><dd><div id="tk2-mtddepl.TF.6.3"><p class="no_margin">For those who are able to cooperate</p></div></dd><dt>4. </dt><dd><div id="tk2-mtddepl.TF.6.4"><p class="no_margin">To evaluate for respiratory insufficiency (alveolar hypoventilation and chronic hypercapnia)</p></div></dd><dt>5. </dt><dd><div id="tk2-mtddepl.TF.6.5"><p class="no_margin">Consider periodic speech/language evaluation by a developmental pediatrician or pediatric neurologist.</p></div></dd></dl></div></div></div></div><div id="tk2-mtddepl.Evaluation_of_Relatives_at_R"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#tk2-mtddepl.Related_Genetic_Counseling_I">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="tk2-mtddepl.Therapies_Under_Investigatio"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="tk2-mtddepl.Genetic_Counseling"><h2 id="_tk2-mtddepl_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="tk2-mtddepl.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>TK2</i>-related mtDNA maintenance defect, myopathic form is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="tk2-mtddepl.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected child are obligate heterozygotes (i.e., carriers of one <i>TK2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>).</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
|
||
<b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
|
||
<b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Most individuals with <i>TK2</i>-related mtDNA maintenance defect, myopathic form have early-onset severe disease and do not survive to reproduce.</div></li><li class="half_rhythm"><div>If individuals with less severe manifestations of a<i>TK2</i>-related mtDNA maintenance defect reproduce, their offspring are obligate heterozygotes for a <i>TK2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li></ul><p><b>Other family members.</b> Each sib of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents is at a 50% risk of being a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> of a <i>TK2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="tk2-mtddepl.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk family members requires prior identification of the <i>TK2</i> pathogenic variants in the family.</p></div><div id="tk2-mtddepl.Related_Genetic_Counseling_I"><h3>Related Genetic Counseling Issues</h3><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk, clarification of <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> status, and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bk_pop" href="#tk2-mtddepl.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="tk2-mtddepl.Prenatal_Testing_and_Preimpl"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>TK2</i> pathogenic variants have been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="tk2-mtddepl.Resources"><h2 id="_tk2-mtddepl_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>The Charlie Gard Foundation</b>
|
||
</div><div>United Kingdom</div><div><b>Email:</b> hello@thecharliegardfoundation.org</div><div>
|
||
<a href="https://www.thecharliegardfoundation.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.thecharliegardfoundation.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>United Mitochondrial Disease Foundation</b>
|
||
</div><div><b>Phone:</b> 888-317-UMDF (8633)</div><div><b>Email:</b> info@umdf.org</div><div>
|
||
<a href="https://www.umdf.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">umdf.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium</b>
|
||
</div><div>
|
||
<a href="https://www.rarediseasesnetwork.org/cms/namdc" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Patient Contact Registry</a>
|
||
</div></li></ul>
|
||
</div><div id="tk2-mtddepl.Molecular_Genetics"><h2 id="_tk2-mtddepl_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 id="tk2-mtddepl.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK114628/table/tk2-mtddepl.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tk2-mtddepl.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_tk2-mtddepl.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_tk2-mtddepl.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_tk2-mtddepl.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_tk2-mtddepl.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_tk2-mtddepl.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_tk2-mtddepl.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_tk2-mtddepl.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/7084" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>TK2</i>
|
||
</a>
|
||
</td><td headers="hd_b_tk2-mtddepl.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=7084" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">16q21</a>
|
||
</td><td headers="hd_b_tk2-mtddepl.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/O00142" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Thymidine kinase 2, mitochondrial</a>
|
||
</td><td headers="hd_b_tk2-mtddepl.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/TK2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TK2 homepage</a>
|
||
</td><td headers="hd_b_tk2-mtddepl.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=TK2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TK2</a>
|
||
</td><td headers="hd_b_tk2-mtddepl.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=TK2[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TK2</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="tk2-mtddepl.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="tk2-mtddepl.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form (<a href="/omim/188250,609560" 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/NBK114628/table/tk2-mtddepl.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tk2-mtddepl.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/188250" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">188250</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THYMIDINE KINASE, MITOCHONDRIAL; TK2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/609560" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">609560</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE); MTDPS2</td></tr></tbody></table></div></div><div id="tk2-mtddepl.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>Mitochondrial DNA (mtDNA) maintenance defect is characterized by a significant reduction in the number of copies of mtDNA in one or more tissues. <i>TK2</i>, encoding thymidine kinase 2 (which mediates the first and rate-limiting step in the phosphorylation of deoxypyrimidine nucleosides in the mitochondrial matrix), was the first <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> to be associated with the myopathic form of mtDNA maintenance defect. To date, <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>TK2</i> account for approximately 20% of myopathic mtDNA maintenance defect [<a class="bk_pop" href="#tk2-mtddepl.REF.mart_.2010.151">Martí et al 2010</a>].</p><p><b>Gene structure.</b>
