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<title>
Entry
- #300352 - CEREBRAL CREATINE DEFICIENCY SYNDROME 1; CCDS1
- OMIM
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<span class="h4">#300352</span>
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<strong>Table of Contents</strong>
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<a href="/clinicalSynopsis/300352"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS300352"> <strong>Phenotypic Series</strong> </a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<div><a href="https://clinicaltrials.gov/search?cond=CEREBRAL CREATINE DEFICIENCY SYNDROME" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0050800" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/300352" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 698290008<br />
<strong>ORPHA:</strong> 52503<br />
<strong>DO:</strong> 0050800<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
300352
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
CEREBRAL CREATINE DEFICIENCY SYNDROME 1; CCDS1
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
CREATINE DEFICIENCY SYNDROME, X-LINKED<br />
CREATINE TRANSPORTER DEFECT<br />
MENTAL RETARDATION, X-LINKED, WITH SEIZURES, SHORT STATURE, AND MIDFACE HYPOPLASIA<br />
MENTAL RETARDATION, X-LINKED, WITH CREATINE TRANSPORT DEFICIENCY
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/X/834?start=-3&limit=10&highlight=834">
Xq28
</a>
</span>
</td>
<td>
<span class="mim-font">
Cerebral creatine deficiency syndrome 1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300352"> 300352 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
SLC6A8
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300036"> 300036 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/300352" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS300352" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/300352" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/300352" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- X-linked recessive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845977</a>, <a href="https://bioportal.bioontology.org/search?q=C1279481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279481</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Height </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Short stature <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422065006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422065006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237836003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237836003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237837007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237837007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E34.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E34.31</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R62.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R62.52</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.43" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.43</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349588&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349588</a>, <a href="https://bioportal.bioontology.org/search?q=C0013336&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013336</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003510</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span><br /> -
Tall stature <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248328003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248328003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241240&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241240</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000098" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000098</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000098" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000098</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Weight </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Low weight <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248342006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248342006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.22</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0041667&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0041667</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004325" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004325</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004325" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004325</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Head </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Decreased head circumference <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271611007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271611007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424688&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424688</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0040195" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0040195</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0040195" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0040195</a>]</span><br /> -
Microcephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1148757008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1148757008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/742.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">742.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551563&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551563</a>, <a href="https://bioportal.bioontology.org/search?q=C0025958&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025958</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Microcephaly-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Broad forehead <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849089&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849089</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000337</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000337</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=40e77945a1b2a5742a89317aeb604f00" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Forehead,Broad-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=40e77945a1b2a5742a89317aeb604f00&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Midface hypoplasia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853242&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853242</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011800" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011800</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011800" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011800</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=f0adae8ae2dc0ad9ed28c3c3e0e8f8a9" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Midface_Retrusion-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=f0adae8ae2dc0ad9ed28c3c3e0e8f8a9&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Long, thin face <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844686&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844686</a>]</span><br /> -
Prominent chin <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/109504005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">109504005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22810007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22810007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M26.213" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M26.213</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/524.23" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">524.23</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0399526&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0399526</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000303" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000303</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000303" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000303</a>]</span><br /> -
Myopathic facies <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26432009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26432009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0332615&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0332615</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002058" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002058</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002058" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002058</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Unfolded superior helices <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845869&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845869</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Exotropia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399252000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399252000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399054005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399054005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.10</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/378.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">378.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/378.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">378.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015310&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015310</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000577" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000577</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000577" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000577</a>]</span><br /> -
Hypermetropia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38101003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38101003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H52.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H52.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/367.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">367.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020490&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020490</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000540" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000540</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000540" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000540</a>]</span><br /> -
Ptosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11934000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11934000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/29696001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">29696001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.409" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.409</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.40</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/374.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.3</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/374.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.30</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0005745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005745</a>, <a href="https://bioportal.bioontology.org/search?q=C0033377&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033377</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000508</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=76abf29563d4adc64d21da86221224b1" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Ptosis-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=76abf29563d4adc64d21da86221224b1&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Prolonged QTc <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969409&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969409</a>]</span><br /> -
Left ventricular enlargement is diastole<br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Constipation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14760008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14760008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/564.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/564.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009806&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009806</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span><br /> -
Megacolon <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/33995003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">33995003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.3</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.39" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.39</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0025160&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025160</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:6000852" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:6000852</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:6000852" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:6000852</a>]</span><br /> -
Ileus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/710572000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">710572000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1258215&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1258215</a>, <a href="https://bioportal.bioontology.org/search?q=C4019039&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4019039</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002595" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002595</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002595" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002595</a>]</span><br /> -
Poor feeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/299698007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">299698007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78164000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0576456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0576456</a>, <a href="https://bioportal.bioontology.org/search?q=C0232466&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232466</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span><br /> -
Vomiting <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422400008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422400008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/300359004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">300359004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249497008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249497008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042963&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042963</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Limbs </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hyperextensible joints <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/788453008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">788453008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1862377&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1862377</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001382" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001382</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001382" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001382</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hands </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Stub thumb <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/890439005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">890439005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0220664&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220664</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005627" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005627</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Feet </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pes cavus (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/205091006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">205091006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36755004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36755004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86900005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86900005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q66.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q66.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/736.73" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">736.73</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/754.71" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.71</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0728829&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0728829</a>, <a href="https://bioportal.bioontology.org/search?q=C0039273&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0039273</a>, <a href="https://bioportal.bioontology.org/search?q=C2239098&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2239098</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001761" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001761</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001761" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001761</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=2ad12e53b20f47e5685234fa29da6610" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Pes_Cavus-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=2ad12e53b20f47e5685234fa29da6610&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypotonia, neonatal <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/205294008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">205294008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2267233&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2267233</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001319</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001319</a>]</span><br /> -
Developmental delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
Motor delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/307653008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">307653008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/57187006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">57187006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F82" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F82</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854301&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854301</a>, <a href="https://bioportal.bioontology.org/search?q=C0520947&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0520947</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001270" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001270</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001270" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001270</a>]</span><br /> -
