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Entry
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- #605899 - GLYCINE ENCEPHALOPATHY 1; GCE1
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- OMIM
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<p>
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<span class="h4">#605899</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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<a href="/clinicalSynopsis/605899"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS605899"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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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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<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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<div><a href="https://clinicaltrials.gov/search?cond=GLYCINE ENCEPHALOPATHY" 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="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=20766&Typ=Pat" title="Neonatal glycine encephalopathy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Neonatal glycine encephalo… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=20767&Typ=Pat" title="Infantile glycine encephalopathy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Infantile glycine encephal… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=20768&Typ=Pat" title="Atypical glycine encephalopathy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Atypical glycine encephalo… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3556&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Glycine encephalopathy </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1357/" 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/nonketotic-hyperglycinemia" 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="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=289857" title="Neonatal glycine encephalopathy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Neonatal glycine encephalo…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=289860" title="Infantile glycine encephalopathy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Infantile glycine encephal…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=289863" title="Atypical glycine encephalopathy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Atypical glycine encephalo…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Glycine encephalopathy</a></div>
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<div style="display: table-cell;">Animal Models</div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0070616" 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/605899" 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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<div><a href="https://omia.org/OMIA002030/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0070616" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</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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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 237939006, 51097006<br />
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<strong>ICD10CM:</strong> E72.51<br />
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<strong>ORPHA:</strong> 289857, 289860, 289863, 407<br />
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<strong>DO:</strong> 0070616<br />
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">ICD+</a>
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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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605899
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</span>
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</span>
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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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GLYCINE ENCEPHALOPATHY 1; GCE1
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GCE<br />
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HYPERGLYCINEMIA, NONKETOTIC; NKH
|
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</span>
|
|
</h4>
|
|
</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>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
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<span class="h3 mim-font">
|
|
HYPERGLYCINEMIA, TRANSIENT NEONATAL, INCLUDED; TNH, INCLUDED
|
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</span>
|
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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>
|
|
<span class="mim-font">
|
|
<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">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
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<th>
|
|
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>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
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</th>
|
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<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/9/41?start=-3&limit=10&highlight=41">
|
|
9p24.1
|
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</a>
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Glycine encephalopathy1
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605899"> 605899 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<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>
|
|
<td>
|
|
<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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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
GLDC
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/238300"> 238300 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/605899" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS605899" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/605899" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/605899" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- 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 />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
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|
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|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Absent corpus callosum (variable) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853873&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853873</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/5102002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">5102002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q04.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q04.0</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001274" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001274</a>]</span><br /> -
|
|
Lethargy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/214264003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">214264003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R53.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R53.83</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023380&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023380</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001254</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001254</a>]</span><br /> -
|
|
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
|
|
Hiccups <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/65958008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">65958008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R06.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R06.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/786.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">786.8</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019521&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019521</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100247" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100247</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100247" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100247</a>]</span><br /> -
|
|
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
|
|
Hyporeflexia to hyperreflexia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853874</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 /> -
|
|
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 /> -
|
|
Burst suppression pattern on neonatal EEG <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853875&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853875</a>]</span><br /> -
|
|
Expressive speech deficit <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853876&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853876</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Behavioral Psychiatric Manifestations </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hyperactivity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44548000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44548000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424295&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424295</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000752" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000752</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000752" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000752</a>]</span><br /> -
|
|
Impulsivity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021125&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021125</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100710" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100710</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100710" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100710</a>]</span><br /> -
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Aggressiveness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/61372001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">61372001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001807&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001807</a>, <a href="https://bioportal.bioontology.org/search?q=C1457883&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1457883</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006919" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006919</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000718</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000718</a>]</span><br /> -
|
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Irritability <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55929007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55929007</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.22</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0022107&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022107</a>, <a href="https://bioportal.bioontology.org/search?q=C2700617&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2700617</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000737" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000737</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000737" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000737</a>]</span><br /> -
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Restlessness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/162221009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">162221009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/47295007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">47295007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/24199005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">24199005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3887612&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887612</a>, <a href="https://bioportal.bioontology.org/search?q=C0085631&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085631</a>, <a href="https://bioportal.bioontology.org/search?q=C3887611&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887611</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000713" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000713</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000711" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000711</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000711" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000711</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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<div>
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </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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- Hyperglycinemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64654004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64654004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268559&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268559</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002154" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002154</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002154" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002154</a>]</span><br /> -
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Hyperglycinuria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0543541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0543541</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003108" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003108</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003108" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003108</a>]</span><br /> -
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Hepatic glycine cleavage defect <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853877&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853877</a>]</span><br /> -
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Elevated CSF glycine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853878&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853878</a>]</span><br /> -
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Elevated CSF/plasma glycine ratio <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853879&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853879</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> MISCELLANEOUS </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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- Death in infancy common for patients with the classic neonatal form<br /> -
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Patients with atypical form have milder disease, with onset in the first months of life and increased survival<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> MOLECULAR BASIS </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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- Caused by mutation in the glycine dehydrogenase gene (GLDC, <a href="/entry/238300#0001">238300.0001</a>)<br /> -
|
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Caused by mutation in the glycine cleavage system H protein gene (GCSH, <a href="/entry/238330#0001">238330.0001</a>)<br /> -
|
|
Caused by mutation in the aminomethyltransferase gene (AMT, <a href="/entry/238310#0001">238310.0001</a>)<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 class="text-right">
|
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<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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<div class="small">
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<div class="row">
|