|
||
<i>TK2</i> comprises ten coding exons. Alternate <a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a> results in multiple transcript variants (see <a href="/books/NBK114628/#tk2-mtddepl.molgen.TA">Table A</a>, <b>Gene</b>). The longest transcript variant is <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_004614.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_004614.4</a>.</p><p><b>Pathogenic variants.</b> To date, more than 30 different <i>TK2</i> pathogenic variants have been reported in persons with myopathic mtDNA depletion (<a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTtk2pathogenicvariantsdi">Table 7</a>) [<a class="bk_pop" href="#tk2-mtddepl.REF.pons.1996.153">Pons et al 1996</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.galbiati.2006.177">Galbiati et al 2006</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.oskoui.2006.1122">Oskoui et al 2006</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.blakely.2008.557">Blakely et al 2008</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.g_tz.2008.2841">Götz et al 2008</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.collins.2009.784">Collins et al 2009</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.lesko.2010.198">Lesko et al 2010</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.mart_.2010.151">Martí et al 2010</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.zhang.2010.53">Zhang et al 2010</a>, <a class="bk_pop" href="#tk2-mtddepl.REF.b_hin.2012.644">Béhin et al 2012</a>].</p><p>About 70% of reported pathogenic variants are <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>; the remainder include <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants and small (1- to 4-nucleotide) deletions and insertions.</p><p>A gross <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> spanning 5.8 kb [<a class="bk_pop" href="#tk2-mtddepl.REF.zhang.2010.53">Zhang et al 2010</a>] and a complex rearrangement (<a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTtk2pathogenicvariantsdi">Table 7</a>) have also been reported.</p><p>All pathogenic variants are <a class="def" href="/books/n/gene/glossary/def-item/private/">private</a> except for the two variants <a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTtk2pathogenicvariantsdi">p.Arg130Trp</a> and <a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTtk2pathogenicvariantsdi">p.Arg183Trp</a>, observed in affected individuals from Finland (<a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object" rid-ob="figobtk2mtddeplTtk2pathogenicvariantsdi">Table 7</a>) – most likely founder variants in the Finnish population [<a class="bk_pop" href="#tk2-mtddepl.REF.g_tz.2008.2841">Götz et al 2008</a>].</p><div id="tk2-mtddepl.T.tk2_pathogenic_variants_di" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p><i>TK2</i> Pathogenic Variants Discussed in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK114628/table/tk2-mtddepl.T.tk2_pathogenic_variants_di/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__tk2-mtddepl.T.tk2_pathogenic_variants_di_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th></tr></thead><tbody><tr><td headers="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.323C>T</td><td headers="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr108Met</td><td headers="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_3" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_004614.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_004614<wbr style="display:inline-block"></wbr>.4</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_004605.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_004605<wbr style="display:inline-block"></wbr>.4</a>
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</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.388C>T</td><td headers="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg130Trp</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.547C>T</td><td headers="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg183Trp</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.575G>A</td><td headers="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg192Lys</td></tr><tr><td headers="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.604_606delAAG</td><td headers="hd_h_tk2-mtddepl.T.tk2_pathogenic_variants_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Lys202del</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><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><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></div></div></div><p><b>Normal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> The TK2 isoform is 265 amino acids. <i>TK2</i> encodes thymidine kinase 2, the first and rate-limiting step in phosphorylation of deoxypyrimidine nucleosides (salvage pathway) in the mitochondrial matrix.</p><p>Deoxynucloside triphosphate (dNTPs) can be synthesized via either the <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> pathway which is cell-cycle regulated or via the salvage pathway in which dNTPs are produced by utilizing preexisting deoxynucleosides to synthesize DNA precursors. Both pathways may be required for mtDNA maintenance in postmitotic tissues. Since mtDNA synthesis is continuous throughout the cell cycle, thymidine kinase 2 becomes indispensable for mtDNA maintenance.</p><p><b>Abnormal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b>