Mental retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a>, <a href="https://bioportal.bioontology.org/search?q=C0025362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
Speech and language delay, severe <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845863&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845863</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/62415009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">62415009</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000750" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000750</a>]</span><br /> -
Poor hand-eye coordination <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845864&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845864</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007057" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007057</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007057" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007057</a>]</span><br /> -
Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
Gait abnormalities <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22325002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22325002</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0575081&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575081</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span><br /> -
Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Decreased creatine signal seen on magnetic resonance spectroscopy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806618&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806618</a>]</span><br /> -
Mild structural abnormalities seen MRI (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806619&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806619</a>]</span><br /> -
Delayed myelination <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/135810007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">135810007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1277241&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1277241</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012448" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012448</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012448" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012448</a>]</span><br /> -
Thin corpus callosum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5441562&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5441562</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033725" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033725</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033725" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033725</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Behavioral changes consistent with an autistic disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845866&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845866</a>]</span><br /> -
Stereotypical motor behaviors <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/84328007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">84328007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038271&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038271</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000733</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000733</a>]</span><br /> -
Impaired social interaction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/88598008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">88598008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F80.82" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F80.82</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4022736&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4022736</a>, <a href="https://bioportal.bioontology.org/search?q=C0150080&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0150080</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012760" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012760</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012760" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012760</a>]</span><br /> -
Aggressive behavior <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/61372001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">61372001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001807&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001807</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006919" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006919</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000718</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000718</a>]</span><br /> -
Attention deficit hyperactivity disorder <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7461003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7461003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/406506008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">406506008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F90.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F90.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/314.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314.01</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/314" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/314.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1263846&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1263846</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000752" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000752</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0007018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007018</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007018</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Impaired creatine uptake in fibroblasts <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845871&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845871</a>]</span><br /> -
Increased urinary creatine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845872&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845872</a>]</span><br /> -
Increased plasma creatine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845873&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845873</a>]</span><br /> -
Increased urinary creatine-to-creatinine ratio <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2678149&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2678149</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset in first months of life<br /> -
Sudden cardiac death (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95281009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95281009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085298&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085298</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001645" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001645</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001645" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001645</a>]</span><br /> -
Carrier females may show neuropsychologic impairment<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the creatine transporter gene (SLC6A8, <a href="/entry/300036#0001">300036.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Cerebral creatine deficiency syndrome
- <a href="/phenotypicSeries/PS300352">PS300352</a>
- 3 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/180?start=-3&limit=10&highlight=180"> 15q21.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612718"> Cerebral creatine deficiency syndrome 3 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612718"> 612718 </a>
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<a href="/entry/602360"> GATM </a>
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<a href="/entry/602360"> 602360 </a>
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<a href="/geneMap/19/52?start=-3&limit=10&highlight=52"> 19p13.3 </a>
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<a href="/entry/612736"> Cerebral creatine deficiency syndrome 2 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/612736"> 612736 </a>
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<a href="/entry/601240"> GAMT </a>
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<a href="/entry/601240"> 601240 </a>
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<a href="/geneMap/X/834?start=-3&limit=10&highlight=834"> Xq28 </a>
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<a href="/entry/300352"> Cerebral creatine deficiency syndrome 1 </a>
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<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/300352"> 300352 </a>
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<a href="/entry/300036"> SLC6A8 </a>
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<a href="/entry/300036"> 300036 </a>
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<p>A number sign (#) is used with this entry because cerebral creatine deficiency syndrome-1 (CCDS1) is caused by mutation in the creatine transporter gene (SLC6A8; <a href="/entry/300036">300036</a>) on chromosome Xq28.</p>
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<p>Cerebral creatine deficiency syndrome-1 (CCDS1) is an X-linked disorder of creatine (Cr) transport characterized by mental retardation, severe speech delay, behavioral abnormalities, and seizures. It has a prevalence of 0.3 to 3.5% in males. Carrier females may show mild neuropsychologic impairment (summary by <a href="#19" class="mim-tip-reference" title="van de Kamp, J. M., Mancini, G. M. S., Pouwels, P. J. W., Betsalel, O. T., van Dooren, S. J. M., de Koning, I., Steenweg, M. E., Jakobs, C., van der Knaap, M. S., Salomons, G. S. &lt;strong&gt;Clinical features and X-inactivation in females heterozygous for creatine transporter defect.&lt;/strong&gt; Clin. Genet. 79: 264-272, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20528887/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20528887&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2010.01460.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20528887">van de Kamp et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20528887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Cerebral Creatine Deficiency Syndrome</em></strong></p><p>
See also CCDS2 (<a href="/entry/612736">612736</a>), caused by mutation in the GAMT gene (<a href="/entry/601240">601240</a>) on chromosome 19p13, and CCDS3 (<a href="/entry/612718">612718</a>), caused by mutation in the AGAT gene (GATM; <a href="/entry/602360">602360</a>) on chromosome 15q21.</p>
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<p><a href="#15" class="mim-tip-reference" title="Salomons, G. S., van Dooren, S. J. M., Verhoeven, N. M., Cecil, K. M., Ball, W. S., Degrauw, T. J., Jakobs, C. &lt;strong&gt;X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 68: 1497-1500, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11326334/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11326334&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11326334[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/320595&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11326334">Salomons et al. (2001)</a> reported a male patient with developmental delay and hypotonia. Proton magnetic resonance spectroscopic imaging (H-MRSI) of his brain revealed absence of the creatine signal. However, creatine in urine and plasma was increased, and guanidinoacetate (see <a href="/entry/612718">612718</a>) levels were normal. Fibroblasts from the index patient were defective in creatine uptake. Three female relatives had mild biochemical abnormalities and learning disabilities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bizzi, A., Bugiani, M., Salomons, G. S., Hunneman, D. H., Moroni, I., Estienne, M., Danesi, U., Jakobs, C., Uziel, G. &lt;strong&gt;X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8.&lt;/strong&gt; Ann. Neurol. 52: 227-231, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12210795/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12210795&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10246&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12210795">Bizzi et al. (2002)</a> reported a child with severe neurologic disturbances including seizures, behavioral problems, speech delay, and inability to engage in structured play, as well as creatine deficiency. H-MRSI showed absence of creatine in the whole brain, which was not corrected by creatine supplementation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Hahn, K. A., Salomons, G. S., Tackels-Horne, D., Wood, T. C., Taylor, H. A., Schroer, R. J., Lubs, H. A., Jakobs, C., Olson, R. L., Holden, K. R., Stevenson, R. E., Schwartz, C. E. &lt;strong&gt;X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28.&lt;/strong&gt; Am. J. Hum. Genet. 70: 1349-1356, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11898126/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11898126&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11898126[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/340092&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11898126">Hahn et al. (2002)</a> described a family in which 5 males in a sibship of 10 had mental retardation with seizures. Head circumference was normal in all. Adult height (162.5-167.5 cm) was less than the adult height of the unaffected brother (175.5 cm). Midface hypoplasia was also described. Gastrointestinal disturbances in the form of chronic constipation, megacolon, gastric and duodenal ulcer disease, and bowel perforation were also observed. Two sisters had mild cognitive impairment, and one of them had chronic behavioral disturbances. Biochemical analyses confirmed a defect in creatine metabolism in this family. In affected males patients, the level of urinary creatine was substantially increased, and creatine uptake in fibroblasts was decreased. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11898126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Schiaffino, M. C., Bellini, C., Costabello, L., Caruso, U., Jakobs, C., Salomons, G. S., Bonioli, E. &lt;strong&gt;X-linked creatine transporter deficiency: clinical description of a patient with a novel SLC6A8 gene mutation.&lt;/strong&gt; Neurogenetics 6: 165-168, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16086185/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16086185&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-005-0002-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16086185">Schiaffino et al. (2005)</a> reported a patient with X-linked creatine deficiency confirmed by genetic analysis (<a href="/entry/300036#0006">300036.0006</a>). The patient was first seen at age 21 months for failure to thrive, recurrent vomiting, and motor delay. His weight, length, and head circumference were all under the third percentile. Neurologic examination showed truncal hypotonia, impaired eye-hand coordination, and severe cognitive and language retardation. EEG showed slow, diffuse hypersynchronisms with abnormal multifocal spikes. Plasma creatine levels were consistently low, and biochemical studies on fibroblasts showed impaired creatine uptake. <a href="#16" class="mim-tip-reference" title="Schiaffino, M. C., Bellini, C., Costabello, L., Caruso, U., Jakobs, C., Salomons, G. S., Bonioli, E. &lt;strong&gt;X-linked creatine transporter deficiency: clinical description of a patient with a novel SLC6A8 gene mutation.&lt;/strong&gt; Neurogenetics 6: 165-168, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16086185/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16086185&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-005-0002-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16086185">Schiaffino et al. (2005)</a> noted that few patients with SLC6A8 deficiency had been described, precluding a definite clinical description. However, most affected males have mental retardation, seizures, and language impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16086185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Kleefstra, T., Rosenberg, E. H., Salomons, G. S., Stroink, H., van Bokhoven, H., Hamel, B. C. J., de Vries, B. B. A. &lt;strong&gt;Progressive intestinal, neurological and psychiatric problems in two adult males with cerebral creatine deficiency cause by an SLC6A8 mutation. (Letter)&lt;/strong&gt; Clin. Genet. 68: 379-381, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16143026/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16143026&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2005.00489.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16143026">Kleefstra et al. (2005)</a> described 2 brothers with X-linked creatine deficiency, in whom <a href="#14" class="mim-tip-reference" title="Rosenberg, E. H., Almeida, L. S., Kleefstra, T., deGrauw, R. S., Yntema, H. G., Bahi, N., Moraine, C., Ropers, H.-H., Fryns, J.-P., deGrauw, T. J., Jakobs, C., Salomons, G. S. &lt;strong&gt;High prevalence of SLC6A8 deficiency in X-linked mental retardation.&lt;/strong&gt; Am. J. Hum. Genet. 75: 97-105, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15154114/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15154114&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15154114[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/422102&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15154114">Rosenberg et al. (2004)</a> had identified a missense mutation in the SLC6A8 gene (<a href="/entry/300036#0007">300036.0007</a>). The older brother, born with severe mental retardation, was examined at age 70 and found to have myopathic facies with ptosis, external ophthalmoplegia, and open, hanging mouth. The younger brother had milder mental retardation and learned to read and write, but underwent regression at age 51 after the death of their father. In his fifties, he had urethral stenosis, chronic constipation, and ileus, and spontaneous luxations of several digits occurred. Neurologic examination at age 67 showed apparent medication-related Parkinsonism, upward gaze paresis, expressionless face, and hanging mouth and shoulders; comparison of photographs at age 57 and 64 revealed the striking progression of clinical features in the latter patient. Their sister, a carrier of the mutation, had short stature, learning difficulties, and developed severe constipation requiring surgical intervention in her fifties. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16143026+15154114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Clark, A. J., Rosenberg, E. H., Almeida, L. S., Wood, T. C., Jakobs, C., Stevenson, R. E., Schwartz, C. E., Salomons, G. S. &lt;strong&gt;X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology.&lt;/strong&gt; Hum. Genet. 119: 604-610, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16738945/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16738945&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-006-0162-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16738945">Clark et al. (2006)</a> reported 6 unrelated males with X-linked mental retardation associated with mutations in the SLC6A8 gene. Clinical features included increased urinary creatine:creatinine (Cr:Crn) ratio, microcephaly, long, narrow face, and prominent chin. Two patients were tall and thin, and 3 had short stature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16738945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Battini, R., Chilosi, A., Mei, D., Casarano, M., Alessandri, M. G., Leuzzi, V., Ferretti, G., Tosetti, M., Bianchi, M. C., Cioni, G. &lt;strong&gt;Mental retardation and verbal dyspraxia in a new patient with de novo creatine transporter (SLC6A8) mutation.&lt;/strong&gt; Am. J. Med. Genet. 143A: 1771-1774, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17603797/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17603797&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31827&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17603797">Battini et al. (2007)</a> reported a 9.5-year-old Italian boy with moderate mental retardation and verbal dyspraxia associated with mutation in the SLC6A8 gene. He had delayed psychomotor development, hypotonia, seizures, and severe language deficit with oral-motor dyspraxia, irritability, and temper tantrums. Detailed language evaluation showed problems in picture naming and phonetics, whereas receptive vocabulary was less severely affected. Social interaction was good despite the severe expressive limitation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17603797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Battini, R., Chilosi, A. M., Casarano, M., Moro, F., Comparini, A., Alessandri, M. G., Leuzzi, V., Tosetti, M., Cioni, G. &lt;strong&gt;Language disorder with mild intellectual disability in a child affected by a novel mutation of SLC6A8 gene.&lt;/strong&gt; Molec. Genet. Metab. 102: 153-156, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21144783/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21144783&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2010.11.005&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21144783">Battini et al. (2011)</a> reported a 6.5-year-old boy with X-linked creatine deficiency syndrome confirmed by genetic analysis. In infancy, he showed poor feeding, hypotonia, and delayed psychomotor development with walking and speaking his first words at age 3 years. Examination at age 5 years showed mild intellectual disability and comparatively severe language delay with mild oromotor dyspraxia and clumsiness. Social interaction was good. Detailed neuropsychologic studies showed a discrepancy between nonverbal and verbal skills, with mild impairment of social personal performance and eye-hand coordination and moderate impairment of speech and practical reasoning. Spontaneous language performance was markedly reduced. Biochemical analysis showed increased urinary Cr, increased Cr/Crn ratio, and undetectable uptake of Cr in fibroblasts, and magnetic resonance spectroscopy showed a reduced Cr peak in the brain. The patient's mother, who also carried the mutation, had a normal biochemical profile, but borderline intellectual functioning with difficulties in reading comprehension. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21144783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Comeaux, M. S., Wang, J., Wang, G., Kleppe, S., Zhang, V. W., Schmitt, E. S., Craigen, W. J., Renaud, D., Sun, Q., Wong, L.-J. &lt;strong&gt;Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes.&lt;/strong&gt; Molec. Genet. Metab. 109: 260-268, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23660394/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23660394&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2013.04.006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23660394">Comeaux et al. (2013)</a> reported 22 patients with confirmed deleterious mutations in the SLC6A8 gene who had clinical information available. Clinical features included developmental delay (86%), seizures (27%), autistic features (18%), speech delay (27%), ataxia (14%), and choreoathetosis (9%). All 6 patients with MRS results had decreased or absent creatine peaks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23660394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="van de Kamp, J. M., Betsalel, O. T., Mercimek-Mahmutoglu, S., Abulhoul, L., Grunewald, S., Anselm, I., Azzouz, H., Bratkovic, D., de Brouwer, A., Hamel, B., Kleefstra, T., Yntema, H., and 48 others. &lt;strong&gt;Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.&lt;/strong&gt; J. Med. Genet. 50: 463-472, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23644449/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23644449&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmedgenet-2013-101658&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23644449">Van de Kamp et al. (2013)</a> performed a retrospective analysis of 101 male patients from 85 families with X-linked creatine transporter deficiency confirmed by genetic analysis. Many of the patients had previously been reported. All patients presented in infancy or early childhood, most often due to delayed psychomotor development. All had intellectual disability of varying degrees, and 85% had behavioral problems. Speech development was especially delayed, but almost a third of patients could speak in sentences. Other features included seizures (59%), hypotonia (40%), spasticity (26%), gastrointestinal symptoms (35%), and ophthalmologic abnormalities (10%). Various facial dysmorphic features were present in 45%. MRI showed mild structural abnormalities in 53 of 76 patients studied, and MRS showed reduced creatine in all 66 patients for whom results were available. Urinary creatine was increased in 81 patients for whom results were available. A few patients studied had unexpectedly high creatine levels in CSF, suggesting that the brain is able to synthesize creatine and that the creatine deficiency is caused by a defect in the reuptake of creatine within neurons. Most patients had missense mutations or deletions of 1 amino acid in the SLC6A8 gene. A third of patients had a de novo mutation in the SLC6A8 gene. However, <a href="#18" class="mim-tip-reference" title="van de Kamp, J. M., Betsalel, O. T., Mercimek-Mahmutoglu, S., Abulhoul, L., Grunewald, S., Anselm, I., Azzouz, H., Bratkovic, D., de Brouwer, A., Hamel, B., Kleefstra, T., Yntema, H., and 48 others. &lt;strong&gt;Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.&lt;/strong&gt; J. Med. Genet. 50: 463-472, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23644449/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23644449&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmedgenet-2013-101658&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23644449">van de Kamp et al. (2013)</a> suggested that a mother with an affected son with a de novo mutation may have a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23644449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Levin, M. D., Bianconi, S., Smith, A., Cawley, N. X., Do, A. D., Hammond, D., Grafstein, J. F., Thurm, A., Miller, J., Perreault, J., Noguchi, A., Springer, D., Kozel, B. A., Spurney, C. F., Wassif, C. A., Yu, Z.-X., Schulze, A., Porter, F. D., Hannah-Shmouni, F. &lt;strong&gt;X-linked creatine transporter deficiency results in prolonged QTc and increased sudden death risk in humans and disease model.&lt;/strong&gt; Genet. Med. 23: 1864-1872, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34050321/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;34050321&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=34050321[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41436-021-01224-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="34050321">Levin et al. (2021)</a> performed a cross-sectional analysis of the cardiac phenotype and risk of sudden death between 2017 and 2020 in 18 boys (average age of 7.4 years, range 3-16 years) with creatine transporter deficiency caused by mutations in SCL6A8. Seven (39%) had prolonged QTc of greater than 470 milliseconds, with a mean of 510.3 +/- 29.0 ms versus 448.3 +/- 15.9 ms in the other 11 subjects. The cohort with prolonged QTc had increased left ventricular internal dimension in diastole and diminished left ventricular posterior wall dimension compared to patients with normal or borderline QTc. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34050321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Carrier Females</em></strong></p><p>
<a href="#19" class="mim-tip-reference" title="van de Kamp, J. M., Mancini, G. M. S., Pouwels, P. J. W., Betsalel, O. T., van Dooren, S. J. M., de Koning, I., Steenweg, M. E., Jakobs, C., van der Knaap, M. S., Salomons, G. S. &lt;strong&gt;Clinical features and X-inactivation in females heterozygous for creatine transporter defect.&lt;/strong&gt; Clin. Genet. 79: 264-272, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20528887/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20528887&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2010.01460.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20528887">Van de Kamp et al. (2011)</a> studied 8 unrelated female carriers of SLC6A8 mutations identified though affected male relatives. One woman had mental retardation, 1 required special education, 3 failed a year during elementary school, and 3 had no learning difficulties. IQ scores ranged from 48 to 96; 2 had scores in the mental retardation range, and 4 had scores in the borderline range. MRI showed mild cerebellar symptoms in 2, and constipation was reported in 2. Only 3 of 8 women had a mildly elevated urine creatine/creatinine ratio. H-MRSI studies showed decreased total creatine concentrations in the brain overall, but individual females had levels overlapping that of controls. X-inactivation studies in cultured fibroblasts showed severely skewed patterns in 2 woman, 1 favoring the mutant allele and 1 favoring the wildtype allele, but this may have been an artifact. <a href="#19" class="mim-tip-reference" title="van de Kamp, J. M., Mancini, G. M. S., Pouwels, P. J. W., Betsalel, O. T., van Dooren, S. J. M., de Koning, I., Steenweg, M. E., Jakobs, C., van der Knaap, M. S., Salomons, G. S. &lt;strong&gt;Clinical features and X-inactivation in females heterozygous for creatine transporter defect.&lt;/strong&gt; Clin. Genet. 79: 264-272, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20528887/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20528887&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2010.01460.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20528887">Van de Kamp et al. (2011)</a> concluded that carrier females may have mild symptoms of the disorder, and suggested that the most accurate diagnostic strategy in females should be molecular diagnosis, as biochemical changes may be subtle or not present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20528887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Mejdahl Nielsen, M., Petersen, E. T., Fenger, C. D., Orngreen, M. C., Siebner, H. R., Boer, V. O., Povazan, M., Lund, A., Gronborg, S. W., Hammer, T. B. &lt;strong&gt;X-linked creatine transporter (SLC6A8) deficiency in females: difficult to recognize, but a potentially treatable disease.&lt;/strong&gt; Molec. Genet. Metab. 140: 107694, 2023.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/37708665/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;37708665&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2023.107694&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="37708665">Mejdahl Nielsen et al. (2023)</a> reported a 16-year-old female with CCDS1 who had a history of learning disabilities and seizures, which started at 10 years of age. She also had a history of autism. Laboratory testing demonstrated a normal urine creatine/creatinine ratio, and brain MR spectroscopy showed reduced cerebral creatine. <a href="#13" class="mim-tip-reference" title="Mejdahl Nielsen, M., Petersen, E. T., Fenger, C. D., Orngreen, M. C., Siebner, H. R., Boer, V. O., Povazan, M., Lund, A., Gronborg, S. W., Hammer, T. B. &lt;strong&gt;X-linked creatine transporter (SLC6A8) deficiency in females: difficult to recognize, but a potentially treatable disease.&lt;/strong&gt; Molec. Genet. Metab. 140: 107694, 2023.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/37708665/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;37708665&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2023.107694&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="37708665">Mejdahl Nielsen et al. (2023)</a> also reviewed 32 previously reported female patients with CCDS1. Clinical features included learning difficulties in 17 patients, language delay in 9 patients, and motor delay in 6 patients. Six patients had epilepsy, 2 had autism, 4 had ADHD, and 1 patient had psychosis. X-linked inactivation was not skewed in the few patients who were tested. Urine creatine/creatinine was normal in 15 of 20 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37708665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The biochemical test for CCDS1 is the urine creatine:creatinine ratio, which should be above 1.5 for a diagnosis of the disorder in males. Among 69 patients referred for SLC6A8 mutation testing, <a href="#5" class="mim-tip-reference" title="Comeaux, M. S., Wang, J., Wang, G., Kleppe, S., Zhang, V. W., Schmitt, E. S., Craigen, W. J., Renaud, D., Sun, Q., Wong, L.-J. &lt;strong&gt;Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes.&lt;/strong&gt; Molec. Genet. Metab. 109: 260-268, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23660394/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23660394&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2013.04.006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23660394">Comeaux et al. (2013)</a> found that 45 had normal primary or secondary urine screens and did not meet the criteria for gene testing. Twelve of the 45 were females, whose ratios may have been uninformative due to random X-chromosome inactivation. Seven males and 2 females with increased ratios in the first screen had normal ratios in a second sample; none of these patients carried SLC6A8 mutations. The negative predictive value of this test in this study was 100%; all 45 patients with urine creatine:creatinine ratios below 1.5, regardless of gender, had no SLC6A8 mutations. <a href="#5" class="mim-tip-reference" title="Comeaux, M. S., Wang, J., Wang, G., Kleppe, S., Zhang, V. W., Schmitt, E. S., Craigen, W. J., Renaud, D., Sun, Q., Wong, L.-J. &lt;strong&gt;Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes.&lt;/strong&gt; Molec. Genet. Metab. 109: 260-268, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23660394/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23660394&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2013.04.006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23660394">Comeaux et al. (2013)</a> emphasized that the urine creatine:creatinine ratio may be misleading because of diet and the possibility of creatine supplementation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23660394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Joncquel-Chevalier Curt, M., Bout, M.-A., Fontaine, M., Kim, I., Huet, G., Bekri, S., Morin, G., Moortgat, S., Moerman, A., Cuisset, J.-M., Cheillan, D., Vamecq, J. &lt;strong&gt;Functional assessment of creatine transporter in control and X-linked SLCA8-deficient fibroblasts.&lt;/strong&gt; Molec. Genet. Metab. 123: 463-471, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29478817/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29478817&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2018.02.010&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29478817">Joncquel-Chevalier Curt et al. (2018)</a> described a creatine uptake assay in patient-derived fibroblasts to aid in measuring creatine transporter activity and in diagnosing creatine transporter deficiency. Using a stable isotope-labeled substrate, D3-creatine, in patient fibroblasts, preceded by a creatine washout step, <a href="#8" class="mim-tip-reference" title="Joncquel-Chevalier Curt, M., Bout, M.-A., Fontaine, M., Kim, I., Huet, G., Bekri, S., Morin, G., Moortgat, S., Moerman, A., Cuisset, J.-M., Cheillan, D., Vamecq, J. &lt;strong&gt;Functional assessment of creatine transporter in control and X-linked SLCA8-deficient fibroblasts.&lt;/strong&gt; Molec. Genet. Metab. 123: 463-471, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29478817/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29478817&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2018.02.010&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29478817">Joncquel-Chevalier Curt et al. (2018)</a> were able to functionally discriminate between hemizygous males and heterozygous females with creatine transport defects versus controls. The authors noted, however, that this method may be limited in diagnosing female patients because transporter activity in fibroblasts may not reflect transporter activity in other cell types due to variation in X-chromosome inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29478817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="clinicalManagement" class="mim-anchor"></a>
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<strong>Clinical Management</strong>
