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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>GDAP1-Related Hereditary Motor and Sensory Neuropathy - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="GDAP1-Related Hereditary Motor and Sensory Neuropathy">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2017/03/30">
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<meta name="citation_author" content="Thomas D Bird">
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<meta name="citation_pmid" content="20301711">
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<meta name="citation_keywords" content="GDAP1-HMSN">
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<meta name="citation_keywords" content="GDAP1-Related Charcot-Marie-Tooth Neuropathy">
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<meta name="citation_keywords" content="GDAP1-HMSN">
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<meta name="citation_keywords" content="GDAP1-Related Charcot-Marie-Tooth Neuropathy">
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<meta name="citation_keywords" content="Ganglioside-induced differentiation-associated protein 1">
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<meta name="citation_keywords" content="GDAP1">
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<meta name="citation_keywords" content="GDAP1-Related Hereditary Motor and Sensory Neuropathy">
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<meta name="DC.Title" content="GDAP1-Related Hereditary Motor and Sensory Neuropathy">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Thomas D Bird">
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<meta name="DC.Date" content="2017/03/30">
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<meta name="description" content="GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is a peripheral neuropathy (also known as a subtype of Charcot-Marie-Tooth disease) that typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Proximal muscles can also become weak. Age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.">
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<meta name="og:title" content="GDAP1-Related Hereditary Motor and Sensory Neuropathy">
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<meta name="og:description" content="GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is a peripheral neuropathy (also known as a subtype of Charcot-Marie-Tooth disease) that typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Proximal muscles can also become weak. Age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.">
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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="_NBK1539_"><span class="title" itemprop="name"><i>GDAP1</i>-Related Hereditary Motor and Sensory Neuropathy</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: <i>GDAP1</i>-HMSN, <i>GDAP1</i>-Related Charcot-Marie-Tooth Neuropathy</div><p class="contribs">Bird TD.</p><p class="fm-aai"><a href="#_NBK1539_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 22 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="cmt-4a.Summary" itemprop="description"><h2 id="_cmt-4a_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>GDAP1</i>-related hereditary motor and sensory neuropathy (<i>GDAP1</i>-HMSN) is a peripheral neuropathy (also known as a subtype of Charcot-Marie-Tooth disease) that typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Proximal muscles can also become weak. Age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>Diagnosis of <i>GDAP1</i>-HMSN is based on clinical findings and confirmed by detection on molecular genetic testing of either biallelic pathogenic variants in <i>GDAP1</i> in those with autosomal recessive inheritance or a heterozygous pathogenic variant in those with autosomal dominant inheritance.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Treatment is symptomatic and involves evaluation and management by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. Treatment may include: daily heel cord stretching exercises to prevent Achilles tendon shortening, ankle/foot orthoses, orthopedic surgery, forearm crutches or canes, wheelchairs, treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents, and career and employment counseling.</p><p><i>Surveillance</i>: Regular evaluation by the multidisciplinary team to determine neurologic status and functional disability.</p><p><i>Agents/circumstances to avoid:</i> Drugs and medications known to cause nerve damage; obesity.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>GDAP1</i>-HMSN is usually inherited in an autosomal recessive (AR) manner; autosomal dominant (AD) inheritance is also observed.</p><ul><li class="half_rhythm"><div><i>AR inheritance:</i> At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible once the pathogenic variants in an affected family member have been identified.</div></li><li class="half_rhythm"><div><i>AD inheritance:</i> Offspring of an individual with AD <i>GDAP1</i>-HMSN have a 50% risk of inheriting the <i>GDAP1</i> pathogenic variant from their affected parent.</div></li></ul><p>Prenatal testing for pregnancies at increased risk for <i>GDAP1</i>-HMSN and preimplantation genetic testing are possible for families in which the pathogenic variant(s) have been identified.</p></div></div><div id="cmt-4a.GeneReview_Scope"><h2 id="_cmt-4a_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcmt4aTc"><a href="/books/NBK1539/table/cmt-4a.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobcmt4aTc"><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="cmt-4a.Tc"><a href="/books/NBK1539/table/cmt-4a.Tc/?report=objectonly" target="object" rid-ob="figobcmt4aTc">Table</a></h4></div></div></div><div id="cmt-4a.Diagnosis"><h2 id="_cmt-4a_Diagnosis_">Diagnosis</h2><div id="cmt-4a.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>GDAP1</i>-related hereditary motor and sensory neuropathy (<i>GDAP1</i>-HMSN) <b>should be suspected</b> in individuals with the following clinical and nerve conduction velocity findings.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Early onset of peripheral neuropathy, presenting especially with foot deformities, muscle wasting, and involvement of the sensory nerves resulting in decreased appreciation of touch, pain, and vibration. Proximal weakness usually comes later.</div></li><li class="half_rhythm"><div>Disability within the first and second decade of life consisting of foot deformity, difficulty walking and claw hand deformity.</div></li><li class="half_rhythm"><div>Vocal cord paresis manifest as a hoarse voice</div></li><li class="half_rhythm"><div>Mild-to-moderate scoliosis</div></li><li class="half_rhythm"><div>Occasional involvement of cranial nerves sometimes resulting in facial weakness.</div></li></ul><p>
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<b>Nerve conduction velocities (NCVs)</b>
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</p><ul><li class="half_rhythm"><div>
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<b>Motor NCVs</b>
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</div><ul><li class="half_rhythm"><div>Most commonly are consistent with an axonal neuropathy with normal NCVs and reduced amplitudes [<a class="bibr" href="#cmt-4a.REF.sevilla.2003.2023" rid="cmt-4a.REF.sevilla.2003.2023">Sevilla et al 2003</a>].</div></li><li class="half_rhythm"><div>Occasionally are consistent with either a demyelinating neuropathy with slowed NCVs (<38 m/s) [<a class="bibr" href="#cmt-4a.REF.baxter.2002.21" rid="cmt-4a.REF.baxter.2002.21">Baxter et al 2002</a>, <a class="bibr" href="#cmt-4a.REF.nelis.2002.1865" rid="cmt-4a.REF.nelis.2002.1865">Nelis et al 2002</a>, <a class="bibr" href="#cmt-4a.REF.ammar.2003.720" rid="cmt-4a.REF.ammar.2003.720">Ammar et al 2003</a>, <a class="bibr" href="#cmt-4a.REF.de_sandregiovannoli.2003.e87" rid="cmt-4a.REF.de_sandregiovannoli.2003.e87">De Sandre-Giovannoli et al 2003</a>] or an intermediate range (30-40 m/s) [<a class="bibr" href="#cmt-4a.REF.senderek.2003.642" rid="cmt-4a.REF.senderek.2003.642">Senderek et al 2003</a>].</div></li></ul></li><li class="half_rhythm"><div><b>Sensory NCVs</b> are moderately reduced.</div></li></ul></div><div id="cmt-4a.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of HMSN <b>is established</b> in a proband with typical clinical findings; the diagnosis of <i>GDAP1</i>-HMSN is established by the detection of either biallelic <i>GDAP1</i> pathogenic variants (in those with autosomal recessive inheritance) or a heterozygous <i>GDAP1</i> pathogenic variant pathogenic variant (in those with autosomal dominant inheritance) (see <a href="/books/NBK1539/table/cmt-4a.