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
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<h5>
|
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Glycine encephalopathy
|
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- <a href="/phenotypicSeries/PS605899">PS605899</a>
|
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- 2 Entries
|
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</h5>
|
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</div>
|
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</div>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
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<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
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<thead>
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<tr>
|
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
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<strong>Location</strong>
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</th>
|
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
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<strong>Phenotype</strong>
|
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</th>
|
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
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<strong>Inheritance</strong>
|
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</th>
|
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
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<strong>Phenotype<br />mapping key</strong>
|
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</th>
|
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
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<strong>Phenotype<br />MIM number</strong>
|
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
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<strong>Gene/Locus</strong>
|
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</th>
|
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
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<strong>Gene/Locus<br />MIM number</strong>
|
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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/3/311?start=-3&limit=10&highlight=311"> 3p21.31 </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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<a href="/entry/620398"> Glycine encephalopathy 2 </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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<a href="/entry/620398"> 620398 </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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<a href="/entry/238310"> AMT </a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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<a href="/entry/238310"> 238310 </a>
|
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</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
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<span class="mim-font">
|
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|
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<a href="/geneMap/9/41?start=-3&limit=10&highlight=41"> 9p24.1 </a>
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/605899"> Glycine encephalopathy1 </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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|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
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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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|
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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/605899"> 605899 </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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<a href="/entry/238300"> GLDC </a>
|
|
</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/238300"> 238300 </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 class="text-right small">
|
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<a href="#mimPhenotypicSeriesFold" 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>
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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="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
|
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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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</span>
|
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that glycine encephalopathy-1 (GCE1) is caused by homozygous or compound heterozygous mutation in the GLDC gene (<a href="/entry/238300">238300</a>), a member of the mitochondrial glycine cleavage system that encodes the P protein, on chromosome 9p24.</p><p><strong><em>Genetic Heterogeneity of Glycine Encephalopathy (Nonketotic Hyperglycinemia)</em></strong></p><p>
|
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Also see GCE2 (<a href="/entry/620398">620398</a>), caused by mutation in the AMT gene (<a href="/entry/238310">238310</a>), which encodes the T protein of the mitochondrial glycine cleavage system.</p><p>A form of GCE was thought to be due to a mutation in the GCSH gene (<a href="/entry/238330#0001">238330.0001</a>), but this variant has been reclassified as a variant of unknown significance.</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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<a id="nomenclature" class="mim-anchor"></a>
|
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<h4 href="#mimNomenclatureFold" id="mimNomenclatureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimNomenclatureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Nomenclature</strong>
|
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</span>
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</h4>
|
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</div>
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<div id="mimNomenclatureFold" class="collapse in mimTextToggleFold">
|
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<span class="mim-text-font">
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<p>Nonketotic hyperglycinemia (NKH) was originally named to distinguish it from ketotic hyperglycinemia, which is now known to be propionic acidemia (<a href="/entry/606054">606054</a>). Since the distinction is no longer required and clinical confusion between hyperglycinemia and hyperglycemia occurs, a more appropriate name for this disorder is glycine encephalopathy (<a href="#19" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 6/16/2001."None>Hamosh, 2001</a>).</p>
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<p><strong><em>Classic Neonatal Form</em></strong></p><p>
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Most patients with GCE have the neonatal phenotype, presenting in the first few days of life with lethargy, hypotonia, and myoclonic jerks, and progressing to apnea, and often to death. Those who regain spontaneous respiration develop intractable seizures and profound mental retardation. In the infantile form of GCE, patients present with seizures and have various degrees of mental retardation after a symptom-free interval and seemingly normal development for up to 6 months. In the mild-episodic form, patients present in childhood with mild mental retardation and episodes of delirium, chorea, and vertical gaze palsy during febrile illness. In the late-onset form, patients present in childhood with progressive spastic diplegia and optic atrophy, but intellectual function is preserved and seizures have not been reported (<a href="#17" class="mim-tip-reference" title="Hamosh, A., Johnston, M. V. <strong>Nonketotic hyperglycinemia. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (8th ed.)</strong> New York: McGraw-Hill (pub.) 2001. Pp. 2065-2078."None>Hamosh and Johnston, 2001</a>). See review by <a href="#33" class="mim-tip-reference" title="Tada, K., Hayasaka, K. <strong>Non-ketotic hyperglycinaemia: clinical and biochemical aspects.</strong> Europ. J. Pediat. 146: 221-227, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3297708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3297708</a>] [<a href="https://doi.org/10.1007/BF00716464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3297708">Tada and Hayasaka (1987)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3297708" 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>Unlike glycinemia with ketoacidosis and leukopenia, also known as propionic acidemia (<a href="/entry/606054">606054</a>), episodic ketoacidosis with vomiting, neutropenia, and thrombocytopenia does not occur in nonketotic hyperglycinemia. Glycine is the only amino acid elevated in serum and urine and the only amino acid harmful to these patients. Some have died in the newborn period after a course characterized by lethargy, weak cry, generalized hypotonia, absent reflexes, and periodic myoclonic jerks (<a href="#5" class="mim-tip-reference" title="Balfe, J. W., Levison, H., Hanley, W. B., Jackson, S. H., Sass-Kortsak, A. <strong>Hyperglycinemia and glycinuria in a newborn. (Abstract)</strong> Canad. Med. Assoc. J. 92: 347, 1965."None>Balfe et al., 1965</a>). The few who attain an older age show severe mental retardation (<a href="#28" class="mim-tip-reference" title="Mabry, C. C., Karam, F. A. <strong>Idiopathic hyperglycinemia and hyperglycinuria. (Abstract)</strong> Sth. Med. J. 56: 1444, 1963."None>Mabry and Karam, 1963</a>; <a href="#16" class="mim-tip-reference" title="Gerritsen, T., Kaveggia, E. G., Waisman, H. A. <strong>A new type of idiopathic hyperglycinemia with hypo-oxaluria.</strong> Pediatrics 36: 882-891, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5846830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5846830</a>]" pmid="5846830">Gerritsen et al., 1965</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5846830" 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="#22" class="mim-tip-reference" title="Hayasaka, K., Tada, K., Kikuchi, G., Winter, S., Nyhan, W. L. <strong>Nonketotic hyperglycinemia: two patients with primary defects of P-protein and T-protein, respectively, in the glycine cleavage system.</strong> Pediat. Res. 17: 967-970, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6336599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6336599</a>] [<a href="https://doi.org/10.1203/00006450-198312000-00008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6336599">Hayasaka et al. (1983)</a> studied the glycine cleavage system in the liver and brain obtained at autopsy in 2 male infants with the typical form of nonketotic hyperglycinemia. In one a defect in the P protein was found; in the second, T protein was defective. The infant with the P protein defect was born of unrelated parents, was lethargic with a poor suck from birth, developed marked hypotonia, intermittent apnea, and poor responsiveness to stimuli, had mildly elevated blood ammonia and markedly elevated glycine in blood and cerebrospinal fluid, and died at age 12 days. Immunochemical analysis indicated absence of the enzyme P protein itself. The second infant appeared well at birth and nursed well the first day. He was hospitalized on the third day with 'lethargy, bordering on coma.' Despite ventilatory support, 7 exchange transfusions to lower blood glycine, and treatment with sodium benzoate and strychnine, he died on the twentieth day. T protein was undetectable in the brain and extremely low in liver. Autopsy in the first case, with P protein deficiency, showed absence of the corpus callosum and spinal cord hydromelia. The authors stated that they had seen a similar structural defect with deficiency of the pyruvate dehydrogenase complex (see <a href="/entry/312170">312170</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6336599" 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="#31" class="mim-tip-reference" title="Schutgens, R. B. H., Ket, J. L., Hayasaka, K., Tada, K. <strong>Non-ketotic hyperglycinaemia due to a deficiency of T-protein in the glycine cleavage system in liver and brain.</strong> J. Inherit. Metab. Dis. 9: 208-214, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3091926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3091926</a>] [<a href="https://doi.org/10.1007/BF01799462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3091926">Schutgens et al. (1986)</a> reported a case with T protein deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3091926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Cataltepe, S., van Marter, L. J., Kozakewich, H., Wessel, D. L., Lee, P. J., Levy, H. L. <strong>Pulmonary hypertension associated with nonketotic hyperglycinaemia.</strong> J. Inherit. Metab. Dis. 23: 137-144, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10801055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10801055</a>] [<a href="https://doi.org/10.1023/a:1005613715351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10801055">Cataltepe et al. (2000)</a> reported 4 patients with nonketotic hyperglycinemia who developed pulmonary hypertension. Two patients had classic neonatal GCE and developed pulmonary hypertension in the newborn period; both died from pulmonary hypertension. The other 2 patients were sibs from Bangladesh with atypical GCE, the first of whom presented with pulmonary hypertension at the age of 6. His brother had documented pulmonary at the age of 4 years, which resolved spontaneously and then recurred in association with thiamine deficiency when he was 21 years old. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10801055" 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="#41" class="mim-tip-reference" title="Van Hove, J. L. K., Kishnani, P. S., Demaerel, P., Kahler, S. G., Miller, C., Jaeken, J., Rutledge, S. L. <strong>Acute hydrocephalus in nonketotic hyperglycinemia.</strong> Neurology 54: 754-756, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10680820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10680820</a>] [<a href="https://doi.org/10.1212/wnl.54.3.754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10680820">Van Hove et al. (2000)</a> reported 4 patients with typical neonatal-onset NKH who developed hydrocephalus requiring shunting in early infancy. Brain imaging revealed acute hydrocephalus, a megacisterna magna or posterior fossa cyst, pronounced atrophy of the white matter, and an extremely thin corpus callosum in all. The 3 older patients had profound developmental disabilities. <a href="#41" class="mim-tip-reference" title="Van Hove, J. L. K., Kishnani, P. S., Demaerel, P., Kahler, S. G., Miller, C., Jaeken, J., Rutledge, S. L. <strong>Acute hydrocephalus in nonketotic hyperglycinemia.</strong> Neurology 54: 754-756, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10680820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10680820</a>] [<a href="https://doi.org/10.1212/wnl.54.3.754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10680820">Van Hove et al. (2000)</a> concluded that the development of hydrocephalus in NKH is an additional poor prognostic sign. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10680820" 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 cells derived from a deceased boy, born of unrelated Serbian parents, with GCE, <a href="#32" class="mim-tip-reference" title="Swanson, M. A., Garcia, S. M., Spector, E., Kronquist, K., Creadon-Swindell, G., Walter, M., Christensen, E., Van Hove, J. L. K., Sass, J. O. <strong>D-glyceric aciduria does not cause nonketotic hyperglycinemia: a historic co-occurrence.