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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2024/04/25">
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<meta name="citation_author" content="Charles K Abrams">
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<meta name="citation_keywords" content="CMTX1">
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<meta name="citation_keywords" content="Gap junction beta-1 protein">
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<meta name="citation_keywords" content="GJB1">
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<meta name="citation_keywords" content="GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes">
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<meta name="description" content="GJB1 disorders are typically characterized by peripheral motor and sensory neuropathy with or without fixed CNS abnormalities and/or acute, self-limited episodes of transient neurologic dysfunction (especially weakness and dysarthria). Peripheral neuropathy typically manifests in affected males between ages five and 25 years. Although both men and women are affected, manifestations tend to be less severe in women, some of whom may remain asymptomatic.">
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<meta name="og:description" content="GJB1 disorders are typically characterized by peripheral motor and sensory neuropathy with or without fixed CNS abnormalities and/or acute, self-limited episodes of transient neurologic dysfunction (especially weakness and dysarthria). Peripheral neuropathy typically manifests in affected males between ages five and 25 years. Although both men and women are affected, manifestations tend to be less severe in women, some of whom may remain asymptomatic.">
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class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1374_"><span class="title" itemprop="name"><i>GJB1</i> Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes</span></h1><p class="contribs">Abrams CK.</p><p class="fm-aai"><a href="#_NBK1374_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 35 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="cmtx.Summary" itemprop="description"><h2 id="_cmtx_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>GJB1</i> disorders are typically characterized by peripheral motor and sensory neuropathy with or without fixed CNS abnormalities and/or acute, self-limited episodes of transient neurologic dysfunction (especially weakness and dysarthria). Peripheral neuropathy typically manifests in affected males between ages five and 25 years. Although both men and women are affected, manifestations tend to be less severe in women, some of whom may remain asymptomatic.</p><p>Less commonly, initial manifestations in some affected individuals are stroke-like episodes (acute fulminant episodes of reversible CNS dysfunction).</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of CMT1X is established in a male by identification of a hemizygous <i>GJB1</i> pathogenic variant on molecular genetic testing and in a female by identification of a heterozygous <i>GJB1</i> pathogenic variant.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Treatment by a multidisciplinary team includes special shoes and/or ankle/foot orthoses to correct foot drop and to aid walking; surgery as needed for severe <i>pes cavus</i>; forearm crutches, canes, wheelchairs as needed for mobility; daily heel cord stretching to prevent Achilles' tendon shortening; exercise as tolerated. Treatment of stroke-like episodes is supportive, as these are self-limited.</p><p><i>Surveillance:</i> Yearly examinations by: a neurologist of motor function and pain; a physical therapist of gross motor skills and activities of daily living (ADL), an occupational therapist of fine motor skills and ADL; a foot care specialist for pressure sores and/or poorly fitting footwear. More frequent self-foot examination by the affected individual.</p><p><i>Agents/circumstances to avoid:</i> Obesity (makes ambulation more difficult); medications that are toxic or potentially toxic to persons with CMT.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>CMT1X is inherited in an X-linked manner. Affected males transmit the <i>GJB1</i> pathogenic variant to all of their daughters and none of their sons. Women with a <i>GJB1</i> pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may have mild-to-no manifestations or, more often, mild-to-moderate manifestations that may progress. Once the <i>GJB1</i> pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk female relatives to determine their genetic status, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.</p></div></div><div id="cmtx.Diagnosis"><h2 id="_cmtx_Diagnosis_">Diagnosis</h2><div id="cmtx.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>GJB1</i> Charcot-Marie-Tooth neuropathy with or without central nervous system dysfunction (CMT1X) <b>should be suspected</b> in an individual with the following clinical findings, electrophysiologic findings, and family history.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div><b>Peripheral motor and sensory neuropathy</b> with or without the following:</div><ul><li class="half_rhythm"><div>Occasionally fixed CNS abnormalities</div></li><li class="half_rhythm"><div>Acute, self-limited episodes of transient neurologic dysfunction, especially weakness and dysarthria</div></li></ul></li><li class="half_rhythm"><div><b>Stroke-like episodes.</b> Acute fulminant episodes of reversible CNS dysfunction, usually with peripheral neuropathy or a family history of peripheral neuropathy</div></li><li class="half_rhythm"><div><b>Familial ataxia</b> with peripheral neuropathy</div></li></ul><p><b>Electrophysiologic findings.</b> Nerve conduction velocities (NCVs):</p><ul><li class="half_rhythm"><div class="half_rhythm">Forearm NCVs are typically in the "intermediate" range of 30-40 m/sec for males; in females NCVs from 30-60 m/sec are seen [<a class="bibr" href="#cmtx.REF.jerath.2016.728" rid="cmtx.REF.jerath.2016.728">Jerath et al 2016</a>].</div></li><li class="half_rhythm"><div class="half_rhythm">Median nerve conductions are more severely affected than those of the ulnar nerve [<a class="bibr" href="#cmtx.REF.tsai.2013.51" rid="cmtx.REF.tsai.2013.51">Tsai et al 2013</a>].</div><div class="half_rhythm">Note: NCV can vary from nerve to nerve in a single individual [<a class="bibr" href="#cmtx.REF.gutierrez.2000.182" rid="cmtx.REF.gutierrez.2000.182">Gutierrez et al 2000</a>]. NCVs can also vary significantly within and between families.</div></li></ul><p><b>Family history</b> is consistent with X-linked inheritance (i.e., no male-to-male inheritance). Because females can be as severely affected as males, some family histories will have multi-generation involvement of males and females. If the family is large enough, the fact that no male-to-male transmission is observed may be helpful.</p></div><div id="cmtx.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p><b>Male proband.</b> The diagnosis of CMT1X <b>is established</b> in a male proband with suggestive findings and a hemizygous pathogenic (or likely pathogenic) variant in <i>GJB1</i> identified by molecular genetic testing (see <a href="/books/NBK1374/table/cmtx.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobcmtxTmoleculargenetictestingusedin">Table 1</a>).</p><p><b>Female proband.</b> The diagnosis of CMT1X <b>is usually established</b> in a female proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in <i>GJB1</i> identified by molecular genetic testing (see <a href="/books/NBK1374/table/cmtx.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobcmtxTmoleculargenetictestingusedin">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bibr" href="#cmtx.REF.richards.2015.405" rid="cmtx.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of a hemizygous or heterozygous <i>GJB1</i> variant of uncertain significance does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.</p><p>Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CMT1X is broad and overlaps with other forms of CMT, individuals with the findings of peripheral neuropathy described in <a href="#cmtx.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing, often using a multigene panel (see <a href="#cmtx.Option_1">Option 1</a>), whereas those with stroke-like episodes in whom the diagnosis of a CMT1X has not been considered are more likely to be diagnosed using genomic testing (see <a href="#cmtx.Option_2">Option 2</a>).</p><div id="cmtx.Option_1"><h4>Option 1</h4><p><b>Single-gene testing</b> is probably most appropriate when X-linked inheritance is possible and the proband has both peripheral nervous system and CNS manifestations typical of CMT1X.</p><p>Sequence analysis of <i>GJB1</i> detects missense, nonsense, and splice site variants and small intragenic deletions/insertions. If no pathogenic variant is found, gene-targeted deletion/duplication analysis is performed to detect intragenic deletions or duplications.</p><p><b>Note:</b> Disease-causing variants have been reported in the upstream regulatory region, 5'UTR, noncoding exons and splice sites, and 3'UTR (see <a href="#cmtx.Molecular_Genetics">Molecular Genetics</a>); therefore, sequence analysis should include these regions of <i>GJB1.</i></p><p>An inherited neuropathy <b>multigene panel</b> that includes <i>GJB1</i> and other genes of interest (see <a href="#cmtx.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (1) The genes included in multigene panels and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Multigene panels generally 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 exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see <a href="/books/NBK1374/table/cmtx.