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<p><a href="#20" class="mim-tip-reference" title="van de Kamp, J. M., Pouwels, P. J. W., Aarsen, F. K., ten Hoopen, L. W., Knol, D. L., de Klerk, J. B., de Coo, I. F., Huijmans, J. G. M., Jakobs, C., van der Knaap, M. S., Salomons, G. S., Mancini, G. M. S. &lt;strong&gt;Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect.&lt;/strong&gt; J. Inherit. Metab. Dis. 35: 141-149, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21556832/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21556832&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21556832[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10545-011-9345-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21556832">Van de Kamp et al. (2012)</a> recorded the long-term follow-up and treatment of 9 boys between the ages of 8 months and 10 years with creatine transporter defect. The patients underwent repeated magnetic resonance spectroscopy (MRS) and neuropsychologic assessments during 4 to 6 years of combination treatment with creatine monohydrate, L-arginine, and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with MRS. After an initial improvement in locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionally, <a href="#20" class="mim-tip-reference" title="van de Kamp, J. M., Pouwels, P. J. W., Aarsen, F. K., ten Hoopen, L. W., Knol, D. L., de Klerk, J. B., de Coo, I. F., Huijmans, J. G. M., Jakobs, C., van der Knaap, M. S., Salomons, G. S., Mancini, G. M. S. &lt;strong&gt;Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect.&lt;/strong&gt; J. Inherit. Metab. Dis. 35: 141-149, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21556832/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21556832&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21556832[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10545-011-9345-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21556832">van de Kamp et al. (2012)</a> noticed an age-related decline in IQ subscales in boys affected with creatine transporter defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21556832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<div class="mim-changed mim-change"><p><a href="#17" class="mim-tip-reference" title="Valayannopoulos, V., Boddaert, N., Chabli, A., Barbier, V., Desguerre, I., Philippe, A., Afenjar, A., Mazzuca, M., Cheillan, D., Munnich, A., de Keyzer, Y., Jakobs, C., Salomons, G. S., de Lonlay, P. &lt;strong&gt;Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect.&lt;/strong&gt; J. Inherit. Metab. Dis. 35: 151-157, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21660517/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21660517&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10545-011-9358-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21660517">Valayannopoulos et al. (2012)</a> reported a series of 6 patients with severe creatine transporter deficiency, 4 males and 2 females. Clinical presentations included mild to severe mental retardation in all 6 patients, associated with psychiatric symptoms (autistic behavior, chronic hallucinatory psychosis) in 5 of 6, seizures in 2 of 6, and muscular symptoms in 2 of the 4 males. Diagnosis was confirmed by molecular analysis in all patients. All patients were treated successively according to the same protocol with creatine alone and then by creatine combined with its precursors L-glycine and L-arginine for 42 months. <a href="#17" class="mim-tip-reference" title="Valayannopoulos, V., Boddaert, N., Chabli, A., Barbier, V., Desguerre, I., Philippe, A., Afenjar, A., Mazzuca, M., Cheillan, D., Munnich, A., de Keyzer, Y., Jakobs, C., Salomons, G. S., de Lonlay, P. &lt;strong&gt;Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect.&lt;/strong&gt; J. Inherit. Metab. Dis. 35: 151-157, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21660517/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21660517&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10545-011-9358-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21660517">Valayannopoulos et al. (2012)</a> reported benefit only in the muscular symptoms of the disease and no improvement in the cognitive and psychiatric manifestations. Treatment failed to modify brain creatine content in either male or female patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21660517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
<p><a href="#6" class="mim-tip-reference" title="Dunbar, M., Jaggumantri, S., Sargent, M., Stockler-Ipsiroglu, S., van Karnebeek, C. D. M. &lt;strong&gt;Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases.&lt;/strong&gt; Molec. Genet. Metab. 112: 259-274, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24953403/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24953403&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2014.05.011&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24953403">Dunbar et al. (2014)</a> performed a systematic literature review (2001-2013) comprising 7 publications that described 25 patients with creatine transporter deficiency, and 3 additional patients treated at the authors' institution. Two patients received creatine-monohydrate supplementation; 7 received L-arginine; 2 received creatine-monohydrate and L-arginine; and 17 received a combination of creatine-monohydrate, L-arginine, and glycine. Median treatment duration was 34.6 months (range 3 months to 5 years). A total of 10 patients (36%) demonstrated response to treatment, manifested by either an increase in cerebral creatine or improved clinical parameters. Seven of the 28 patients had quantified pre- and posttreatment creatine, and it was significantly increased posttreatment. All of the patients with increased cerebral creatine also experienced clinical improvement. In addition, the majority of patients with clinical improvement had detectable cerebral creatine prior to treatment. Ninety percent of the patients who improved were initiated on treatment before 9 years of age. <a href="#6" class="mim-tip-reference" title="Dunbar, M., Jaggumantri, S., Sargent, M., Stockler-Ipsiroglu, S., van Karnebeek, C. D. M. &lt;strong&gt;Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases.&lt;/strong&gt; Molec. Genet. Metab. 112: 259-274, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24953403/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24953403&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2014.05.011&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24953403">Dunbar et al. (2014)</a> proposed systematic screening for creatine transporter deficiency in patients with intellectual disability, to allow early initiation of treatment with oral creatine, arginine, and/or glycine supplementation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24953403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p><a href="#13" class="mim-tip-reference" title="Mejdahl Nielsen, M., Petersen, E. T., Fenger, C. D., Orngreen, M. C., Siebner, H. R., Boer, V. O., Povazan, M., Lund, A., Gronborg, S. W., Hammer, T. B. &lt;strong&gt;X-linked creatine transporter (SLC6A8) deficiency in females: difficult to recognize, but a potentially treatable disease.&lt;/strong&gt; Molec. Genet. Metab. 140: 107694, 2023.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/37708665/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;37708665&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2023.107694&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="37708665">Mejdahl Nielsen et al. (2023)</a> reported that treatment with creatine, arginine, and glycine resulted in reduced seizure frequency, improved energy, and improved well-being in a female patient with CCDS1. In addition, brain MR spectroscopy showed improved cerebral creatine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37708665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<div class="mim-changed mim-change"><p><a href="#12" class="mim-tip-reference" title="Longo, N., Voss, L. A., Frigeni, M., Balakrishnan, B., Pasquali, M. &lt;strong&gt;Response to therapy of creatine transporter deficiency caused by a hypomorphic variant in SLC6A8.&lt;/strong&gt; Molec. Genet. Metab. 143: 108595, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/39418753/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;39418753&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2024.108595&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="39418753">Longo et al. (2024)</a> reported clinical features and treatment in a boy with CCDS1. He presented with speech delay and seizures at 2 years of age and was found to have reduced cerebral creatine and a mutation in the SLC6A8 gene. At age 3 years and 2 months, he was initiated on treatment with creatine, arginine, and glycine. Two months after starting therapy, his seizures resolved, and he had improvement in spoken language and behaviors. He continued to make developmental progress, and at 5.5 years of age S-adenosylmethionine was added to his therapy, which was changed to betaine at 9 years of age. At 10 years of age, he was in a regular fourth grade class with extra help in math and reading. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39418753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<p>In a male patient with developmental delay and defective creatine uptake, <a href="#15" class="mim-tip-reference" title="Salomons, G. S., van Dooren, S. J. M., Verhoeven, N. M., Cecil, K. M., Ball, W. S., Degrauw, T. J., Jakobs, C. &lt;strong&gt;X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 68: 1497-1500, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11326334/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11326334&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11326334[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/320595&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11326334">Salomons et al. (2001)</a> identified a hemizygous nonsense mutation in the SLC6A8 gene (<a href="/entry/300036#0001">300036.0001</a>). Three mildly affected female relatives were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p>In the child with severe neurologic deficits and creatine deficiency, <a href="#3" class="mim-tip-reference" title="Bizzi, A., Bugiani, M., Salomons, G. S., Hunneman, D. H., Moroni, I., Estienne, M., Danesi, U., Jakobs, C., Uziel, G. &lt;strong&gt;X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8.&lt;/strong&gt; Ann. Neurol. 52: 227-231, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12210795/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12210795&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10246&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12210795">Bizzi et al. (2002)</a> identified a hemizygous 3-bp deletion in the SLC6A8 gene (<a href="/entry/300036#0003">300036.0003</a>). The patient's mother was heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p>In the family described by <a href="#7" class="mim-tip-reference" title="Hahn, K. A., Salomons, G. S., Tackels-Horne, D., Wood, T. C., Taylor, H. A., Schroer, R. J., Lubs, H. A., Jakobs, C., Olson, R. L., Holden, K. R., Stevenson, R. E., Schwartz, C. E. &lt;strong&gt;X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28.&lt;/strong&gt; Am. J. Hum. Genet. 70: 1349-1356, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11898126/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11898126&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11898126[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/340092&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11898126">Hahn et al. (2002)</a>, linkage to Xq28 was indicated by a lod score of 2.40 at zero recombination with 7 markers. Mutation analysis of candidate genes in that region revealed a splice site mutation in the SLC6A8 gene (<a href="/entry/300036#0002">300036.0002</a>). Two sisters of the 5 affected males were heterozygous for the SLC6A8 mutation and exhibited mild mental retardation with behavior and learning problems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11898126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p><a href="#14" class="mim-tip-reference" title="Rosenberg, E. H., Almeida, L. S., Kleefstra, T., deGrauw, R. S., Yntema, H. G., Bahi, N., Moraine, C., Ropers, H.-H., Fryns, J.-P., deGrauw, T. J., Jakobs, C., Salomons, G. S. &lt;strong&gt;High prevalence of SLC6A8 deficiency in X-linked mental retardation.&lt;/strong&gt; Am. J. Hum. Genet. 75: 97-105, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15154114/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15154114&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15154114[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/422102&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15154114">Rosenberg et al. (2004)</a> identified 2 different mutations in the SLC6A8 gene (<a href="/entry/300036#0004">300036.0004</a>; <a href="/entry/300036#0005">300036.0005</a>) in affected members of 2 unrelated families with X-linked mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15154114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p><a href="#4" class="mim-tip-reference" title="Clark, A. J., Rosenberg, E. H., Almeida, L. S., Wood, T. C., Jakobs, C., Stevenson, R. E., Schwartz, C. E., Salomons, G. S. &lt;strong&gt;X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology.&lt;/strong&gt; Hum. Genet. 119: 604-610, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16738945/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16738945&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-006-0162-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16738945">Clark et al. (2006)</a> identified 4 pathogenic (see, e.g., <a href="/entry/300036#0010">300036.0010</a>) and 2 potentially pathogenic mutations in the SLC6A8 gene in 6 of 478 unrelated males with X-linked mental retardation, yielding a frequency of approximately 1%. The authors stated that a total of 18 pathogenic mutations in the SLC6A8 gene had been reported, and suggested that urinary screening for an increased creatine:creatinine ratio could lead to focused mutation testing among appropriate patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16738945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<div class="mim-changed mim-change"><p><a href="#11" class="mim-tip-reference" title="Lion-Francois, L., Cheillan, D., Pitelet, G., Acquaviva-Bourdain, C., Bussy, G., Cotton, F., Guibaud, L., Gerard, D., Rivier, C., Vianey-Saban, C., Jakobs, C., Salomons, G. S., des Portes, V. &lt;strong&gt;High frequency of creatine deficiency syndromes in patients with unexplained mental retardation.&lt;/strong&gt; Neurology 67: 1713-1714, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17101918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17101918&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000239153.39710.81&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17101918">Lion-Francois et al. (2006)</a> identified 4 unrelated boys with severe mental retardation due to X-linked creatine deficiency. Four different mutations were identified in the SLC6A8 gene (see, e.g., <a href="/entry/300036#0008">300036.0008</a>; <a href="/entry/300036#0009">300036.0009</a>). Together with a fifth case of creatine deficiency due to mutation in the GAMT gene (<a href="/entry/612736">612736</a>), <a href="#11" class="mim-tip-reference" title="Lion-Francois, L., Cheillan, D., Pitelet, G., Acquaviva-Bourdain, C., Bussy, G., Cotton, F., Guibaud, L., Gerard, D., Rivier, C., Vianey-Saban, C., Jakobs, C., Salomons, G. S., des Portes, V. &lt;strong&gt;High frequency of creatine deficiency syndromes in patients with unexplained mental retardation.&lt;/strong&gt; Neurology 67: 1713-1714, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17101918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17101918&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000239153.39710.81&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17101918">Lion-Francois et al. (2006)</a> found that the prevalence of cerebral creatine deficiency syndromes was 2.7% in their study population of 188 children with mental retardation. The prevalence rose to 4.4% when only boys were considered. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17101918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
<div class="mim-changed mim-change"><p>In a boy with CCDS1, <a href="#12" class="mim-tip-reference" title="Longo, N., Voss, L. A., Frigeni, M., Balakrishnan, B., Pasquali, M. &lt;strong&gt;Response to therapy of creatine transporter deficiency caused by a hypomorphic variant in SLC6A8.&lt;/strong&gt; Molec. Genet. Metab. 143: 108595, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/39418753/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;39418753&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2024.108595&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="39418753">Longo et al. (2024)</a> identified hemizygosity for a missense mutation in the SLC6A8 gene (R278C; <a href="/entry/300036#0011">300036.0011</a>). The mutation was identified by sequencing of the SLC6A8 gene. Creatine uptake in patient fibroblasts was 25% of normal activity, and cerebral creatine was 20% of the normal range as measured on MRS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39418753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><a href="#10" class="mim-tip-reference" title="Levin, M. D., Bianconi, S., Smith, A., Cawley, N. X., Do, A. D., Hammond, D., Grafstein, J. F., Thurm, A., Miller, J., Perreault, J., Noguchi, A., Springer, D., Kozel, B. A., Spurney, C. F., Wassif, C. A., Yu, Z.-X., Schulze, A., Porter, F. D., Hannah-Shmouni, F. &lt;strong&gt;X-linked creatine transporter deficiency results in prolonged QTc and increased sudden death risk in humans and disease model.&lt;/strong&gt; Genet. Med. 23: 1864-1872, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34050321/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;34050321&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=34050321[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41436-021-01224-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="34050321">Levin et al. (2021)</a> found that hemizygous male Scl6a8-null mice had prolonged QTc and left ventricular dilation by 3 months, as well as increased chamber wall thickness, a phenotype not seen in humans. Left ventricular function was normal and unchanged at 9 months. Mouse exercise stress test showed diminished work capacity, and decreased time to exhaustion. Among hemizygous male Scl6a8-null mice, there was remarkable increase in sudden death: 12 of 28 (43%) hemizygous null mice died unexpectedly, while only 1 of 70 (1.4%) wildtype mice died during 40 weeks of observation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34050321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="Battini2011" class="mim-anchor"></a>
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Battini, R., Chilosi, A. M., Casarano, M., Moro, F., Comparini, A., Alessandri, M. G., Leuzzi, V., Tosetti, M., Cioni, G.