</strong> Molec. Genet. Metab. 121: 80-82, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28462797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28462797</a>] [<a href="https://doi.org/10.1016/j.ymgme.2017.04.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28462797">Swanson et al. (2017)</a> identified a homozygous missense mutation in the AMT gene (S117L; <a href="/entry/238310#0009">238310.0009</a>). In vitro functional expression studies showed that the mutant AMT protein was unstable and had only 9% residual enzymatic activity compared to controls. The patient was unusual because he had originally been reported as having D-glyceric aciduria (<a href="/entry/220120">220120</a>) caused by a homozygous frameshift mutation in the GLYCTK gene (<a href="/entry/610516#0001">610516.0001</a>) (<a href="#8" class="mim-tip-reference" title="Brandt, N. J., Brandt, S., Rasmussen, K., Schonheyder, F. <strong>Hyperglycericacidaemia with hyperglycinaemia: a new inborn error of metabolism. (Letter)</strong> Brit. Med. J. 4: 344 only, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4434100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4434100</a>] [<a href="https://doi.org/10.1136/bmj.4.5940.344-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4434100">Brandt et al., 1974</a>; <a href="#30" class="mim-tip-reference" title="Sass, J. O., Fischer, K., Wang, R., Christensen, E., Scholl-Burgi, S., Chang, R., Kapelari, K., Walter, M. <strong>D-glyceric aciduria is caused by genetic deficiency of D-glycerate kinase (GLYCTK).</strong> Hum. Mutat. 31: 1280-1285, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20949620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20949620</a>] [<a href="https://doi.org/10.1002/humu.21375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20949620">Sass et al., 2010</a>). Increased glycine in the patient had been thought to be secondary to the GLYCTK defect; however, the molecular findings confirmed that the patient had the unusual cooccurrence of 2 inborn errors of metabolism. <a href="#32" class="mim-tip-reference" title="Swanson, M. A., Garcia, S. M., Spector, E., Kronquist, K., Creadon-Swindell, G., Walter, M., Christensen, E., Van Hove, J. L. K., Sass, J. O. <strong>D-glyceric aciduria does not cause nonketotic hyperglycinemia: a historic co-occurrence.</strong> Molec. Genet. Metab. 121: 80-82, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28462797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28462797</a>] [<a href="https://doi.org/10.1016/j.ymgme.2017.04.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28462797">Swanson et al. (2017)</a> concluded that D-glyceric aciduria does not cause deficient glycine cleavage enzyme activity or nonketotic hyperglycinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28462797+20949620+4434100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Atypical Mild Form</em></strong></p><p>
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Unlike the classic neonatal form of the disorder, atypical or mild glycine encephalopathy is phenotypically heterogeneous and nonspecific, making diagnosis difficult (<a href="#14" class="mim-tip-reference" title="Flusser, H., Korman, S. H., Sato, K., Matsubara, Y., Galil, A., Kure, S. <strong>Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation.</strong> Neurology 64: 1426-1430, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15851735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15851735</a>] [<a href="https://doi.org/10.1212/01.WNL.0000158475.12907.D6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15851735">Flusser et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15851735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Cole, D. E. C., Meek, D. C. <strong>Juvenile non-ketotic hyperglycinaemia in three siblings.</strong> J. Inherit. Metab. Dis. 8: 123-124, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3930859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3930859</a>] [<a href="https://doi.org/10.1007/BF01811489" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3930859">Cole and Meek (1985)</a> emphasized the occurrence of an expressive speech deficit and neurologic abnormalities during intercurrent infections as striking features of the milder form of the disease. The cases of <a href="#1" class="mim-tip-reference" title="Ando, T., Nyhan, W. L., Bicknell, J., Harris, R., Stern, J. <strong>Non-ketotic hyperglycinaemia in a family with an unusual phenotype.</strong> J. Inherit. Metab. Dis. 1: 79-83, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/116082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">116082</a>] [<a href="https://doi.org/10.1007/BF01805677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="116082">Ando et al. (1978)</a>, <a href="#15" class="mim-tip-reference" title="Frazier, D. M., Summer, G. K., Chamberlin, H. R. <strong>Hyperglycinuria and hyperglycinemia in two siblings with mild developmental delays.</strong> Am. J. Dis. Child. 132: 777-781, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/80128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">80128</a>] [<a href="https://doi.org/10.1001/archpedi.1978.02120330049013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="80128">Frazier et al. (1978)</a>, and <a href="#13" class="mim-tip-reference" title="Flannery, D. B., Pellock, J., Bousonis, D., Hunt, P., Nance, C., Wolf, B. <strong>Non-ketotic hyperglycinemia in two retarded adults: a mild form of infantile non-ketotic hyperglycinemia.</strong> Neurology 33: 1064-1066, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6683804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6683804</a>] [<a href="https://doi.org/10.1212/wnl.33.8.1064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6683804">Flannery et al. (1983)</a> also fall into this category. <a href="#21" class="mim-tip-reference" title="Hayasaka, K., Tada, K., Fueki, N., Nakamura, Y., Nyhan, W. L., Schmidt, K., Packman, S., Seashore, M. R., Haan, E., Danks, D. M., Schutgens, R. B. H. <strong>Nonketotic hyperglycinemia: analyses of glycine cleavage system in typical and atypical cases.</strong> J. Pediat. 110: 873-877, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3585602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3585602</a>] [<a href="https://doi.org/10.1016/s0022-3476(87)80399-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3585602">Hayasaka et al. (1987)</a> cited one patient with atypical GCE and features of progressive degeneration of the central nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6683804+80128+3930859+116082+3585602" 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="Dinopoulos, A., Kure, S., Chuck, G., Sato, K., Gilbert, D. L., Matsubara, Y., Degrauw, T. <strong>Glycine decarboxylase mutations: a distinctive phenotype of nonketotic hyperglycinemia in adults.</strong> Neurology 64: 1255-1257, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824356</a>] [<a href="https://doi.org/10.1212/01.WNL.0000156800.23776.40" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15824356">Dinopoulos et al. (2005)</a> reported 3 unrelated adults with a mild form of glycine encephalopathy confirmed by genetic analysis (<a href="/entry/238300#0008">238300.0008</a>; <a href="/entry/238300#0009">238300.0009</a>). All 3 patients showed hypotonia as infants and had developmental delay. One patient showed appendicular ataxia and choreoathetoid movements at age 4 years. Between ages 5 and 12 years, he had frequent outbursts of aggressiveness. He attended special education classes and graduated from high school. The second patient was hypotonic at birth and developed seizures during the first week of life. Aggressive behavior was noted at age 12 years; he was fully dependent on his family. The third patient developed hypotonia at age 6 months. He was diagnosed with attention deficit-hyperactivity disorder (ADHD) and had outbursts of aggression and impulsivity. Treatment with dextromethorphan was ineffective. He graduated from school in special education classes. Biochemical analysis showed residual GLDC activity ranging from 6 to 8%, which <a href="#12" class="mim-tip-reference" title="Dinopoulos, A., Kure, S., Chuck, G., Sato, K., Gilbert, D. L., Matsubara, Y., Degrauw, T. <strong>Glycine decarboxylase mutations: a distinctive phenotype of nonketotic hyperglycinemia in adults.</strong> Neurology 64: 1255-1257, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824356</a>] [<a href="https://doi.org/10.1212/01.WNL.0000156800.23776.40" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15824356">Dinopoulos et al. (2005)</a> suggested may explain the milder clinical phenotype. The authors emphasized the clinical heterogeneity of the mild form of GCE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15824356" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Flusser, H., Korman, S. H., Sato, K., Matsubara, Y., Galil, A., Kure, S. <strong>Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation.</strong> Neurology 64: 1426-1430, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15851735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15851735</a>] [<a href="https://doi.org/10.1212/01.WNL.0000158475.12907.D6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15851735">Flusser et al. (2005)</a> reported a large consanguineous Israeli Bedouin kindred in which 9 members had atypical GCE confirmed by genetic analysis (<a href="/entry/238300#0010">238300.0010</a>). Most patients presented during the first months of life with abnormal movements, including mild to moderate generalized hypotonia, lateral head nodding, choreoathetoid hand movements, and pill rolling. Seven patients had seizures with generalized spike and slow wave abnormalities in EEG; 2 had infantile spasms with hypsarrhythmia. All had delayed motor development, moderate mental retardation, and limited expressive language. The patients also showed irritability and restlessness as infants and later showed aggressive and destructive behavior. Treatment was ineffective. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15851735" 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="#44" class="mim-tip-reference" title="Yu, T. W., Chahrour, M. H., Coulter, M. E., Jiralerspong, S., Okamura-Ikeda, K., Ataman, B., Schmitz-Abe, K., Harmin, D. A., Adli, M., Malik, A. N., D'Gama, A. M., Lim, E. T., and 37 others. <strong>Using whole-exome sequencing to identify inherited causes of autism.</strong> Neuron 77: 259-273, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23352163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23352163</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23352163[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2012.11.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23352163">Yu et al. (2013)</a> described 3 children from a consanguineous family who had autism spectrum disorder and who carried a homozygous mutation in the AMT gene. While individually nondiagnostic, the 3 affected children exhibited a range of neurologic symptoms that in aggregate were strongly suggestive of NKH. The eldest child was 12 years of age and had, in addition to a diagnosis of autism spectrum disorder, a history of severe epilepsy, with first seizures presenting at 10 months of age. The second child was 9 years of age and suffered from autism and epilepsy, but her seizures were milder. The third child was 2 years of age and had language and motor delays and carried a diagnosis of pervasive developmental disorder (PDD), but had had only 1 febrile seizure. Direct biochemical analysis of the mutation (ile308 to phe, I308F) demonstrated reduced activity. When compared to classical NKH-associated values, glycine cleavage activity of the mutated allele was at the mild end of the range of reported values, suggesting that the affected children in this family suffered from undiagnosed atypical NKH presenting as autism spectrum disorder and seizures. Plasma amino acid screening was normal in the 2 older children, a result that is typically seen in milder forms of NKH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23352163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Transient Neonatal Hyperglycinemia</em></strong></p><p>
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Transient neonatal hyperglycinemia (TNH) is characterized by elevated plasma and CSF glycine levels at birth that are normalized within 2 to 8 weeks. TNH is clinically and biochemically indistinguishable from typical nonketotic hyperglycinemia at onset. <a href="#4" class="mim-tip-reference" title="Applegarth, D. A., Toone, J. R. <strong>Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis.</strong> Molec. Genet. Metab. 74: 139-146, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11592811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11592811</a>] [<a href="https://doi.org/10.1006/mgme.2001.3224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11592811">Applegarth and Toone (2001)</a> reviewed 7 cases of transient NKH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11592811" 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="#23" class="mim-tip-reference" title="Korman, S. H., Boneh, A., Ichinohe, A., Kojima, K., Sato, K., Ergaz, Z., Gomori, J. M., Gutman, A., Kure, S. <strong>Persistent NKH with transient or absent symptoms and a homozygous GLDC mutation.</strong> Ann. Neurol. 56: 139-143, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15236413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15236413</a>] [<a href="https://doi.org/10.1002/ana.20159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15236413">Korman et al. (2004)</a> reported 3 sibs from a consanguineous Muslim Palestinian family who had an unusual NKH phenotype. All 3 sibs were diagnosed with NKH within the first 3 days of life with characteristic elevated CSF and plasma glycine levels and elevated CSF-to-plasma glycine ratios. However, none of them developed neurologic symptoms, and all showed appropriate development, including good school performance in the 2 children of school age. The 2 older children showed persistent hyperglycinemia. A patient from a second unrelated family diagnosed with NKH had mild neurologic sequelae. In all 4 patients, <a href="#23" class="mim-tip-reference" title="Korman, S. H., Boneh, A., Ichinohe, A., Kojima, K., Sato, K., Ergaz, Z., Gomori, J. M., Gutman, A., Kure, S. <strong>Persistent NKH with transient or absent symptoms and a homozygous GLDC mutation.</strong> Ann. Neurol. 56: 139-143, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15236413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15236413</a>] [<a href="https://doi.org/10.1002/ana.20159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15236413">Korman et al. (2004)</a> identified a homozygous mutation in the GLDC gene (<a href="/entry/238300#0006">238300.0006</a>), which was shown to retain 32% residual enzyme activity in vitro. The authors suggested that these patients exhibited a new phenotype of NKH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15236413" 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="#16" class="mim-tip-reference" title="Gerritsen, T., Kaveggia, E. G., Waisman, H. A. <strong>A new type of idiopathic hyperglycinemia with hypo-oxaluria.</strong> Pediatrics 36: 882-891, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5846830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5846830</a>]" pmid="5846830">Gerritsen et al. (1965)</a> described abnormally low oxalate excretion in the urine and postulated a defect in glycine oxidase. <a href="#2" class="mim-tip-reference" title="Ando, T., Nyhan, W. L., Gerritsen, T., Gong, L., Heiner, D. C., Bray, P. F. <strong>Metabolism of glycine in the nonketotic form of hyperglycinemia.