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobcmtxTmoleculargenetictestingusedin">Table 1</a>). (5) Variants in upstream regulatory regions, 5' untranslated regions, and putative splice sites as well as 3' UTR variants have been shown to cause CMT1X [<a class="bibr" href="#cmtx.REF.tomaselli.2017.1445" rid="cmtx.REF.tomaselli.2017.1445">Tomaselli et al 2017</a>]. Because these variants are outside of typically sequenced gene regions, they may not be identified in inherited neuropathy panels (see <a href="#cmtx.Molecular_Genetics">Molecular Genetics</a>).</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="cmtx.Option_2"><h4>Option 2</h4><p><b>Comprehensive genomic testing</b> does not require the clinician to determine which gene(s) are likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>If exome sequencing is not diagnostic, <b>exome array</b> (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcmtxTmoleculargenetictestingusedin"><a href="/books/NBK1374/table/cmtx.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobcmtxTmoleculargenetictestingusedin"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cmtx.T.molecular_genetic_testing_used_in"><a href="/books/NBK1374/table/cmtx.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobcmtxTmoleculargenetictestingusedin">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>GJB1</i> Charcot-Marie-Tooth Neuropathy with or without CNS Dysfunction (CMT1X) </p></div></div></div></div></div><div id="cmtx.Clinical_Characteristics"><h2 id="_cmtx_Clinical_Characteristics_">Clinical Characteristics</h2><div id="cmtx.Clinical_Description"><h3>Clinical Description</h3><p><b>Neuropathy.</b> Manifestations typically develop between ages five and 25 years; many males are symptomatic by early adolescence [<a class="bibr" href="#cmtx.REF.dubourg.2001.1958" rid="cmtx.REF.dubourg.2001.1958">Dubourg et al 2001</a>, <a class="bibr" href="#cmtx.REF.shy.2007.849" rid="cmtx.REF.shy.2007.849">Shy et al 2007</a>]. Earlier onset with delayed walking in infancy as well as later onset in the fourth and subsequent decades can occur. In some individuals, manifestations can be extremely mild and go unrecognized by the individual and/or physician. Clinical manifestations can vary, even within the same family.</p><p>Although both men and women are affected, manifestations tend to be less severe in women because of X-chromosome inactivation, as a result of which some women may remain asymptomatic [<a class="bibr" href="#cmtx.REF.siskind.2011.102" rid="cmtx.REF.siskind.2011.102">Siskind et al 2011</a>, <a class="bibr" href="#cmtx.REF.jerath.2016.728" rid="cmtx.REF.jerath.2016.728">Jerath et al 2016</a>].</p><p>Signs and symptoms are those of progressive peripheral motor and sensory neuropathy including sensory loss, weakness and atrophy of the distal muscles of the upper and lower extremities, and loss of deep tendon reflexes. The typical affected adult has bilateral foot drop, symmetric atrophy of muscles below the knee (stork leg appearance), <i>pes cavus</i>, atrophy of intrinsic hand muscles (especially the thenar muscles of the thumb), and absent tendon reflexes in upper and lower extremities. The dominant hand may be more involved than the non-dominant one [<a class="bibr" href="#cmtx.REF.arthurfarraj.2012.622" rid="cmtx.REF.arthurfarraj.2012.622">Arthur-Farraj et al 2012</a>]. Proximal muscles usually remain strong.</p><p>Mild-to-moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet.</p><p><b>Fixed CNS abnormalities</b> can include fixed dysarthria, ataxia, spasticity, hyperreflexia, extensor plantar response, and/or MRI abnormalities in the myelinated tracts of the brain. These have been recently reviewed [<a class="bibr" href="#cmtx.REF.abrams.2019.91" rid="cmtx.REF.abrams.2019.91">Abrams 2019</a>].</p><p><b>Stroke-like episodes</b> are acute self-limited often recurrent episodes of CNS dysfunction. Findings typically include upper motor neuron weakness and dysarthria. Ataxia, respiratory distress, dysphagia, and altered consciousness have also been described. Symptoms last between a few hours and a few weeks. While some episodes appear to occur without provocation [<a class="bibr" href="#cmtx.REF.halbrich.2008.372" rid="cmtx.REF.halbrich.2008.372">Halbrich et al 2008</a>, <a class="bibr" href="#cmtx.REF.srinivasan.2008.293" rid="cmtx.REF.srinivasan.2008.293">Srinivasan et al 2008</a>], most are associated with stressors such as hyperventilation or exertion [<a class="bibr" href="#cmtx.REF.hanemann.2003.605" rid="cmtx.REF.hanemann.2003.605">Hanemann et al 2003</a>, <a class="bibr" href="#cmtx.REF.taylor.2003.1475" rid="cmtx.REF.taylor.2003.1475">Taylor et al 2003</a>, <a class="bibr" href="#cmtx.REF.srinivasan.2008.293" rid="cmtx.REF.srinivasan.2008.293">Srinivasan et al 2008</a>, <a class="bibr" href="#cmtx.REF.basu.2011.1205" rid="cmtx.REF.basu.2011.1205">Basu et al 2011</a>], re-acclimatization after return from high altitude [<a class="bibr" href="#cmtx.REF.paulson.2002.429" rid="cmtx.REF.paulson.2002.429">Paulson et al 2002</a>, <a class="bibr" href="#cmtx.REF.sagnelli.2014.183" rid="cmtx.REF.sagnelli.2014.183">Sagnelli et al 2014</a>], fever [<a class="bibr" href="#cmtx.REF.schelhaas.2002.2007" rid="cmtx.REF.schelhaas.2002.2007">Schelhaas et al 2002</a>, <a class="bibr" href="#cmtx.REF.fusco.2010.759" rid="cmtx.REF.fusco.2010.759">Fusco et al 2010</a>], head trauma [<a class="bibr" href="#cmtx.REF.halbrich.2008.372" rid="cmtx.REF.halbrich.2008.372">Halbrich et al 2008</a>], or minor infections [<a class="bibr" href="#cmtx.REF.hanemann.2003.605" rid="cmtx.REF.hanemann.2003.605">Hanemann et al 2003</a>, <a class="bibr" href="#cmtx.REF.anand.2010.677" rid="cmtx.REF.anand.2010.677">Anand et al 2010</a>].</p><p>MRI changes, seen on both diffusion-weighted and T<sub>2</sub>-weighted sequences, preferentially involve subcortical white matter and the splenium of the corpus callosum [<a class="bibr" href="#cmtx.REF.paulson.2002.429" rid="cmtx.REF.paulson.2002.429">Paulson et al 2002</a>, <a class="bibr" href="#cmtx.REF.schelhaas.2002.2007" rid="cmtx.REF.schelhaas.2002.2007">Schelhaas et al 2002</a>, <a class="bibr" href="#cmtx.REF.hanemann.2003.605" rid="cmtx.REF.hanemann.2003.605">Hanemann et al 2003</a>, <a class="bibr" href="#cmtx.REF.halbrich.2008.372" rid="cmtx.REF.halbrich.2008.372">Halbrich et al 2008</a>, <a class="bibr" href="#cmtx.REF.srinivasan.2008.293" rid="cmtx.REF.srinivasan.2008.293">Srinivasan et al 2008</a>, <a class="bibr" href="#cmtx.REF.anand.2010.677" rid="cmtx.REF.anand.2010.677">Anand et al 2010</a>, <a class="bibr" href="#cmtx.REF.fusco.2010.759" rid="cmtx.REF.fusco.2010.759">Fusco et al 2010</a>, <a class="bibr" href="#cmtx.REF.rosser.2010.1013" rid="cmtx.REF.rosser.2010.1013">Rosser et al 2010</a>, <a class="bibr" href="#cmtx.REF.kim.2014.e270" rid="cmtx.REF.kim.2014.e270">Kim et al 2014</a>]. While diffusion-weighted abnormalities tend to resolve within weeks, T<sub>2</sub>-weighted changes may persist longer. Most of these episodes have been reported in males, typically younger than age 21 years [<a class="bibr" href="#cmtx.REF.almateen.2014.342" rid="cmtx.REF.almateen.2014.342">Al-Mateen et al 2014</a>]; females with stroke like episodes have also been described [<a class="bibr" href="#cmtx.REF.hanemann.2003.605" rid="cmtx.REF.hanemann.2003.605">Hanemann et al 2003</a>, <a class="bibr" href="#cmtx.REF.kim.2014.e270" rid="cmtx.REF.kim.2014.e270">Kim et al 2014</a>]. In rare instances stroke-like episodes may precede peripheral neuropathy [<a class="bibr" href="#cmtx.REF.sagnelli.2014.183" rid="cmtx.REF.sagnelli.2014.183">Sagnelli et al 2014</a>].</p><p><b>Other fixed central nervous system involvement,</b> reported on occasion:</p><ul><li class="half_rhythm"><div>Extensor plantar responses [<a class="bibr" href="#cmtx.REF.marques.1999.803" rid="cmtx.REF.marques.1999.803">Marques et al 1999</a>, <a class="bibr" href="#cmtx.REF.hisama.2001.1891" rid="cmtx.REF.hisama.2001.1891">Hisama et al 2001</a>, <a class="bibr" href="#cmtx.REF.lee.2002.304" rid="cmtx.REF.lee.2002.304">Lee et al 2002</a>, <a class="bibr" href="#cmtx.REF.kassubek.2005.588" rid="cmtx.REF.kassubek.2005.588">Kassubek et al 2005</a>, <a class="bibr" href="#cmtx.REF.karadima.2006.263" rid="cmtx.REF.karadima.2006.263">Karadima et al 2006</a>, <a class="bibr" href="#cmtx.REF.kleopa.2006.396" rid="cmtx.REF.kleopa.2006.396">Kleopa et al 2006</a>]</div></li><li class="half_rhythm"><div>Hyperreflexia and/or spasticity [<a class="bibr" href="#cmtx.REF.hisama.2001.1891" rid="cmtx.REF.hisama.2001.1891">Hisama et al 2001</a>, <a class="bibr" href="#cmtx.REF.kleopa.2006.396" rid="cmtx.REF.kleopa.2006.396">Kleopa et al 2006</a>]</div></li><li class="half_rhythm"><div>Ataxia with upper motor neuron signs in a large kindred (SCA-X1) [<a class="bibr" href="#cmtx.REF.caramins.2013.4329" rid="cmtx.REF.caramins.2013.4329">Caramins et al 2013</a>] and ataxia with dysarthria [<a class="bibr" href="#cmtx.REF.siskind.2009.109" rid="cmtx.REF.siskind.2009.109">Siskind et al 2009</a>]</div></li><li class="half_rhythm"><div>Vocal cord paresis with dysphonia and dysphagia (reported in 4/8 affected members of a single family) [<a class="bibr" href="#cmtx.REF.chung.2005.159" rid="cmtx.REF.chung.2005.159">Chung et al 2005</a>]</div></li><li class="half_rhythm"><div>Hearing loss (occasionally reported) [<a class="bibr" href="#cmtx.REF.stojkovic.1999.1010" rid="cmtx.REF.stojkovic.1999.1010">Stojkovic et al 1999</a>, <a class="bibr" href="#cmtx.REF.lee.2002.304" rid="cmtx.REF.lee.2002.304">Lee et al 2002</a>, <a class="bibr" href="#cmtx.REF.takashima.2003.31" rid="cmtx.REF.takashima.2003.31">Takashima et al 2003</a>]</div></li></ul><p><b>Other imaging findings</b> can include:</p><ul><li class="half_rhythm"><div>MRI evidence of fixed pathology in CNS myelin [<a class="bibr" href="#cmtx.REF.bort.1997.746" rid="cmtx.REF.bort.1997.746">Bort et al 1997</a>, <a class="bibr" href="#cmtx.REF.hisama.2001.1891" rid="cmtx.REF.hisama.2001.1891">Hisama et al 2001</a>, <a class="bibr" href="#cmtx.REF.lee.2002.304" rid="cmtx.REF.lee.2002.304">Lee et al 2002</a>, <a class="bibr" href="#cmtx.REF.kassubek.2005.588" rid="cmtx.REF.kassubek.2005.588">Kassubek et al 2005</a>, <a class="bibr" href="#cmtx.REF.karadima.2006.263" rid="cmtx.REF.karadima.2006.263">Karadima et al 2006</a>, <a class="bibr" href="#cmtx.REF.basri.2007.1023" rid="cmtx.REF.basri.2007.1023">Basri et al 2007</a>, <a class="bibr" href="#cmtx.REF.siskind.2009.109" rid="cmtx.REF.siskind.2009.109">Siskind et al 2009</a>];</div></li><li class="half_rhythm"><div>Reduced cerebellar blood flow on SPECT analysis [<a class="bibr" href="#cmtx.REF.kawakami.2002.923" rid="cmtx.REF.kawakami.2002.923">Kawakami et al 2002</a>].</div></li></ul><p>
