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Entry
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- #612736 - CEREBRAL CREATINE DEFICIENCY SYNDROME 2; CCDS2
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- OMIM
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<p>
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<span class="h4">#612736</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/612736"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS300352"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</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="#populationGenetics">Population Genetics</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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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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</span>
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</span>
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<div class="panel-body small mim-panel-body">
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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><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=1726&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK3794/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/guanidinoacetate-methyltransferase-deficiency" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=612736[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=382" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/e5533235-27d7-4a9c-97a2-d02fea648beb/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0050799" 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>
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<div><a href="http://www.informatics.jax.org/disease/612736" 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>
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<span>
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<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.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 124239003<br />
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<strong>ORPHA:</strong> 382<br />
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<strong>DO:</strong> 0050799<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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612736
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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CEREBRAL CREATINE DEFICIENCY SYNDROME 2; CCDS2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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GUANIDINOACETATE METHYLTRANSFERASE DEFICIENCY<br />
|
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GAMT DEFICIENCY<br />
|
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CREATINE DEFICIENCY SYNDROME DUE TO GAMT DEFICIENCY
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/19/52?start=-3&limit=10&highlight=52">
|
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19p13.3
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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Cerebral creatine deficiency syndrome 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/612736"> 612736 </a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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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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</span>
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</td>
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<td>
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<span class="mim-font">
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GAMT
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/601240"> 601240 </a>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/612736" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<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')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS300352" class="btn btn-info" role="button"> Phenotypic Series </a>
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<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')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/612736" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/612736" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<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>
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<div>
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<p />
|
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> MUSCLE, SOFT TISSUES </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<div>
|
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<span class="mim-font">
|
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|
|
- Hypotonia in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860834&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860834</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008947" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008947</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008947" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008947</a>]</span><br />
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</span>
|
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Progressive extrapyramidal movement disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748610&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748610</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007153" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007153</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007153" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007153</a>]</span><br /> -
|
|
Developmental delay or regression <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748611&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748611</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 /> -
|
|
Ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20262006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20262006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39384006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39384006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.84</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004134</a>, <a href="https://bioportal.bioontology.org/search?q=C1135207&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1135207</a>, <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0010867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010867</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br /> -
|
|
Seizures, intractable <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674422&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674422</a>]</span><br /> -
|
|
Absent or limited speech development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748612&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748612</a>]</span><br /> -
|
|
Increased muscle tone in lower limbs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674843&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674843</a>]</span><br /> -
|
|
Increased deep tendon reflexes <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86854008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86854008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151889</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span><br /> -
|
|
Myoclonic jerks <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/17450006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">17450006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G25.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G25.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/333.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">333.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027066&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027066</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001336" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001336</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001336" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001336</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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</div>
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</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Extremely low creatine excretion <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748613&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748613</a>]</span><br /> -