</strong> Pediat. Res. 2: 254-263, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5669662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5669662</a>] [<a href="https://doi.org/10.1203/00006450-196807000-00004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5669662">Ando et al. (1968)</a> located the defect to glycine formiminotransferase. <a href="#34" class="mim-tip-reference" title="Tada, K., Narisawa, K., Yoshida, T., Konno, T., Yokoyama, Y., Nakagawa, H., Tanno, K., Mochizuki, K., Arakawa, T. <strong>Hyperglycinemia: a defect in glycine cleavage reaction.</strong> Tohoku J. Exp. Med. 98: 289-296, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5307488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5307488</a>] [<a href="https://doi.org/10.1620/tjem.98.289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5307488">Tada et al. (1969)</a> concluded that the primary lesion in hyperglycinemia of the nonketotic variety is in the glycine cleavage reaction. <a href="#6" class="mim-tip-reference" title="Baumgartner, R., Ando, T., Nyhan, W. L. <strong>Nonketotic hyperglycinemia.</strong> J. Pediat. 75: 1022-1030, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5352828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5352828</a>] [<a href="https://doi.org/10.1016/s0022-3476(69)80341-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5352828">Baumgartner et al. (1969)</a> showed that the nonketotic variety can have a fulminant early onset. The defect concerns the enzyme involved in the conversion of glycine to CO2, NH3 and hydroxymethyltetrahydrofolic acid. <a href="#11" class="mim-tip-reference" title="De Groot, C. J., Troelstra, J. A., Hommes, F. A. <strong>Nonketotic hyperglycinemia: an in vitro study of the glycine-serine conversion in liver of three patients and the effect of dietary methionine.</strong> Pediat. Res. 4: 238-243, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5423161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5423161</a>] [<a href="https://doi.org/10.1203/00006450-197005000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5423161">De Groot et al. (1970)</a> described 2 affected sisters with consanguineous parents and presented evidence indicating that the defect lies in glycine decarboxylase, rather than in glycine oxidase. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5669662+5423161+5352828+5307488+5846830" 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="#38" class="mim-tip-reference" title="Toone, J. R., Applegarth, D. A., Levy, H. L., Coulter-Mackie, M. B., Lee, G. <strong>Molecular genetic and potential biochemical characteristics of patients with T-protein deficiency as a cause of glycine encephalopathy (NKH).</strong> Molec. Genet. Metab. 79: 272-280, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12948742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12948742</a>] [<a href="https://doi.org/10.1016/s1096-7192(03)00115-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12948742">Toone et al. (2003)</a> performed a retrospective analysis of a group of NKH patients and found that greater than 50% had T protein (<a href="/entry/238310">238310</a>) mutations. The patients studied had 1 or more unusual biochemical findings: residual glycine cleavage system activity in liver, residual glycine cleavage system activity in lymphoblasts, and/or increased amniotic fluid glycine-to-serine ratio with a normal amniotic fluid glycine level in prenatal diagnosis. The selected patients had a much higher incidence of T-protein defects than expected in the general NKH patient population. <a href="#38" class="mim-tip-reference" title="Toone, J. R., Applegarth, D. A., Levy, H. L., Coulter-Mackie, M. B., Lee, G. <strong>Molecular genetic and potential biochemical characteristics of patients with T-protein deficiency as a cause of glycine encephalopathy (NKH).</strong> Molec. Genet. Metab. 79: 272-280, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12948742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12948742</a>] [<a href="https://doi.org/10.1016/s1096-7192(03)00115-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12948742">Toone et al. (2003)</a> reported 3 novel mutations and 5 polymorphisms of the T protein gene, PCR/restriction enzyme methods for 1 mutation and 2 polymorphisms, and an estimation of their frequency in normal controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12948742" 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 high frequency of glycine encephalopathy has been found in Finland; the incidence has been estimated to be 1 in 55,000 newborns overall, and 1 in 12,000 in northern Finland (<a href="#43" class="mim-tip-reference" title="von Wendt, L., Simila, S. <strong>Nonketotic hyperglycinemia (NKH). In: Eriksson, A. W.; Forsius, H. R.; Nevanlinna, H. R.; Workman, P. L.; Norio, R. K. (eds.): Population Structure and Genetic Disorders.</strong> New York: Academic Press (pub.) 1980. Pp. 652-655."None>von Wendt and Simila, 1980</a>; <a href="#7" class="mim-tip-reference" title="Boneh, A., Korman, S. H., Sato, K., Kanno, J., Matsubara, Y., Lerer, I., Ben-Neriah, Z., Kure, S. <strong>A single nucleotide substitution that abolishes the initiator methionine codon of the GLDC gene is prevalent among patients with glycine encephalopathy in Jerusalem.</strong> J. Hum. Genet. 50: 230-234, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15864413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15864413</a>] [<a href="https://doi.org/10.1007/s10038-005-0243-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15864413">Boneh et al., 2005</a>). High incidences have also been reported in British Columbia and in small Arab villages in Israel (<a href="#7" class="mim-tip-reference" title="Boneh, A., Korman, S. H., Sato, K., Kanno, J., Matsubara, Y., Lerer, I., Ben-Neriah, Z., Kure, S. <strong>A single nucleotide substitution that abolishes the initiator methionine codon of the GLDC gene is prevalent among patients with glycine encephalopathy in Jerusalem.</strong> J. Hum. Genet. 50: 230-234, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15864413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15864413</a>] [<a href="https://doi.org/10.1007/s10038-005-0243-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15864413">Boneh et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15864413" 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="#4" class="mim-tip-reference" title="Applegarth, D. A., Toone, J. R. <strong>Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis.</strong> Molec. Genet. Metab. 74: 139-146, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11592811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11592811</a>] [<a href="https://doi.org/10.1006/mgme.2001.3224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11592811">Applegarth and Toone (2001)</a> reviewed the laboratory diagnosis of glycine encephalopathy and confirmed 9 mutations in the T protein and 8 mutations in the P protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11592811" 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="#36" class="mim-tip-reference" title="Tan, E. S., Wiley, V., Carpenter, K., Wilcken, B. <strong>Non-ketotic hyperglycinemia is usually not detectable by tandem mass spectrometry newborn screening.</strong> Molec. Genet. Metab. 90: 446-448, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17207649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17207649</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.11.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17207649">Tan et al. (2007)</a> reported that they screened 733,527 babies over 8 years as part of the New South Wales Newborn Screening Program and subsequently diagnosed 9 babies with nonketotic hyperglycinemia. Two had newborn glycine levels above their cutoff and presented within 72 hours. The remaining patients could not have been diagnosed by newborn screening without an unacceptably high recall rate. <a href="#36" class="mim-tip-reference" title="Tan, E. S., Wiley, V., Carpenter, K., Wilcken, B. <strong>Non-ketotic hyperglycinemia is usually not detectable by tandem mass spectrometry newborn screening.</strong> Molec. Genet. Metab. 90: 446-448, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17207649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17207649</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.11.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17207649">Tan et al. (2007)</a> concluded that babies with nonketotic hyperglycinemia were not usually identifiable by newborn screening strategies available at that time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17207649" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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<a href="#20" class="mim-tip-reference" title="Hayasaka, K., Tada, K., Fueki, N., Aikawa, J. <strong>Prenatal diagnosis of nonketotic hyperglycinemia: enzymatic analysis of the glycine cleavage system in chorionic villi.</strong> J. Pediat. 116: 444-445, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2308039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2308039</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)82841-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2308039">Hayasaka et al. (1990)</a> described prenatal diagnosis of nonketotic hyperglycinemia by enzymatic analysis of the glycine cleavage system in chorionic villi. <a href="#39" class="mim-tip-reference" title="Toone, J. R., Applegarth, D. A., Levy, H. L. <strong>Prenatal diagnosis of non-ketotic hyperglycinaemia: experience in 50 at-risk pregnancies.</strong> J. Inherit. Metab. Dis. 17: 342-344, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7807948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7807948</a>] [<a href="https://doi.org/10.1007/BF00711825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7807948">Toone et al. (1994)</a> described their experience with direct assay of glycine cleavage enzyme in chorionic villus samples in 50 at-risk pregnancies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7807948+2308039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Applegarth, D. A., Toone, J. R., Rolland, M. O., Black, S. H., Yim, D. K. C., Bemis, G. <strong>Non-concordance of CVS and liver glycine cleavage enzyme in three families with non-ketotic hyperglycinaemia (NKH) leading to false negative prenatal diagnoses.</strong> Prenatal Diag. 20: 367-370, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10820402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10820402</a>] [<a href="https://doi.org/10.1002/(sici)1097-0223(200005)20:5<367::aid-pd814>3.0.co;2-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10820402">Applegarth et al. (2000)</a> reported 3 false-negative prenatal diagnostic results using direct measurement of glycine cleavage enzyme activity in uncultured chorionic villus tissue from 290 pregnancies at risk for glycine encephalopathy. Because of these false negatives, <a href="#3" class="mim-tip-reference" title="Applegarth, D. A., Toone, J. R., Rolland, M. O., Black, S. H., Yim, D. K. C., Bemis, G. <strong>Non-concordance of CVS and liver glycine cleavage enzyme in three families with non-ketotic hyperglycinaemia (NKH) leading to false negative prenatal diagnoses.</strong> Prenatal Diag. 20: 367-370, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10820402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10820402</a>] [<a href="https://doi.org/10.1002/(sici)1097-0223(200005)20:5<367::aid-pd814>3.0.co;2-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10820402">Applegarth et al. (2000)</a> counseled that there is a gray zone of uninterpretable activity where affected and normal enzyme values overlap, and suggested that there is an approximately 1% chance of a pregnancy with a normal chorionic villus sample activity resulting in an affected child. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10820402" 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="#26" class="mim-tip-reference" title="Kure, S., Rolland, M.-O., Leisti, J., Mandel, H., Sakata, Y., Tada, K., Matsubara, Y., Narisawa, K. <strong>Prenatal diagnosis of non-ketotic hyperglycinaemia: enzymatic diagnosis in 28 families and DNA diagnosis detecting prevalent Finnish and Israeli-Arab mutations.</strong> Prenatal Diag. 19: 717-720, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10451514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10451514</a>] [<a href="https://doi.org/10.1002/(sici)1097-0223(199908)19:8<717::aid-pd625>3.0.co;2-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10451514">Kure et al. (1999)</a> performed prenatal diagnosis for NKH by enzymatic analysis of chorionic villus samples in 28 families and by DNA analysis in 2 families. In 26 families, enzymatic analysis of the glycine cleavage system (GCS) yielded an unambiguous diagnosis; inconclusive results in 2 families were due to borderline GCS activity. A second chorionic sample was analyzed in both these families. In one case, GCS activity was normal in the second specimen and the baby did not have NKH. In the other case, <a href="#26" class="mim-tip-reference" title="Kure, S., Rolland, M.-O., Leisti, J., Mandel, H., Sakata, Y., Tada, K., Matsubara, Y., Narisawa, K. <strong>Prenatal diagnosis of non-ketotic hyperglycinaemia: enzymatic diagnosis in 28 families and DNA diagnosis detecting prevalent Finnish and Israeli-Arab mutations.</strong> Prenatal Diag. 19: 717-720, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10451514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10451514</a>] [<a href="https://doi.org/10.1002/(sici)1097-0223(199908)19:8<717::aid-pd625>3.0.co;2-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10451514">Kure et al. (1999)</a> again found extremely low GCS activity in a second specimen, but a healthy baby was born. The cause of this false-positive result was unknown. <a href="#26" class="mim-tip-reference" title="Kure, S., Rolland, M.-O., Leisti, J., Mandel, H., Sakata, Y., Tada, K., Matsubara, Y., Narisawa, K. <strong>Prenatal diagnosis of non-ketotic hyperglycinaemia: enzymatic diagnosis in 28 families and DNA diagnosis detecting prevalent Finnish and Israeli-Arab mutations.</strong> Prenatal Diag. 19: 717-720, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10451514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10451514</a>] [<a href="https://doi.org/10.1002/(sici)1097-0223(199908)19:8<717::aid-pd625>3.0.co;2-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10451514">Kure et al. (1999)</a> also reported the ability to obtain unambiguous prenatal diagnosis in both Finnish and Israeli Arab families due to prevalent mutations in those populations. The H42R mutation in the T protein (<a href="/entry/238310#0003">238310.0003</a>) may lead to ambiguous enzymatic activity, suggesting an advantage for DNA analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10451514" 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="#18" class="mim-tip-reference" title="Hamosh, A., McDonald, J. W., Valle, D., Francomano, C. A., Niedermeyer, E., Johnston, M. V. <strong>Dextromethorphan and high-dose benzoate therapy for nonketotic hyperglycinemia in an infant.</strong> J. Pediat. 