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<b>Other electrophysiologic findings</b>
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</p><ul><li class="half_rhythm"><div>Most affected individuals show abnormalities in visual, brain stem auditory, and/or somatosensory evoked responses (reviewed in <a class="bibr" href="#cmtx.REF.abrams.2015.659" rid="cmtx.REF.abrams.2015.659">Abrams & Freidin [2015]</a>).</div></li><li class="half_rhythm"><div>Most <i>GJB1</i> variants cause subclinical abnormalities of visual evoked responses and brain stem auditory evoked responsess [<a class="bibr" href="#cmtx.REF.nicholson.1996.43" rid="cmtx.REF.nicholson.1996.43">Nicholson & Corbett 1996</a>, <a class="bibr" href="#cmtx.REF.cao.1998.31" rid="cmtx.REF.cao.1998.31">Cao et al 1998</a>, <a class="bibr" href="#cmtx.REF.nicholson.1998.1412" rid="cmtx.REF.nicholson.1998.1412">Nicholson et al 1998</a>, <a class="bibr" href="#cmtx.REF.panas.1998.947" rid="cmtx.REF.panas.1998.947">Panas et al 1998</a>, <a class="bibr" href="#cmtx.REF.b_hr.1999.202" rid="cmtx.REF.b_hr.1999.202">Bähr et al 1999</a>, <a class="bibr" href="#cmtx.REF.stojkovic.1999.1010" rid="cmtx.REF.stojkovic.1999.1010">Stojkovic et al 1999</a>, <a class="bibr" href="#cmtx.REF.seeman.2001.461" rid="cmtx.REF.seeman.2001.461">Seeman et al 2001</a>, <a class="bibr" href="#cmtx.REF.huang.2005.7111" rid="cmtx.REF.huang.2005.7111">Huang et al 2005</a>, <a class="bibr" href="#cmtx.REF.murru.2006.18" rid="cmtx.REF.murru.2006.18">Murru et al 2006</a>, <a class="bibr" href="#cmtx.REF.srinivasan.2008.293" rid="cmtx.REF.srinivasan.2008.293">Srinivasan et al 2008</a>].</div></li><li class="half_rhythm"><div>Abnormal motor evoked potentials [<a class="bibr" href="#cmtx.REF.kassubek.2005.588" rid="cmtx.REF.kassubek.2005.588">Kassubek et al 2005</a>], sensory evoked potentials [<a class="bibr" href="#cmtx.REF.kawakami.2002.923" rid="cmtx.REF.kawakami.2002.923">Kawakami et al 2002</a>], and transcranial magnetic stimulation evoked central motor conduction [<a class="bibr" href="#cmtx.REF.zambelis.2008.44" rid="cmtx.REF.zambelis.2008.44">Zambelis et al 2008</a>] have also been reported.</div></li></ul><p><b>Nerve biopsy.</b> Light microscopy typically reveals axonal loss with evidence of regeneration. Scattered onion bulbs as well as thinly myelinated fibers, resulting from either regeneration and associated remyelination or segmental demyelination and remyelination, are also seen.</p><p>Electron microscopy reveals widened collars of adaxonal Schwann cell cytoplasm and separation of axons from their surrounding myelin sheaths [<a class="bibr" href="#cmtx.REF.senderek.1998.443" rid="cmtx.REF.senderek.1998.443">Senderek et al 1998</a>, <a class="bibr" href="#cmtx.REF.senderek.1999.90" rid="cmtx.REF.senderek.1999.90">Senderek et al 1999</a>, <a class="bibr" href="#cmtx.REF.tabaraud.1999.1442" rid="cmtx.REF.tabaraud.1999.1442">Tabaraud et al 1999</a>, <a class="bibr" href="#cmtx.REF.hahn.2001.129" rid="cmtx.REF.hahn.2001.129">Hahn et al 2001</a>, <a class="bibr" href="#cmtx.REF.vital.2001.79" rid="cmtx.REF.vital.2001.79">Vital et al 2001</a>].</p><p>Nerve biopsies rarely show nerve hypertrophy or generalized onion bulb formation, findings considered to be typical for demyelinating CMT(e.g., CMT type 1A caused by a duplication of a ~1-MB region of chromosome 17 that includes <i>PMP22</i>).</p><p>Note that the widespread availability of molecular genetic testing has rendered nerve biopsy unnecessary for diagnosis unless genetic testing is unrevealing.</p></div><div id="cmtx.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>The six variants that have been reported in multiple unrelated individuals with stroke-like episodes and which may confer a higher risk for this phenotype are included in <a href="/books/NBK1374/table/cmtx.T.notable_gjb1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobcmtxTnotablegjb1pathogenicvariants">Table 4</a>. Of note, approximately 20 additional variants have been reported in a single individual or family with stroke-like episodes.</p><p>From a severity standpoint, most pathogenic variants cause a similar phenotype [<a class="bibr" href="#cmtx.REF.shy.2007.849" rid="cmtx.REF.shy.2007.849">Shy et al 2007</a>, <a class="bibr" href="#cmtx.REF.record.2023.4336" rid="cmtx.REF.record.2023.4336">Record et al 2023</a>]. Some data suggest that the relatively common <a href="/books/NBK1374/table/cmtx.T.notable_gjb1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobcmtxTnotablegjb1pathogenicvariants">c.-17G>A</a> pathogenic variant produces a more severe phenotype than other common pathogenic variants, while missense pathogenic variants in the intracellular domain of <i>GJB1</i> cause a less severe phenotype [<a class="bibr" href="#cmtx.REF.record.2023.4336" rid="cmtx.REF.record.2023.4336">Record et al 2023</a>].</p></div><div id="cmtx.Nomenclature"><h3>Nomenclature</h3><p>The term XL-CMTIn-<i>GJB1</i> may be used to describe CMT1X. This term is based on the classification system proposed by <a class="bibr" href="#cmtx.REF.magy.2018.e870" rid="cmtx.REF.magy.2018.e870">Magy et al [2018]</a> in which expression of a particular type of CMT combines three elements: mode of inheritance, neuropathy type (i.e., axonal, demyelinating, or intermediate), and the gene involved.</p><p>See <a href="/books/n/gene/cmt/?report=reader">CMT Overview</a> for a review of other approaches to CMT classification.</p></div><div id="cmtx.Prevalence"><h3>Prevalence</h3><p>The overall prevalence of hereditary neuropathies is estimated at 30:100,000 population. More than half of these cases are CMT type 1 (15 to 20:100,000).</p><p>CMT1X represents at least 10%-20% of those with the CMT neuropathy (see <a href="/books/n/gene/cmt/?report=reader">CMT Overview</a>).</p></div></div><div id="cmtx.Genetically_Related_Allelic_Disorde"><h2 id="_cmtx_Genetically_Related_Allelic_Disorde_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>GJB1</i>.</p></div><div id="cmtx.Differential_Diagnosis"><h2 id="_cmtx_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Neuropathy.</b> See <a href="/books/n/gene/cmt/?report=reader">CMT Overview</a>.</p><p><b>Stroke-like episodes and peripheral neuropathy.</b> Disorders to consider in the differential diagnosis include the following:</p><ul><li class="half_rhythm"><div><a href="/books/n/gene/melas/?report=reader">MELAS</a> (mitochondrial encephalopathy lactic acidosis and stroke) due mitochondrial DNA (mtDNA) variants</div></li><li class="half_rhythm"><div><a href="/books/n/gene/alpers/?report=reader"><i>POLG</i>-related disorders</a> [<a class="bibr" href="#cmtx.REF.pareyson.2013.1011" rid="cmtx.REF.pareyson.2013.1011">Pareyson et al 2013</a>]</div></li><li class="half_rhythm"><div><a href="/books/n/gene/cadasil/?report=reader">CADASIL</a> [<a class="bibr" href="#cmtx.REF.sicurelli.2005.1206" rid="cmtx.REF.sicurelli.2005.1206">Sicurelli et al 2005</a>]; however, peripheral neuropathy has not been seen in all studies [<a class="bibr" href="#cmtx.REF.kang.2009.1724" rid="cmtx.REF.kang.2009.1724">Kang et al 2009</a>].</div></li><li class="half_rhythm"><div><a href="/books/n/gene/fabry/?report=reader">Fabry disease</a> manifesting with ischemic stroke and small fiber neuropathy</div></li><li class="half_rhythm"><div>Metabolic encephalopathy or ischemia due to complications of diabetes mellitus, kidney disease, or liver disease</div></li><li class="half_rhythm"><div>Neurosarcoidosis [<a class="bibr" href="#cmtx.REF.hodge.2007.84" rid="cmtx.REF.hodge.2007.84">Hodge et al 2007</a>]</div></li><li class="half_rhythm"><div>Lupus and other collagen vascular diseases</div></li><li class="half_rhythm"><div>Vasculitis</div></li></ul><p><b>Isolated stroke-like episodes.</b> The vast differential diagnosis includes many genetic and acquired conditions. In particular, the autosomal recessive disorder acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) (OMIM <a href="https://omim.org/entry/618384" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">618384</a>), caused by biallelic pathogenic variants in <i>SLC13A3</i>, should be considered, as the phenotype is remarkably similar to that seen in CMT1X [<a class="bibr" href="#cmtx.REF.dewulf.2019.385" rid="cmtx.REF.dewulf.2019.385">Dewulf et al 2019</a>].</p></div><div id="cmtx.Management"><h2 id="_cmtx_Management_">Management</h2><p>Individuals with <i>GJB1</i> Charcot-Marie-Tooth neuropathy with or without central nervous system dysfunction (CMT1X) are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical therapists, and occupational therapists.</p><div id="cmtx.Evaluations_Following_Initial_Diagn"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with CMT1X , the evaluations summarized in <a href="/books/NBK1374/table/cmtx.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobcmtxTrecommendedevaluationsfollowing">Table 2</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcmtxTrecommendedevaluationsfollowing"><a href="/books/NBK1374/table/cmtx.T.recommended_evaluations_following/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobcmtxTrecommendedevaluationsfollowing"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cmtx.T.recommended_evaluations_following"><a href="/books/NBK1374/table/cmtx.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobcmtxTrecommendedevaluationsfollowing">Table 2. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with CMT1X </p></div></div></div><div id="cmtx.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment is symptomatic.</p><div id="cmtx.Neuropathy"><h4>Neuropathy</h4><p>Special shoes, including those with good ankle support, may be needed.</p><p>Ankle/foot orthoses (AFO) are often required to correct foot drop and aid walking. Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.</p><p>Orthopedic surgery may be required to correct severe <i>pes cavus</i> deformity interfering with ambulation; however, it should be reserved for affected individuals in whom the gait cannot be corrected by use of appropriate orthotic devices.</p><p>Forearm crutches or canes may be required for gait stability. Use of a wheelchair may occasionally be required.</p><p>Exercise is encouraged within the individual's capability, as many affected individuals remain physically active.</p></div><div id="cmtx.StrokeLike_Episodes"><h4>Stroke-Like Episodes</h4><p>Treatment is supportive, as these are self-limited. See <a href="#cmtx.AgentsCircumstances_to_Avoid">Agents/Circumstances to Avoid</a> for lifestyle recommendations to potentially reduce the risk of these episodes.</p></div></div><div id="cmtx.Surveillance"><h3>Surveillance</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcmtxTrecommendedsurveillanceforindi"><a href="/books/NBK1374/table/cmtx.T.recommended_surveillance_for_indi/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobcmtxTrecommendedsurveillanceforindi"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cmtx.T.recommended_surveillance_for_indi"><a href="/books/NBK1374/table/cmtx.T.recommended_surveillance_for_indi/?report=objectonly" target="object" rid-ob="figobcmtxTrecommendedsurveillanceforindi">Table 3. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with CMT1X </p></div></div></div><div id="cmtx.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Obesity is to be avoided because it makes walking more difficult.</p><p>Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association <a href="https://www.cmtausa.org/living-with-cmt/managing-cmt/medications/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">website</a> (pdf) for an up-to-date list.</p><p>Affected individuals should be informed of the small possibility of stroke-like episodes, which appears to be higher in younger individuals with a family history or in individuals who have a variant previously associated with such events (see <a href="/books/NBK1374/table/cmtx.T.notable_gjb1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobcmtxTnotablegjb1pathogenicvariants">Table 4</a>). The author recommends advising affected individuals that the avoidance of known precipitants such as hyperventilation or exertion [<a class="bibr" href="#cmtx.REF.hanemann.2003.605" rid="cmtx.REF.hanemann.2003.605">Hanemann et al 2003</a>, <a class="bibr" href="#cmtx.REF.taylor.2003.1475" rid="cmtx.REF.taylor.2003.1475">Taylor et al 2003</a>, <a class="bibr" href="#cmtx.REF.srinivasan.2008.293" rid="cmtx.REF.srinivasan.2008.293">Srinivasan et al 2008</a>, <a class="bibr" href="#cmtx.REF.basu.2011.1205" rid="cmtx.REF.basu.2011.1205">Basu et al 2011</a>], re-acclimatization after return from high altitude [<a class="bibr" href="#cmtx.REF.paulson.2002.429" rid="cmtx.REF.paulson.2002.429">Paulson et al 2002</a>, <a class="bibr" href="#cmtx.REF.sagnelli.2014.183" rid="cmtx.REF.sagnelli.2014.183">Sagnelli et al 2014</a>], fever [<a class="bibr" href="#cmtx.REF.schelhaas.2002.2007" rid="cmtx.REF.schelhaas.2002.2007">Schelhaas et al 2002</a>, <a class="bibr" href="#cmtx.REF.fusco.2010.759" rid="cmtx.REF.fusco.2010.759">Fusco et al 2010</a>], head trauma [<a class="bibr" href="#cmtx.REF.halbrich.2008.372" rid="cmtx.REF.halbrich.2008.372">Halbrich et al 2008</a>], or minor infections [<a class="bibr" href="#cmtx.REF.hanemann.2003.605" rid="cmtx.REF.hanemann.2003.605">Hanemann et al 2003</a>, <a class="bibr" href="#cmtx.REF.anand.2010.677" rid="cmtx.REF.anand.2010.677">Anand et al 2010</a>] <b>may</b> reduce the likelihood of such events. However, these recommendations must be balanced with quality-of-life considerations.</p></div><div id="cmtx.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>Examination of at-risk relatives is recommended since individuals with few manifestations may go unrecognized. Even individuals with few manifestations may benefit from use of orthotics.</p><p>It may be appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual when the apparent risk for stroke-like episodes may be higher (family history or a variant previously associated with such episodes; see <a href="/books/NBK1374/table/cmtx.T.notable_gjb1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobcmtxTnotablegjb1pathogenicvariants">Table 4</a>), since avoidance of precipitating factors may be warranted to help reduce the incidence of such events.</p><p>See <a href="#cmtx.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="cmtx.Therapies_Under_Investigation"><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 information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="cmtx.Genetic_Counseling"><h2 id="_cmtx_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="cmtx.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>GJB1</i> Charcot-Marie-Tooth neuropathy with or without central nervous system dysfunction (CMT1X) is inherited in an X-linked manner.</p></div><div id="cmtx.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a male proband</b>
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</p><ul><li class="half_rhythm"><div>The father of an affected male will not have the disorder nor will he be hemizygous for the <i>GJB1</i> pathogenic variant; therefore, he does not require further evaluation/testing.</div></li><li class="half_rhythm"><div>In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the <i>GJB1</i> pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. Presumed somatic and germline mosaicism has been reported in CMT1X [<a class="bibr" href="#cmtx.REF.borgulov_.2013.189" rid="cmtx.REF.borgulov_.2013.189">Borgulová et al 2013</a>].</div></li><li class="half_rhythm"><div>If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a <i>de novo</i>
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<i>GJB1</i> pathogenic variant (in which case the mother is not a heterozygote). About 5% to 10% of affected males represent apparently simplex cases. While <a class="bibr" href="#cmtx.REF.dubourg.2001.1958" rid="cmtx.REF.dubourg.2001.1958">Dubourg et al [2001]</a> estimated that 5% of individuals had a <i>de novo</i> pathogenic variant, no <i>de novo</i> variants were identified in a more recent study of 40 individuals with CMT1X [<a class="bibr" href="#cmtx.REF.rudniksch_neborn.2016.34" rid="cmtx.REF.rudniksch_neborn.2016.34">Rudnik-Schöneborn et al 2016</a>].</div></li></ul><p>
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<b>Parents of a female proband</b>
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</p><ul><li class="half_rhythm"><div>A female proband may have inherited the <i>GJB1</i> pathogenic variant from either her mother or her father, or the pathogenic variant may be <i>de novo</i>.</div></li><li class="half_rhythm"><div>Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a <i>de novo</i>
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<i>GJB1</i> pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can determine if the pathogenic variant was inherited.</div></li></ul><p><b>Sibs of a male proband.</b> The risk to sibs depends on the genetic status of the mother:</p><ul><li class="half_rhythm"><div>If the mother of the proband has a <i>GJB1</i> pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may have mild-to-no manifestations or, more often, have mild-to-moderate signs and symptoms that may progress.</div></li><li class="half_rhythm"><div>If the proband represents a simplex case and if the <i>GJB1</i> pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism.</div></li></ul><p><b>Sibs of a female proband.</b> The risk to sibs depends on the genetic status of the parents:</p><ul><li class="half_rhythm"><div>If the mother of the proband has a <i>GJB1</i> pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may have mild-to-no manifestations or, more often, have mild-to-moderate signs and symptoms that may progress</div></li><li class="half_rhythm"><div>If the father of the proband has a <i>GJB1</i> pathogenic variant, he will transmit it to all his daughters and none of his sons.</div></li><li class="half_rhythm"><div>If the proband represents a simplex case (i.e., a single occurrence in a family) and if the <i>GJB1</i> pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.</div></li></ul><p><b>Offspring of a male proband.</b> Affected males transmit the <i>GJB1</i> pathogenic variant to all of their daughters and none of their sons.</p><p><b>Offspring of a female proband.</b> Women with a <i>GJB1</i> pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child.</p><p><b>Other family members.</b> If a parent of the proband also has a <i>GJB1</i> pathogenic variant, the parent's family members may be at risk of having a <i>GJB1</i> pathogenic variant.</p><p>Note: Molecular genetic testing may be able to identify the family member in whom a <i>de novo</i> pathogenic variant arose – information that could help determine genetic risk status of the extended family.</p></div><div id="cmtx.Heterozygote_Detection"><h3>Heterozygote Detection</h3><p>Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the <i>GJB1</i> pathogenic variant has been identified in the proband.</p><p>Note: (1) Females who are heterozygous for this X-linked disorder may have no clinical findings of peripheral neuropathy (but an abnormal EMG/NCV); or, more often, have mild-to-moderate signs and symptoms that may progress (see <a href="#cmtx.Clinical_Description">Clinical Description</a>). (2) Identification of female heterozygotes requires either (a) prior identification of the <i>GJB1</i> pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.</p></div><div id="cmtx.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adult males who are affected (i.e., hemizygous) or females who are known to be heterozygous or who are at increased risk of being heterozygotes.</div></li></ul></div><div id="cmtx.Prenatal_Testing_and_Preimplantatio"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>GJB1</i> pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="cmtx.Resources"><h2 id="_cmtx_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>Association CMT France</b>