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobcmt4aTmoleculargenetictestingused">Table 1</a>) on molecular genetic testing.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing or a multigene panel) and <b>genomic testing</b> (comprehensive 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 <i>GDAP1</i>-HMSN is broad, individuals with the distinctive findings described in <a href="#cmt-4a.Suggestive_Findings">Suggestive Findings</a> may be diagnosed using gene-targeted testing (see <a href="#cmt-4a.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other hereditary motor and sensory neuropathies are more likely to be diagnosed using genomic testing (see <a href="#cmt-4a.Option_2">Option 2</a>).</p><div id="cmt-4a.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of <i>GDAP1</i>-HMSN, molecular genetic testing approaches can include <b>single-gene testing</b> or use of a hereditary motor and sensory neuropathy (Charcot-Marie-Tooth disease) <b>multigene panel</b>.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>GDAP1</i> is performed first. If only one pathogenic variant is found, gene-targeted deletion/duplication analysis can be considered; however, to date no exon or whole-gene deletions have been reported.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A hereditary motor and sensory neuropathy (Charcot-Marie-Tooth disease) multigene panel</b> that includes <i>GDAP1</i> and other genes of interest (see <a href="/books/n/gene/cmt/?report=reader">Charcot-Marie-Tooth Hereditary Neuropathy Overview</a> and <a href="#cmt-4a.Differential_Diagnosis">Differential Diagnosis</a>) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some HMSN (CMT) multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Of note, given the rarity of <i>GDAP1</i>-HMSN many panels for HMSN may not include this gene. (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.</div><div class="half_rhythm">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>.</div></li></ul></div><div id="cmt-4a.Option_2"><h4>Option 2</h4><p>When the phenotype is indistinguishable from many other hereditary motor and sensory neuropathies, molecular genetic testing approaches can include <b>comprehensive</b>
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<b>genomic testing</b> (sequencing) and/or <b>gene-targeted testing</b> (multigene panel).</p><ul><li class="half_rhythm"><div><b>Comprehensive genomic testing</b> (when clinically available) includes exome sequencing and genome sequencing. 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>.</div></li><li class="half_rhythm"><div><b>A hereditary motor and sensory neuropathy (Charcot-Marie-Tooth disease) multigene panel</b> may also be consdered.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcmt4aTmoleculargenetictestingused"><a href="/books/NBK1539/table/cmt-4a.T.molecular_genetic_testing_used/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobcmt4aTmoleculargenetictestingused"><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="cmt-4a.T.molecular_genetic_testing_used"><a href="/books/NBK1539/table/cmt-4a.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobcmt4aTmoleculargenetictestingused">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>GDAP1</i>-Related Hereditary Motor and Sensory Neuropathy </p></div></div></div></div></div><div id="cmt-4a.Clinical_Characteristics"><h2 id="_cmt-4a_Clinical_Characteristics_">Clinical Characteristics</h2><div id="cmt-4a.Clinical_Description"><h3>Clinical Description</h3><p><i>GDAP1</i>-related hereditary motor and sensory neuropathy (<i>GDAP1</i>-HMSN) can be inherited in either an autosomal recessive (AR) manner (more common) or an autosomal dominant (AD) manner. The phenotype of AR <i>GDAP1</i>-HMSN is more severe than that of AD <i>GDAP1</i>-HMSN.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcmt4aTcomparisonofautosomalrecessi"><a href="/books/NBK1539/table/cmt-4a.T.comparison_of_autosomal_recessi/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobcmt4aTcomparisonofautosomalrecessi"><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="cmt-4a.T.comparison_of_autosomal_recessi"><a href="/books/NBK1539/table/cmt-4a.T.comparison_of_autosomal_recessi/?report=objectonly" target="object" rid-ob="figobcmt4aTcomparisonofautosomalrecessi">Table 2. </a></h4><p class="float-caption no_bottom_margin">Comparison of Autosomal Recessive and Autosomal Dominant <i>GDAP1</i>-Related Hereditary Motor and Sensory Neuropathy </p></div></div><div id="cmt-4a.Autosomal_Recessive_AR_GDAP1HMSN"><h4>Autosomal Recessive (AR) <i>GDAP1</i>-HMSN</h4><p><b>AR <i>GDAP1</i>-HMSN</b> is an aggressive severe form with early onset and unusual manifestations. The disease is confined to the peripheral nervous system. Intellect is normal.</p><p>When onset of motor nerve involvement is in utero, affected newborns are hypotonic (i.e., a "floppy infant"). Onset can be in infancy, often before age two years. Affected children can show delayed achievement of motor milestones, including walking.</p><p>Initial manifestations are typically in the distal lower extremities, including the following:</p><ul><li class="half_rhythm"><div>Foot deformities (high arch; hammertoe; <i>pes cavus</i> or equinovarus; severe clubfoot deformity [<a class="bibr" href="#cmt-4a.REF.bouhouche.2007.1062" rid="cmt-4a.REF.bouhouche.2007.1062">Bouhouche et al 2007</a>])</div></li><li class="half_rhythm"><div>Muscle wasting</div></li><li class="half_rhythm"><div>Areflexia</div></li><li class="half_rhythm"><div>Sensory loss</div></li></ul><p>Most authors describe early involvement of the upper extremities with distal muscle weakness and wasting and finger contractures (claw hands).</p><p>Sensory involvement leads to decreased appreciation in distal upper and lower limbs of touch, pain, vibration, and joint position.</p><p>In the majority of persons with AR <i>GDAP1</i>-HMSN nerve conduction velocities (NCVs) (see <a href="#cmt-4a.Suggestive_Findings">Suggestive Findings</a>) are consistent with an <b>axonal</b> neuropathy. However, in a few persons NCVs are consistent with either a <b>demyelinating</b> neuropathy or an <b>intermediate-range</b> neuropathy. The clinical manifestations are not consistently distinct among these three neuropathy types.</p><p>As the neuropathy progresses the voice becomes hoarse as a result of vocal cord paresis [<a class="bibr" href="#cmt-4a.REF.sevilla.2003.2023" rid="cmt-4a.REF.sevilla.2003.2023">Sevilla et al 2003</a>, <a class="bibr" href="#cmt-4a.REF.stojkovic.2004.261" rid="cmt-4a.REF.stojkovic.2004.261">Stojkovic et al 2004</a>]. In some series, vocal cord paresis has been reported more often with axonal neuropathy than with demyelinating neuropathy [<a class="bibr" href="#cmt-4a.REF.cuesta.2002.22" rid="cmt-4a.REF.cuesta.2002.22">Cuesta et al 2002</a>], whereas in other series the converse has been observed [<a class="bibr" href="#cmt-4a.REF.boerkoel.2003.400" rid="cmt-4a.REF.boerkoel.2003.400">Boerkoel et al 2003</a>].</p><p>Rare manifestations of AR <i>GDAP1</i>-related neuropathy include the following:</p><ul><li class="half_rhythm"><div>Spinal deformities [<a class="bibr" href="#cmt-4a.REF.birouk.2003.598" rid="cmt-4a.REF.birouk.2003.598">Birouk et al 2003</a>, <a class="bibr" href="#cmt-4a.REF.de_sandregiovannoli.2003.e87" rid="cmt-4a.REF.de_sandregiovannoli.2003.e87">De Sandre-Giovannoli et al 2003</a>, <a class="bibr" href="#cmt-4a.REF.sevilla.2003.2023" rid="cmt-4a.REF.sevilla.2003.2023">Sevilla et al 2003</a>]</div></li><li class="half_rhythm"><div>Facial weakness [<a class="bibr" href="#cmt-4a.REF.boerkoel.2003.400" rid="cmt-4a.REF.boerkoel.2003.400">Boerkoel et al 2003</a>]</div></li><li class="half_rhythm"><div>Painless lower-leg ulcers [<a class="bibr" href="#cmt-4a.REF.nelis.2002.1865" rid="cmt-4a.REF.nelis.2002.1865">Nelis et al 2002</a>]</div></li></ul><p>Progression of the neuropathy leads to disability of the lower and upper extremities. At the end of the second decade, most individuals are wheelchair bound. Phrenic nerve paresis has sometimes led to restrictive respiratory function [<a class="bibr" href="#cmt-4a.REF.sevilla.2008.3051" rid="cmt-4a.REF.sevilla.2008.3051">Sevilla et al 2008</a>]. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.</p><p>Although persons with AR <i>GDAP1-HMSN</i> are usually more severely affected than those with AD inheritance, <a class="bibr" href="#cmt-4a.REF.kabzi_ska.2010.357" rid="cmt-4a.REF.kabzi_ska.2010.357">Kabzińska et al [2010]</a> reported a founder variant in Europe (p.Leu239Phe) associated with a milder phenotype.