121: 131-135, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1385627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1385627</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)82559-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1385627">Hamosh et al. (1992)</a> reported clinical and electrophysiologic improvement in a child with GCE who was treated with dextromethorphan and sodium benzoate beginning with the twelfth day of life. Dextromethorphan is a noncompetitive antagonist of the NMDA type of glutamate receptor, which can be stimulated by glycine. <a href="#45" class="mim-tip-reference" title="Zammarchi, E., Donati, M. A., Ciani, F., Pasquini, E., Pela, I., Fiorini, P. <strong>Failure of early dextromethorphan and sodium benzoate therapy in an infant with nonketotic hyperglycemia.</strong> Neuropediatrics 25: 274-276, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7885541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7885541</a>] [<a href="https://doi.org/10.1055/s-2008-1073037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7885541">Zammarchi et al. (1994)</a> reported only transient improvement on the same regimen when the treatment was instituted at 65 hours of life. The child died at 5 months and 7 days of age in spite of increasing doses of dextromethorphan as high as 40 mg per kilogram per day. The enzymatic basis for the GCE in either the successfully or unsuccessfully treated infant was not specified. The authors speculated that the different responses may reflect genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1385627+7885541" 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>Treatment of patients with GCE with high doses of benzoate can result in decreased CSF glycine levels and will improve seizure control and wakefulness (<a href="#18" class="mim-tip-reference" title="Hamosh, A., McDonald, J. W., Valle, D., Francomano, C. A., Niedermeyer, E., Johnston, M. V. <strong>Dextromethorphan and high-dose benzoate therapy for nonketotic hyperglycinemia in an infant.</strong> J. Pediat. 121: 131-135, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1385627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1385627</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)82559-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1385627">Hamosh et al., 1992</a>), thus improving the quality of life in surviving infants, but even when started early, may not prevent the development of mental retardation (<a href="#45" class="mim-tip-reference" title="Zammarchi, E., Donati, M. A., Ciani, F., Pasquini, E., Pela, I., Fiorini, P. <strong>Failure of early dextromethorphan and sodium benzoate therapy in an infant with nonketotic hyperglycemia.</strong> Neuropediatrics 25: 274-276, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7885541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7885541</a>] [<a href="https://doi.org/10.1055/s-2008-1073037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7885541">Zammarchi et al., 1994</a>). Episodes of lethargy, coma, and increased seizures can be caused both by hyperglycinemia from underdosing benzoate, or by toxicity due to overdosing. <a href="#40" class="mim-tip-reference" title="Van Hove, J. L. K., Kishnani, P., Muenzer, J., Wenstrup, R. J., Summar, M. L., Brummond, M. R., Lachiewicz, A. M., Millington, D. S., Kahler, S. G. <strong>Benzoate therapy and carnitine deficiency in non-ketotic hyperglycemia.</strong> Am. J. Med. Genet. 59: 444-453, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8585564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8585564</a>] [<a href="https://doi.org/10.1002/ajmg.1320590410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8585564">Van Hove et al. (1995)</a> found plasma carnitine deficiency in 3 of 4 patients with GCE treated with sodium benzoate, and benzoylcarnitine was identified in plasma, urine, and CSF. Treatment with L-carnitine normalized plasma-free carnitine. Close monitoring of glycine, benzoate and carnitine levels is advisable in patients receiving benzoate. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8585564+1385627+7885541" 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="#29" class="mim-tip-reference" title="Neuberger, J. M., Schweitzer, S., Rolland, M.-O., Burghard, R. <strong>Effect of sodium benzoate in the treatment of atypical nonketotic hyperglycinaemia.</strong> J. Inherit. Metab. Dis. 23: 22-26, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10682305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10682305</a>] [<a href="https://doi.org/10.1023/a:1005642728513" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10682305">Neuberger et al. (2000)</a> reported a 6-month-old girl who presented with hypotonia and mild psychomotor retardation who was subsequently found to have NKH confirmed by decreased glycine cleavage system activity in the liver. After the patient developed hypsarrhythmia and had a single seizure, treatment with both sodium benzoate and dextromethorphan was started. During the following year, the girl was free of seizures with improvement of EEG activity and showed retarded but continuously progressing psychomotor development. At the age of 20 months she began to walk freely but had generalized muscular hypotonia and moderate mental retardation. Discontinuation of dextromethorphan after one year did not change the clinical or EEG status. However, after cessation of sodium benzoate, epileptic activity in the EEG and behavioral changes occurred. These changes disappeared promptly after sodium benzoate therapy was reinstituted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10682305" 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="#24" class="mim-tip-reference" title="Korman, S. H., Wexler, I. D., Gutman, A., Rolland, M.-O., Kanno, J., Kure, S. <strong>Treatment from birth of nonketotic hyperglycinemia due to a novel GLDC mutation.</strong> Ann. Neurol. 59: 411-415, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16404748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16404748</a>] [<a href="https://doi.org/10.1002/ana.20759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16404748">Korman et al. (2006)</a> reported a patient with NKH caused by a homozygous mutation in the GLDC gene. He was born of first-cousin Palestinian Arabs. The patient was diagnosed prenatally and treated from birth with oral sodium benzoate and the NMDA receptor antagonist ketamine. Although neonatal hypotonia and apnea did not occur, the long-term outcome at age 11 months was poor, with intractable seizures and severe psychomotor retardation. <a href="#24" class="mim-tip-reference" title="Korman, S. H., Wexler, I. D., Gutman, A., Rolland, M.-O., Kanno, J., Kure, S. <strong>Treatment from birth of nonketotic hyperglycinemia due to a novel GLDC mutation.</strong> Ann. Neurol. 59: 411-415, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16404748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16404748</a>] [<a href="https://doi.org/10.1002/ana.20759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16404748">Korman et al. (2006)</a> noted that the plasma glycine level in this child was normal at birth, presumably reflecting placental clearance, whereas the CSF glycine level was markedly elevated, suggesting that the developing brain had been exposed prenatally to the potential toxicity of glycine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16404748" 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 high frequency of glycine encephalopathy has been found in some counties of Finland (<a href="#43" class="mim-tip-reference" title="von Wendt, L., Simila, S. <strong>Nonketotic hyperglycinemia (NKH). In: Eriksson, A. W.; Forsius, H. R.; Nevanlinna, H. R.; Workman, P. L.; Norio, R. K. (eds.): Population Structure and Genetic Disorders.</strong> New York: Academic Press (pub.) 1980. Pp. 652-655."None>von Wendt and Simila, 1980</a>). In 13 heterozygotes in Finland, <a href="#42" class="mim-tip-reference" title="von Wendt, L., Alanko, H., Sorri, M., Toivakka, E., Saukkonen, A.-L., Simila, S. <strong>Clinical and neurophysiological findings in heterozygotes for nonketotic hyperglycinemia.</strong> Clin. Genet. 19: 94-100, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7471513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7471513</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1981.tb00677.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7471513">von Wendt et al. (1981)</a> found minor dysfunctions of the central nervous system which they suggested may be due to a slightly abnormal degradation of glycine (which has a neurotransmitter role). <a href="#27" class="mim-tip-reference" title="Kure, S., Takayanagi, M., Narisawa, K., Tada, K., Leisti, J. <strong>Identification of a common mutation in Finnish patients with nonketotic hyperglycinemia.</strong> J. Clin. Invest. 90: 160-164, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1634607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1634607</a>] [<a href="https://doi.org/10.1172/JCI115831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1634607">Kure et al. (1992)</a> found that 14 of 20 P protein alleles in Finnish patients carried a missense mutation in the GLCD gene (S564I; <a href="/entry/238300#0001">238300.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7471513+1634607" 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="Applegarth, D. A., Toone, J. R. <strong>Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis.</strong> Molec. Genet. Metab. 74: 139-146, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11592811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11592811</a>] [<a href="https://doi.org/10.1006/mgme.2001.3224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11592811">Applegarth and Toone (2001)</a> reported that a gly71-to-arg (G71R; <a href="/entry/238300#0005">238300.0005</a>) variant in GLDC, reported originally by Kure et al. (1999), is present in 8% of NKH Finnish alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11592811" 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 Japanese boy with glycine encephalopathy, <a href="#35" class="mim-tip-reference" title="Takayanagi, M., Kure, S., Sakata, Y., Kurihara, Y., Ohya, Y., Kajita, M., Tada, K., Matsubara, Y., Narisawa, K. <strong>Human glycine decarboxylase gene (GLDC) and its highly conserved processed pseudogene (psi-GLDC): their structure and expression, and the identification of a large deletion in a family with nonketotic hyperglycinemia.</strong> Hum. Genet. 106: 298-305, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10798358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10798358</a>] [<a href="https://doi.org/10.1007/s004390051041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10798358">Takayanagi et al. (2000)</a> identified a large homozygous deletion (at least 30 kb) in the GLDC gene (<a href="/entry/238300#0003">238300.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10798358" 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="#37" class="mim-tip-reference" title="Toone, J. R., Applegarth, D. A., Coulter-Mackie, M. B., James, E. R. <strong>Biochemical and molecular investigations of patients with nonketotic hyperglycinemia.</strong> Molec. Genet. Metab. 70: 116-121, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10873393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10873393</a>] [<a href="https://doi.org/10.1006/mgme.2000.3000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10873393">Toone et al. (2000)</a> identified a recurrent mutation in the P protein (R515S; <a href="/entry/238300#0004">238300.0004</a>) in heterozygosity in 2 unrelated patients with glycine encephalopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10873393" 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 4 affected patients from 2 unrelated families with glycine encephalopathy, <a href="#23" class="mim-tip-reference" title="Korman, S. H., Boneh, A., Ichinohe, A., Kojima, K., Sato, K., Ergaz, Z., Gomori, J. M., Gutman, A., Kure, S. <strong>Persistent NKH with transient or absent symptoms and a homozygous GLDC mutation.</strong> Ann. Neurol. 56: 139-143, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15236413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15236413</a>] [<a href="https://doi.org/10.1002/ana.20159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15236413">Korman et al. (2004)</a> identified a homozygous ala802-to-val mutation (A802V; <a href="/entry/238300#0006">238300.0006</a>) in the GLDC gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15236413" 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 8 Arab patients with glycine encephalopathy, <a href="#7" class="mim-tip-reference" title="Boneh, A., Korman, S. H., Sato, K., Kanno, J., Matsubara, Y., Lerer, I., Ben-Neriah, Z., Kure, S. <strong>A single nucleotide substitution that abolishes the initiator methionine codon of the GLDC gene is prevalent among patients with glycine encephalopathy in Jerusalem.</strong> J. Hum. Genet. 50: 230-234, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15864413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15864413</a>] [<a href="https://doi.org/10.1007/s10038-005-0243-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15864413">Boneh et al. (2005)</a> identified a homozygous met1-to-thr (M1T; <a href="/entry/238300#0007">238300.0007</a>) in the GLDC gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15864413" 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 unrelated patients with a mild form of glycine encephalopathy, <a href="#12" class="mim-tip-reference" title="Dinopoulos, A., Kure, S., Chuck, G., Sato, K., Gilbert, D. L., Matsubara, Y., Degrauw, T. <strong>Glycine decarboxylase mutations: a distinctive phenotype of nonketotic hyperglycinemia in adults.</strong> Neurology 64: 1255-1257, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824356</a>] [<a href="https://doi.org/10.1212/01.WNL.0000156800.23776.40" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15824356">Dinopoulos et al. (2005)</a> identified homozygosity for an ala389-to-val (A389V; <a href="/entry/238300#0008">238300.0008</a>) mutation in the GLDC gene. In another patient with a mild form of the disorder, they identified a homozygous arg739-to-his mutation (R739H; <a href="/entry/238300#0009">238300.0009</a>) in GLDC. Functional expression studies showed that the mutant enzyme retained 7.9% and 6.1% residual activity, respectively, which may explain the milder phenotype in these patients <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15824356" 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 9 affected members of a large consanguineous Israeli Bedouin kindred with atypical glycine encephalopathy, <a href="#14" class="mim-tip-reference" title="Flusser, H., Korman, S. H., Sato, K., Matsubara, Y., Galil, A., Kure, S. <strong>Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation.</strong> Neurology 64: 1426-1430, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15851735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15851735</a>] [<a href="https://doi.org/10.1212/01.WNL.0000158475.12907.D6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15851735">Flusser et al. (2005)</a> identified homozygosity for a c.2607G-A substitution in the GLDC gene (<a href="/entry/238300#0010">238300.0010</a>) that affects a splice site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15851735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Krieger1974" class="mim-tip-reference" title="Krieger, I., Hart, Z. W. <strong>Valine-sensitive nonketotic hyperglycemia: case report.</strong> J. Pediat. 85: 43-48, 1974.">Krieger and Hart (1974)</a>
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Ando, T., Nyhan, W. L., Bicknell, J., Harris, R., Stern, J.