|
|
Low CSF creatine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748614&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748614</a>]</span><br /> -
|
|
Low CSF creatinine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748615&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748615</a>]</span><br /> -
|
|
Deficiency of creatine phosphate in brain <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748616&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748616</a>]</span><br /> -
|
|
Accumulation of guanidinoacetate in brain <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748617&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748617</a>]</span><br /> -
|
|
Guanidinoacetate methyltransferase (GAMT) deficiency <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748618&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748618</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/124239003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">124239003</a>]</span><br />
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</span>
|
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<div>
|
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<span class="mim-font">
|
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|
|
- Clinical and biochemical symptoms improved with oral administration of creatine monohydrate<br />
|
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</span>
|
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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|
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<div>
|
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<span class="mim-font">
|
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|
|
- Caused by mutation in the guanidinoacetate methyltransferase gene (GAMT, <a href="/entry/601240#0001">601240.0001</a>)<br />
|
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|
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</span>
|
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</div>
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</div>
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</div>
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<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
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</div>
|
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</div>
|
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
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Cerebral creatine deficiency syndrome
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- <a href="/phenotypicSeries/PS300352">PS300352</a>
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- 3 Entries
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<strong>Phenotype</strong>
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<a href="/geneMap/15/180?start=-3&limit=10&highlight=180"> 15q21.1 </a>
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<span class="mim-font">
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<a href="/entry/612718"> Cerebral creatine deficiency syndrome 3 </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/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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<span class="mim-font">
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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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<span class="mim-font">
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<a href="/entry/300036"> 300036 </a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because cerebral creatine deficiency syndrome-2 (CCDS2), also known as guanidinoacetate methyltransferase (GAMT) deficiency, is caused by homozygous or compound heterozygous mutation in the GAMT gene (<a href="/entry/601240">601240</a>) on chromosome 19p13.</p>
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<p>Guanidinoacetate methyltransferase deficiency, an autosomal recessive inborn error of creatine synthesis, is characterized by developmental delay/regression, mental retardation, severe disturbance of expressive and cognitive speech, intractable seizures and movement disturbances, severe depletion of creatine/phosphocreatine in the brain, and accumulation of guanidinoacetic acid (GAA) in brain and body fluids (summary by <a href="#8" class="mim-tip-reference" title="Schulze, A. <strong>Creatine deficiency syndromes.</strong> Molec. Cell Biochem. 244: 143-150, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12701824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12701824</a>]" pmid="12701824">Schulze, 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12701824" 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>For a general phenotypic description and a discussion of genetic heterogeneity of CCDS, see CCDS1 (<a href="/entry/300352">300352</a>).</p>
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<p><a href="#9" class="mim-tip-reference" title="Stockler, S., Holzbach, U., Hanefeld, F., Marquardt, I., Helms, G., Requart, M., Hanicke, W., Frahm, J. <strong>Creatine deficiency in the brain: a new, treatable inborn error of metabolism.</strong> Pediat. Res. 36: 409-413, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7808840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7808840</a>] [<a href="https://doi.org/10.1203/00006450-199409000-00023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7808840">Stockler et al. (1994)</a> reported a 22-month-old male infant with muscular hypotonia, progressive extrapyramidal movement disorder, an extremely low excretion of creatine, deficiency of creatine and creatine phosphate, and simultaneous accumulation of guanidinoacetate in brain, as detected by in vivo proton and phosphorus magnetic resonance spectroscopy. The clinical symptoms and biochemical abnormalities improved significantly after oral administration of creatine monohydrate. The observations suggested an enzyme defect in creatine biosynthesis at the level of GAMT activity. <a href="#10" class="mim-tip-reference" title="Stockler, S., Isbrandt, D., Hanefeld, F., Schmidt, B., von Figura, K. <strong>Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man.</strong> Am. J. Hum. Genet. 58: 914-922, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651275</a>]" pmid="8651275">Stockler et al. (1996)</a> studied a second patient, aged 4 years, with similar biochemical and spectroscopic findings and severe developmental delay, muscular hypotonia, ataxia, and intractable seizures as the predominant clinical symptoms. Deficiency of GAMT in liver was demonstrated. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8651275+7808840" 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="Schulze, A., Hess, T., Wevers, R., Mayatepek, E., Bachert, P., Marescau, B., Knopp, M. V., De Deyn, P. P., Bremer, H. J., Rating, D. <strong>Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism.</strong> J. Pediat. 131: 626-631, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9386672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9386672</a>] [<a href="https://doi.org/10.1016/s0022-3476(97)70075-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9386672">Schulze et al. (1997)</a> reported findings in a female infant born of first-cousin Kurdish parents. She had psychomotor retardation at age 2.5 years. At 3 years she began to lose acquired skills. From 14 months she had intractable grand mal and absence seizures. This child also exhibited dyskinetic and dystonic involuntary movements and pyramidal signs including increased muscle tone of the lower limbs, increased deep tendon reflexes, and myoclonic jerks. MRI revealed marked myelination delay. Plasma creatinine was in the low normal range, and 24-hour creatinine excretion was markedly reduced. Urinary excretion of guanidinoacetic acid was greatly increased. In this infant, creatine therapy did not influence the course of epilepsy and its sequelae. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9386672" 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="Caldeira Araujo, H., Smit, W., Verhoeven, N. M., Salomons, G. S., Silva, S., Vasconcelos, R., Tomas, H., Tavares de Almeida, I., Jakobs, C., Duran, M. <strong>Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation.</strong> Am. J. Med. Genet. 133A: 122-127, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15651030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15651030</a>] [<a href="https://doi.org/10.1002/ajmg.a.30226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15651030">Caldeira Araujo et al. (2005)</a> investigated 180 institutionalized patients with a severe mental handicap for urine and plasma uric acid and creatinine. Patients with an increased urinary uric acid/creatinine ratio and/or decreased creatinine were subjected to the analysis of guanidinoacetate. Four patients were identified with GAMT deficiency: 2 sisters, aged 26 and 29 years, respectively, and their 8-year-old male third cousin, and an isolated case in an unrelated family who was 19 years old at the time of report. A fifth patient had died before a biochemical diagnosis could be made. All patients had shown normal psychomotor development in the first year of life, after which they developed profound mental retardation. Three of 4 had convulsions and all 4 totally lacked the development of speech. Their GAMT activity in lymphoblasts was impaired. <a href="#2" class="mim-tip-reference" title="Caldeira Araujo, H., Smit, W., Verhoeven, N. M., Salomons, G. S., Silva, S., Vasconcelos, R., Tomas, H., Tavares de Almeida, I., Jakobs, C., Duran, M. <strong>Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation.</strong> Am. J. Med. Genet. 133A: 122-127, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15651030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15651030</a>] [<a href="https://doi.org/10.1002/ajmg.a.30226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15651030">Caldeira Araujo et al. (2005)</a> concluded that GAMT deficiency in adults is associated with severe mental retardation and absent or limited speech development; convulsions may be prominent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15651030" 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><a href="#7" class="mim-tip-reference" title="Schulze, A., Hess, T., Wevers, R., Mayatepek, E., Bachert, P., Marescau, B., Knopp, M. V., De Deyn, P. P., Bremer, H. J., Rating, D. <strong>Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism.</strong> J. Pediat. 131: 626-631, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9386672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9386672</a>] [<a href="https://doi.org/10.1016/s0022-3476(97)70075-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9386672">Schulze et al. (1997)</a> noted that the finding of low CSF creatine and creatinine constitutes a reliable diagnostic method for GAMT deficiency. Magnetic resonance spectroscopy of brain is diagnostic in that it reveals creatine depletion and guanidinoacetate phosphate accumulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9386672" 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="#12" class="mim-tip-reference" title="Verhoeven, N. M., Guerand, W. S., Struys, E. A., Bouman, A. A., van der Knaap, M. S., Jakobs, C. <strong>Plasma creatinine assessment in creatine deficiency: a diagnostic pitfall.</strong> J. Inherit. Metab. Dis. 23: 835-840, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11196109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11196109</a>] [<a href="https://doi.org/10.1023/a:1026764703486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11196109">Verhoeven et al. (2000)</a> reported that creatinine in plasma from 2 GAMT-deficient patients appeared normal when measured by the Jaffe method but was decreased when measured enzymatically or by HPLC. The apparently normal levels of creatinine as measured by the Jaffe method were not caused by guanidinoacetate. In urine, the Jaffe method and the enzymatic method gave similar results, indicating that in urine no false elevations of creatinine can be expected. As the Jaffe method is still widely used for routine plasma creatinine measurements, <a href="#12" class="mim-tip-reference" title="Verhoeven, N. M., Guerand, W. S., Struys, E. A., Bouman, A. A., van der Knaap, M. S., Jakobs, C. <strong>Plasma creatinine assessment in creatine deficiency: a diagnostic pitfall.</strong> J. Inherit. Metab. Dis. 23: 835-840, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11196109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11196109</a>] [<a href="https://doi.org/10.1023/a:1026764703486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11196109">Verhoeven et al. (2000)</a> concluded that it is important to know that it cannot be used to exclude GAMT deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11196109" 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>GAMT-deficient patients have elevated plasma guanidinoacetate (GAA). Among 33 patients referred for genetic testing for mutations in the GAMT gene who had biochemical data available, <a href="#3" 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. <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://doi.org/10.1016/j.ymgme.2013.04.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23660394">Comeaux et al. (2013)</a> found that 16 had normal GAA plasma levels and were not sequenced for GAMT mutations. Abnormal results were found in 17 patients: 8 carried mutations and 9 were negative for mutations. Four of the 9 who were negative for mutations were found to have normal GAA levels on repeat testing, and the other 5 had only nonspecific marginally increased GAA. The findings indicated that plasma GAA levels as a biomarker has 100% specificity for GAMT mutations (no individuals with normal GAA had mutations), but low sensitivity (marginally high GAA does not necessarily indicate GAMT mutations). <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="#4" class="mim-tip-reference" title="Hart, K., Rohrwasser, A., Wallis, H., Golsan, H., Shao, J., Anderson, T., Wang, X., Szabo-Fresnais, N., Morrissey, M., Kay, D. M., Wojcik, M., Galvin-Partin, P. A., Longo, N., Caggana, M., Pasquali, M. <strong>Prospective identification by neonatal screening of patients with guanidinoacetate methyltransferase deficiency.</strong> Molec. Genet. Metab. 134: 60-64, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34389248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34389248</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34389248">Hart et al. (2021)</a> reported the identification of 2 infants diagnosed with GAMT deficiency by newborn screening to detect elevated guanidinoacetate levels on a bloodspot. Of a total of 537,408 infants screened in New York starting in 2018, 23 infants were referred for follow-up testing and 1 infant was diagnosed with GAMT deficiency. Of a total of 273,902 infants screened in Utah starting in 2015, 3 infants were referred for follow-up testing and 1 was diagnosed with GAMT deficiency. In Utah, where 2 newborn screens are performed on infants, GAA levels were similar between the first newborn screen at 24 hours of life and the second newborn screen at 7 to 16 days of life. <a href="#4" class="mim-tip-reference" title="Hart, K., Rohrwasser, A., Wallis, H., Golsan, H., Shao, J., Anderson, T., Wang, X., Szabo-Fresnais, N., Morrissey, M., Kay, D. M., Wojcik, M., Galvin-Partin, P. A., Longo, N., Caggana, M., Pasquali, M. <strong>Prospective identification by neonatal screening of patients with guanidinoacetate methyltransferase deficiency.</strong> Molec. Genet. Metab. 134: 60-64, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34389248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34389248</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34389248">Hart et al. (2021)</a> concluded that newborn screening for GAMT had a low false-positive rate and could prospectively identify affected children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34389248" 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><a href="#1" class="mim-tip-reference" title="Almeida, L. S., Vilarinho, L., Darmin, P. S., Rosenberg, E. H., Martinez-Munoz, C., Jakobs, C., Salomons, G. S. <strong>A prevalent pathogenic GAMT mutation (c.59G-C) in Portugal.</strong> Molec. Genet. Metab. 91: 1-6, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17336114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17336114</a>] [<a href="https://doi.org/10.1016/j.ymgme.2007.01.