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</div><div>France</div><div><b>Phone:</b> 820 077 540; 2 47 27 96 41 </div><div>
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<a href="http://www.cmt-france.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.cmt-france.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Charcot-Marie-Tooth Association (CMTA)</b>
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</div><div><b>Phone:</b> 800-606-2682</div><div><b>Email:</b> info@cmtausa.org</div><div>
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<a href="http://www.cmtausa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">cmtausa.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>CMT Research Foundation</b>
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</div><div><b>Phone:</b> 404-806-7180</div><div><b>Email:</b> info@cmtrf.org</div><div>
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<a href="https://cmtrf.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.cmtrf.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>European Charcot-Marie-Tooth Consortium</b>
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</div><div>Department of Molecular Genetics</div><div>University of Antwerp</div><div>Antwerp Antwerpen B-2610</div><div>Belgium</div><div><b>Fax:</b> 03 2651002</div><div><b>Email:</b> gisele.smeyers@ua.ac.be</div></li><li class="half_rhythm"><div>
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<b>Hereditary Neuropathy Foundation</b>
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</div><div><b>Phone:</b> 855-435-7268 (toll-free); 212-722-8396</div><div><b>Fax:</b> 917-591-2758</div><div><b>Email:</b> info@hnf-cure.org</div><div>
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<a href="http://www.hnf-cure.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.hnf-cure.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Medical Home Portal</b>
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</div><div>
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<a href="https://www.medicalhomeportal.org/diagnoses-and-conditions/charcot-marie-tooth-disease" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Charcot-Marie-Tooth Disease (Hereditary Motor Sensory Neuropathy)</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Library of Medicine Genetics Home Reference</b>
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</div><div>
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<a href="https://ghr.nlm.nih.gov/condition/charcotmarietoothdisease" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Charcot-Marie-Tooth disease</a>
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</div></li><li class="half_rhythm"><div>
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<b>NCBI Genes and Disease</b>
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</div><div>
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<a href="/books/NBK22241/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Charcot-Marie-Tooth syndrome</a>
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</div></li><li class="half_rhythm"><div>
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<b>TREAT-NMD</b>
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</div><div>Institute of Translational and Clinical Research</div><div>University of Newcastle upon Tyne </div><div>International Centre for Life </div><div> Newcastle upon Tyne NE1 3BZ</div><div>United Kingdom</div><div><b>Phone:</b> 44 (0)191 241 8617</div><div><b>Fax:</b> 44 (0)191 241 8770</div><div><b>Email:</b> info@treat-nmd.eu</div><div>
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<a href="https://treat-nmd.org/treat-nmd-diseases/charcot-marie-tooth/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Charcot-Marie-Tooth Disease</a>
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</div></li><li class="half_rhythm"><div>
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<b>Association Francaise contre les Myopathies (AFM)</b>
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</div><div>France</div><div><b>Phone:</b> +33 01 69 47 28 28</div><div><b>Email:</b> dmc@afm.genethon.fr</div><div>
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<a href="http://www.afm-telethon.fr" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">afm-telethon.fr </a>
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</div></li><li class="half_rhythm"><div>
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<b>European Neuromuscular Centre (ENMC)</b>
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</div><div>Netherlands</div><div><b>Phone:</b> 31 35 5480481</div><div><b>Email:</b> enmc@enmc.org</div><div>
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<a href="http://www.enmc.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">enmc.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Muscular Dystrophy Association (MDA) - USA</b>
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</div><div><b>Phone:</b> 833-275-6321</div><div><b>Email:</b> ResourceCenter@mdausa.org</div><div>
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<a href="http://www.mda.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">mda.org</a>
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</div></li><li class="half_rhythm"><div>
|
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<b>Muscular Dystrophy UK</b>
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</div><div>United Kingdom</div><div><b>Phone:</b> 0800 652 6352</div><div>
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<a href="http://www.musculardystrophyuk.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">musculardystrophyuk.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>RDCRN Patient Contact Registry: Inherited Neuropathies Consortium</b>
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|
</div><div>
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<a href="https://www.rarediseasesnetwork.org/cms/inc" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Patient Contact Registry</a>
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</div></li></ul>
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</div><div id="cmtx.Molecular_Genetics"><h2 id="_cmtx_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcmtxmolgenTA"><a href="/books/NBK1374/table/cmtx.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobcmtxmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cmtx.molgen.TA"><a href="/books/NBK1374/table/cmtx.molgen.TA/?report=objectonly" target="object" rid-ob="figobcmtxmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcmtxmolgenTB"><a href="/books/NBK1374/table/cmtx.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobcmtxmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cmtx.molgen.TB"><a href="/books/NBK1374/table/cmtx.molgen.TB/?report=objectonly" target="object" rid-ob="figobcmtxmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes (View All in OMIM) </p></div></div><p><i>GJB1</i> encodes gap junction beta-1 protein (GJB1; also known as connexin 32 or Cx32), which is expressed in peripheral myelin and specifically located in uncompacted folds of Schwann cell cytoplasm at the nodes of Ranvier and at Schmidt-Lanterman incisures. It is also found in central myelin. GJB1 has two extracellular loops, four transmembrane domains, and three cytoplasmic domains. Gap junctions form direct channels between cells that facilitate transfer of ions and small molecules. Six connexins oligomerize to form hemichannels, or connexons. When properly apposed to each other on cell membranes, two connexins form gap junction channels that permit the diffusion of ions and small molecules [<a class="bibr" href="#cmtx.REF.abrams.2019.91" rid="cmtx.REF.abrams.2019.91">Abrams 2019</a>].</p><p><b>Mechanism of disease causation</b>. The exact mechanism by which <i>GJB1</i> pathogenic variants produce disease is unknown. Some variants likely lead to little or no protein production, including deletion of the entire coding sequence for Cx32 [<a class="bibr" href="#cmtx.REF.ainsworth.1998.242" rid="cmtx.REF.ainsworth.1998.242">Ainsworth et al 1998</a>, <a class="bibr" href="#cmtx.REF.lin.1999.239" rid="cmtx.REF.lin.1999.239">Lin et al 1999</a>, <a class="bibr" href="#cmtx.REF.hahn.2000.s39" rid="cmtx.REF.hahn.2000.s39">Hahn et al 2000</a>, <a class="bibr" href="#cmtx.REF.nakagawa.2001.31" rid="cmtx.REF.nakagawa.2001.31">Nakagawa et al 2001</a>, <a class="bibr" href="#cmtx.REF.takashima.2003.31" rid="cmtx.REF.takashima.2003.31">Takashima et al 2003</a>, <a class="bibr" href="#cmtx.REF.capponi.2015.406" rid="cmtx.REF.capponi.2015.406">Capponi et al 2015</a>], start codon [<a class="bibr" href="#cmtx.REF.brozkov_.2010.3" rid="cmtx.REF.brozkov_.2010.3">Brozková et al 2010</a>, <a class="bibr" href="#cmtx.REF.chen.2011.887" rid="cmtx.REF.chen.2011.887">Chen et al 2011</a>, <a class="bibr" href="#cmtx.REF.schabh_ttl.2014.970" rid="cmtx.REF.schabh_ttl.2014.970">Schabhüttl et al 2014</a>, <a class="bibr" href="#cmtx.REF.hong.2017.172" rid="cmtx.REF.hong.2017.172">Hong et al 2017</a>] and nonsense variants in the upstream part of the coding sequence [<a class="bibr" href="#cmtx.REF.ionasescu.1996a.486" rid="cmtx.REF.ionasescu.1996a.486">Ionasescu et al 1996a</a>, <a class="bibr" href="#cmtx.REF.panosyan.2017.927" rid="cmtx.REF.panosyan.2017.927">Panosyan et al 2017</a>]. Pathogenic variants in the upstream regulatory region, 5' untranslated region, splice junctions of non-coding exons, and 3' untranslated region [<a class="bibr" href="#cmtx.REF.ionasescu.1996b.541" rid="cmtx.REF.ionasescu.1996b.541">Ionasescu et al 1996b</a>, <a class="bibr" href="#cmtx.REF.flagiello.1998.361" rid="cmtx.REF.flagiello.1998.361">Flagiello et al 1998</a>, <a class="bibr" href="#cmtx.REF.houlden.2004.730" rid="cmtx.REF.houlden.2004.730">Houlden et al 2004</a>, <a class="bibr" href="#cmtx.REF.beauvais.2006.14" rid="cmtx.REF.beauvais.2006.14">Beauvais et al 2006</a>, <a class="bibr" href="#cmtx.REF.li.2009.14" rid="cmtx.REF.li.2009.14">Li et al 2009</a>, <a class="bibr" href="#cmtx.REF.kabzi_ska.2011.359" rid="cmtx.REF.kabzi_ska.2011.359">Kabzińska et al 2011</a>, <a class="bibr" href="#cmtx.REF.murphy.2011.65" rid="cmtx.REF.murphy.2011.65">Murphy et al 2011</a>, <a class="bibr" href="#cmtx.REF.tsai.2013.51" rid="cmtx.REF.tsai.2013.51">Tsai et al 2013</a>, <a class="bibr" href="#cmtx.REF.kulshrestha.2017.766" rid="cmtx.REF.kulshrestha.2017.766">Kulshrestha et al 2017</a>, <a class="bibr" href="#cmtx.REF.panosyan.2017.927" rid="cmtx.REF.panosyan.2017.927">Panosyan et al 2017</a>, <a class="bibr" href="#cmtx.REF.tomaselli.2017.1445" rid="cmtx.REF.tomaselli.2017.1445">Tomaselli et al 2017</a>] are also likely to reduce or eliminate protein expression.