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<i>TK2</i> pathogenic variants result in dysfunction of the enzyme thymidine kinase 2 resulting in impaired synthesis of mtDNA precursors leading to mtDNA depletion.</p></div></div><div id="tk2-mtddepl.Chapter_Notes"><h2 id="_tk2-mtddepl_Chapter_Notes_">Chapter Notes</h2><div id="tk2-mtddepl.Author_History"><h3>Author History</h3><p>Sirisak Chanprasert, MD; Baylor College of Medicine (2012-2018)<br />Ayman W El-Hattab, MD, FAAP, FACMG (2018-present)<br />Fernando Scaglia, MD, FACMG; Baylor College of Medicine (2012-2018)<br />Jing Wang, MD; Baylor College of Medicine (2012-2018)<br />Julia Wang, BS (2018-present)<br />Lee-Jun C Wong, PhD, FACMG (2012-present)</p></div><div id="tk2-mtddepl.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>26 July 2018 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>6 December 2012 (me) Review posted live</div></li><li class="half_rhythm"><div>23 August 2012 (fs) Original submission</div></li></ul></div></div><div id="tk2-mtddepl.References"><h2 id="_tk2-mtddepl_References_">References</h2><div id="tk2-mtddepl.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.b_hin.2012.644">Béhin A, Jardel C, Claeys KG, Fagart J, Louha M, Romero NB, Laforet P, Eymard B, Lombes A. Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum. <span><span class="ref-journal">Neurology. </span>2012;<span class="ref-vol">78</span>:644–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22345218" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22345218</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.blakely.2008.557">Blakely E, He L, Gardner JL, Hudson G, Walter J, Hughes I, Turnbull DM, Taylor RW. Novel mutationin the TK2 gene associated with fatal mitochondrial DNA depletion myopathy. <span><span class="ref-journal">Neuromuscul Disord. </span>2008;<span class="ref-vol">18</span>:557–60.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18508266" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18508266</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.collins.2009.784">Collins J, Bove KE, Dimmock D, Morehart P, Wong LJ, Wong B. Progressive myofiber loss with extensive fibro-fatty replacement in a child with mitochondrial DNA depletion syndrome and novel thymidine kinase 2 gene mutations. <span><span class="ref-journal">Neuromuscul Disord. </span>2009;<span class="ref-vol">19</span>:784–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19736010" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19736010</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.galbiati.2006.177">Galbiati S, Bordoni A, Papadimitriou D, Toscano A, Rodolico C, Katsarou E, Sciacco M, Garufi A, Prelle A, Aguennouz M, Bonsignore M, Crimi M, Martinussi A, Bresolin N, Papadimitriou A, Comi GP. New mutation in TK2 gene associated with mitochondrial DNA depletion. <span><span class="ref-journal">Pediatr Neurol. </span>2006;<span class="ref-vol">34</span>:177–85.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16504786" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16504786</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.garone.2018.515">Garone C, Taylor RW, Nascimento A, Poulton J, Fratter C, Domínguez-González C, Evans JC, Loos M, Isohanni P, Suomalainen A, Ram D, Hughes MI, McFarland R, Barca E, Lopez Gomez C, Jayawant S, Thomas ND, Manzur AY, Kleinsteuber K, Martin MA, Kerr T, Gorman GS, Sommerville EW, Chinnery PF, Hofer M, Karch C, Ralph J, Cámara Y, Madruga-Garrido M, Domínguez-Carral J, Ortez C, Emperador S, Montoya J, Chakrapani A, Kriger JF, Schoenaker R, Levin B, Thompson JLP, Long Y, Rahman S, Donati MA, DiMauro S, Hirano M. Retrospective natural history of thymidine kinase 2 deficiency. <span><span class="ref-journal">J Med Genet. </span>2018;<span class="ref-vol">55</span>:515–21.</span> [<a href="/pmc/articles/PMC6073909/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6073909</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29602790" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29602790</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.g_tz.2008.2841">Götz A, Isohanni P, Pihko H, Paetau A, Herva R, Saarenpää-Heikkilä O, Valanne L, Marjavaara S, Suomalainen A. Thymidine kinase 3 defects can cause multi-tissue mtDNA depletion syndrome. <span><span class="ref-journal">Brain. </span>2008;<span class="ref-vol">131</span>:2841–50.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18819985" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18819985</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.huang.2022.389">Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. <span><span class="ref-journal">J Community Genet. </span>2022;<span class="ref-vol">13</span>:389–97.</span> [<a href="/pmc/articles/PMC9314484/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9314484</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35834113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35834113</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.leshinskysilver.2008.309">Leshinsky-Silver E, Michelson M, Cohen S, Ginsberg M, Sadeh M, Barash V, Lerman-Sagie T, Lev D. A defect in thymidine kinase 2 gene causing isolated mitochondrial myopathy without mtDNA depletion. <span><span class="ref-journal">Eur J Paediatr Neurol. </span>2008;<span class="ref-vol">12</span>:309–13.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17951082" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17951082</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.lesko.2010.198">Lesko N, Naess K, Wibom R, Solaroli N, Nennesmo I, von Dobeln U, Karlsson A, Larsson NG. Two novel mutations in thymidine kinase-2 cause early onset fatal encephalomyopathy and severe mtDNA depletion. <span><span class="ref-journal">Neuromuscul Disord. </span>2010;<span class="ref-vol">20</span>:198–203.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20083405" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20083405</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.mart_.2010.151">Martí R, Nascimento A, Colomer J, Lara MC, Lopez-gallardo E, Ruiz-Pesini E, Montaya J, Andreu AL, Briones P, Pineda M. Hearing loss in a patient with the myopathic form of mitochondrial DNA depletion syndrome and novel mutation in the TK2 gene. <span><span class="ref-journal">Pediatr Res. </span>2010;<span class="ref-vol">68</span>:151–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20421844" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20421844</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.oskoui.2006.1122">Oskoui M, Davidzon G, Pascual J, Erazo R, Gurgel-Giannetti J, Krishna S, Bonilla E, De Vivo DC, Shanske S, Dimauro S. Clinical spectrum of mitochondrial DNA depletion due to mutation in the thymidine kinase 2 gene. <span><span class="ref-journal">Arch Neurol. </span>2006;<span class="ref-vol">63</span>:1122–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16908738" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16908738</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.pons.1996.153">Pons R, Andreetta F, Wang CH, Vu TH, Bonilla E, DiMauro S, De Vivo DC. Mitochondrial myopathy simulating spinal muscular atrophy. <span><span class="ref-journal">Pediatr Neurol. </span>1996;<span class="ref-vol">15</span>:153–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8888051" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8888051</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.poulton.2009.1109">Poulton J, Hirano M, Spinazzola A, Arenas Hernandez M, Jardel C, Lombès A, Czermin B, Horvath R, Taanman JW, Rotig A, Zeviani M, Fratter C. Collated mutations in mitochondrial DNA (mtDNA) depletion syndrome (excluding the mitochondrial gamma polymerase, POLG1). <span><span class="ref-journal">Biochim Biophys Acta. </span>2009;<span class="ref-vol">1792</span>:1109–12.