</p><p>Intrafamilial variability in disease progression was observed in one family in which the proband was wheelchair bound by age 20 years and his sister remained ambulatory with a crutch at age 26 years [<a class="bibr" href="#cmt-4a.REF.azzedine.2003.341" rid="cmt-4a.REF.azzedine.2003.341">Azzedine et al 2003</a>].</p><p>Heterozygotes in families with AR <i>GDAP1</i>-HMSN are usually unaffected; however, exceptions are two families with the p.Glu222Lys pathogenic variant in which some heterozygotes had mild manifestations [<a class="bibr" href="#cmt-4a.REF.kabzi_ska.2014.739" rid="cmt-4a.REF.kabzi_ska.2014.739">Kabzińska et al 2014</a>].</p><p><b>Neuropathology.</b> Both demyelinating and axonal peripheral nerve lesions have been observed. Prominent loss of medium-sized and large myelinated fibers has been described [<a class="bibr" href="#cmt-4a.REF.nelis.2002.1865" rid="cmt-4a.REF.nelis.2002.1865">Nelis et al 2002</a>, <a class="bibr" href="#cmt-4a.REF.ammar.2003.720" rid="cmt-4a.REF.ammar.2003.720">Ammar et al 2003</a>, <a class="bibr" href="#cmt-4a.REF.boerkoel.2003.400" rid="cmt-4a.REF.boerkoel.2003.400">Boerkoel et al 2003</a>, <a class="bibr" href="#cmt-4a.REF.sevilla.2003.2023" rid="cmt-4a.REF.sevilla.2003.2023">Sevilla et al 2003</a>]. Onion bulb formations as well as thinly myelinated and unmyelinated axons have been observed [<a class="bibr" href="#cmt-4a.REF.nelis.2002.1865" rid="cmt-4a.REF.nelis.2002.1865">Nelis et al 2002</a>, <a class="bibr" href="#cmt-4a.REF.de_sandregiovannoli.2003.e87" rid="cmt-4a.REF.de_sandregiovannoli.2003.e87">De Sandre-Giovannoli et al 2003</a>]. In one study, findings were interpreted as an intermediate type of neuropathy [<a class="bibr" href="#cmt-4a.REF.senderek.2003.642" rid="cmt-4a.REF.senderek.2003.642">Senderek et al 2003</a>]. Focally folded myelin is not a feature.</p></div><div id="cmt-4a.Autosomal_Dominant_AD_GDAP1HMSN"><h4>Autosomal Dominant (AD) <i>GDAP1</i>-HMSN</h4><p><b>AD <i>GDAP1</i>-HMSN</b> – compared with AR <i>GDAP1</i>-HMSN – is typically associated with a milder phenotype that is slowly progressive.</p><p>AD <i>GDAP1</i>-HMSN has been reported in the following:</p><ul><li class="half_rhythm"><div>Three Spanish families. In two families segregating the variant <a href="/books/NBK1539/table/cmt-4a.T.selected_gdap1_pathogenic_varia/?report=objectonly" target="object" rid-ob="figobcmt4aTselectedgdap1pathogenicvaria">p.Arg120Trp</a> and in a third family the variant <a href="/books/NBK1539/table/cmt-4a.T.selected_gdap1_pathogenic_varia/?report=objectonly" target="object" rid-ob="figobcmt4aTselectedgdap1pathogenicvaria">p.Thr157Pro</a> occurred <i>de novo</i> in the proband (whose paternity was confirmed) [<a class="bibr" href="#cmt-4a.REF.claramunt.2005.358" rid="cmt-4a.REF.claramunt.2005.358">Claramunt et al 2005</a>].</div></li><li class="half_rhythm"><div>Eight families (in which 3 demonstrated reduced penetrance) with four different missense variants, including three families with the variant <a href="/books/NBK1539/table/cmt-4a.T.selected_gdap1_pathogenic_varia/?report=objectonly" target="object" rid-ob="figobcmt4aTselectedgdap1pathogenicvaria">p.Arg120Trp</a> [<a class="bibr" href="#cmt-4a.REF.zimo_.2011.540" rid="cmt-4a.REF.zimo_.2011.540">Zimoń et al 2011</a>]</div></li></ul><p>Onset varies from childhood to late adulthood. Difficulty with walking is the most common initial manifestation. Weakness and atrophy are usually restricted to distal muscles of the upper and lower limbs. Vocal cord paresis and thoracic scoliosis are uncommon. Disease progression is slow; affected persons generally remain ambulatory.</p></div></div><div id="cmt-4a.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Possible genotype-phenotype correlations have been reported but are not common enough to be confirmed. An exception is the founder variant in eastern Europe, <a href="/books/NBK1539/table/cmt-4a.T.selected_gdap1_pathogenic_varia/?report=objectonly" target="object" rid-ob="figobcmt4aTselectedgdap1pathogenicvaria">p.Leu239Phe</a>, which appears to be associated with a comparably milder phenotype [<a class="bibr" href="#cmt-4a.REF.kabzi_ska.2010.357" rid="cmt-4a.REF.kabzi_ska.2010.357">Kabzińska et al 2010</a>].</p><p>The <i>GDAP1</i> pathogenic variant, p.Glu222Lys, may be uniquely associated with both AR <i>GDAP1</i>-HMSN and (in rare cases) AD <i>GDAP1</i>-HMSN [<a class="bibr" href="#cmt-4a.REF.kabzi_ska.2014.739" rid="cmt-4a.REF.kabzi_ska.2014.739">Kabzińska et al 2014</a>].</p><p><b>Co-occurrence of pathogenic variants in genes causing two different types of HMSN.</b> The co-occurrence of two HMSN-related pathogenic variants presumably resulted in an additive effect and suggests consideration of simultaneous variants in two HMSN-related genes as an explanation in unusual or severe cases:</p><ul><li class="half_rhythm"><div><b><i>GDAP1</i> and <i>MFN2.</i></b>
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<a class="bibr" href="#cmt-4a.REF.kosterapruszczyk.2014.242" rid="cmt-4a.REF.kosterapruszczyk.2014.242">Kostera-Pruszczyk et al [2014]</a> reported a child with severe HMSN who was found to be heterozygous for the <i>GDAP1</i> pathogenic variant, <a href="/books/NBK1539/table/cmt-4a.T.selected_gdap1_pathogenic_varia/?report=objectonly" target="object" rid-ob="figobcmt4aTselectedgdap1pathogenicvaria">p.His123Arg</a>, and the <i>MFN2</i> pathogenic variant, p.Thr236Met<i>.</i> The co-occurrence of pathogenic variants in these two genes was also reported by <a class="bibr" href="#cmt-4a.REF.cassereau.2011.1524" rid="cmt-4a.REF.cassereau.2011.1524">Cassereau et al [2011]</a> and <a class="bibr" href="#cmt-4a.REF.vital.2012.735" rid="cmt-4a.REF.vital.2012.735">Vital et al [2012]</a>.</div></li><li class="half_rhythm"><div><b><i>GDAP1</i> and <i>PRX</i>.</b>
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<a class="bibr" href="#cmt-4a.REF.auergrumbach.2008.33" rid="cmt-4a.REF.auergrumbach.2008.33">Auer-Grumbach et al [2008]</a> reported two novel <i>GDAP1</i> and <i>PRX</i> variants associated with early-onset HMSN.</div></li></ul></div><div id="cmt-4a.Penetrance"><h3>Penetrance</h3><p>Reduced penetrance has been reported in AD <i>GDAP1</i>-HMSN. Several heterozygotes have been reported to be mildly affected or asymptomatic at an advanced age [<a class="bibr" href="#cmt-4a.REF.zimo_.2011.540" rid="cmt-4a.REF.zimo_.2011.540">Zimoń et al 2011</a>].</p></div><div id="cmt-4a.Nomenclature"><h3>Nomenclature</h3><p>Hereditary motor and sensory neuropathy is most commonly referred to by the eponymous name, "Charcot-Marie-Tooth (CMT) neuropathy" or "Charcot-Marie-Tooth disease."</p><p>Based on an older classification system in which subtypes were defined by clinical parameters such as mode of inheritance, clinical findings, neuropathy type (defined by electrophysiologic findings), and involved gene, <i>GDAP1</i>-related hereditary motor and sensory neuropathy has been referred to in the past as:</p><ul><li class="half_rhythm"><div>CMT4A, autosomal recessive, demyelinating HMSN</div></li><li class="half_rhythm"><div>CMT2H, autosomal recessive, axonal HMSN</div></li><li class="half_rhythm"><div>CMTRIA, autosomal recessive, intermediate HMSN</div></li><li class="half_rhythm"><div>CMT2K, autosomal dominant, axonal HMSN</div></li></ul><p>However, classification using these clinically defined parameters becomes difficult when pathogenic variants in a single gene (e.g., <i>GDAP1</i>) are associated with more than one mode of inheritance (e.g., both autosomal dominant and autosomal recessive inheritance), and/or more than one neuropathy type (axonal, demyelinating, and/or intermediate). To disambiguate, the general term <i>GDAP1</i>-related hereditary motor and sensory neuropathy (<i>GDAP1</i>-HMSN) is used in this <i>GeneReview</i>. For further review of nomenclature, see the <a href="/books/n/gene/cmt/?report=reader">Charcot-Marie-Tooth Hereditary Neuropathy Overview</a>.</p></div><div id="cmt-4a.Prevalence"><h3>Prevalence</h3><p>Currently, autosomal recessive <i>GDAP1</i>-HMSN is considered one of the most common autosomal recessive hereditary neuropathies.</p><p>Molecular genetic testing has shown the following proportion of individuals with HMSN (also known as CMT) with <i>GDAP1</i> pathogenic variants:</p><ul><li class="half_rhythm"><div>Three of 69 (4.3%) unrelated Czech individuals with autosomal recessive CMT [<a class="bibr" href="#cmt-4a.REF.bar_nkov_.2007.482" rid="cmt-4a.REF.bar_nkov_.2007.482">Baránková et al 2007</a>]</div></li><li class="half_rhythm"><div>Eight of 197 (5.4%) individuals in an Italian population with CMT [<a class="bibr" href="#cmt-4a.REF.manganelli.2014.292" rid="cmt-4a.REF.manganelli.2014.292">Manganelli et al 2014</a>]</div></li><li class="half_rhythm"><div>Five of 174 (2.8%) families from Europe with autosomal recessive CMT screened for thirteen genes known to be associated with AR-HMSN [<a class="bibr" href="#cmt-4a.REF.zimo_.2015.33" rid="cmt-4a.REF.zimo_.2015.33">Zimoń et al 2015</a>]</div></li><li class="half_rhythm"><div>1% of 1000 individuals with an inherited peripheral neuropathy in Japan [<a class="bibr" href="#cmt-4a.REF.yoshimura.2017.274" rid="cmt-4a.REF.yoshimura.2017.274">Yoshimura et al 2017</a>]</div></li></ul></div></div><div id="cmt-4a.Genetically_Related_Allelic_Disor"><h2 id="_cmt-4a_Genetically_Related_Allelic_Disor_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> have been associated with pathogenic variants in <i>GDAP1</i>.