<strong>Language disorder with mild intellectual disability in a child affected by a novel mutation of SLC6A8 gene.</strong>
Molec. Genet. Metab. 102: 153-156, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21144783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21144783</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21144783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ymgme.2010.11.005" target="_blank">Full Text</a>]
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<a id="Battini2007" class="mim-anchor"></a>
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Battini, R., Chilosi, A., Mei, D., Casarano, M., Alessandri, M. G., Leuzzi, V., Ferretti, G., Tosetti, M., Bianchi, M. C., Cioni, G.
<strong>Mental retardation and verbal dyspraxia in a new patient with de novo creatine transporter (SLC6A8) mutation.</strong>
Am. J. Med. Genet. 143A: 1771-1774, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17603797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17603797</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17603797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.31827" target="_blank">Full Text</a>]
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<a id="Bizzi2002" class="mim-anchor"></a>
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Bizzi, A., Bugiani, M., Salomons, G. S., Hunneman, D. H., Moroni, I., Estienne, M., Danesi, U., Jakobs, C., Uziel, G.
<strong>X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8.</strong>
Ann. Neurol. 52: 227-231, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210795</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.10246" target="_blank">Full Text</a>]
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<a id="Clark2006" class="mim-anchor"></a>
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Clark, A. J., Rosenberg, E. H., Almeida, L. S., Wood, T. C., Jakobs, C., Stevenson, R. E., Schwartz, C. E., Salomons, G. S.
<strong>X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology.</strong>
Hum. Genet. 119: 604-610, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16738945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16738945</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16738945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s00439-006-0162-9" target="_blank">Full Text</a>]
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<a id="Comeaux2013" class="mim-anchor"></a>
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Comeaux, M. S., Wang, J., Wang, G., Kleppe, S., Zhang, V. W., Schmitt, E. S., Craigen, W. J., Renaud, D., Sun, Q., Wong, L.-J.
<strong>Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes.</strong>
Molec. Genet. Metab. 109: 260-268, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23660394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23660394</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23660394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ymgme.2013.04.006" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="6" class="mim-anchor"></a>
<a id="Dunbar2014" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Dunbar, M., Jaggumantri, S., Sargent, M., Stockler-Ipsiroglu, S., van Karnebeek, C. D. M.
<strong>Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases.</strong>
Molec. Genet. Metab. 112: 259-274, 2014.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24953403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24953403</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24953403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ymgme.2014.05.011" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="7" class="mim-anchor"></a>
<a id="Hahn2002" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hahn, K. A., Salomons, G. S., Tackels-Horne, D., Wood, T. C., Taylor, H. A., Schroer, R. J., Lubs, H. A., Jakobs, C., Olson, R. L., Holden, K. R., Stevenson, R. E., Schwartz, C. E.
<strong>X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28.</strong>
Am. J. Hum. Genet. 70: 1349-1356, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11898126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11898126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11898126[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11898126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/340092" target="_blank">Full Text</a>]
</p>
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<a id="8" class="mim-anchor"></a>
<a id="Joncquel-Chevalier Curt2018" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Joncquel-Chevalier Curt, M., Bout, M.-A., Fontaine, M., Kim, I., Huet, G., Bekri, S., Morin, G., Moortgat, S., Moerman, A., Cuisset, J.-M., Cheillan, D., Vamecq, J.
<strong>Functional assessment of creatine transporter in control and X-linked SLCA8-deficient fibroblasts.</strong>
Molec. Genet. Metab. 123: 463-471, 2018.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29478817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29478817</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29478817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ymgme.2018.02.010" target="_blank">Full Text</a>]
</p>
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<a id="9" class="mim-anchor"></a>
<a id="Kleefstra2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kleefstra, T., Rosenberg, E. H., Salomons, G. S., Stroink, H., van Bokhoven, H., Hamel, B. C. J., de Vries, B. B. A.
<strong>Progressive intestinal, neurological and psychiatric problems in two adult males with cerebral creatine deficiency cause by an SLC6A8 mutation. (Letter)</strong>
Clin. Genet. 68: 379-381, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16143026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16143026</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16143026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.2005.00489.x" target="_blank">Full Text</a>]
</p>
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<li>
<a id="10" class="mim-anchor"></a>
<a id="Levin2021" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Levin, M. D., Bianconi, S., Smith, A., Cawley, N. X., Do, A. D., Hammond, D., Grafstein, J. F., Thurm, A., Miller, J., Perreault, J., Noguchi, A., Springer, D., Kozel, B. A., Spurney, C. F., Wassif, C. A., Yu, Z.-X., Schulze, A., Porter, F. D., Hannah-Shmouni, F.
<strong>X-linked creatine transporter deficiency results in prolonged QTc and increased sudden death risk in humans and disease model.</strong>
Genet. Med. 23: 1864-1872, 2021.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34050321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34050321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34050321[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34050321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/s41436-021-01224-8" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
<a id="Lion-Francois2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lion-Francois, L., Cheillan, D., Pitelet, G., Acquaviva-Bourdain, C., Bussy, G., Cotton, F., Guibaud, L., Gerard, D., Rivier, C., Vianey-Saban, C., Jakobs, C., Salomons, G. S., des Portes, V.
<strong>High frequency of creatine deficiency syndromes in patients with unexplained mental retardation.</strong>
Neurology 67: 1713-1714, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17101918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17101918</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17101918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/01.wnl.0000239153.39710.81" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
<a id="Longo2024" class="mim-anchor"></a>
<div class="mim-changed mim-change">
<p class="mim-text-font">
Longo, N., Voss, L. A., Frigeni, M., Balakrishnan, B., Pasquali, M.
<strong>Response to therapy of creatine transporter deficiency caused by a hypomorphic variant in SLC6A8.</strong>
Molec. Genet. Metab. 143: 108595, 2024.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39418753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39418753</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39418753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ymgme.2024.108595" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
<a id="Mejdahl Nielsen2023" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Mejdahl Nielsen, M., Petersen, E. T., Fenger, C. D., Orngreen, M. C., Siebner, H. R., Boer, V. O., Povazan, M., Lund, A., Gronborg, S. W., Hammer, T. B.
<strong>X-linked creatine transporter (SLC6A8) deficiency in females: difficult to recognize, but a potentially treatable disease.</strong>
Molec. Genet. Metab. 140: 107694, 2023.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37708665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37708665</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37708665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ymgme.2023.107694" target="_blank">Full Text</a>]
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<a id="Rosenberg2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rosenberg, E. H., Almeida, L. S., Kleefstra, T., deGrauw, R. S., Yntema, H. G., Bahi, N., Moraine, C., Ropers, H.-H., Fryns, J.-P., deGrauw, T. J., Jakobs, C., Salomons, G. S.
<strong>High prevalence of SLC6A8 deficiency in X-linked mental retardation.</strong>
Am. J. Hum. Genet. 75: 97-105, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15154114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15154114</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15154114[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15154114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/422102" target="_blank">Full Text</a>]
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<a id="15" class="mim-anchor"></a>
<a id="Salomons2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Salomons, G. S., van Dooren, S. J. M., Verhoeven, N. M., Cecil, K. M., Ball, W. S., Degrauw, T. J., Jakobs, C.
<strong>X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome.</strong>
Am. J. Hum. Genet. 68: 1497-1500, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11326334[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/320595" target="_blank">Full Text</a>]
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<a id="Schiaffino2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Schiaffino, M. C., Bellini, C., Costabello, L., Caruso, U., Jakobs, C., Salomons, G. S., Bonioli, E.
<strong>X-linked creatine transporter deficiency: clinical description of a patient with a novel SLC6A8 gene mutation.</strong>
Neurogenetics 6: 165-168, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16086185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16086185</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16086185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s10048-005-0002-4" target="_blank">Full Text</a>]
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<a id="Valayannopoulos2012" class="mim-anchor"></a>
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<p class="mim-text-font">
Valayannopoulos, V., Boddaert, N., Chabli, A., Barbier, V., Desguerre, I., Philippe, A., Afenjar, A., Mazzuca, M., Cheillan, D., Munnich, A., de Keyzer, Y., Jakobs, C., Salomons, G. S., de Lonlay, P.
<strong>Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect.</strong>
J. Inherit. Metab. Dis. 35: 151-157, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21660517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21660517</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21660517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s10545-011-9358-9" target="_blank">Full Text</a>]
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<a id="van de Kamp2013" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
van de Kamp, J. M., Betsalel, O. T., Mercimek-Mahmutoglu, S., Abulhoul, L., Grunewald, S., Anselm, I., Azzouz, H., Bratkovic, D., de Brouwer, A., Hamel, B., Kleefstra, T., Yntema, H., and 48 others.