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19748572" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19748572</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.richards.2015.405">Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. <span><span class="ref-journal">Genet Med. </span>2015;<span class="ref-vol">17</span>:405–24.</span> [<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.vil_.2003.1203">Vilà MR, Segovia-Silvestre T, Gámez J, Marina A, Naini AB, Meseguer A, Lombès A, Bonilla E, DiMauro S, Hirano M, Andreu AL. Reversion of mtDNA depletion in a patient with TK2 deficiency. <span><span class="ref-journal">Neurology. </span>2003;<span class="ref-vol">60</span>:1203–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12682338" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12682338</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.wang.2018.124">Wang J, Kim E, Dai H, Stefans V, Vogel H, Al Jasmi F, Vergano SA, Castro D, Bernes S, Bhambhani V, Long C. Spectrum of clinical and molecular aspects of thymidine kinase 2-related mtDNA maintenance defect. <span><span class="ref-journal">Mol Genet Metab. </span>2018;<span class="ref-vol">124</span>:124–30.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/29735374" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29735374</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="tk2-mtddepl.REF.zhang.2010.53">Zhang S, Li FY, Bass HN, Pursley A, Schmitt ES, Brown BL, Brundage EK, Mardach R, Wong LJ. Application of oligonucleotide array CGH to the simultaneous detection of a deletion in the nuclear TK2 gene and mtDNA depletion. <span><span class="ref-journal">Mol Genet Metab. </span>2010;<span class="ref-vol">99</span>:53–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19815440" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19815440</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div><div class="small"><span class="label">Bookshelf ID: NBK114628</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/23230576" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">23230576</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/thoc6-id/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/traps/" title="Next page in this title">Next ></a></div></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK114628/?report=reader">PubReader</a></li><li><a href="/books/NBK114628/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK114628" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK114628" style="display:none" title="Cite this Page"><div class="bk_tt">Wang J, El-Hattab AW, Wong LJC. TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form. 2012 Dec 6 [Updated 2018 Jul 26]. 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></div></div></li><li><a href="/books/NBK114628/pdf/Bookshelf_NBK114628.pdf">PDF version of this page</a> (506K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#tk2-mtddepl.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#tk2-mtddepl.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#tk2-mtddepl.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#tk2-mtddepl.Genetically_Related_Allelic" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#tk2-mtddepl.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#tk2-mtddepl.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#tk2-mtddepl.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#tk2-mtddepl.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#tk2-mtddepl.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#tk2-mtddepl.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#tk2-mtddepl.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=7084[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">TK2</a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=NBK114628+AND+genereviews[submitter]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri">Variations from this GeneReview in ClinVar</a>
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</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=2993968" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=2993968" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=2993968" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=2993968" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301382" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Single Large-Scale Mitochondrial DNA Deletion Syndromes.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Single Large-Scale Mitochondrial DNA Deletion Syndromes.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Goldstein A, Falk MJ. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301510" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Dietz H. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301656" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Hershfield M, Tarrant T. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/25032271" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Dihydrolipoamide Dehydrogenase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Dihydrolipoamide Dehydrogenase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Quinonez SC, Thoene JG. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301631" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Citrullinemia Type I.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Citrullinemia Type I.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Quinonez SC, Lee KN. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=23230576" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=23230576" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent 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