</p></div><div id="cmt-4a.Differential_Diagnosis"><h2 id="_cmt-4a_Differential_Diagnosis_">Differential Diagnosis</h2><p>See <a href="/books/n/gene/cmt/?report=reader">Charcot-Marie-Tooth Hereditary Neuropathy Overview</a>.</p><p>Vocal cord paresis, which is often seen in autosomal recessive <i>GDAP1</i>-related HMSN, also occurs in other types of CMT, such as <a href="/books/n/gene/cmt2c/?report=reader"><i>TRPV4</i>-related hereditary neuropathy</a>.</p><p>While AR <i>GDAP1</i>-HMSN is considered one of the most common causes of autosomal recessive CMT, <i>SH3TC2-</i>HMSN is equally common in some studies [<a class="bibr" href="#cmt-4a.REF.rudniksch_neborn.2016.34" rid="cmt-4a.REF.rudniksch_neborn.2016.34">Rudnik-Schöneborn et al 2016</a>].</p></div><div id="cmt-4a.Management"><h2 id="_cmt-4a_Management_">Management</h2><div id="cmt-4a.Evaluations_Following_Initial_Dia"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with a <i>GDAP1</i>-related hereditary motor and sensory neuropathy (<i>GDAP1</i>-HMSN), the following evaluations are recommended:</p><ul><li class="half_rhythm"><div>Neurologic examination to determine extent of weakness and atrophy, <i>pes cavus</i>, gait stability, and sensory loss</div></li><li class="half_rhythm"><div>Physical therapy and occupational therapy assessments regarding muscle weakness and gait and need for ankle foot orthoses, walking aids, and/or a wheelchair [<a class="bibr" href="#cmt-4a.REF.kennedy.2016.317" rid="cmt-4a.REF.kennedy.2016.317">Kennedy et al 2016</a>]</div></li><li class="half_rhythm"><div>Speech therapy assessment if hoarseness is present or vocal cord paresis is suspected</div></li><li class="half_rhythm"><div>Consultation with a clinical geneticist and/or genetic counselor</div></li></ul></div><div id="cmt-4a.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Individuals with <i>GDAP1</i>-HMSN are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [<a class="bibr" href="#cmt-4a.REF.corrado.2016.e3278" rid="cmt-4a.REF.corrado.2016.e3278">Corrado et al 2016</a>, <a class="bibr" href="#cmt-4a.REF.mccorquodale.2016.7" rid="cmt-4a.REF.mccorquodale.2016.7">McCorquodale et al 2016</a>]. Treatment is symptomatic and may include the following [<a class="bibr" href="#cmt-4a.REF.mathis.2015.355" rid="cmt-4a.REF.mathis.2015.355">Mathis et al [2015]</a>:</p><ul><li class="half_rhythm"><div class="half_rhythm">Daily heel cord stretching exercises to prevent Achilles tendon shortening.</div></li><li class="half_rhythm"><div class="half_rhythm">Exercise within the affected individual's capability</div><div class="half_rhythm">Note: (1) Fatigue may improve with exercise; (2) unconfirmed anecdotal observations suggest benefit from the stimulant modafinil [<a class="bibr" href="#cmt-4a.REF.carter.2006.412" rid="cmt-4a.REF.carter.2006.412">Carter et al 2006</a>, <a class="bibr" href="#cmt-4a.REF.ramdharry.2012.s208" rid="cmt-4a.REF.ramdharry.2012.s208">Ramdharry et al 2012</a>].</div></li><li class="half_rhythm"><div class="half_rhythm">Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [<a class="bibr" href="#cmt-4a.REF.guillebastre.2011.619" rid="cmt-4a.REF.guillebastre.2011.619">Guillebastre et al 2011</a>, <a class="bibr" href="#cmt-4a.REF.phillips.2012.534" rid="cmt-4a.REF.phillips.2012.534">Phillips et al 2012</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">Orthopedic surgery to correct severe <i>pes cavus</i> deformity [<a class="bibr" href="#cmt-4a.REF.boffeli.2015.701" rid="cmt-4a.REF.boffeli.2015.701">Boffeli & Tabatt 2015</a>, <a class="bibr" href="#cmt-4a.REF.faldini.2015.e30" rid="cmt-4a.REF.faldini.2015.e30">Faldini et al 2015</a>, <a class="bibr" href="#cmt-4a.REF.ferraro.2017.788" rid="cmt-4a.REF.ferraro.2017.788">Ferraro et al 2017</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">Forearm crutches or canes for gait stability</div></li><li class="half_rhythm"><div class="half_rhythm">Wheelchair for mobility because of gait instability</div></li><li class="half_rhythm"><div class="half_rhythm">Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs [<a class="bibr" href="#cmt-4a.REF.kroenke.2009.206" rid="cmt-4a.REF.kroenke.2009.206">Kroenke et al 2009</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin [<a class="bibr" href="#cmt-4a.REF.shy.2006.255" rid="cmt-4a.REF.shy.2006.255">Shy 2006</a>, <a class="bibr" href="#cmt-4a.REF.bril.2011.910" rid="cmt-4a.REF.bril.2011.910">Bril et al 2011</a>, <a class="bibr" href="#cmt-4a.REF.ribiere.2012.160" rid="cmt-4a.REF.ribiere.2012.160">Ribiere et al 2012</a>, <a class="bibr" href="#cmt-4a.REF.jeong.2013.397" rid="cmt-4a.REF.jeong.2013.397">Jeong et al 2013</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">Weight control to avoid obesity, which has a negative effect on gait and balance</div></li><li class="half_rhythm"><div class="half_rhythm">Career and employment counseling because of persistent weakness of hands and/or feet</div></li><li class="half_rhythm"><div class="half_rhythm">Individual psychotherapy, group therapy, and/or antidepressant medication for depression [<a class="bibr" href="#cmt-4a.REF.cordeiro.2014.185" rid="cmt-4a.REF.cordeiro.2014.185">Cordeiro et al 2014</a>]</div></li></ul><p>Treatment may require involvement of specialists to evaluate and manage potential complications, including the following:</p><ul><li class="half_rhythm"><div>Lower urinary tract involvement [<a class="bibr" href="#cmt-4a.REF.krhut.2014.319" rid="cmt-4a.REF.krhut.2014.319">Krhut et al 2014</a>]</div></li><li class="half_rhythm"><div>Obstructive sleep apnea and restless legs [<a class="bibr" href="#cmt-4a.REF.boentert.2014.319" rid="cmt-4a.REF.boentert.2014.319">Boentert et al 2014</a>]</div></li><li class="half_rhythm"><div>Pulmonary compromise and/or phrenic nerve involvement [<a class="bibr" href="#cmt-4a.REF.aboussouan.2007.1" rid="cmt-4a.REF.aboussouan.2007.1">Aboussouan et al 2007</a>]</div></li><li class="half_rhythm"><div>Vocal cord paresis</div></li><li class="half_rhythm"><div>Hip dysplasia [<a class="bibr" href="#cmt-4a.REF.bamford.2009.408" rid="cmt-4a.REF.bamford.2009.408">Bamford et al 2009</a>, <a class="bibr" href="#cmt-4a.REF.novais.2014.665" rid="cmt-4a.REF.novais.2014.665">Novais et al 2014</a>]</div></li></ul><p>Note: No special diet (including supplements with essential fatty acids, vitamin E, or creatine) has been shown to be beneficial [<a class="bibr" href="#cmt-4a.REF.mathis.2015.355" rid="cmt-4a.REF.mathis.2015.355">Mathis et al 2015</a>].</p></div><div id="cmt-4a.Surveillance"><h3>Surveillance</h3><p>Regular evaluations to determine:</p><ul><li class="half_rhythm"><div>Neurologic status and need for treatment (or change in treatment) for musculoskeletal and/or neuropathic pain;</div></li><li class="half_rhythm"><div>Functional disability and need for change in physical therapy regime and/or augmentative devices for activities of daily living and mobility;</div></li><li class="half_rhythm"><div>Need for change in diet to control weight;</div></li><li class="half_rhythm"><div>Need to involve specialists to evaluate and treat potential complications.</div></li></ul></div><div id="cmt-4a.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>The following should be avoided:</p><ul><li class="half_rhythm"><div>Obesity because of its negative effect on gait and balance</div></li><li class="half_rhythm"><div>Medications that are toxic or potentially toxic to persons with HMSN (CMT) 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> for an up-to-date list.</div></li></ul></div><div id="cmt-4a.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and knowledge about <a href="#cmt-4a.AgentsCircumstances_to_Avoid">agents/circumstances to avoid</a>.</p><p>See <a href="#cmt-4a.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="cmt-4a.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p><a class="bibr" href="#cmt-4a.REF.mathis.2015.355" rid="cmt-4a.REF.mathis.2015.355">Mathis et al [2015]</a> discuss more speculative possible future therapies for HMSN including neurotrophic factors, targeting transport defects, enhancement of autophagy-lysosomal pathways, and neuroregeneration.