<strong>Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.</strong>
J. Med. Genet. 50: 463-472, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23644449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23644449</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23644449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmedgenet-2013-101658" target="_blank">Full Text</a>]
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<a id="van de Kamp2011" class="mim-anchor"></a>
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<p class="mim-text-font">
van de Kamp, J. M., Mancini, G. M. S., Pouwels, P. J. W., Betsalel, O. T., van Dooren, S. J. M., de Koning, I., Steenweg, M. E., Jakobs, C., van der Knaap, M. S., Salomons, G. S.
<strong>Clinical features and X-inactivation in females heterozygous for creatine transporter defect.</strong>
Clin. Genet. 79: 264-272, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20528887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20528887</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20528887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.2010.01460.x" target="_blank">Full Text</a>]
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<a id="van de Kamp2012" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
van de Kamp, J. M., Pouwels, P. J. W., Aarsen, F. K., ten Hoopen, L. W., Knol, D. L., de Klerk, J. B., de Coo, I. F., Huijmans, J. G. M., Jakobs, C., van der Knaap, M. S., Salomons, G. S., Mancini, G. M. S.
<strong>Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect.</strong>
J. Inherit. Metab. Dis. 35: 141-149, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21556832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21556832</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21556832[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21556832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s10545-011-9345-1" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 12/06/2024
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Ada Hamosh - updated : 09/17/2024<br>Hilary J. Vernon - updated : 12/22/2023<br>Hilary J. Vernon - updated : 03/09/2021<br>Ada Hamosh - updated : 11/25/2014<br>Ada Hamosh - updated : 10/20/2014<br>Cassandra L. Kniffin - updated : 7/23/2013<br>Cassandra L. Kniffin - updated : 7/16/2013<br>Cassandra L. Kniffin - updated : 6/19/2012<br>Cassandra L. Kniffin - updated : 7/20/2011<br>Cassandra L. Kniffin - updated : 9/3/2008<br>Cassandra L. Kniffin - updated : 2/7/2008<br>Cassandra L. Kniffin - updated : 8/28/2006<br>Marla J. F. O'Neill - updated : 11/23/2005<br>Cassandra L. Kniffin - updated : 11/9/2005<br>Cassandra L. Kniffin - updated : 10/2/2002
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Victor A. McKusick : 8/6/2001
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carol : 12/06/2024
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alopez : 09/17/2024<br>carol : 12/22/2023<br>carol : 03/10/2021<br>carol : 03/09/2021<br>carol : 04/12/2016<br>alopez : 11/25/2014<br>alopez : 11/25/2014<br>alopez : 10/20/2014<br>carol : 7/25/2013<br>ckniffin : 7/23/2013<br>carol : 7/17/2013<br>ckniffin : 7/16/2013<br>carol : 6/20/2012<br>terry : 6/20/2012<br>ckniffin : 6/19/2012<br>wwang : 7/27/2011<br>ckniffin : 7/20/2011<br>carol : 4/20/2009<br>wwang : 9/24/2008<br>ckniffin : 9/3/2008<br>wwang : 2/20/2008<br>ckniffin : 2/7/2008<br>wwang : 9/5/2006<br>ckniffin : 8/28/2006<br>wwang : 11/23/2005<br>wwang : 11/22/2005<br>ckniffin : 11/9/2005<br>terry : 2/19/2004<br>tkritzer : 10/25/2002<br>ckniffin : 10/2/2002<br>carol : 8/6/2001<br>carol : 8/6/2001
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<strong>#</strong> 300352
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CEREBRAL CREATINE DEFICIENCY SYNDROME 1; CCDS1
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<div>
<div >
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
CREATINE DEFICIENCY SYNDROME, X-LINKED<br />
CREATINE TRANSPORTER DEFECT<br />
MENTAL RETARDATION, X-LINKED, WITH SEIZURES, SHORT STATURE, AND MIDFACE HYPOPLASIA<br />
MENTAL RETARDATION, X-LINKED, WITH CREATINE TRANSPORT DEFICIENCY
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</h4>
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<p>
<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 698290008; &nbsp;
<strong>ORPHA:</strong> 52503; &nbsp;
<strong>DO:</strong> 0050800; &nbsp;
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</p>
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<div>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
Xq28
</span>
</td>
<td>
<span class="mim-font">
Cerebral creatine deficiency syndrome 1
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</td>
<td>
<span class="mim-font">
300352
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</td>
<td>
<span class="mim-font">
X-linked recessive
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</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
SLC6A8
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</td>
<td>
<span class="mim-font">
300036
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</td>
</tr>
</tbody>
</table>
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<div>
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<h4>
<span class="mim-font">
<strong>TEXT</strong>
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</h4>
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because cerebral creatine deficiency syndrome-1 (CCDS1) is caused by mutation in the creatine transporter gene (SLC6A8; 300036) on chromosome Xq28.</p>
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<div>
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<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
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</h4>
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<span class="mim-text-font">
<p>Cerebral creatine deficiency syndrome-1 (CCDS1) is an X-linked disorder of creatine (Cr) transport characterized by mental retardation, severe speech delay, behavioral abnormalities, and seizures. It has a prevalence of 0.3 to 3.5% in males. Carrier females may show mild neuropsychologic impairment (summary by van de Kamp et al., 2011). </p><p><strong><em>Genetic Heterogeneity of Cerebral Creatine Deficiency Syndrome</em></strong></p><p>
See also CCDS2 (612736), caused by mutation in the GAMT gene (601240) on chromosome 19p13, and CCDS3 (612718), caused by mutation in the AGAT gene (GATM; 602360) on chromosome 15q21.</p>
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<div>
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<h4>
<span class="mim-font">
<strong>Clinical Features</strong>
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</h4>
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<span class="mim-text-font">
<p>Salomons et al. (2001) reported a male patient with developmental delay and hypotonia. Proton magnetic resonance spectroscopic imaging (H-MRSI) of his brain revealed absence of the creatine signal. However, creatine in urine and plasma was increased, and guanidinoacetate (see 612718) levels were normal. Fibroblasts from the index patient were defective in creatine uptake. Three female relatives had mild biochemical abnormalities and learning disabilities. </p><p>Bizzi et al. (2002) reported a child with severe neurologic disturbances including seizures, behavioral problems, speech delay, and inability to engage in structured play, as well as creatine deficiency. H-MRSI showed absence of creatine in the whole brain, which was not corrected by creatine supplementation. </p><p>Hahn et al. (2002) described a family in which 5 males in a sibship of 10 had mental retardation with seizures. Head circumference was normal in all. Adult height (162.5-167.5 cm) was less than the adult height of the unaffected brother (175.5 cm). Midface hypoplasia was also described. Gastrointestinal disturbances in the form of chronic constipation, megacolon, gastric and duodenal ulcer disease, and bowel perforation were also observed. Two sisters had mild cognitive impairment, and one of them had chronic behavioral disturbances. Biochemical analyses confirmed a defect in creatine metabolism in this family. In affected males patients, the level of urinary creatine was substantially increased, and creatine uptake in fibroblasts was decreased. </p><p>Schiaffino et al. (2005) reported a patient with X-linked creatine deficiency confirmed by genetic analysis (300036.0006). The patient was first seen at age 21 months for failure to thrive, recurrent vomiting, and motor delay. His weight, length, and head circumference were all under the third percentile. Neurologic examination showed truncal hypotonia, impaired eye-hand coordination, and severe cognitive and language retardation. EEG showed slow, diffuse hypersynchronisms with abnormal multifocal spikes. Plasma creatine levels were consistently low, and biochemical studies on fibroblasts showed impaired creatine uptake. Schiaffino et al. (2005) noted that few patients with SLC6A8 deficiency had been described, precluding a definite clinical description. However, most affected males have mental retardation, seizures, and language impairment. </p><p>Kleefstra et al. (2005) described 2 brothers with X-linked creatine deficiency, in whom Rosenberg et al. (2004) had identified a missense mutation in the SLC6A8 gene (300036.0007). The older brother, born with severe mental retardation, was examined at age 70 and found to have myopathic facies with ptosis, external ophthalmoplegia, and open, hanging mouth. The younger brother had milder mental retardation and learned to read and write, but underwent regression at age 51 after the death of their father. In his fifties, he had urethral stenosis, chronic constipation, and ileus, and spontaneous luxations of several digits occurred. Neurologic examination at age 67 showed apparent medication-related Parkinsonism, upward gaze paresis, expressionless face, and hanging mouth and shoulders; comparison of photographs at age 57 and 64 revealed the striking progression of clinical features in the latter patient. Their sister, a carrier of the mutation, had short stature, learning difficulties, and developed severe constipation requiring surgical intervention in her fifties. </p><p>Clark et al. (2006) reported 6 unrelated males with X-linked mental retardation associated with mutations in the SLC6A8 gene. Clinical features included increased urinary creatine:creatinine (Cr:Crn) ratio, microcephaly, long, narrow face, and prominent chin. Two patients were tall and thin, and 3 had short stature. </p><p>Battini et al. (2007) reported a 9.5-year-old Italian boy with moderate mental retardation and verbal dyspraxia associated with mutation in the SLC6A8 gene. He had delayed psychomotor development, hypotonia, seizures, and severe language deficit with oral-motor dyspraxia, irritability, and temper tantrums. Detailed language evaluation showed problems in picture naming and phonetics, whereas receptive vocabulary was less severely affected. Social interaction was good despite the severe expressive limitation. </p><p>Battini et al. (2011) reported a 6.5-year-old boy with X-linked creatine deficiency syndrome confirmed by genetic analysis. In infancy, he showed poor feeding, hypotonia, and delayed psychomotor development with walking and speaking his first words at age 3 years. Examination at age 5 years showed mild intellectual disability and comparatively severe language delay with mild oromotor dyspraxia and clumsiness. Social interaction was good. Detailed neuropsychologic studies showed a discrepancy between nonverbal and verbal skills, with mild impairment of social personal performance and eye-hand coordination and moderate impairment of speech and practical reasoning. Spontaneous language performance was markedly reduced. Biochemical analysis showed increased urinary Cr, increased Cr/Crn ratio, and undetectable uptake of Cr in fibroblasts, and magnetic resonance spectroscopy showed a reduced Cr peak in the brain. The patient's mother, who also carried the mutation, had a normal biochemical profile, but borderline intellectual functioning with difficulties in reading comprehension. </p><p>Comeaux et al. (2013) reported 22 patients with confirmed deleterious mutations in the SLC6A8 gene who had clinical information available. Clinical features included developmental delay (86%), seizures (27%), autistic features (18%), speech delay (27%), ataxia (14%), and choreoathetosis (9%). All 6 patients with MRS results had decreased or absent creatine peaks. </p><p>Van de Kamp et al. (2013) performed a retrospective analysis of 101 male patients from 85 families with X-linked creatine transporter deficiency confirmed by genetic analysis. Many of the patients had previously been reported. All patients presented in infancy or early childhood, most often due to delayed psychomotor development. All had intellectual disability of varying degrees, and 85% had behavioral problems. Speech development was especially delayed, but almost a third of patients could speak in sentences. Other features included seizures (59%), hypotonia (40%), spasticity (26%), gastrointestinal symptoms (35%), and ophthalmologic abnormalities (10%). Various facial dysmorphic features were present in 45%. MRI showed mild structural abnormalities in 53 of 76 patients studied, and MRS showed reduced creatine in all 66 patients for whom results were available. Urinary creatine was increased in 81 patients for whom results were available. A few patients studied had unexpectedly high creatine levels in CSF, suggesting that the brain is able to synthesize creatine and that the creatine deficiency is caused by a defect in the reuptake of creatine within neurons. Most patients had missense mutations or deletions of 1 amino acid in the SLC6A8 gene. A third of patients had a de novo mutation in the SLC6A8 gene. However, van de Kamp et al. (2013) suggested that a mother with an affected son with a de novo mutation may have a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. </p><p>Levin et al. (2021) performed a cross-sectional analysis of the cardiac phenotype and risk of sudden death between 2017 and 2020 in 18 boys (average age of 7.4 years, range 3-16 years) with creatine transporter deficiency caused by mutations in SCL6A8. Seven (39%) had prolonged QTc of greater than 470 milliseconds, with a mean of 510.3 +/- 29.0 ms versus 448.3 +/- 15.9 ms in the other 11 subjects. The cohort with prolonged QTc had increased left ventricular internal dimension in diastole and diminished left ventricular posterior wall dimension compared to patients with normal or borderline QTc. </p><p><strong><em>Carrier Females</em></strong></p><p>