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<strong>Non-ketotic hyperglycinaemia in a family with an unusual phenotype.</strong>
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J. Inherit. Metab. Dis. 1: 79-83, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/116082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">116082</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=116082" 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/10.1007/BF01805677" target="_blank">Full Text</a>]
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Ando, T., Nyhan, W. L., Gerritsen, T., Gong, L., Heiner, D. C., Bray, P. F.
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<strong>Metabolism of glycine in the nonketotic form of hyperglycinemia.</strong>
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Pediat. Res. 2: 254-263, 1968.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5669662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5669662</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5669662" 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/10.1203/00006450-196807000-00004" target="_blank">Full Text</a>]
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Applegarth, D. A., Toone, J. R., Rolland, M. O., Black, S. H., Yim, D. K. C., Bemis, G.
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<strong>Non-concordance of CVS and liver glycine cleavage enzyme in three families with non-ketotic hyperglycinaemia (NKH) leading to false negative prenatal diagnoses.</strong>
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Prenatal Diag. 20: 367-370, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10820402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10820402</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10820402" 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/(sici)1097-0223(200005)20:5<367::aid-pd814>3.0.co;2-e" target="_blank">Full Text</a>]
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Applegarth, D. A., Toone, J. R.
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<strong>Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis.</strong>
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Molec. Genet. Metab. 74: 139-146, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11592811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11592811</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11592811" 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/10.1006/mgme.2001.3224" target="_blank">Full Text</a>]
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Balfe, J. W., Levison, H., Hanley, W. B., Jackson, S. H., Sass-Kortsak, A.
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<strong>Hyperglycinemia and glycinuria in a newborn. (Abstract)</strong>
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Canad. Med. Assoc. J. 92: 347, 1965.
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Baumgartner, R., Ando, T., Nyhan, W. L.
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J. Pediat. 75: 1022-1030, 1969.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5352828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5352828</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5352828" 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(69)80341-0" target="_blank">Full Text</a>]
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Boneh, A., Korman, S. H., Sato, K., Kanno, J., Matsubara, Y., Lerer, I., Ben-Neriah, Z., Kure, S.
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<strong>A single nucleotide substitution that abolishes the initiator methionine codon of the GLDC gene is prevalent among patients with glycine encephalopathy in Jerusalem.</strong>
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J. Hum. Genet. 50: 230-234, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15864413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15864413</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15864413" 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/10.1007/s10038-005-0243-y" target="_blank">Full Text</a>]
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Brandt, N. J., Brandt, S., Rasmussen, K., Schonheyder, F.
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<strong>Hyperglycericacidaemia with hyperglycinaemia: a new inborn error of metabolism. (Letter)</strong>
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Brit. Med. J. 4: 344 only, 1974.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4434100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4434100</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4434100" 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:1005613715351" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01811489" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-197005000-00002" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.WNL.0000156800.23776.40" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.33.8.1064" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.WNL.0000158475.12907.D6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(05)82559-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(05)82841-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(87)80399-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-198312000-00008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20159" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2012.11.002" target="_blank">Full Text</a>]
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Zammarchi, E., Donati, M. A., Ciani, F., Pasquini, E., Pela, I., Fiorini, P.
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<strong>Failure of early dextromethorphan and sodium benzoate therapy in an infant with nonketotic hyperglycemia.</strong>
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Neuropediatrics 25: 274-276, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7885541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7885541</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7885541" 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/10.1055/s-2008-1073037" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 05/31/2023
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Cassandra L. Kniffin - updated : 07/18/2017<br>Ada Hamosh - updated : 6/6/2014<br>Ada Hamosh - updated : 6/14/2007<br>Cassandra L. Kniffin - updated : 4/13/2006<br>Cassandra L. Kniffin - updated : 8/18/2005<br>Cassandra L. Kniffin - updated : 7/22/2005<br>Cassandra L. Kniffin - updated : 8/19/2004<br>Ada Hamosh - updated : 10/9/2003<br>Cassandra L. Kniffin - updated : 12/20/2002<br>Ada Hamosh - updated : 2/21/2002<br>Ada Hamosh - updated : 2/20/2002
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Ada Hamosh : 5/2/2001
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alopez : 06/20/2023
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carol : 05/31/2023<br>carol : 04/28/2018<br>carol : 04/26/2018<br>alopez : 07/18/2017<br>ckniffin : 07/18/2017<br>carol : 06/19/2017<br>carol : 06/16/2017<br>carol : 07/09/2016<br>alopez : 6/6/2014<br>carol : 8/4/2010<br>wwang : 7/29/2009<br>alopez : 6/22/2007<br>terry : 6/14/2007<br>wwang : 4/18/2006<br>ckniffin : 4/13/2006<br>carol : 10/12/2005<br>wwang : 8/22/2005<br>ckniffin : 8/18/2005<br>wwang : 7/26/2005<br>ckniffin : 7/22/2005<br>tkritzer : 8/26/2004<br>ckniffin : 8/19/2004<br>alopez : 10/9/2003<br>terry : 10/9/2003<br>ckniffin : 1/10/2003<br>ckniffin : 12/20/2002<br>terry : 3/12/2002<br>alopez : 2/22/2002<br>terry : 2/21/2002<br>terry : 2/20/2002<br>carol : 6/22/2001<br>carol : 6/20/2001<br>carol : 5/3/2001<br>carol : 5/3/2001<br>terry : 5/3/2001<br>terry : 5/3/2001<br>carol : 5/2/2001<br>carol : 5/2/2001
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<strong>#</strong> 605899
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GLYCINE ENCEPHALOPATHY 1; GCE1
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<em>Alternative titles; symbols</em>
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GCE<br />
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HYPERGLYCINEMIA, NONKETOTIC; NKH
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Other entities represented in this entry:
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HYPERGLYCINEMIA, TRANSIENT NEONATAL, INCLUDED; TNH, INCLUDED
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<strong>SNOMEDCT:</strong> 237939006, 51097006;
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<strong>ICD10CM:</strong> E72.51;
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<strong>ORPHA:</strong> 289857, 289860, 289863, 407;
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<strong>DO:</strong> 0070616;
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Phenotype
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Inheritance
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9p24.1
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Glycine encephalopathy1
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605899
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Autosomal recessive
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GLDC
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238300
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<p>A number sign (#) is used with this entry because of evidence that glycine encephalopathy-1 (GCE1) is caused by homozygous or compound heterozygous mutation in the GLDC gene (238300), a member of the mitochondrial glycine cleavage system that encodes the P protein, on chromosome 9p24.</p><p><strong><em>Genetic Heterogeneity of Glycine Encephalopathy (Nonketotic Hyperglycinemia)</em></strong></p><p>
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Also see GCE2 (620398), caused by mutation in the AMT gene (238310), which encodes the T protein of the mitochondrial glycine cleavage system.</p><p>A form of GCE was thought to be due to a mutation in the GCSH gene (238330.0001), but this variant has been reclassified as a variant of unknown significance.</p>
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<p>Nonketotic hyperglycinemia (NKH) was originally named to distinguish it from ketotic hyperglycinemia, which is now known to be propionic acidemia (606054). Since the distinction is no longer required and clinical confusion between hyperglycinemia and hyperglycemia occurs, a more appropriate name for this disorder is glycine encephalopathy (Hamosh, 2001).</p>
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<p><strong><em>Classic Neonatal Form</em></strong></p><p>
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Most patients with GCE have the neonatal phenotype, presenting in the first few days of life with lethargy, hypotonia, and myoclonic jerks, and progressing to apnea, and often to death. Those who regain spontaneous respiration develop intractable seizures and profound mental retardation. In the infantile form of GCE, patients present with seizures and have various degrees of mental retardation after a symptom-free interval and seemingly normal development for up to 6 months. In the mild-episodic form, patients present in childhood with mild mental retardation and episodes of delirium, chorea, and vertical gaze palsy during febrile illness. In the late-onset form, patients present in childhood with progressive spastic diplegia and optic atrophy, but intellectual function is preserved and seizures have not been reported (Hamosh and Johnston, 2001). See review by Tada and Hayasaka (1987). </p><p>Unlike glycinemia with ketoacidosis and leukopenia, also known as propionic acidemia (606054), episodic ketoacidosis with vomiting, neutropenia, and thrombocytopenia does not occur in nonketotic hyperglycinemia. Glycine is the only amino acid elevated in serum and urine and the only amino acid harmful to these patients. Some have died in the newborn period after a course characterized by lethargy, weak cry, generalized hypotonia, absent reflexes, and periodic myoclonic jerks (Balfe et al., 1965). The few who attain an older age show severe mental retardation (Mabry and Karam, 1963; Gerritsen et al., 1965). </p><p>Hayasaka et al. (1983) studied the glycine cleavage system in the liver and brain obtained at autopsy in 2 male infants with the typical form of nonketotic hyperglycinemia. In one a defect in the P protein was found; in the second, T protein was defective. The infant with the P protein defect was born of unrelated parents, was