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17336114">Almeida et al. (2007)</a> noted that of the 29 known patients with CCDS2, 10 were of Portuguese origin. Seventeen of the GAMT alleles in the Portuguese patients carried the W20S mutation (<a href="/entry/601240#0003">601240.0003</a>). <a href="#1" class="mim-tip-reference" title="Almeida, L. S., Vilarinho, L., Darmin, P. S., Rosenberg, E. H., Martinez-Munoz, C., Jakobs, C., Salomons, G. S. <strong>A prevalent pathogenic GAMT mutation (c.59G-C) in Portugal.</strong> Molec. Genet. Metab. 91: 1-6, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17336114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17336114</a>] [<a href="https://doi.org/10.1016/j.ymgme.2007.01.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17336114">Almeida et al. (2007)</a> found an overall carrier rate of 0.8% for this mutation in several regions of Portugal and a carrier rate of 1.7% in the Archipelagos region, suggesting a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17336114" 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>In a physician-based survey of 48 patients from 38 families with CCDS2, <a href="#11" class="mim-tip-reference" title="Stockler-Ipsiroglu, S., van Karnebeek, C., Longo, N., Korenke, G. C., Mercimek-Mahmutoglu, S., Marquart, I., Barshop, B., Grolik, C., Schlune, A., Angle, B., Caldeira Araujo, H., Coskun, T., and 20 others. <strong>Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring.</strong> Molec. Genet. Metab. 111: 16-25, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24268530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24268530</a>] [<a href="https://doi.org/10.1016/j.ymgme.2013.10.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24268530">Stockler-Ipsiroglu et al. (2014)</a> evaluated the effectiveness of treatment of the disorder with various combinations/dosages of creatine-monohydrate, L-ornithine, sodium benzoate, and protein/arginine-restricted diets. Forty-four patients, all treated after 9 months of age, including 2 who had never received treatment, had developmental delay or intellectual disability. Thirty-five patients had seizures, and 13 had a movement disorder. Therapy was associated with improvement or stabilization of symptoms in all symptomatic cases. The 4 patients treated before age 9 months had normal or almost normal developmental outcomes. Reduction of plasma guanidinoacetate levels appeared to improve long-term outcomes. <a href="#11" class="mim-tip-reference" title="Stockler-Ipsiroglu, S., van Karnebeek, C., Longo, N., Korenke, G. C., Mercimek-Mahmutoglu, S., Marquart, I., Barshop, B., Grolik, C., Schlune, A., Angle, B., Caldeira Araujo, H., Coskun, T., and 20 others. <strong>Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring.</strong> Molec. Genet. Metab. 111: 16-25, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24268530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24268530</a>] [<a href="https://doi.org/10.1016/j.ymgme.2013.10.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24268530">Stockler-Ipsiroglu et al. (2014)</a> provided consensus recommendations for the diagnosis, treatment, and monitoring of patients with CCDS2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24268530" 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>In 2 patients with GAMT deficiency, <a href="#10" class="mim-tip-reference" title="Stockler, S., Isbrandt, D., Hanefeld, F., Schmidt, B., von Figura, K. <strong>Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man.</strong> Am. J. Hum. Genet. 58: 914-922, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651275</a>]" pmid="8651275">Stockler et al. (1996)</a> identified mutations in the GAMT gene; one patient was homozygous and the other was compound heterozygous (see <a href="/entry/601240#0001">601240.0001</a> and <a href="/entry/601240#0002">601240.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8651275" 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 3 family members and an isolated patient with GAMT deficiency, <a href="#2" class="mim-tip-reference" title="Caldeira Araujo, H., Smit, W., Verhoeven, N. M., Salomons, G. S., Silva, S., Vasconcelos, R., Tomas, H., Tavares de Almeida, I., Jakobs, C., Duran, M. <strong>Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation.</strong> Am. J. Med. Genet. 133A: 122-127, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15651030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15651030</a>] [<a href="https://doi.org/10.1002/ajmg.a.30226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15651030">Caldeira Araujo et al. (2005)</a> identified homozygous mutations in the GAMT gene (<a href="/entry/601240#0003">601240.0003</a>-<a href="/entry/601240#0004">601240.0004</a>, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15651030" 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 a North African patient with GAMT deficiency and severe mental retardation, born of consanguineous parents, <a href="#5" 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. <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://doi.org/10.1212/01.wnl.0000239153.39710.81" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17101918">Lion-Francois et al. (2006)</a> identified a homozygous missense mutation in the GAMT gene (<a href="/entry/601240#0005">601240.0005</a>). The patient had delayed onset of walking, seizures, and autistic features. <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><p>In 2 infants with GAMT deficiency, <a href="#4" class="mim-tip-reference" title="Hart, K., Rohrwasser, A., Wallis, H., Golsan, H., Shao, J., Anderson, T., Wang, X., Szabo-Fresnais, N., Morrissey, M., Kay, D. M., Wojcik, M., Galvin-Partin, P. A., Longo, N., Caggana, M., Pasquali, M. <strong>Prospective identification by neonatal screening of patients with guanidinoacetate methyltransferase deficiency.</strong> Molec. Genet. Metab. 134: 60-64, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34389248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34389248</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34389248">Hart et al. (2021)</a> identified homozygous or compound heterozygous mutations in the GAMT gene (<a href="/entry/601240#0006">601240.0006</a>-<a href="/entry/601240#0008">601240.0008</a>). Both infants were initially identified by newborn screening showing elevated guanidinoacetate level on a bloodspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34389248" 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><a href="#6" class="mim-tip-reference" title="Schmidt, A., Marescau, B., Boehm, E. A., Renema, W. K. J., Peco, R., Das, A., Steinfeld, R., Chan, S., Wallis, J., Davidoff, M., Ullrich, K., Waldschutz, R., Heerschap, A., De Deyn, P. P., Neubauer, S., Isbrandt, D. <strong>Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency.</strong> Hum. Molec. Genet. 13: 905-921, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15028668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15028668</a>] [<a href="https://doi.org/10.1093/hmg/ddh112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15028668">Schmidt et al. (2004)</a> generated a knockout mouse model for GAMT deficiency by gene targeting in embryonic stem cells. Gamt -/- mice had markedly increased guanidinoacetate and reduced creatine and creatinine levels in brain, serum, and urine, similar to human GAMT patients. In vivo 31P magnetic resonance spectroscopy showed high levels of PGAA and reduced levels of creatine phosphate in heart, skeletal muscle, and brain. GAMT deficiency was associated with increased neonatal mortality, muscular hypotonia, decreased male fertility, and a non-leptin-mediated lifelong reduction in body weight due to reduced body fat mass. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15028668" 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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Molec. Genet. Metab. 91: 1-6, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17336114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17336114</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17336114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2007.01.005" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
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<a id="Caldeira Araujo2005" class="mim-anchor"></a>
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Caldeira Araujo, H., Smit, W., Verhoeven, N. M., Salomons, G. S., Silva, S., Vasconcelos, R., Tomas, H., Tavares de Almeida, I., Jakobs, C., Duran, M.