</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="cmt-4a.Genetic_Counseling"><h2 id="_cmt-4a_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="cmt-4a.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>GDAP1</i>-related hereditary motor and sensory neuropathy (<i>GDAP1</i>-HMSN) is inherited in an autosomal recessive manner (AR <i>GDAP1</i>-HMSN) or, less frequently, autosomal dominant manner (AD <i>GDAP1</i>-HMSN).</p></div><div id="cmt-4a.Autosomal_Recessive_Inheritance"><h3>Autosomal Recessive Inheritance – Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>The parents of a child with AR <i>GDAP1</i>-HMSN are obligate heterozygotes for a <i>GDAP1</i> pathogenic variant.</div></li><li class="half_rhythm"><div>Heterozygotes are typically asymptomatic (see <a href="#cmt-4a.Clinical_Description">Clinical Description</a>).</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not heterozygous.</div></li><li class="half_rhythm"><div>The phenotype is generally consistent among family members with the same genotype; however, intrafamilial variability has been observed in one family with AR <i>GDAP1</i>-HMSN [<a class="bibr" href="#cmt-4a.REF.azzedine.2003.341" rid="cmt-4a.REF.azzedine.2003.341">Azzedine et al 2003</a>].</div></li><li class="half_rhythm"><div>Heterozygotes are typically asymptomatic (see <a href="#cmt-4a.Clinical_Description">Clinical Description</a>).</div></li></ul><p><b>Offspring of a proband.</b> The offspring of an individual with AR <i>GDAP1</i>-HMSN are obligate heterozygotes for a <i>GDAP1</i> pathogenic variant and are typically asymptomatic (see <a href="#cmt-4a.Clinical_Description">Clinical Description</a>).</p><p><b>Other family members.</b> Each sib of the proband's parents are at a 50% risk of being heterozygous for a <i>GDAP1</i> pathogenic variant.</p><div id="cmt-4a.Carrier_Detection"><h4>Carrier Detection</h4><p>Carrier testing for at-risk relatives requires prior identification of the <i>GDAP1</i> pathogenic variants in the family.</p></div></div><div id="cmt-4a.Autosomal_Dominant_Inheritance__R"><h3>Autosomal Dominant Inheritance – Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>Most individuals diagnosed with AD <i>GDAP1</i>-HMSN have an affected parent.</div></li><li class="half_rhythm"><div>The proportion of cases caused by a <i>de novo</i> pathogenic variant is unknown.</div></li><li class="half_rhythm"><div>Molecular genetic testing of the parents for the <i>GDAP1</i> pathogenic variant identified in the proband is recommended.</div></li><li class="half_rhythm"><div>If the <i>GDAP1</i> pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a <i>de novo</i> pathogenic variant in the proband or germline mosaicism in a parent (though theoretically possible, no instances of germline mosaicism have been reported).</div></li></ul><p><b>Sibs of a proband.</b> The risk to the sibs of the proband depends on the genetic status of the proband’s parents:</p><ul><li class="half_rhythm"><div>If a parent of the proband has the <i>GDAP1</i> pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Intrafamilial clinical variability and reduced penetrance have been observed [<a class="bibr" href="#cmt-4a.REF.zimo_.2011.540" rid="cmt-4a.REF.zimo_.2011.540">Zimoń et al 2011</a>].</div></li><li class="half_rhythm"><div>If the <i>GDAP1</i> pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with AD <i>GDAP1</i>-HMSN has a 50% chance of inheriting the pathogenic variant.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: if a parent has the <i>GDAP1</i> pathogenic variant, his or her family members may be at risk.</p></div><div id="cmt-4a.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#cmt-4a.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
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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, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.</div></li></ul></div><div id="cmt-4a.Prenatal_Testing_and_Preimplantat"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>GDAP1</i> pathogenic variant(s) have 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="cmt-4a.Resources"><h2 id="_cmt-4a_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>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>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>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="cmt-4a.Molecular_Genetics"><h2 id="_cmt-4a_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="figcmt4amolgenTA"><a href="/books/NBK1539/table/cmt-4a.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobcmt4amolgenTA"><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="cmt-4a.molgen.TA"><a href="/books/NBK1539/table/cmt-4a.molgen.TA/?report=objectonly" target="object" rid-ob="figobcmt4amolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">GDAP1-Related Hereditary Motor and Sensory Neuropathy: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcmt4amolgenTB"><a href="/books/NBK1539/table/cmt-4a.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobcmt4amolgenTB"><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="cmt-4a.molgen.TB"><a href="/books/NBK1539/table/cmt-4a.molgen.TB/?report=objectonly" target="object" rid-ob="figobcmt4amolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for GDAP1-Related Hereditary Motor and Sensory Neuropathy (View All in OMIM) </p></div></div><p><b>Gene structure.</b>
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<i>GDAP1</i> comprises six exons spanning about 14 kb. For a detailed summary of gene and protein information, see <a href="/books/NBK1539/?report=reader#cmt-4a.molgen.TA">Table A</a>, <b>Gene</b>.</p><p><b>Pathogenic variants.</b> To date, more than 80 pathogenic variants have been identified. Known pathogenic variants include deletions, insertions, and nonsense, missense, and splice site variants throughout the gene (see <a href="/books/NBK1539/?report=reader#cmt-4a.molgen.TA">Table A</a>).</p><p>The following variants have been detected in specific populations:</p><ul><li class="half_rhythm"><div>p.Gln163Ter in a Hispanic population [<a class="bibr" href="#cmt-4a.REF.boerkoel.2003.400" rid="cmt-4a.REF.boerkoel.2003.400">Boerkoel et al 2003</a>]</div></li><li class="half_rhythm"><div>p.Leu239Phe in central and eastern European populations [<a class="bibr" href="#cmt-4a.REF.kabzi_ska.2010.357" rid="cmt-4a.REF.kabzi_ska.2010.357">Kabzińska et al 2010</a>]</div></li></ul><p>Note: A number of <i>GDAP1</i> pathogenic variants associated with AD <i>GDAP1</i>-HMSN (formerly known as CMT2K) have been described. See <a href="/books/n/gene/cmt/?report=reader">CMT Overview</a> [<a class="bibr" href="#cmt-4a.REF.claramunt.2005.358" rid="cmt-4a.REF.claramunt.2005.358">Claramunt et al 2005</a>, <a class="bibr" href="#cmt-4a.REF.chung.2008.360" rid="cmt-4a.REF.chung.2008.360">Chung et al 2008</a>, <a class="bibr" href="#cmt-4a.REF.sahincalapoglu.2009.106" rid="cmt-4a.REF.sahincalapoglu.2009.106">Sahin-Calapoglu et al 2009</a>].</p><p>The <i>GDAP1</i> pathogenic variant, p.Glu222Lys, may be uniquely associated with both AR <i>GDAP1</i>-HMSN and (in rare cases) AD <i>GDAP1</i>-HMSN [<a class="bibr" href="#cmt-4a.REF.kabzi_ska.2014.739" rid="cmt-4a.REF.kabzi_ska.2014.739">Kabzińska et al 2014</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcmt4aTselectedgdap1pathogenicvaria"><a href="/books/NBK1539/table/cmt-4a.T.selected_gdap1_pathogenic_varia/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobcmt4aTselectedgdap1pathogenicvaria"><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="cmt-4a.T.selected_gdap1_pathogenic_varia"><a href="/books/NBK1539/table/cmt-4a.T.selected_gdap1_pathogenic_varia/?report=objectonly" target="object" rid-ob="figobcmt4aTselectedgdap1pathogenicvaria">Table 3. </a></h4><p class="float-caption no_bottom_margin">Selected <i>GDAP1</i> Pathogenic Variants </p></div></div><p><b>Normal gene product.</b> The protein ganglioside-induced differentiation-associated protein-1 comprises 358 amino acids. It contains a glutathione-S-transferase (GST) domain and belongs to a new class of GST-like proteins, which have a transmembrane domain in the C-terminal extension [<a class="bibr" href="#cmt-4a.REF.marco.2004.176" rid="cmt-4a.REF.marco.2004.176">Marco et al 2004</a>]. <a class="bibr" href="#cmt-4a.REF.pedrola.2005.1087" rid="cmt-4a.REF.pedrola.2005.1087">Pedrola et al [2005]</a> investigated a human neuroblastoma cell line that transiently over-expressed GDAP1 and found co-localization with mitochondrial marker proteins. Western blots of subcellular fractions confirmed this finding. They also showed that C-terminal transmembrane domains are necessary for the correct localization in mitochondria; however, missense variants did not change the mitochondrial pattern of the wild-type protein [<a class="bibr" href="#cmt-4a.REF.pedrola.2005.1087" rid="cmt-4a.REF.pedrola.2005.1087">Pedrola et al 2005</a>].