lethargic with a poor suck from birth, developed marked hypotonia, intermittent apnea, and poor responsiveness to stimuli, had mildly elevated blood ammonia and markedly elevated glycine in blood and cerebrospinal fluid, and died at age 12 days. Immunochemical analysis indicated absence of the enzyme P protein itself. The second infant appeared well at birth and nursed well the first day. He was hospitalized on the third day with 'lethargy, bordering on coma.' Despite ventilatory support, 7 exchange transfusions to lower blood glycine, and treatment with sodium benzoate and strychnine, he died on the twentieth day. T protein was undetectable in the brain and extremely low in liver. Autopsy in the first case, with P protein deficiency, showed absence of the corpus callosum and spinal cord hydromelia. The authors stated that they had seen a similar structural defect with deficiency of the pyruvate dehydrogenase complex (see 312170). </p><p>Schutgens et al. (1986) reported a case with T protein deficiency. </p><p>Cataltepe et al. (2000) reported 4 patients with nonketotic hyperglycinemia who developed pulmonary hypertension. Two patients had classic neonatal GCE and developed pulmonary hypertension in the newborn period; both died from pulmonary hypertension. The other 2 patients were sibs from Bangladesh with atypical GCE, the first of whom presented with pulmonary hypertension at the age of 6. His brother had documented pulmonary at the age of 4 years, which resolved spontaneously and then recurred in association with thiamine deficiency when he was 21 years old. </p><p>Van Hove et al. (2000) reported 4 patients with typical neonatal-onset NKH who developed hydrocephalus requiring shunting in early infancy. Brain imaging revealed acute hydrocephalus, a megacisterna magna or posterior fossa cyst, pronounced atrophy of the white matter, and an extremely thin corpus callosum in all. The 3 older patients had profound developmental disabilities. Van Hove et al. (2000) concluded that the development of hydrocephalus in NKH is an additional poor prognostic sign. </p><p>In cells derived from a deceased boy, born of unrelated Serbian parents, with GCE, Swanson et al. (2017) identified a homozygous missense mutation in the AMT gene (S117L; 238310.0009). In vitro functional expression studies showed that the mutant AMT protein was unstable and had only 9% residual enzymatic activity compared to controls. The patient was unusual because he had originally been reported as having D-glyceric aciduria (220120) caused by a homozygous frameshift mutation in the GLYCTK gene (610516.0001) (Brandt et al., 1974; Sass et al., 2010). Increased glycine in the patient had been thought to be secondary to the GLYCTK defect; however, the molecular findings confirmed that the patient had the unusual cooccurrence of 2 inborn errors of metabolism. Swanson et al. (2017) concluded that D-glyceric aciduria does not cause deficient glycine cleavage enzyme activity or nonketotic hyperglycinemia. </p><p><strong><em>Atypical Mild Form</em></strong></p><p>
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Unlike the classic neonatal form of the disorder, atypical or mild glycine encephalopathy is phenotypically heterogeneous and nonspecific, making diagnosis difficult (Flusser et al., 2005). </p><p>Cole and Meek (1985) emphasized the occurrence of an expressive speech deficit and neurologic abnormalities during intercurrent infections as striking features of the milder form of the disease. The cases of Ando et al. (1978), Frazier et al. (1978), and Flannery et al. (1983) also fall into this category. Hayasaka et al. (1987) cited one patient with atypical GCE and features of progressive degeneration of the central nervous system. </p><p>Dinopoulos et al. (2005) reported 3 unrelated adults with a mild form of glycine encephalopathy confirmed by genetic analysis (238300.0008; 238300.0009). All 3 patients showed hypotonia as infants and had developmental delay. One patient showed appendicular ataxia and choreoathetoid movements at age 4 years. Between ages 5 and 12 years, he had frequent outbursts of aggressiveness. He attended special education classes and graduated from high school. The second patient was hypotonic at birth and developed seizures during the first week of life. Aggressive behavior was noted at age 12 years; he was fully dependent on his family. The third patient developed hypotonia at age 6 months. He was diagnosed with attention deficit-hyperactivity disorder (ADHD) and had outbursts of aggression and impulsivity. Treatment with dextromethorphan was ineffective. He graduated from school in special education classes. Biochemical analysis showed residual GLDC activity ranging from 6 to 8%, which Dinopoulos et al. (2005) suggested may explain the milder clinical phenotype. The authors emphasized the clinical heterogeneity of the mild form of GCE. </p><p>Flusser et al. (2005) reported a large consanguineous Israeli Bedouin kindred in which 9 members had atypical GCE confirmed by genetic analysis (238300.0010). Most patients presented during the first months of life with abnormal movements, including mild to moderate generalized hypotonia, lateral head nodding, choreoathetoid hand movements, and pill rolling. Seven patients had seizures with generalized spike and slow wave abnormalities in EEG; 2 had infantile spasms with hypsarrhythmia. All had delayed motor development, moderate mental retardation, and limited expressive language. The patients also showed irritability and restlessness as infants and later showed aggressive and destructive behavior. Treatment was ineffective. </p><p>Yu et al. (2013) described 3 children from a consanguineous family who had autism spectrum disorder and who carried a homozygous mutation in the AMT gene. While individually nondiagnostic, the 3 affected children exhibited a range of neurologic symptoms that in aggregate were strongly suggestive of NKH. The eldest child was 12 years of age and had, in addition to a diagnosis of autism spectrum disorder, a history of severe epilepsy, with first seizures presenting at 10 months of age. The second child was 9 years of age and suffered from autism and epilepsy, but her seizures were milder. The third child was 2 years of age and had language and motor delays and carried a diagnosis of pervasive developmental disorder (PDD), but had had only 1 febrile seizure. Direct biochemical analysis of the mutation (ile308 to phe, I308F) demonstrated reduced activity. When compared to classical NKH-associated values, glycine cleavage activity of the mutated allele was at the mild end of the range of reported values, suggesting that the affected children in this family suffered from undiagnosed atypical NKH presenting as autism spectrum disorder and seizures. Plasma amino acid screening was normal in the 2 older children, a result that is typically seen in milder forms of NKH. </p><p><strong><em>Transient Neonatal Hyperglycinemia</em></strong></p><p>
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Transient neonatal hyperglycinemia (TNH) is characterized by elevated plasma and CSF glycine levels at birth that are normalized within 2 to 8 weeks. TNH is clinically and biochemically indistinguishable from typical nonketotic hyperglycinemia at onset. Applegarth and Toone (2001) reviewed 7 cases of transient NKH. </p><p>Korman et al. (2004) reported 3 sibs from a consanguineous Muslim Palestinian family who had an unusual NKH phenotype. All 3 sibs were diagnosed with NKH within the first 3 days of life with characteristic elevated CSF and plasma glycine levels and elevated CSF-to-plasma glycine ratios. However, none of them developed neurologic symptoms, and all showed appropriate development, including good school performance in the 2 children of school age. The 2 older children showed persistent hyperglycinemia. A patient from a second unrelated family diagnosed with NKH had mild neurologic sequelae. In all 4 patients, Korman et al. (2004) identified a homozygous mutation in the GLDC gene (238300.0006), which was shown to retain 32% residual enzyme activity in vitro. The authors suggested that these patients exhibited a new phenotype of NKH. </p>
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<p>Nonketotic hyperglycinemia is inherited as an autosomal recessive trait.</p>
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<p>Gerritsen et al. (1965) described abnormally low oxalate excretion in the urine and postulated a defect in glycine oxidase. Ando et al. (1968) located the defect to glycine formiminotransferase. Tada et al. (1969) concluded that the primary lesion in hyperglycinemia of the nonketotic variety is in the glycine cleavage reaction. Baumgartner et al. (1969) showed that the nonketotic variety can have a fulminant early onset. The defect concerns the enzyme involved in the conversion of glycine to CO2, NH3 and hydroxymethyltetrahydrofolic acid. De Groot et al. (1970) described 2 affected sisters with consanguineous parents and presented evidence indicating that the defect lies in glycine decarboxylase, rather than in glycine oxidase. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Pathogenesis</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>Toone et al. (2003) performed a retrospective analysis of a group of NKH patients and found that greater than 50% had T protein (238310) mutations. The patients studied had 1 or more unusual biochemical findings: residual glycine cleavage system activity in liver, residual glycine cleavage system activity in lymphoblasts, and/or increased amniotic fluid glycine-to-serine ratio with a normal amniotic fluid glycine level in prenatal diagnosis. The selected patients had a much higher incidence of T-protein defects than expected in the general NKH patient population. Toone et al. (2003) reported 3 novel mutations and 5 polymorphisms of the T protein gene, PCR/restriction enzyme methods for 1 mutation and 2 polymorphisms, and an estimation of their frequency in normal controls. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</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 high frequency of glycine encephalopathy has been found in Finland; the incidence has been estimated to be 1 in 55,000 newborns overall, and 1 in 12,000 in northern Finland (von Wendt and Simila, 1980; Boneh et al., 2005). High incidences have also been reported in British Columbia and in small Arab villages in Israel (Boneh et al., 2005). </p>
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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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<span class="mim-text-font">
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<p>Applegarth and Toone (2001) reviewed the laboratory diagnosis of glycine encephalopathy and confirmed 9 mutations in the T protein and 8 mutations in the P protein. </p><p>Tan et al. (2007) reported that they screened 733,527 babies over 8 years as part of the New South Wales Newborn Screening Program and subsequently diagnosed 9 babies with nonketotic hyperglycinemia. Two had newborn glycine levels above their cutoff and presented within 72 hours. The remaining patients could not have been diagnosed by newborn screening without an unacceptably high recall rate. Tan et al. (2007) concluded that babies with nonketotic hyperglycinemia were not usually identifiable by newborn screening strategies available at that time. </p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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Hayasaka et al. (1990) described prenatal diagnosis of nonketotic hyperglycinemia by enzymatic analysis of the glycine cleavage system in chorionic villi. Toone et al. (1994) described their experience with direct assay of glycine cleavage enzyme in chorionic villus samples in 50 at-risk pregnancies. </p><p>Applegarth et al. (2000) reported 3 false-negative prenatal diagnostic results using direct measurement of glycine cleavage enzyme activity in uncultured chorionic villus tissue from 290 pregnancies at risk for glycine encephalopathy. Because of these false negatives, Applegarth et al. (2000) counseled that there is a gray zone of uninterpretable activity where affected and normal enzyme values overlap, and suggested that there is an approximately 1% chance of a pregnancy with a normal chorionic villus sample activity resulting in an affected child. </p><p>Kure et al. (1999) performed prenatal diagnosis for NKH by enzymatic analysis of chorionic villus samples in 28 families and by DNA analysis in 2 families. In 26 families, enzymatic analysis of the glycine cleavage system (GCS) yielded an unambiguous diagnosis; inconclusive results in 2 families were due to borderline GCS activity. A second chorionic sample was analyzed in both these families. In one case, GCS activity was normal in the second specimen and the baby did not have NKH. In the other case, Kure et al. (1999) again found extremely low GCS activity in a second specimen, but a healthy baby was born. The cause of this false-positive result was unknown. Kure et al. (1999) also reported the ability to obtain unambiguous prenatal diagnosis in both Finnish and Israeli Arab families due to prevalent mutations in those populations. The H42R mutation in the T protein (238310.0003) may lead to ambiguous enzymatic activity, suggesting an advantage for DNA analysis. </p>