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<strong>Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation.</strong>
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Am. J. Med. Genet. 133A: 122-127, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15651030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15651030</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15651030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30226" 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.
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<strong>Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes.</strong>
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Molec. Genet. Metab. 109: 260-268, 2013.
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[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>]
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[<a href="https://doi.org/10.1016/j.ymgme.2013.04.006" target="_blank">Full Text</a>]
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<a id="Hart2021" class="mim-anchor"></a>
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Hart, K., Rohrwasser, A., Wallis, H., Golsan, H., Shao, J., Anderson, T., Wang, X., Szabo-Fresnais, N., Morrissey, M., Kay, D. M., Wojcik, M., Galvin-Partin, P. A., Longo, N., Caggana, M., Pasquali, M.
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<strong>Prospective identification by neonatal screening of patients with guanidinoacetate methyltransferase deficiency.</strong>
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Molec. Genet. Metab. 134: 60-64, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34389248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34389248</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34389248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2021.07.012" target="_blank">Full Text</a>]
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<a id="Lion-Francois2006" class="mim-anchor"></a>
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<div class="">
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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.
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<strong>High frequency of creatine deficiency syndromes in patients with unexplained mental retardation.</strong>
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Neurology 67: 1713-1714, 2006.
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[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>]
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[<a href="https://doi.org/10.1212/01.wnl.0000239153.39710.81" target="_blank">Full Text</a>]
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Schmidt, A., Marescau, B., Boehm, E. A., Renema, W. K. J., Peco, R., Das, A., Steinfeld, R., Chan, S., Wallis, J., Davidoff, M., Ullrich, K., Waldschutz, R., Heerschap, A., De Deyn, P. P., Neubauer, S., Isbrandt, D.
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<strong>Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency.</strong>
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Hum. Molec. Genet. 13: 905-921, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15028668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15028668</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15028668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh112" target="_blank">Full Text</a>]
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<a id="Schulze1997" class="mim-anchor"></a>
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Schulze, A., Hess, T., Wevers, R., Mayatepek, E., Bachert, P., Marescau, B., Knopp, M. V., De Deyn, P. P., Bremer, H. J., Rating, D.
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<strong>Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism.</strong>
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J. Pediat. 131: 626-631, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9386672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9386672</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9386672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(97)70075-1" target="_blank">Full Text</a>]
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<a id="Schulze2003" class="mim-anchor"></a>
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Schulze, A.
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<strong>Creatine deficiency syndromes.</strong>
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Molec. Cell Biochem. 244: 143-150, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12701824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12701824</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12701824" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Stockler1994" class="mim-anchor"></a>
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Stockler, S., Holzbach, U., Hanefeld, F., Marquardt, I., Helms, G., Requart, M., Hanicke, W., Frahm, J.
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<strong>Creatine deficiency in the brain: a new, treatable inborn error of metabolism.</strong>
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Pediat. Res. 36: 409-413, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7808840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7808840</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7808840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1203/00006450-199409000-00023" target="_blank">Full Text</a>]
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Stockler, S., Isbrandt, D., Hanefeld, F., Schmidt, B., von Figura, K.
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<strong>Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man.</strong>
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Am. J. Hum. Genet. 58: 914-922, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651275</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8651275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Stockler-Ipsiroglu2014" class="mim-anchor"></a>
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Stockler-Ipsiroglu, S., van Karnebeek, C., Longo, N., Korenke, G. C., Mercimek-Mahmutoglu, S., Marquart, I., Barshop, B., Grolik, C., Schlune, A., Angle, B., Caldeira Araujo, H., Coskun, T., and 20 others.
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<strong>Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring.</strong>
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Molec. Genet. Metab. 111: 16-25, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24268530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24268530</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24268530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2013.10.018" target="_blank">Full Text</a>]
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<a id="Verhoeven2000" class="mim-anchor"></a>
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Verhoeven, N. M., Guerand, W. S., Struys, E. A., Bouman, A. A., van der Knaap, M. S., Jakobs, C.