</p><p><a class="bibr" href="#cmt-4a.REF.niemann.2005.1067" rid="cmt-4a.REF.niemann.2005.1067">Niemann et al [2005]</a> showed that GDAP1 is located in the mitochondrial outer membrane and regulates the mitochondrial network. GDAP1 induces fragmentation (fission) of mitochondria, the opposite function of mitofusin-2, encoded by <i>MFN2</i>, pathogenic variants in which cause <a href="/books/n/gene/cmt2a/?report=reader">CMT2A</a>.</p><p><b>Abnormal gene product.</b> Loss of ganglioside-induced differentiation-associated protein-1 results in loss of mitochondrial fragmentation activity. Disease-associated missense variants also result in reduced activity [<a class="bibr" href="#cmt-4a.REF.niemann.2005.1067" rid="cmt-4a.REF.niemann.2005.1067">Niemann et al 2005</a>, <a class="bibr" href="#cmt-4a.REF.pareyson.2015.66" rid="cmt-4a.REF.pareyson.2015.66">Pareyson et al 2015</a>]. Pathogenic variants have been reported in all regions of the protein. Variants associated with AR and AD disease include both loss-of-function and missense variants</p></div><div id="cmt-4a.References"><h2 id="_cmt-4a_References_">References</h2><div id="cmt-4a.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.aboussouan.2007.1">Aboussouan LS, Lewis RA, Shy ME. Disorders of pulmonary function, sleep, and the upper airway in Charcot-Marie-Tooth disease. <span><span class="ref-journal">Lung. </span>2007;2007;<span class="ref-vol">185</span>:1–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17294338" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17294338</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.ammar.2003.720">Ammar N, Nelis E, Merlini L, Barisic N, Amouri R, Ceuterick C, Martin JJ, Timmerman V, Hentati F, De Jonghe P. Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease. <span><span class="ref-journal">Neuromuscul Disord. </span>2003;<span class="ref-vol">13</span>:720–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14561495" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14561495</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.auergrumbach.2008.33">Auer-Grumbach M, Fischer C, Papić L, John E, Plecko B, Bittner RE, Bernert G, Pieber TR, Miltenberger G, Schwarz R, Windpassinger C, Grill F, Timmerman V, Speicher MR, Janecke AR. Two novel mutations in the GDAP1 and PRX genes in early onset Charcot-Marie-Tooth syndrome. <span><span class="ref-journal">Neuropediatrics. </span>2008;<span class="ref-vol">39</span>:33–8.</span> [<a href="/pmc/articles/PMC3272394/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3272394</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18504680" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18504680</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.azzedine.2003.341">Azzedine H, Ruberg M, Ente D, Gilardeau C, Périé S, Wechsler B, Brice A, LeGuern E, Dubourg O. Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene. <span><span class="ref-journal">Neuromuscul Disord. </span>2003;<span class="ref-vol">13</span>:341–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12868504" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12868504</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.bamford.2009.408">Bamford NS, White KK, Robinett SA, Otto RK, Gospe SM Jr. Neuromuscular hip dysplasia in Charcot-Marie-Tooth disease type 1A. <span><span class="ref-journal">Dev Med Child Neurol. </span>2009;<span class="ref-vol">51</span>:408–11.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19388151" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19388151</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.bar_nkov_.2007.482">Baránková L, Vyhnálková E, Züchner S, Mazanec R, Sakmaryová I, Vondrácek P, Merlini L, Bojar M, Nelis E, De Jonghe P, Seeman P. GDAP1 mutations in Czech families with early-onset CMT. <span><span class="ref-journal">Neuromuscul Disord. </span>2007;<span class="ref-vol">17</span>:482–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17433678" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17433678</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.baxter.2002.21">Baxter RV, Ben Othmane K, Rochelle JM, Stajich JE, Hulette C, Dew-Knight S, Hentati F, Ben Hamida M, Bel S, Stenger JE, Gilbert JR, Pericak-Vance MA, Vance JM. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. <span><span class="ref-journal">Nat Genet. </span>2002;<span class="ref-vol">30</span>:21–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11743579" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11743579</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.birouk.2003.598">Birouk N, Azzedine H, Dubourg O, Muriel MP, Benomar A, Hamadouche T, Maisonobe T, Ouazzani R, Brice A, Yahyaoui M, Chkili T, Le Guern E. Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene. <span><span class="ref-journal">Arch Neurol. </span>2003;<span class="ref-vol">60</span>:598–604.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12707075" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12707075</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.boentert.2014.319">Boentert M, Knop K, Schuhmacher C, Gess B, Okegwo A, Young P. Sleep disorders in Charcot-Marie-Tooth disease type 1. <span><span class="ref-journal">J Neurol Neurosurg Psychiatry. </span>2014;<span class="ref-vol">85</span>:319–25.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23704315" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23704315</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.boerkoel.2003.400">Boerkoel CF, Takashima H, Nakagawa M, Izumo S, Armstrong D, Butler I, Mancias P, Papasozomenos SC, Stern LZ, Lupski JR. CMT4A: identification of a Hispanic GDAP1 founder mutation. <span><span class="ref-journal">Ann Neurol. </span>2003;<span class="ref-vol">53</span>:400–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12601710" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12601710</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.boffeli.2015.701">Boffeli TJ, Tabatt JA. Minimally invasive early operative treatment of progressive foot and ankle deformity associated with Charcot-Marie-Tooth disease. <span><span class="ref-journal">J Foot Ankle Surg. </span>2015;<span class="ref-vol">54</span>:701–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25131389" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25131389</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.bouhouche.2007.1062">Bouhouche A, Birouk N, Azzedine H, Benomar A, Durosier G, Ente D, Muriel MP, Ruberg M, Slassi I, Yahyaoui M, Dubourg O, Ouazzani R, LeGuern E. Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families. <span><span class="ref-journal">Brain. </span>2007;2007;<span class="ref-vol">130</span>:1062–75.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17347251" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17347251</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.bril.2011.910">Bril V, England JD, Franklin GM, Backonja M, Cohen JA, Del Toro DR, Feldman EL, Iverson DJ, Perkins B, Russell JW, Zochodne DW, et al. Evidence-based guideline: treatment of painful diabetic neuropathy--report of the American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Neurology, and the American Academy of Physical Medicine & Rehabilitation. <span><span class="ref-journal">Muscle Nerve. </span>2011;<span class="ref-vol">43</span>:910–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21484835" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21484835</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.carter.2006.412">Carter GT, Han JJ, Mayadev A, Weiss MD. Modafinil reduces fatigue in Charcot-Marie-Tooth disease type 1A: a case series. <span><span class="ref-journal">Am J Hosp Palliat Care. </span>2006;<span class="ref-vol">23</span>:412–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17060310" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17060310</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.cassereau.2011.1524">Cassereau J, Casasnovas C, Gueguen N, Malinge MC, Guillet V, Reynier P, Bonneau D, Amati-Bonneau P, Banchs I, Volpini V, Procaccio V, Chevrollier A. Simultaneous MFN2 and GDAP1 mutations cause major mitochondrial defects in a patient with CMT. <span><span class="ref-journal">Neurology. </span>2011;<span class="ref-vol">76</span>:1524–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21519004" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21519004</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.chung.2008.360">Chung KW, Kim SM, Sunwoo IN, Cho SY, Hwang SJ, Kim J, Kang SH, Park KD, Choi KG, Choi IS, Choi BO. A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease. <span><span class="ref-journal">J Hum Genet. </span>2008;<span class="ref-vol">53</span>:360–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18231710" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18231710</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.claramunt.2005.358">Claramunt R, Pedrola L, Sevilla T, Lopez de Munain A, Berciano J, Cuesta A, Sanchez-Navarro B, Millan JM, Saifi GM, Lupski JR, Vilchez JJ, Espinos C, Palau F. Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. <span><span class="ref-journal">J Med Genet. </span>2005;<span class="ref-vol">42</span>:358–65.</span> [<a href="/pmc/articles/PMC1736030/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1736030</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15805163" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15805163</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.cordeiro.2014.185">Cordeiro JL, Marques W, Hallak JE, Osório FL. Charcot-Marie-Tooth disease, psychiatric indicators and quality of life: a systematic review. <span><span class="ref-journal">ASN Neuro. </span>2014;<span class="ref-vol">6</span>:185–92.</span> [<a href="/pmc/articles/PMC4034707/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4034707</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24654889" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24654889</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.corrado.2016.e3278">Corrado B, Ciardi G, Bargigli C. 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Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants. <span><span class="ref-journal">Clin Genet. </span>2017;<span class="ref-vol">92</span>:274–80.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28244113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28244113</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.zimo_.2011.540">Zimoń M, Baets J, Fabrizi GM, Jaakkola E, Kabzińska D, Pilch J, Schindler AB, Cornblath DR, Fischbeck KH, Auer-Grumbach M, Guelly C, Huber N, De Vriendt E, Timmerman V, Suter U, Hausmanowa-Petrusewicz I, Niemann A, Kochański A, De Jonghe P, Jordanova A. Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. <span><span class="ref-journal">Neurology. </span>2011;<span class="ref-vol">77</span>:540–8.</span> [<a href="/pmc/articles/PMC3272385/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3272385</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21753178" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21753178</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cmt-4a.REF.zimo_.2015.33">Zimoń M, Battaloğlu E, Parman Y, Erdem S, Baets J, De Vriendt E, Atkinson D, Almeida-Souza L, Deconinck T, Ozes B, Goossens D, Cirak S, Van Damme P, Shboul M, Voit T, Van Maldergem L, Dan B, El-Khateeb MS, Guergueltcheva V, Lopez-Laso E, Goemans N, Masri A, Züchner S, Timmerman V, Topaloğlu H, De Jonghe P, Jordanova A. Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach. <span><span class="ref-journal">Neurogenetics. </span>2015;<span class="ref-vol">16</span>:33–42.</span> [<a href="/pmc/articles/PMC4917005/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4917005</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25231362" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25231362</span></a>]</div></p></li></ul></div></div><div id="cmt-4a.Chapter_Notes"><h2 id="_cmt-4a_Chapter_Notes_">Chapter Notes</h2><div id="cmt-4a.Author_History"><h3>Author History</h3><p>Thomas D Bird, MD (2017-present)<br />Jeffery M Vance, MD, PhD; University of Miami (2004-2017)<br />Stephan Züchner, MD; University of Miami (2004-2017)</p></div><div id="cmt-4a.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>30 March 2017 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 February 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>3 June 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>6 March 2007 (jv) Revision: prenatal testing available</div></li><li class="half_rhythm"><div>23 June 2006 (ca) Comprehensive update posted live</div></li><li class="half_rhythm"><div>11 May 2004 (me) Review posted live</div></li><li class="half_rhythm"><div>23 February 2004 (jv,sz) Original submission</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1539_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Thomas D Bird</span>, MD<div class="affiliation small">Seattle VA Medical Center
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Departments of Neurology and Medicine
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University of Washington
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Seattle, Washington<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.wu@zornmot" class="oemail">ude.wu@zornmot</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">May 11, 2004</span>; Last Update: <span itemprop="dateModified">March 30, 2017</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Bird TD. GDAP1-Related Hereditary Motor and Sensory Neuropathy. 2004 May 11 [Updated 2017 Mar 30]. 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/apbd/?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/cmtx/?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="figobcmt4aTc"><div id="cmt-4a.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1539/table/cmt-4a.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmt-4a.Tc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cmt-4a.Tc_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_cmt-4a.Tc_1_1_1_1" style="text-align:left;vertical-align:middle;"><i>GDAP1</i>-Related Hereditary Motor and Sensory Neuropathy Subtype</th><th id="hd_h_cmt-4a.Tc_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_cmt-4a.Tc_1_1_1_2" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_cmt-4a.Tc_1_1_1_3" colspan="3" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Neuropathy Type</th></tr><tr><th headers="hd_h_cmt-4a.Tc_1_1_1_3" id="hd_h_cmt-4a.Tc_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Demyelinating</th><th headers="hd_h_cmt-4a.Tc_1_1_1_3" id="hd_h_cmt-4a.Tc_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Axonal</th><th headers="hd_h_cmt-4a.Tc_1_1_1_3" id="hd_h_cmt-4a.Tc_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intermediate</th></tr></thead><tbody><tr><td headers="hd_h_cmt-4a.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CMT4A</td><td headers="hd_h_cmt-4a.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_cmt-4a.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CMT2H</td><td headers="hd_h_cmt-4a.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_cmt-4a.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CMTRIA</td><td headers="hd_h_cmt-4a.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td></tr><tr><td headers="hd_h_cmt-4a.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CMT2K</td><td headers="hd_h_cmt-4a.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X</td><td headers="hd_h_cmt-4a.Tc_1_1_1_3 hd_h_cmt-4a.Tc_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; CMT = Charcot-Marie-Tooth neuropathy; CMTRIA = Charcot-Marie-Tooth Neuropathy, recessive intermediate A</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Hereditary motor and sensory neuropathy is also referred to as "Charcot-Marie-Tooth neuropathy"; see <a href="#cmt-4a.Nomenclature">Nomenclature</a> for further discussion of term usage.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcmt4aTmoleculargenetictestingused"><div id="cmt-4a.T.molecular_genetic_testing_used" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>GDAP1</i>-Related Hereditary Motor and Sensory Neuropathy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1539/table/cmt-4a.T.molecular_genetic_testing_used/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmt-4a.T.molecular_genetic_testing_used_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cmt-4a.T.molecular_genetic_testing_used_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_cmt-4a.T.molecular_genetic_testing_used_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_cmt-4a.T.molecular_genetic_testing_used_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_cmt-4a.T.molecular_genetic_testing_used_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GDAP1</i>