</p><p>Almost all disease-associated variants are predicted to be loss-of-function variants. Some cause Cx32 to traffic inappropriately, thus leading to a failure to form gap junction plaques [<a class="bibr" href="#cmtx.REF.omori.1996.907" rid="cmtx.REF.omori.1996.907">Omori et al 1996</a>, <a class="bibr" href="#cmtx.REF.desch_nes.1997.9077" rid="cmtx.REF.desch_nes.1997.9077">Deschênes et al 1997</a>, <a class="bibr" href="#cmtx.REF.martin.2000.711" rid="cmtx.REF.martin.2000.711">Martin et al 2000</a>, <a class="bibr" href="#cmtx.REF.matsuyama.2001.307" rid="cmtx.REF.matsuyama.2001.307">Matsuyama et al 2001</a>, <a class="bibr" href="#cmtx.REF.kleopa.2002.522" rid="cmtx.REF.kleopa.2002.522">Kleopa et al 2002</a>, <a class="bibr" href="#cmtx.REF.yum.2002.43" rid="cmtx.REF.yum.2002.43">Yum et al 2002</a>, <a class="bibr" href="#cmtx.REF.abrams.2003.10548" rid="cmtx.REF.abrams.2003.10548">Abrams et al 2003</a>]. Others form gap junctions but interfere with gap junction function by reducing pore size [<a class="bibr" href="#cmtx.REF.oh.1997.927" rid="cmtx.REF.oh.1997.927">Oh et al 1997</a>, <a class="bibr" href="#cmtx.REF.bicego.2006.607" rid="cmtx.REF.bicego.2006.607">Bicego et al 2006</a>], increasing sensitivity to acidification-induced closure [<a class="bibr" href="#cmtx.REF.ressot.1998.4063" rid="cmtx.REF.ressot.1998.4063">Ressot et al 1998</a>, <a class="bibr" href="#cmtx.REF.abrams.2003.10548" rid="cmtx.REF.abrams.2003.10548">Abrams et al 2003</a>], or most commonly by stabilizing the closed state of the channel [<a class="bibr" href="#cmtx.REF.oh.1997.927" rid="cmtx.REF.oh.1997.927">Oh et al 1997</a>, <a class="bibr" href="#cmtx.REF.ri.1999.2887" rid="cmtx.REF.ri.1999.2887">Ri et al 1999</a>, <a class="bibr" href="#cmtx.REF.abrams.2000.203" rid="cmtx.REF.abrams.2000.203">Abrams et al 2000</a>, <a class="bibr" href="#cmtx.REF.abrams.2013.3609" rid="cmtx.REF.abrams.2013.3609">Abrams et al 2013</a>]. See recent reviews for further details [<a class="bibr" href="#cmtx.REF.abrams.2015.659" rid="cmtx.REF.abrams.2015.659">Abrams & Freidin 2015</a>, <a class="bibr" href="#cmtx.REF.abrams.2019.91" rid="cmtx.REF.abrams.2019.91">Abrams 2019</a>]. Evidence suggests that in the central nervous system some variants have a toxic gain-of-function consequence [<a class="bibr" href="#cmtx.REF.olympiou.2016.95" rid="cmtx.REF.olympiou.2016.95">Olympiou et al 2016</a>].</p><p>Gap junction-independent mechanisms may also play a role. At least one disease-associated <i>GJB1</i> variant shows increased opening of hemichannels that may damage cells through loss of ionic gradients and increased influx of Ca<sup>++</sup> [<a class="bibr" href="#cmtx.REF.abrams.2002.3980" rid="cmtx.REF.abrams.2002.3980">Abrams et al 2002</a>]. A number of studies have suggested roles for connexins in regulation of cell growth [<a class="bibr" href="#cmtx.REF.omori.1998.446" rid="cmtx.REF.omori.1998.446">Omori & Yamasaki 1998</a>, <a class="bibr" href="#cmtx.REF.moorby.2001.238" rid="cmtx.REF.moorby.2001.238">Moorby & Patel 2001</a>, <a class="bibr" href="#cmtx.REF.qin.2002.29132" rid="cmtx.REF.qin.2002.29132">Qin et al 2002</a>, <a class="bibr" href="#cmtx.REF.freidin.2009.3567" rid="cmtx.REF.freidin.2009.3567">Freidin et al 2009</a>] and resistance to both apoptotic and necrotic cell death [<a class="bibr" href="#cmtx.REF.abdipranoto.2003.2177" rid="cmtx.REF.abdipranoto.2003.2177">Abdipranoto et al 2003</a>], independent of formation of functional gap junction channels. One example is the demonstration that Schwann cell proliferation is regulated by Cx32 in a gap junction-independent manner [<a class="bibr" href="#cmtx.REF.freidin.2009.3567" rid="cmtx.REF.freidin.2009.3567">Freidin et al 2009</a>]. Other non-junctional actions of connexins include binding to other proteins and possibly acting as trafficking or scaffolding proteins [<a class="bibr" href="#cmtx.REF.giepmans.2004.233" rid="cmtx.REF.giepmans.2004.233">Giepmans 2004</a>, <a class="bibr" href="#cmtx.REF.stout.2004.507" rid="cmtx.REF.stout.2004.507">Stout et al 2004</a>].</p><p><b><i>GJB1</i>-specific laboratory technical considerations.</b>
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<i>GJB1</i> consists of two promotors – P1 and P2 – that are expressed in a tissue-specific manner [<a class="bibr" href="#cmtx.REF.neuhaus.1996.239" rid="cmtx.REF.neuhaus.1996.239">Neuhaus et al 1996</a>]. The P1 promotor is upstream of the P2 promotor and each promoter produces a transcript with a unique noncoding exon 1 and the entire coding sequence in a single exon 2. It is thought that only the P2 promoted transcript (NM_000166) is expressed in Schwann cells. Therefore, noncoding variants that fall outside of this transcript and its regulatory regions are highly unlikely to be causal for CMT1X. (Note that in the literature the first [P1 promoted] exon is sometimes referred to as 1A, the second [P2 promoted] exon as 1B, and the third coding exon as exon 2.) As noted and referenced in <a href="#cmtx.Establishing_the_Diagnosis">Establishing the Diagnosis</a>, pathogenic variants have been identified in the upstream regulatory region, 5' untranslated region, splice between exon one and exon two, and 3' untranslated region of NM_000166.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcmtxTnotablegjb1pathogenicvariants"><a href="/books/NBK1374/table/cmtx.T.notable_gjb1_pathogenic_variants/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobcmtxTnotablegjb1pathogenicvariants"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cmtx.T.notable_gjb1_pathogenic_variants"><a href="/books/NBK1374/table/cmtx.T.notable_gjb1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobcmtxTnotablegjb1pathogenicvariants">Table 4. </a></h4><p class="float-caption no_bottom_margin">Notable <i>GJB1</i> Pathogenic Variants </p></div></div></div><div id="cmtx.Chapter_Notes"><h2 id="_cmtx_Chapter_Notes_">Chapter Notes</h2><div id="cmtx.Author_Notes"><h3>Author Notes</h3><p>
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<a href="https://chicago.medicine.uic.edu/departments/academic-departments/neurology-rehabilitation/neurology-research-clinical-research-epidemiology/dr-charles-abrams-lab/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Author's laboratory website</a>
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</p><p>Charles K Abrams directs a laboratory at the University of Illinois College of Medicine at Chicago (UIC) studying the role of connexins including connexin 32 in the central and peripheral nervous system. A major area of focus is understanding how pathogenic variants in <i>GJB1</i> cause CMT1X. He also directs the CMTA association sponsored inherited peripheral neuropathies clinic at UIC.</p></div><div id="cmtx.Acknowledgments"><h3>Acknowledgments</h3><p>Dr Abrams acts as a paid consultant for Atheneum Partners, Sarepta Therapeutics, and Stealth Biotherapeutics. Dr Abrams' work on CMT1X is supported by grants from the MDA, CMTA, and NIH.</p></div><div id="cmtx.Author_History"><h3>Author History</h3><p>Charles K Abrams, MD, PhD (2020-present)<br />Thomas D Bird, MD; Seattle VA Medical Center (1998-2020)</p></div><div id="cmtx.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>25 April 2024 (tb) Revision: add new findings from <a class="bibr" href="#cmtx.REF.record.2023.4336" rid="cmtx.REF.record.2023.4336">Record et al [2023]</a></div></li><li class="half_rhythm"><div>20 February 2020 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>15 April 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>26 June 2007 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>15 April 2005 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>10 April 2003 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>25 August 2000 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>18 June 1998 (pb) Review posted live</div></li><li class="half_rhythm"><div>April 1996 (tb) Original submission</div></li></ul></div></div><div id="cmtx.References"><h2 id="_cmtx_References_">References</h2><div id="cmtx.Published_Guidelines__Consensus_Sta"><h3>Published Guidelines / Consensus Statements</h3><ul class="simple-list"><li class="half_rhythm"><div>Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available <a href="https://pediatrics.aappublications.org/content/131/3/620.full.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">online</a>. 2013. Accessed 1-19-22.</div></li><li class="half_rhythm"><div>National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available <a href="https://www.nsgc.org/Policy-Research-and-Publications/Position-Statements/Position-Statements/Post/genetic-testing-of-minors-for-adult-onset-conditions" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">online</a>. 2018. Accessed 1-19-22.</div></li></ul></div><div id="cmtx.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.abdipranoto.2003.2177">Abdipranoto
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A, Liu
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GJ, Werry
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EL, Bennett
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MR. Mechanisms of secretion of ATP from cortical astrocytes triggered by uridine triphosphate.