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<strong>Plasma creatinine assessment in creatine deficiency: a diagnostic pitfall.</strong>
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J. Inherit. Metab. Dis. 23: 835-840, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11196109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11196109</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11196109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1023/a:1026764703486" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 06/23/2022
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 04/17/2020<br>Cassandra L. Kniffin - updated : 6/16/2014<br>Cassandra L. Kniffin - updated : 7/16/2013
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Creation Date:
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Carol A. Bocchini : 4/20/2009
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carol : 06/23/2022
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carol : 04/17/2020<br>carol : 06/18/2014<br>mcolton : 6/18/2014<br>ckniffin : 6/16/2014<br>carol : 7/17/2013<br>ckniffin : 7/16/2013<br>carol : 3/15/2012<br>terry : 4/20/2009<br>carol : 4/20/2009
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<strong>#</strong> 612736
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CEREBRAL CREATINE DEFICIENCY SYNDROME 2; CCDS2
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GUANIDINOACETATE METHYLTRANSFERASE DEFICIENCY<br />
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GAMT DEFICIENCY<br />
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CREATINE DEFICIENCY SYNDROME DUE TO GAMT DEFICIENCY
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<strong>SNOMEDCT:</strong> 124239003;
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<strong>ORPHA:</strong> 382;
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<strong>DO:</strong> 0050799;
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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19p13.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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Cerebral creatine deficiency syndrome 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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612736
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
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GAMT
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</span>
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</td>
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<td>
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<span class="mim-font">
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601240
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because cerebral creatine deficiency syndrome-2 (CCDS2), also known as guanidinoacetate methyltransferase (GAMT) deficiency, is caused by homozygous or compound heterozygous mutation in the GAMT gene (601240) on chromosome 19p13.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Guanidinoacetate methyltransferase deficiency, an autosomal recessive inborn error of creatine synthesis, is characterized by developmental delay/regression, mental retardation, severe disturbance of expressive and cognitive speech, intractable seizures and movement disturbances, severe depletion of creatine/phosphocreatine in the brain, and accumulation of guanidinoacetic acid (GAA) in brain and body fluids (summary by Schulze, 2003). </p><p>For a general phenotypic description and a discussion of genetic heterogeneity of CCDS, see CCDS1 (300352).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Stockler et al. (1994) reported a 22-month-old male infant with muscular hypotonia, progressive extrapyramidal movement disorder, an extremely low excretion of creatine, deficiency of creatine and creatine phosphate, and simultaneous accumulation of guanidinoacetate in brain, as detected by in vivo proton and phosphorus magnetic resonance spectroscopy. The clinical symptoms and biochemical abnormalities improved significantly after oral administration of creatine monohydrate. The observations suggested an enzyme defect in creatine biosynthesis at the level of GAMT activity. Stockler et al. (1996) studied a second patient, aged 4 years, with similar biochemical and spectroscopic findings and severe developmental delay, muscular hypotonia, ataxia, and intractable seizures as the predominant clinical symptoms. Deficiency of GAMT in liver was demonstrated. </p><p>Schulze et al. (1997) reported findings in a female infant born of first-cousin Kurdish parents. She had psychomotor retardation at age 2.5 years. At 3 years she began to lose acquired skills. From 14 months she had intractable grand mal and absence seizures. This child also exhibited dyskinetic and dystonic involuntary movements and pyramidal signs including increased muscle tone of the lower limbs, increased deep tendon reflexes, and myoclonic jerks. MRI revealed marked myelination delay. Plasma creatinine was in the low normal range, and 24-hour creatinine excretion was markedly reduced. Urinary excretion of guanidinoacetic acid was greatly increased. In this infant, creatine therapy did not influence the course of epilepsy and its sequelae. </p><p>Caldeira Araujo et al. (2005) investigated 180 institutionalized patients with a severe mental handicap for urine and plasma uric acid and creatinine. Patients with an increased urinary uric acid/creatinine ratio and/or decreased creatinine were subjected to the analysis of guanidinoacetate. Four patients were identified with GAMT deficiency: 2 sisters, aged 26 and 29 years, respectively, and their 8-year-old male third cousin, and an isolated case in an unrelated family who was 19 years old at the time of report. A fifth patient had died before a biochemical diagnosis could be made. All patients had shown normal psychomotor development in the first year of life, after which they developed profound mental retardation. Three of 4 had convulsions and all 4 totally lacked the development of speech. Their GAMT activity in lymphoblasts was impaired. Caldeira Araujo et al. (2005) concluded that GAMT deficiency in adults is associated with severe mental retardation and absent or limited speech development; convulsions may be prominent. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Diagnosis</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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|