Van de Kamp et al. (2011) studied 8 unrelated female carriers of SLC6A8 mutations identified though affected male relatives. One woman had mental retardation, 1 required special education, 3 failed a year during elementary school, and 3 had no learning difficulties. IQ scores ranged from 48 to 96; 2 had scores in the mental retardation range, and 4 had scores in the borderline range. MRI showed mild cerebellar symptoms in 2, and constipation was reported in 2. Only 3 of 8 women had a mildly elevated urine creatine/creatinine ratio. H-MRSI studies showed decreased total creatine concentrations in the brain overall, but individual females had levels overlapping that of controls. X-inactivation studies in cultured fibroblasts showed severely skewed patterns in 2 woman, 1 favoring the mutant allele and 1 favoring the wildtype allele, but this may have been an artifact. Van de Kamp et al. (2011) concluded that carrier females may have mild symptoms of the disorder, and suggested that the most accurate diagnostic strategy in females should be molecular diagnosis, as biochemical changes may be subtle or not present. </p><p>Mejdahl Nielsen et al. (2023) reported a 16-year-old female with CCDS1 who had a history of learning disabilities and seizures, which started at 10 years of age. She also had a history of autism. Laboratory testing demonstrated a normal urine creatine/creatinine ratio, and brain MR spectroscopy showed reduced cerebral creatine. Mejdahl Nielsen et al. (2023) also reviewed 32 previously reported female patients with CCDS1. Clinical features included learning difficulties in 17 patients, language delay in 9 patients, and motor delay in 6 patients. Six patients had epilepsy, 2 had autism, 4 had ADHD, and 1 patient had psychosis. X-linked inactivation was not skewed in the few patients who were tested. Urine creatine/creatinine was normal in 15 of 20 patients. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The biochemical test for CCDS1 is the urine creatine:creatinine ratio, which should be above 1.5 for a diagnosis of the disorder in males. Among 69 patients referred for SLC6A8 mutation testing, Comeaux et al. (2013) found that 45 had normal primary or secondary urine screens and did not meet the criteria for gene testing. Twelve of the 45 were females, whose ratios may have been uninformative due to random X-chromosome inactivation. Seven males and 2 females with increased ratios in the first screen had normal ratios in a second sample; none of these patients carried SLC6A8 mutations. The negative predictive value of this test in this study was 100%; all 45 patients with urine creatine:creatinine ratios below 1.5, regardless of gender, had no SLC6A8 mutations. Comeaux et al. (2013) emphasized that the urine creatine:creatinine ratio may be misleading because of diet and the possibility of creatine supplementation. </p><p>Joncquel-Chevalier Curt et al. (2018) described a creatine uptake assay in patient-derived fibroblasts to aid in measuring creatine transporter activity and in diagnosing creatine transporter deficiency. Using a stable isotope-labeled substrate, D3-creatine, in patient fibroblasts, preceded by a creatine washout step, Joncquel-Chevalier Curt et al. (2018) were able to functionally discriminate between hemizygous males and heterozygous females with creatine transport defects versus controls. The authors noted, however, that this method may be limited in diagnosing female patients because transporter activity in fibroblasts may not reflect transporter activity in other cell types due to variation in X-chromosome inactivation. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Van de Kamp et al. (2012) recorded the long-term follow-up and treatment of 9 boys between the ages of 8 months and 10 years with creatine transporter defect. The patients underwent repeated magnetic resonance spectroscopy (MRS) and neuropsychologic assessments during 4 to 6 years of combination treatment with creatine monohydrate, L-arginine, and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with MRS. After an initial improvement in locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionally, van de Kamp et al. (2012) noticed an age-related decline in IQ subscales in boys affected with creatine transporter defect. </p><p>Valayannopoulos et al. (2012) reported a series of 6 patients with severe creatine transporter deficiency, 4 males and 2 females. Clinical presentations included mild to severe mental retardation in all 6 patients, associated with psychiatric symptoms (autistic behavior, chronic hallucinatory psychosis) in 5 of 6, seizures in 2 of 6, and muscular symptoms in 2 of the 4 males. Diagnosis was confirmed by molecular analysis in all patients. All patients were treated successively according to the same protocol with creatine alone and then by creatine combined with its precursors L-glycine and L-arginine for 42 months. Valayannopoulos et al. (2012) reported benefit only in the muscular symptoms of the disease and no improvement in the cognitive and psychiatric manifestations. Treatment failed to modify brain creatine content in either male or female patients. </p><p>Dunbar et al. (2014) performed a systematic literature review (2001-2013) comprising 7 publications that described 25 patients with creatine transporter deficiency, and 3 additional patients treated at the authors' institution. Two patients received creatine-monohydrate supplementation; 7 received L-arginine; 2 received creatine-monohydrate and L-arginine; and 17 received a combination of creatine-monohydrate, L-arginine, and glycine. Median treatment duration was 34.6 months (range 3 months to 5 years). A total of 10 patients (36%) demonstrated response to treatment, manifested by either an increase in cerebral creatine or improved clinical parameters. Seven of the 28 patients had quantified pre- and posttreatment creatine, and it was significantly increased posttreatment. All of the patients with increased cerebral creatine also experienced clinical improvement. In addition, the majority of patients with clinical improvement had detectable cerebral creatine prior to treatment. Ninety percent of the patients who improved were initiated on treatment before 9 years of age. Dunbar et al. (2014) proposed systematic screening for creatine transporter deficiency in patients with intellectual disability, to allow early initiation of treatment with oral creatine, arginine, and/or glycine supplementation. </p><p>Mejdahl Nielsen et al. (2023) reported that treatment with creatine, arginine, and glycine resulted in reduced seizure frequency, improved energy, and improved well-being in a female patient with CCDS1. In addition, brain MR spectroscopy showed improved cerebral creatine. </p><p>Longo et al. (2024) reported clinical features and treatment in a boy with CCDS1. He presented with speech delay and seizures at 2 years of age and was found to have reduced cerebral creatine and a mutation in the SLC6A8 gene. At age 3 years and 2 months, he was initiated on treatment with creatine, arginine, and glycine. Two months after starting therapy, his seizures resolved, and he had improvement in spoken language and behaviors. He continued to make developmental progress, and at 5.5 years of age S-adenosylmethionine was added to his therapy, which was changed to betaine at 9 years of age. At 10 years of age, he was in a regular fourth grade class with extra help in math and reading. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In a male patient with developmental delay and defective creatine uptake, Salomons et al. (2001) identified a hemizygous nonsense mutation in the SLC6A8 gene (300036.0001). Three mildly affected female relatives were heterozygous for the mutation. </p><p>In the child with severe neurologic deficits and creatine deficiency, Bizzi et al. (2002) identified a hemizygous 3-bp deletion in the SLC6A8 gene (300036.0003). The patient's mother was heterozygous for the mutation. </p><p>In the family described by Hahn et al. (2002), linkage to Xq28 was indicated by a lod score of 2.40 at zero recombination with 7 markers. Mutation analysis of candidate genes in that region revealed a splice site mutation in the SLC6A8 gene (300036.0002). Two sisters of the 5 affected males were heterozygous for the SLC6A8 mutation and exhibited mild mental retardation with behavior and learning problems. </p><p>Rosenberg et al. (2004) identified 2 different mutations in the SLC6A8 gene (300036.0004; 300036.0005) in affected members of 2 unrelated families with X-linked mental retardation. </p><p>Clark et al. (2006) identified 4 pathogenic (see, e.g., 300036.0010) and 2 potentially pathogenic mutations in the SLC6A8 gene in 6 of 478 unrelated males with X-linked mental retardation, yielding a frequency of approximately 1%. The authors stated that a total of 18 pathogenic mutations in the SLC6A8 gene had been reported, and suggested that urinary screening for an increased creatine:creatinine ratio could lead to focused mutation testing among appropriate patients. </p><p>Lion-Francois et al. (2006) identified 4 unrelated boys with severe mental retardation due to X-linked creatine deficiency. Four different mutations were identified in the SLC6A8 gene (see, e.g., 300036.0008; 300036.0009). Together with a fifth case of creatine deficiency due to mutation in the GAMT gene (612736), Lion-Francois et al. (2006) found that the prevalence of cerebral creatine deficiency syndromes was 2.7% in their study population of 188 children with mental retardation. The prevalence rose to 4.4% when only boys were considered. </p><p>In a boy with CCDS1, Longo et al. (2024) identified hemizygosity for a missense mutation in the SLC6A8 gene (R278C; 300036.0011). The mutation was identified by sequencing of the SLC6A8 gene. Creatine uptake in patient fibroblasts was 25% of normal activity, and cerebral creatine was 20% of the normal range as measured on MRS. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Levin et al. (2021) found that hemizygous male Scl6a8-null mice had prolonged QTc and left ventricular dilation by 3 months, as well as increased chamber wall thickness, a phenotype not seen in humans. Left ventricular function was normal and unchanged at 9 months. Mouse exercise stress test showed diminished work capacity, and decreased time to exhaustion. Among hemizygous male Scl6a8-null mice, there was remarkable increase in sudden death: 12 of 28 (43%) hemizygous null mice died unexpectedly, while only 1 of 70 (1.4%) wildtype mice died during 40 weeks of observation. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Battini, R., Chilosi, A. M., Casarano, M., Moro, F., Comparini, A., Alessandri, M. G., Leuzzi, V., Tosetti, M., Cioni, G.
<strong>Language disorder with mild intellectual disability in a child affected by a novel mutation of SLC6A8 gene.</strong>
Molec. Genet. Metab. 102: 153-156, 2011.