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Neuroreport.
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2003;14:2177-81.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/14625443" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14625443</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.abrams.2019.91">Abrams
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CK. Diseases of connexins expressed in myelinating glia.
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Neurosci Lett.
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2019;695:91-9.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/28545922" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28545922</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.abrams.2002.3980">Abrams
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CK, Bennett
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MV, Verselis
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VK, Bargiello
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TA. Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked Charcot-Marie-Tooth disease.
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Proc Natl Acad Sci U S A.
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2002;99:3980-4.
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[<a href="/pmc/articles/PMC122634/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC122634</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11891346" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11891346</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.abrams.2015.659">Abrams
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CK, Freidin
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M. GJB1-associated X-linked Charcot-Marie-Tooth disease, a disorder affecting the central and peripheral nervous systems.
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Cell Tissue Res.
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2015;360:659-73.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/25370202" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25370202</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.abrams.2003.10548">Abrams
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CK, Freidin
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M, Bukauskas
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F, Dobrenis
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K, Bargiello
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TA, Verselis
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VK, Bennett
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MV, Chen
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L, Sahenk
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Z. Pathogenesis of X-linked Charcot-Marie-Tooth disease: differential effects of two mutations in connexin 32.
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J Neurosci.
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2003;23:10548-58.
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[<a href="/pmc/articles/PMC4513672/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4513672</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14627639" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14627639</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.abrams.2013.3609">Abrams
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CK, Islam
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M, Mahmoud
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R, Kwon
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T, Bargiello
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TA, Freidin
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MM. Functional requirement for a highly conserved charged residue at position 75 in the gap junction protein connexin 32.
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J Biol Chem.
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2013;288:3609-19.
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[<a href="/pmc/articles/PMC3561579/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3561579</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23209285" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23209285</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.abrams.2000.203">Abrams
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CK, Oh
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S, Ri
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Y, Bargiello
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TA. Mutations in connexin 32: the molecular and biophysical bases for the X-linked form of Charcot-Marie-Tooth disease.
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Brain Res Brain Res Rev.
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2000;32:203-14.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/10751671" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10751671</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.ainsworth.1998.242">Ainsworth
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PJ, Bolton
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CF, Murphy
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BC, Stuart
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JA, Hahn
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AF. Genotype/phenotype correlation in affected individuals of a family with a deletion of the entire coding sequence of the connexin 32 gene.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/15827866" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15827866</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.siskind.2009.109">Siskind
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H, Nakagawa
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[<a href="https://pubmed.ncbi.nlm.nih.gov/12542510" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12542510</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.taylor.2003.1475">Taylor
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RA, Simon
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SS. The CNS phenotype of X-linked Charcot-Marie-Tooth disease: more than a peripheral problem.
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PJ, Rossor
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AM, Horga
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A, Jaunmuktane
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Z, Carr
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A, Saveri
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P, Piscosquito
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G, Pareyson
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D, Laura
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MM. Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT.
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[<a href="/pmc/articles/PMC5386440/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5386440</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28283593" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28283593</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.tsai.2013.51">Tsai
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PC, Chen
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CH, Liu
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AB, Chen
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YC, Soong
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BW, Lin
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KP, Yet
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YC. Mutational analysis of the 5' non-coding region of GJB1 in a Taiwanese cohort with Charcot-Marie-Tooth neuropathy.
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J Neurol Sci.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/23827825" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23827825</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.vital.2001.79">Vital
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A, Ferrer
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X, Lagueny
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A, Vandenberghe
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A, Latour
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P, Goizet
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C, Canron
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MH, Louiset
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P, Petry
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KG, Vital
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C. Histopathological features of X-linked Charcot-Marie-Tooth disease in 8 patients from 6 families with different connexin32 mutations.
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J Peripher Nerv Syst.
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2001;6:79-84.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/11446387" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11446387</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.yuan.2018.1454">Yuan
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JH, Sakiyama
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Y, Hashiguchi
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A, Ando
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M, Okamoto
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Y, Yoshimura
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H. Genetic and phenotypic profile of 112 patients with X-linked Charcot-Marie-Tooth disease type 1.
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2018;25:1454-61.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/29998508" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29998508</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.yum.2002.43">Yum
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SW, Kleopa
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KA, Shumas
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S, Scherer
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SS. Diverse trafficking abnormalities of connexin32 mutants causing CMTX.
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Neurobiol Dis.
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2002;11:43-52.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/12460545" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12460545</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmtx.REF.zambelis.2008.44">Zambelis
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T, Panas
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M, Kokotis
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P, Karadima
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G, Kararizou
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E, Karandreas
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N. Central motor and sensory pathway involvement in an X-linked Charcot-Marie-Tooth family.
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Acta Neurol Belg.
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2008;108:44-7.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/18795595" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18795595</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1374_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Charles K Abrams</span>, MD, PhD<div class="affiliation small">Department of Neurology and Rehabilitation<br />University of Illinois at Chicago College of Medicine<br />Chicago, Illinois<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.ciu@1smarbac" class="oemail">ude.ciu@1smarbac</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">June 18, 1998</span>; Last Revision: <span itemprop="dateModified">April 25, 2024</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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a registered trademark of the University of Washington, Seattle. All rights
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reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
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hereby granted to reproduce, distribute, and translate copies of content materials for
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noncommercial research purposes only, provided that (i) credit for source (<a href="http://www.genereviews.org/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">http://www.genereviews.org/</a>) and copyright (© 1993-2025 University of
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Washington) are included with each copy; (ii) a link to the original material is provided
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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Disclaimer</a>. No further modifications are allowed. For clarity, excerpts
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of GeneReviews chapters for use in lab reports and clinic notes are a permitted
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use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Abrams CK. GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes. 1998 Jun 18 [Updated 2024 Apr 25]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/cmt-4a/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/dfnb1/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobcmtxTmoleculargenetictestingusedin"><div id="cmtx.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>GJB1</i> Charcot-Marie-Tooth Neuropathy with or without CNS Dysfunction (CMT1X)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1374/table/cmtx.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmtx.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cmtx.T.molecular_genetic_testing_used_in_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_cmtx.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_cmtx.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_cmtx.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GJB1</i>
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</td><td headers="hd_h_cmtx.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3, 4</sup></td><td headers="hd_h_cmtx.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>99% <sup>4, 5</sup></td></tr><tr><td headers="hd_h_cmtx.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>6</sup></td><td headers="hd_h_cmtx.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare <sup>7</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="cmtx.TF.1.1"><p class="no_margin">See <a href="/books/NBK1374/?report=reader#cmtx.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="cmtx.TF.1.2"><p class="no_margin">See <a href="#cmtx.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="cmtx.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="cmtx.TF.1.4"><p class="no_margin"><a class="bibr" href="#cmtx.REF.kulshrestha.2017.766" rid="cmtx.REF.kulshrestha.2017.766">Kulshrestha et al [2017]</a>, <a class="bibr" href="#cmtx.REF.panosyan.2017.927" rid="cmtx.REF.panosyan.2017.927">Panosyan et al [2017]</a>, <a class="bibr" href="#cmtx.REF.yuan.2018.1454" rid="cmtx.REF.yuan.2018.1454">Yuan et al [2018]</a>, <a class="bibr" href="#cmtx.REF.hsu.2019.1090" rid="cmtx.REF.hsu.2019.1090">Hsu et al [2019]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="cmtx.TF.1.5"><p class="no_margin">Note, disease-associated variants in the upstream regulatory region, 5'UTR, non-coding exons, and 3'UTR are frequently associated with disease; therefore, sequence analysis should include these regions [<a class="bibr" href="#cmtx.REF.tomaselli.2017.1445" rid="cmtx.REF.tomaselli.2017.1445">Tomaselli et al 2017</a>]. See <a href="#cmtx.Molecular_Genetics">Molecular Genetics</a> for additional details.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="cmtx.TF.1.6"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="cmtx.TF.1.7"><p class="no_margin"><a class="bibr" href="#cmtx.REF.ainsworth.1998.242" rid="cmtx.REF.ainsworth.1998.242">Ainsworth et al [1998]</a>, <a class="bibr" href="#cmtx.REF.nakagawa.2001.31" rid="cmtx.REF.nakagawa.2001.31">Nakagawa et al [2001]</a>, <a class="bibr" href="#cmtx.REF.takashima.2003.31" rid="cmtx.REF.takashima.2003.31">Takashima et al [2003]</a>, <a class="bibr" href="#cmtx.REF.gonzagajauregui.2010.465" rid="cmtx.REF.gonzagajauregui.2010.465">Gonzaga-Jauregui et al [2010]</a>, <a class="bibr" href="#cmtx.REF.capponi.2015.406" rid="cmtx.REF.capponi.2015.406">Capponi et al [2015]</a></p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcmtxTrecommendedevaluationsfollowing"><div id="cmtx.T.recommended_evaluations_following" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with CMT1X</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1374/table/cmtx.T.recommended_evaluations_following/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmtx.T.recommended_evaluations_following_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cmtx.T.recommended_evaluations_following_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_cmtx.T.recommended_evaluations_following_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_cmtx.T.recommended_evaluations_following_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_cmtx.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_cmtx.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_cmtx.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To determine extent of weakness & atrophy, <i>pes cavus</i>, gait stability, & sensory loss</div></li><li class="half_rhythm"><div>To evaluate for pain</div></li><li class="half_rhythm"><div>To evaluate for less common fixed manifestations (e.g., spasticity, hyperreflexia, ataxia)</div></li><li class="half_rhythm"><div>To determine if affected person &/or any family member has had episodes of acute transient neurologic dysfunction</div></li></ul>