<p>Schulze et al. (1997) noted that the finding of low CSF creatine and creatinine constitutes a reliable diagnostic method for GAMT deficiency. Magnetic resonance spectroscopy of brain is diagnostic in that it reveals creatine depletion and guanidinoacetate phosphate accumulation. </p><p>Verhoeven et al. (2000) reported that creatinine in plasma from 2 GAMT-deficient patients appeared normal when measured by the Jaffe method but was decreased when measured enzymatically or by HPLC. The apparently normal levels of creatinine as measured by the Jaffe method were not caused by guanidinoacetate. In urine, the Jaffe method and the enzymatic method gave similar results, indicating that in urine no false elevations of creatinine can be expected. As the Jaffe method is still widely used for routine plasma creatinine measurements, Verhoeven et al. (2000) concluded that it is important to know that it cannot be used to exclude GAMT deficiency. </p><p>GAMT-deficient patients have elevated plasma guanidinoacetate (GAA). Among 33 patients referred for genetic testing for mutations in the GAMT gene who had biochemical data available, Comeaux et al. (2013) found that 16 had normal GAA plasma levels and were not sequenced for GAMT mutations. Abnormal results were found in 17 patients: 8 carried mutations and 9 were negative for mutations. Four of the 9 who were negative for mutations were found to have normal GAA levels on repeat testing, and the other 5 had only nonspecific marginally increased GAA. The findings indicated that plasma GAA levels as a biomarker has 100% specificity for GAMT mutations (no individuals with normal GAA had mutations), but low sensitivity (marginally high GAA does not necessarily indicate GAMT mutations). </p><p>Hart et al. (2021) reported the identification of 2 infants diagnosed with GAMT deficiency by newborn screening to detect elevated guanidinoacetate levels on a bloodspot. Of a total of 537,408 infants screened in New York starting in 2018, 23 infants were referred for follow-up testing and 1 infant was diagnosed with GAMT deficiency. Of a total of 273,902 infants screened in Utah starting in 2015, 3 infants were referred for follow-up testing and 1 was diagnosed with GAMT deficiency. In Utah, where 2 newborn screens are performed on infants, GAA levels were similar between the first newborn screen at 24 hours of life and the second newborn screen at 7 to 16 days of life. Hart et al. (2021) concluded that newborn screening for GAMT had a low false-positive rate and could prospectively identify affected children. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Population Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
|
<p>Almeida et al. (2007) noted that of the 29 known patients with CCDS2, 10 were of Portuguese origin. Seventeen of the GAMT alleles in the Portuguese patients carried the W20S mutation (601240.0003). Almeida et al. (2007) found an overall carrier rate of 0.8% for this mutation in several regions of Portugal and a carrier rate of 1.7% in the Archipelagos region, suggesting a founder effect. </p>
|
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</span>
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<div>
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<br />
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</div>
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|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Clinical Management</strong>
|
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</span>
|
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</h4>
|
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</div>
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|
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<span class="mim-text-font">
|
|
<p>In a physician-based survey of 48 patients from 38 families with CCDS2, Stockler-Ipsiroglu et al. (2014) evaluated the effectiveness of treatment of the disorder with various combinations/dosages of creatine-monohydrate, L-ornithine, sodium benzoate, and protein/arginine-restricted diets. Forty-four patients, all treated after 9 months of age, including 2 who had never received treatment, had developmental delay or intellectual disability. Thirty-five patients had seizures, and 13 had a movement disorder. Therapy was associated with improvement or stabilization of symptoms in all symptomatic cases. The 4 patients treated before age 9 months had normal or almost normal developmental outcomes. Reduction of plasma guanidinoacetate levels appeared to improve long-term outcomes. Stockler-Ipsiroglu et al. (2014) provided consensus recommendations for the diagnosis, treatment, and monitoring of patients with CCDS2. </p>
|
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</span>
|
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<div>
|
|
<br />
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</div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
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</span>
|
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</h4>
|
|
</div>
|
|
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|
|
|
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with GAMT deficiency, Stockler et al. (1996) identified mutations in the GAMT gene; one patient was homozygous and the other was compound heterozygous (see 601240.0001 and 601240.0002). </p><p>In 3 family members and an isolated patient with GAMT deficiency, Caldeira Araujo et al. (2005) identified homozygous mutations in the GAMT gene (601240.0003-601240.0004, respectively). </p><p>In a North African patient with GAMT deficiency and severe mental retardation, born of consanguineous parents, Lion-Francois et al. (2006) identified a homozygous missense mutation in the GAMT gene (601240.0005). The patient had delayed onset of walking, seizures, and autistic features. </p><p>In 2 infants with GAMT deficiency, Hart et al. (2021) identified homozygous or compound heterozygous mutations in the GAMT gene (601240.0006-601240.0008). Both infants were initially identified by newborn screening showing elevated guanidinoacetate level on a bloodspot. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Schmidt et al. (2004) generated a knockout mouse model for GAMT deficiency by gene targeting in embryonic stem cells. Gamt -/- mice had markedly increased guanidinoacetate and reduced creatine and creatinine levels in brain, serum, and urine, similar to human GAMT patients. In vivo 31P magnetic resonance spectroscopy showed high levels of PGAA and reduced levels of creatine phosphate in heart, skeletal muscle, and brain. GAMT deficiency was associated with increased neonatal mortality, muscular hypotonia, decreased male fertility, and a non-leptin-mediated lifelong reduction in body weight due to reduced body fat mass. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Almeida, L. S., Vilarinho, L., Darmin, P. S., Rosenberg, E. H., Martinez-Munoz, C., Jakobs, C., Salomons, G. S.
|
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<strong>A prevalent pathogenic GAMT mutation (c.59G-C) in Portugal.</strong>
|
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Molec. Genet. Metab. 91: 1-6, 2007.