[PubMed: 21144783]
[Full Text: https://doi.org/10.1016/j.ymgme.2010.11.005]
</p>
</li>
<li>
<p class="mim-text-font">
Battini, R., Chilosi, A., Mei, D., Casarano, M., Alessandri, M. G., Leuzzi, V., Ferretti, G., Tosetti, M., Bianchi, M. C., Cioni, G.
<strong>Mental retardation and verbal dyspraxia in a new patient with de novo creatine transporter (SLC6A8) mutation.</strong>
Am. J. Med. Genet. 143A: 1771-1774, 2007.
[PubMed: 17603797]
[Full Text: https://doi.org/10.1002/ajmg.a.31827]
</p>
</li>
<li>
<p class="mim-text-font">
Bizzi, A., Bugiani, M., Salomons, G. S., Hunneman, D. H., Moroni, I., Estienne, M., Danesi, U., Jakobs, C., Uziel, G.
<strong>X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8.</strong>
Ann. Neurol. 52: 227-231, 2002.
[PubMed: 12210795]
[Full Text: https://doi.org/10.1002/ana.10246]
</p>
</li>
<li>
<p class="mim-text-font">
Clark, A. J., Rosenberg, E. H., Almeida, L. S., Wood, T. C., Jakobs, C., Stevenson, R. E., Schwartz, C. E., Salomons, G. S.
<strong>X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology.</strong>
Hum. Genet. 119: 604-610, 2006.
[PubMed: 16738945]
[Full Text: https://doi.org/10.1007/s00439-006-0162-9]
</p>
</li>
<li>
<p class="mim-text-font">
Comeaux, M. S., Wang, J., Wang, G., Kleppe, S., Zhang, V. W., Schmitt, E. S., Craigen, W. J., Renaud, D., Sun, Q., Wong, L.-J.
<strong>Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes.</strong>
Molec. Genet. Metab. 109: 260-268, 2013.
[PubMed: 23660394]
[Full Text: https://doi.org/10.1016/j.ymgme.2013.04.006]
</p>
</li>
<li>
<p class="mim-text-font">
Dunbar, M., Jaggumantri, S., Sargent, M., Stockler-Ipsiroglu, S., van Karnebeek, C. D. M.
<strong>Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases.</strong>
Molec. Genet. Metab. 112: 259-274, 2014.
[PubMed: 24953403]
[Full Text: https://doi.org/10.1016/j.ymgme.2014.05.011]
</p>
</li>
<li>
<p class="mim-text-font">
Hahn, K. A., Salomons, G. S., Tackels-Horne, D., Wood, T. C., Taylor, H. A., Schroer, R. J., Lubs, H. A., Jakobs, C., Olson, R. L., Holden, K. R., Stevenson, R. E., Schwartz, C. E.
<strong>X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28.</strong>
Am. J. Hum. Genet. 70: 1349-1356, 2002.
[PubMed: 11898126]
[Full Text: https://doi.org/10.1086/340092]
</p>
</li>
<li>
<p class="mim-text-font">
Joncquel-Chevalier Curt, M., Bout, M.-A., Fontaine, M., Kim, I., Huet, G., Bekri, S., Morin, G., Moortgat, S., Moerman, A., Cuisset, J.-M., Cheillan, D., Vamecq, J.
<strong>Functional assessment of creatine transporter in control and X-linked SLCA8-deficient fibroblasts.</strong>
Molec. Genet. Metab. 123: 463-471, 2018.
[PubMed: 29478817]
[Full Text: https://doi.org/10.1016/j.ymgme.2018.02.010]
</p>
</li>
<li>
<p class="mim-text-font">
Kleefstra, T., Rosenberg, E. H., Salomons, G. S., Stroink, H., van Bokhoven, H., Hamel, B. C. J., de Vries, B. B. A.
<strong>Progressive intestinal, neurological and psychiatric problems in two adult males with cerebral creatine deficiency cause by an SLC6A8 mutation. (Letter)</strong>
Clin. Genet. 68: 379-381, 2005.
[PubMed: 16143026]
[Full Text: https://doi.org/10.1111/j.1399-0004.2005.00489.x]
</p>
</li>
<li>
<p class="mim-text-font">
Levin, M. D., Bianconi, S., Smith, A., Cawley, N. X., Do, A. D., Hammond, D., Grafstein, J. F., Thurm, A., Miller, J., Perreault, J., Noguchi, A., Springer, D., Kozel, B. A., Spurney, C. F., Wassif, C. A., Yu, Z.-X., Schulze, A., Porter, F. D., Hannah-Shmouni, F.
<strong>X-linked creatine transporter deficiency results in prolonged QTc and increased sudden death risk in humans and disease model.</strong>
Genet. Med. 23: 1864-1872, 2021.
[PubMed: 34050321]
[Full Text: https://doi.org/10.1038/s41436-021-01224-8]
</p>
</li>
<li>
<p class="mim-text-font">
Lion-Francois, L., Cheillan, D., Pitelet, G., Acquaviva-Bourdain, C., Bussy, G., Cotton, F., Guibaud, L., Gerard, D., Rivier, C., Vianey-Saban, C., Jakobs, C., Salomons, G. S., des Portes, V.
<strong>High frequency of creatine deficiency syndromes in patients with unexplained mental retardation.</strong>
Neurology 67: 1713-1714, 2006.
[PubMed: 17101918]
[Full Text: https://doi.org/10.1212/01.wnl.0000239153.39710.81]
</p>
</li>
<li>
<p class="mim-text-font">
Longo, N., Voss, L. A., Frigeni, M., Balakrishnan, B., Pasquali, M.
<strong>Response to therapy of creatine transporter deficiency caused by a hypomorphic variant in SLC6A8.</strong>
Molec. Genet. Metab. 143: 108595, 2024.
[PubMed: 39418753]
[Full Text: https://doi.org/10.1016/j.ymgme.2024.108595]
</p>
</li>
<li>
<p class="mim-text-font">
Mejdahl Nielsen, M., Petersen, E. T., Fenger, C. D., Orngreen, M. C., Siebner, H. R., Boer, V. O., Povazan, M., Lund, A., Gronborg, S. W., Hammer, T. B.
<strong>X-linked creatine transporter (SLC6A8) deficiency in females: difficult to recognize, but a potentially treatable disease.</strong>
Molec. Genet. Metab. 140: 107694, 2023.
[PubMed: 37708665]
[Full Text: https://doi.org/10.1016/j.ymgme.2023.107694]
</p>
</li>
<li>
<p class="mim-text-font">
Rosenberg, E. H., Almeida, L. S., Kleefstra, T., deGrauw, R. S., Yntema, H. G., Bahi, N., Moraine, C., Ropers, H.-H., Fryns, J.-P., deGrauw, T. J., Jakobs, C., Salomons, G. S.
<strong>High prevalence of SLC6A8 deficiency in X-linked mental retardation.</strong>
Am. J. Hum. Genet. 75: 97-105, 2004.
[PubMed: 15154114]
[Full Text: https://doi.org/10.1086/422102]
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<li>
<p class="mim-text-font">
Salomons, G. S., van Dooren, S. J. M., Verhoeven, N. M., Cecil, K. M., Ball, W. S., Degrauw, T. J., Jakobs, C.
<strong>X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome.</strong>
Am. J. Hum. Genet. 68: 1497-1500, 2001.
[PubMed: 11326334]
[Full Text: https://doi.org/10.1086/320595]
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<li>
<p class="mim-text-font">
Schiaffino, M. C., Bellini, C., Costabello, L., Caruso, U., Jakobs, C., Salomons, G. S., Bonioli, E.
<strong>X-linked creatine transporter deficiency: clinical description of a patient with a novel SLC6A8 gene mutation.</strong>
Neurogenetics 6: 165-168, 2005.
[PubMed: 16086185]
[Full Text: https://doi.org/10.1007/s10048-005-0002-4]
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</li>
<li>
<p class="mim-text-font">
Valayannopoulos, V., Boddaert, N., Chabli, A., Barbier, V., Desguerre, I., Philippe, A., Afenjar, A., Mazzuca, M., Cheillan, D., Munnich, A., de Keyzer, Y., Jakobs, C., Salomons, G. S., de Lonlay, P.
<strong>Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect.</strong>
J. Inherit. Metab. Dis. 35: 151-157, 2012.
[PubMed: 21660517]
[Full Text: https://doi.org/10.1007/s10545-011-9358-9]
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</li>
<li>
<p class="mim-text-font">
van de Kamp, J. M., Betsalel, O. T., Mercimek-Mahmutoglu, S., Abulhoul, L., Grunewald, S., Anselm, I., Azzouz, H., Bratkovic, D., de Brouwer, A., Hamel, B., Kleefstra, T., Yntema, H., and 48 others.
<strong>Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.</strong>
J. Med. Genet. 50: 463-472, 2013.
[PubMed: 23644449]
[Full Text: https://doi.org/10.1136/jmedgenet-2013-101658]
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</li>
<li>
<p class="mim-text-font">
van de Kamp, J. M., Mancini, G. M. S., Pouwels, P. J. W., Betsalel, O. T., van Dooren, S. J. M., de Koning, I., Steenweg, M. E., Jakobs, C., van der Knaap, M. S., Salomons, G. S.
<strong>Clinical features and X-inactivation in females heterozygous for creatine transporter defect.</strong>
Clin. Genet. 79: 264-272, 2011.
[PubMed: 20528887]
[Full Text: https://doi.org/10.1111/j.1399-0004.2010.01460.x]
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<li>
<p class="mim-text-font">
van de Kamp, J. M., Pouwels, P. J. W., Aarsen, F. K., ten Hoopen, L. W., Knol, D. L., de Klerk, J. B., de Coo, I. F., Huijmans, J. G. M., Jakobs, C., van der Knaap, M. S., Salomons, G. S., Mancini, G. M. S.
<strong>Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect.</strong>
J. Inherit. Metab. Dis. 35: 141-149, 2012.
[PubMed: 21556832]
[Full Text: https://doi.org/10.1007/s10545-011-9345-1]
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Hilary J. Vernon - updated : 12/06/2024<br>Ada Hamosh - updated : 09/17/2024<br>Hilary J. Vernon - updated : 12/22/2023<br>Hilary J. Vernon - updated : 03/09/2021<br>Ada Hamosh - updated : 11/25/2014<br>Ada Hamosh - updated : 10/20/2014<br>Cassandra L. Kniffin - updated : 7/23/2013<br>Cassandra L. Kniffin - updated : 7/16/2013<br>Cassandra L. Kniffin - updated : 6/19/2012<br>Cassandra L. Kniffin - updated : 7/20/2011<br>Cassandra L. Kniffin - updated : 9/3/2008<br>Cassandra L. Kniffin - updated : 2/7/2008<br>Cassandra L. Kniffin - updated : 8/28/2006<br>Marla J. F. O&#x27;Neill - updated : 11/23/2005<br>Cassandra L. Kniffin - updated : 11/9/2005<br>Cassandra L. Kniffin - updated : 10/2/2002
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Victor A. McKusick : 8/6/2001
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