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</td></tr><tr><td headers="hd_h_cmtx.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Musculoskeletal</b>
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</td><td headers="hd_h_cmtx.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT/OT eval</td><td headers="hd_h_cmtx.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl assessment of:
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<ul><li class="half_rhythm"><div>Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)</div></li><li class="half_rhythm"><div>Feet for evidence of <i>pes cavus</i>, need for AFOs, specialized shoes</div></li><li class="half_rhythm"><div>Mobility, activities of daily living, & need for adaptive devices</div></li><li class="half_rhythm"><div>Need for handicapped parking</div></li></ul>
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</td></tr><tr><td headers="hd_h_cmtx.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hearing</b>
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</td><td headers="hd_h_cmtx.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic eval</td><td headers="hd_h_cmtx.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for hearing loss if concerns</td></tr><tr><td headers="hd_h_cmtx.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Miscellaneous/</b>
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<br />
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<b>Other</b>
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</td><td headers="hd_h_cmtx.T.recommended_evaluations_following_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_cmtx.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl genetic counseling</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">OT = occupational therapy; PT = physical therapy</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcmtxTrecommendedsurveillanceforindi"><div id="cmtx.T.recommended_surveillance_for_indi" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with CMT1X</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1374/table/cmtx.T.recommended_surveillance_for_indi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmtx.T.recommended_surveillance_for_indi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cmtx.T.recommended_surveillance_for_indi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_cmtx.T.recommended_surveillance_for_indi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_cmtx.T.recommended_surveillance_for_indi_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_cmtx.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_cmtx.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Screening neurologic exam focused on motor system & cerebellar function</div></li><li class="half_rhythm"><div>Eval for pain</div></li></ul>
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</td><td headers="hd_h_cmtx.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_cmtx.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Musculoskeletal</b>
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</td><td headers="hd_h_cmtx.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>PT (gross motor skills) & ADL</div></li><li class="half_rhythm"><div>OT (fine motor skills) & ADL</div></li></ul>
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</td></tr><tr><td headers="hd_h_cmtx.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Foot exam</b>
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</td><td headers="hd_h_cmtx.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For pressure sores or poorly fitting footwear</td><td headers="hd_h_cmtx.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually by physician; more often by affected person</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">ADL = activities of daily living; OT = occupational therapy; PT = physical therapy</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcmtxmolgenTA"><div id="cmtx.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1374/table/cmtx.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmtx.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_cmtx.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_cmtx.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_cmtx.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_cmtx.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_cmtx.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_cmtx.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_cmtx.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/2705" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>GJB1</i>
|
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</a>
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</td><td headers="hd_b_cmtx.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=2705" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Xq13<wbr style="display:inline-block"></wbr>​.1</a>
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</td><td headers="hd_b_cmtx.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/P08034" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Gap junction beta-1 protein</a>
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</td><td headers="hd_b_cmtx.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://databases.lovd.nl/shared/genes/GJB1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GJB1 homepage - Leiden Muscular Dystrophy pages</a>
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<br />
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<a href="http://hihg.med.miami.edu/code/http/cmt/public_html/index.html#/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Inherited Neuropathy Variant Browser</a>
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<br />
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<a href="http://perelman.crg.es/deafness/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">The Connexin-deafness homepage (GJB1)</a>
|
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</td><td headers="hd_b_cmtx.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GJB1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GJB1</a>
|
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</td><td headers="hd_b_cmtx.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=GJB1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GJB1</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="cmtx.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
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chromosome locus from
|
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcmtxmolgenTB"><div id="cmtx.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes (<a href="/omim/302800,304040" 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/NBK1374/table/cmtx.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmtx.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<a href="/omim/302800" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">302800</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CHARCOT-MARIE-TOOTH DISEASE, X-LINKED DOMINANT, 1; CMTX1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/304040" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">304040</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GAP JUNCTION PROTEIN, BETA-1; GJB1</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobcmtxTnotablegjb1pathogenicvariants"><div id="cmtx.T.notable_gjb1_pathogenic_variants" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Notable <i>GJB1</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1374/table/cmtx.T.notable_gjb1_pathogenic_variants/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmtx.T.notable_gjb1_pathogenic_variants_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference<br />Sequences</th><th id="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA<br />Nucleotide<br />Change (Alias <sup>1</sup>)</th><th id="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted<br />Protein<br />Change</th><th id="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000166.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000166<wbr style="display:inline-block"></wbr>​.5</a>
|
|
</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.-103C>T<br />(-459C>T)</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent pathogenic variant in noncoding exon (1B) [<a class="bibr" href="#cmtx.REF.ionasescu.1996b.541" rid="cmtx.REF.ionasescu.1996b.541">Ionasescu et al 1996b</a>, <a class="bibr" href="#cmtx.REF.li.2009.14" rid="cmtx.REF.li.2009.14">Li et al 2009</a>, <a class="bibr" href="#cmtx.REF.tsai.2013.51" rid="cmtx.REF.tsai.2013.51">Tsai et al 2013</a>, <a class="bibr" href="#cmtx.REF.tomaselli.2017.1445" rid="cmtx.REF.tomaselli.2017.1445">Tomaselli et al 2017</a>]</td></tr><tr><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.-17G>A</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most common noncoding pathogenic variant in a large international study (4% of total) at splice site [<a class="bibr" href="#cmtx.REF.panosyan.2017.927" rid="cmtx.REF.panosyan.2017.927">Panosyan et al 2017</a>]; phenotype is more severe than the phenotypes assoc w/a number of single-nucleotide variants [<a class="bibr" href="#cmtx.REF.record.2023.4336" rid="cmtx.REF.record.2023.4336">Record et al 2023</a>].</td></tr><tr><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_1" rowspan="9" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000166.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000166<wbr style="display:inline-block"></wbr>​.5</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000157.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000157<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.44G>A</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg15Gln</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most common coding pathogenic variant ~7% of total in a large international study [<a class="bibr" href="#cmtx.REF.panosyan.2017.927" rid="cmtx.REF.panosyan.2017.927">Panosyan et al 2017</a>]</td></tr><tr><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.65G>A</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg22Gln</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Observed in 2 unrelated cases w/stroke-like episodes [<a class="bibr" href="#cmtx.REF.srinivasan.2008.293" rid="cmtx.REF.srinivasan.2008.293">Srinivasan et al 2008</a>, <a class="bibr" href="#cmtx.REF.rosser.2010.1013" rid="cmtx.REF.rosser.2010.1013">Rosser et al 2010</a>]</td></tr><tr><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.223C>T</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg75Trp</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Observed in 3 unrelated cases w/stroke-like episodes [<a class="bibr" href="#cmtx.REF.taylor.2003.1475" rid="cmtx.REF.taylor.2003.1475">Taylor et al 2003</a>; <a class="bibr" href="#cmtx.REF.parissis.2017.234" rid="cmtx.REF.parissis.2017.234">Parissis et al 2017</a>; SS Scherer, personal communication]</td></tr><tr><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.283G>A</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val95Met</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Apparently common pathogenic variant in Korea (6/63 families) [<a class="bibr" href="#cmtx.REF.hong.2017.172" rid="cmtx.REF.hong.2017.172">Hong et al 2017</a>]</td></tr><tr><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.415G>A</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val139Met</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2 unrelated cases w/stroke like episodes [<a class="bibr" href="#cmtx.REF.halbrich.2008.372" rid="cmtx.REF.halbrich.2008.372">Halbrich et al 2008</a>, <a class="bibr" href="#cmtx.REF.almateen.2014.342" rid="cmtx.REF.almateen.2014.342">Al-Mateen et al 2014</a>]</td></tr><tr><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.424C>T</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg142Trp</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Observed in 3 unrelated cases w/stroke-like episodes [<a class="bibr" href="#cmtx.REF.paulson.2002.429" rid="cmtx.REF.paulson.2002.429">Paulson et al 2002</a>; SS Scherer, personal communication]</td></tr><tr><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.425G>A</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg142Gln</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Observed in 2 unrelated cases w/stroke-like episodes [<a class="bibr" href="#cmtx.REF.kulkarni.2015.111" rid="cmtx.REF.kulkarni.2015.111">Kulkarni et al 2015</a>, <a class="bibr" href="#cmtx.REF.lu.2017.1049" rid="cmtx.REF.lu.2017.1049">Lu et al 2017</a>]</td></tr><tr><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.490C>T</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg164Trp</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Observed in 2 unrelated cases w/stroke-like episodes [<a class="bibr" href="#cmtx.REF.schelhaas.2002.2007" rid="cmtx.REF.schelhaas.2002.2007">Schelhaas et al 2002</a>, <a class="bibr" href="#cmtx.REF.isoardo.2005.1672" rid="cmtx.REF.isoardo.2005.1672">Isoardo et al 2005</a>]; common pathogenic variant in Korea (4/63 families) [<a class="bibr" href="#cmtx.REF.hong.2017.172" rid="cmtx.REF.hong.2017.172">Hong et al 2017</a>]</td></tr><tr><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.491G>A</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg164Gln</td><td headers="hd_h_cmtx.T.notable_gjb1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Apparently common pathogenic variant in Korea (5/63 families) [<a class="bibr" href="#cmtx.REF.hong.2017.172" rid="cmtx.REF.hong.2017.172">Hong et al 2017</a>]</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the author. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="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/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="cmtx.TF.4.1"><p class="no_margin">Variant designation that does not conform to current naming conventions</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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