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</td><td headers="hd_h_cmt-4a.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_cmt-4a.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~100% <sup>4</sup></td></tr><tr><td headers="hd_h_cmt-4a.T.molecular_genetic_testing_used_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_cmt-4a.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>4</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="cmt-4a.TF.1.1"><p class="no_margin">See <a href="/books/NBK1539/?report=reader#cmt-4a.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="cmt-4a.TF.1.2"><p class="no_margin">See <a href="#cmt-4a.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="cmt-4a.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 small intragenic deletions/insertions and missense, nonsense, and splice site variants; 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="cmt-4a.TF.1.4"><p class="no_margin">Pathogenic variants in <i>GDAP1</i> are identified in nearly 100% of individuals with autosomal recessive CMT whose disease has been mapped to 8q13-q21.1 [<a class="bibr" href="#cmt-4a.REF.manganelli.2014.292" rid="cmt-4a.REF.manganelli.2014.292">Manganelli et al 2014</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="cmt-4a.TF.1.5"><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>6. </dt><dd><div id="cmt-4a.TF.1.6"><p class="no_margin">No data on detection rate of gene-targeted deletion/duplication analysis are available.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcmt4aTcomparisonofautosomalrecessi"><div id="cmt-4a.T.comparison_of_autosomal_recessi" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Comparison of Autosomal Recessive and Autosomal Dominant <i>GDAP1</i>-Related Hereditary Motor and Sensory Neuropathy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1539/table/cmt-4a.T.comparison_of_autosomal_recessi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmt-4a.T.comparison_of_autosomal_recessi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>GDAP1</i>-HMSN Subtype</th><th id="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropathy Type</th><th id="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Severity</th><th id="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Age of Onset</th><th id="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Vocal Paresis</th><th id="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_6" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disease Progression</th></tr></thead><tbody><tr><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>AR <i>GDAP1</i>-HMSN (CMT4A, CMT2H, & CMTRIA)</b>
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</td><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically axonal; demyelinating & intermediate also observed</td><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Aggressive</td><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Early (onset can be infancy)</td><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common</td><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most individuals wheelchair bound by end of 2nd decade</td></tr><tr><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>AD <i>GDAP1</i>-HMSN (CMT2K)</b>
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</td><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically axonal or demyelinating; intermediate also observed</td><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mild relative to AR CMT</td><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Varies from childhood to late adulthood</td><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_cmt-4a.T.comparison_of_autosomal_recessi_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Slow disease progression</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">CMT = Charcot-Marie-Tooth neuropathy; CMTRIA = Charcot-Marie-Tooth Neuropathy, recessive intermediate A; HMSN = hereditary motor and sensory neuropathy; also referred to as "Charcot-Marie-Tooth neuropathy." See <a href="#cmt-4a.Nomenclature">Nomenclature</a> for further discussion of term usage.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcmt4amolgenTA"><div id="cmt-4a.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>GDAP1-Related Hereditary Motor and Sensory Neuropathy: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1539/table/cmt-4a.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmt-4a.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_cmt-4a.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_cmt-4a.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_cmt-4a.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_cmt-4a.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_cmt-4a.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_cmt-4a.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_cmt-4a.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/54332" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>GDAP1</i>
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</a>
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</td><td headers="hd_b_cmt-4a.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=54332" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">8q21<wbr style="display:inline-block"></wbr>​.11</a>
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</td><td headers="hd_b_cmt-4a.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/Q8TB36" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Ganglioside-induced differentiation-associated protein 1</a>
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</td><td headers="hd_b_cmt-4a.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/GDAP1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GDAP1 homepage - Leiden Muscular Dystrophy pages</a>
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</td><td headers="hd_b_cmt-4a.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=GDAP1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GDAP1</a>
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</td><td headers="hd_b_cmt-4a.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=GDAP1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GDAP1</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="cmt-4a.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="figobcmt4amolgenTB"><div id="cmt-4a.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for GDAP1-Related Hereditary Motor and Sensory Neuropathy (<a href="/omim/606598,608340" 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/NBK1539/table/cmt-4a.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmt-4a.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/606598" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">606598</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/608340" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">608340</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A; CMTRIA</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobcmt4aTselectedgdap1pathogenicvaria"><div id="cmt-4a.T.selected_gdap1_pathogenic_varia" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Selected <i>GDAP1</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1539/table/cmt-4a.T.selected_gdap1_pathogenic_varia/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cmt-4a.T.selected_gdap1_pathogenic_varia_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th></tr></thead><tbody><tr><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.347T>G</td><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Met116Arg</td><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_3" rowspan="6" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/108773796" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_018972<wbr style="display:inline-block"></wbr>​.2</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/108773797" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_061845<wbr style="display:inline-block"></wbr>​.2</a>
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</td></tr><tr><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.358C>T</td><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg120Trp</td></tr><tr><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.368A>G</td><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.His123Arg</td></tr><tr><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.469A>C</td><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr157Pro</td></tr><tr><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.487C>T</td><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln163Ter</td></tr><tr><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.715C>T</td><td headers="hd_h_cmt-4a.T.selected_gdap1_pathogenic_varia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu239Phe</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://www.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></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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