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[PubMed: 17336114]
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[Full Text: https://doi.org/10.1016/j.ymgme.2007.01.005]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Caldeira Araujo, H., Smit, W., Verhoeven, N. M., Salomons, G. S., Silva, S., Vasconcelos, R., Tomas, H., Tavares de Almeida, I., Jakobs, C., Duran, M.
|
|
<strong>Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation.</strong>
|
|
Am. J. Med. Genet. 133A: 122-127, 2005.
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[PubMed: 15651030]
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[Full Text: https://doi.org/10.1002/ajmg.a.30226]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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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>
|
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Molec. Genet. Metab. 109: 260-268, 2013.
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[PubMed: 23660394]
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[Full Text: https://doi.org/10.1016/j.ymgme.2013.04.006]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Hart, K., Rohrwasser, A., Wallis, H., Golsan, H., Shao, J., Anderson, T., Wang, X., Szabo-Fresnais, N., Morrissey, M., Kay, D. M., Wojcik, M., Galvin-Partin, P. A., Longo, N., Caggana, M., Pasquali, M.
|
|
<strong>Prospective identification by neonatal screening of patients with guanidinoacetate methyltransferase deficiency.</strong>
|
|
Molec. Genet. Metab. 134: 60-64, 2021.
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[PubMed: 34389248]
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[Full Text: https://doi.org/10.1016/j.ymgme.2021.07.012]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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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.
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|
<strong>High frequency of creatine deficiency syndromes in patients with unexplained mental retardation.</strong>
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Neurology 67: 1713-1714, 2006.
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[PubMed: 17101918]
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[Full Text: https://doi.org/10.1212/01.wnl.0000239153.39710.81]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Schmidt, A., Marescau, B., Boehm, E. A., Renema, W. K. J., Peco, R., Das, A., Steinfeld, R., Chan, S., Wallis, J., Davidoff, M., Ullrich, K., Waldschutz, R., Heerschap, A., De Deyn, P. P., Neubauer, S., Isbrandt, D.
|
|
<strong>Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency.</strong>
|
|
Hum. Molec. Genet. 13: 905-921, 2004.
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[PubMed: 15028668]
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[Full Text: https://doi.org/10.1093/hmg/ddh112]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Schulze, A., Hess, T., Wevers, R., Mayatepek, E., Bachert, P., Marescau, B., Knopp, M. V., De Deyn, P. P., Bremer, H. J., Rating, D.
|
|
<strong>Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism.</strong>
|
|
J. Pediat. 131: 626-631, 1997.
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[PubMed: 9386672]
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[Full Text: https://doi.org/10.1016/s0022-3476(97)70075-1]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Schulze, A.
|
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<strong>Creatine deficiency syndromes.</strong>
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Molec. Cell Biochem. 244: 143-150, 2003.
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[PubMed: 12701824]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Stockler, S., Holzbach, U., Hanefeld, F., Marquardt, I., Helms, G., Requart, M., Hanicke, W., Frahm, J.
|
|
<strong>Creatine deficiency in the brain: a new, treatable inborn error of metabolism.</strong>
|
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Pediat. Res. 36: 409-413, 1994.
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[PubMed: 7808840]
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[Full Text: https://doi.org/10.1203/00006450-199409000-00023]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Stockler, S., Isbrandt, D., Hanefeld, F., Schmidt, B., von Figura, K.
|
|
<strong>Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man.</strong>
|
|
Am. J. Hum. Genet. 58: 914-922, 1996.
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[PubMed: 8651275]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Stockler-Ipsiroglu, S., van Karnebeek, C., Longo, N., Korenke, G. C., Mercimek-Mahmutoglu, S., Marquart, I., Barshop, B., Grolik, C., Schlune, A., Angle, B., Caldeira Araujo, H., Coskun, T., and 20 others.
|
|
<strong>Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring.</strong>
|
|
Molec. Genet. Metab. 111: 16-25, 2014.
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|
[PubMed: 24268530]
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[Full Text: https://doi.org/10.1016/j.ymgme.2013.10.018]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Verhoeven, N. M., Guerand, W. S., Struys, E. A., Bouman, A. A., van der Knaap, M. S., Jakobs, C.
|
|
<strong>Plasma creatinine assessment in creatine deficiency: a diagnostic pitfall.</strong>
|
|
J. Inherit. Metab. Dis. 23: 835-840, 2000.
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|
|
[PubMed: 11196109]
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[Full Text: https://doi.org/10.1023/a:1026764703486]
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</p>
|
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<div class="row">
|
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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Hilary J. Vernon - updated : 06/23/2022<br>Hilary J. Vernon - updated : 04/17/2020<br>Cassandra L. Kniffin - updated : 6/16/2014<br>Cassandra L. Kniffin - updated : 7/16/2013
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carol : 06/23/2022<br>carol : 04/17/2020<br>carol : 06/18/2014<br>mcolton : 6/18/2014<br>ckniffin : 6/16/2014<br>carol : 7/17/2013<br>ckniffin : 7/16/2013<br>carol : 3/15/2012<br>terry : 4/20/2009<br>carol : 4/20/2009
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