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</span>
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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 Management</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>Hamosh et al. (1992) reported clinical and electrophysiologic improvement in a child with GCE who was treated with dextromethorphan and sodium benzoate beginning with the twelfth day of life. Dextromethorphan is a noncompetitive antagonist of the NMDA type of glutamate receptor, which can be stimulated by glycine. Zammarchi et al. (1994) reported only transient improvement on the same regimen when the treatment was instituted at 65 hours of life. The child died at 5 months and 7 days of age in spite of increasing doses of dextromethorphan as high as 40 mg per kilogram per day. The enzymatic basis for the GCE in either the successfully or unsuccessfully treated infant was not specified. The authors speculated that the different responses may reflect genetic heterogeneity. </p><p>Treatment of patients with GCE with high doses of benzoate can result in decreased CSF glycine levels and will improve seizure control and wakefulness (Hamosh et al., 1992), thus improving the quality of life in surviving infants, but even when started early, may not prevent the development of mental retardation (Zammarchi et al., 1994). Episodes of lethargy, coma, and increased seizures can be caused both by hyperglycinemia from underdosing benzoate, or by toxicity due to overdosing. Van Hove et al. (1995) found plasma carnitine deficiency in 3 of 4 patients with GCE treated with sodium benzoate, and benzoylcarnitine was identified in plasma, urine, and CSF. Treatment with L-carnitine normalized plasma-free carnitine. Close monitoring of glycine, benzoate and carnitine levels is advisable in patients receiving benzoate. </p><p>Neuberger et al. (2000) reported a 6-month-old girl who presented with hypotonia and mild psychomotor retardation who was subsequently found to have NKH confirmed by decreased glycine cleavage system activity in the liver. After the patient developed hypsarrhythmia and had a single seizure, treatment with both sodium benzoate and dextromethorphan was started. During the following year, the girl was free of seizures with improvement of EEG activity and showed retarded but continuously progressing psychomotor development. At the age of 20 months she began to walk freely but had generalized muscular hypotonia and moderate mental retardation. Discontinuation of dextromethorphan after one year did not change the clinical or EEG status. However, after cessation of sodium benzoate, epileptic activity in the EEG and behavioral changes occurred. These changes disappeared promptly after sodium benzoate therapy was reinstituted. </p><p>Korman et al. (2006) reported a patient with NKH caused by a homozygous mutation in the GLDC gene. He was born of first-cousin Palestinian Arabs. The patient was diagnosed prenatally and treated from birth with oral sodium benzoate and the NMDA receptor antagonist ketamine. Although neonatal hypotonia and apnea did not occur, the long-term outcome at age 11 months was poor, with intractable seizures and severe psychomotor retardation. Korman et al. (2006) noted that the plasma glycine level in this child was normal at birth, presumably reflecting placental clearance, whereas the CSF glycine level was markedly elevated, suggesting that the developing brain had been exposed prenatally to the potential toxicity of glycine. </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>Molecular 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">
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<p>A high frequency of glycine encephalopathy has been found in some counties of Finland (von Wendt and Simila, 1980). In 13 heterozygotes in Finland, von Wendt et al. (1981) found minor dysfunctions of the central nervous system which they suggested may be due to a slightly abnormal degradation of glycine (which has a neurotransmitter role). Kure et al. (1992) found that 14 of 20 P protein alleles in Finnish patients carried a missense mutation in the GLCD gene (S564I; 238300.0001). </p><p>Applegarth and Toone (2001) reported that a gly71-to-arg (G71R; 238300.0005) variant in GLDC, reported originally by Kure et al. (1999), is present in 8% of NKH Finnish alleles. </p><p>In a Japanese boy with glycine encephalopathy, Takayanagi et al. (2000) identified a large homozygous deletion (at least 30 kb) in the GLDC gene (238300.0003). </p><p>Toone et al. (2000) identified a recurrent mutation in the P protein (R515S; 238300.0004) in heterozygosity in 2 unrelated patients with glycine encephalopathy. </p><p>In 4 affected patients from 2 unrelated families with glycine encephalopathy, Korman et al. (2004) identified a homozygous ala802-to-val mutation (A802V; 238300.0006) in the GLDC gene. </p><p>In 8 Arab patients with glycine encephalopathy, Boneh et al. (2005) identified a homozygous met1-to-thr (M1T; 238300.0007) in the GLDC gene. </p><p>In 2 unrelated patients with a mild form of glycine encephalopathy, Dinopoulos et al. (2005) identified homozygosity for an ala389-to-val (A389V; 238300.0008) mutation in the GLDC gene. In another patient with a mild form of the disorder, they identified a homozygous arg739-to-his mutation (R739H; 238300.0009) in GLDC. Functional expression studies showed that the mutant enzyme retained 7.9% and 6.1% residual activity, respectively, which may explain the milder phenotype in these patients </p><p>In 9 affected members of a large consanguineous Israeli Bedouin kindred with atypical glycine encephalopathy, Flusser et al. (2005) identified homozygosity for a c.2607G-A substitution in the GLDC gene (238300.0010) that affects a splice site. </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">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Krieger and Hart (1974)
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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">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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Ando, T., Nyhan, W. L., Bicknell, J., Harris, R., Stern, J.
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<strong>Non-ketotic hyperglycinaemia in a family with an unusual phenotype.</strong>
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J. Inherit. Metab. Dis. 1: 79-83, 1978.
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[PubMed: 116082]
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Ando, T., Nyhan, W. L., Gerritsen, T., Gong, L., Heiner, D. C., Bray, P. F.
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<strong>Metabolism of glycine in the nonketotic form of hyperglycinemia.</strong>
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Pediat. Res. 2: 254-263, 1968.
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Applegarth, D. A., Toone, J. R., Rolland, M. O., Black, S. H., Yim, D. K. C., Bemis, G.
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<strong>Non-concordance of CVS and liver glycine cleavage enzyme in three families with non-ketotic hyperglycinaemia (NKH) leading to false negative prenatal diagnoses.</strong>
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Applegarth, D. A., Toone, J. R.
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Balfe, J. W., Levison, H., Hanley, W. B., Jackson, S. H., Sass-Kortsak, A.
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Boneh, A., Korman, S. H., Sato, K., Kanno, J., Matsubara, Y., Lerer, I., Ben-Neriah, Z., Kure, S.
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<strong>A single nucleotide substitution that abolishes the initiator methionine codon of the GLDC gene is prevalent among patients with glycine encephalopathy in Jerusalem.</strong>
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Brandt, N. J., Brandt, S., Rasmussen, K., Schonheyder, F.
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Cataltepe, S., van Marter, L. J., Kozakewich, H., Wessel, D. L., Lee, P. J., Levy, H. L.
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De Groot, C. J., Troelstra, J. A., Hommes, F. A.
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<strong>Nonketotic hyperglycinemia: an in vitro study of the glycine-serine conversion in liver of three patients and the effect of dietary methionine.</strong>
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Dinopoulos, A., Kure, S., Chuck, G., Sato, K., Gilbert, D. L., Matsubara, Y., Degrauw, T.
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<strong>Glycine decarboxylase mutations: a distinctive phenotype of nonketotic hyperglycinemia in adults.</strong>
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Flannery, D. B., Pellock, J., Bousonis, D., Hunt, P., Nance, C., Wolf, B.
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Neurology 33: 1064-1066, 1983.
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Flusser, H., Korman, S. H., Sato, K., Matsubara, Y., Galil, A., Kure, S.
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<strong>Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation.</strong>
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[PubMed: 15851735]
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[Full Text: https://doi.org/10.1212/01.WNL.0000158475.12907.D6]
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Frazier, D. M., Summer, G. K., Chamberlin, H. R.
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<strong>Hyperglycinuria and hyperglycinemia in two siblings with mild developmental delays.</strong>
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Am. J. Dis. Child. 132: 777-781, 1978.
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Gerritsen, T., Kaveggia, E. G., Waisman, H. A.
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<strong>A new type of idiopathic hyperglycinemia with hypo-oxaluria.</strong>
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Pediatrics 36: 882-891, 1965.
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[PubMed: 5846830]
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<strong>Nonketotic hyperglycinemia. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (8th ed.)</strong>
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Hamosh, A., McDonald, J. W., Valle, D., Francomano, C. A., Niedermeyer, E., Johnston, M. V.
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<strong>Dextromethorphan and high-dose benzoate therapy for nonketotic hyperglycinemia in an infant.</strong>
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[PubMed: 1385627]
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 6/16/2001.
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</p>
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<p class="mim-text-font">
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Hayasaka, K., Tada, K., Fueki, N., Aikawa, J.
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<strong>Prenatal diagnosis of nonketotic hyperglycinemia: enzymatic analysis of the glycine cleavage system in chorionic villi.</strong>
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J. Pediat. 116: 444-445, 1990.
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[PubMed: 2308039]
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[Full Text: https://doi.org/10.1016/s0022-3476(05)82841-0]
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</p>
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