3596 lines
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Entry
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- #238970 - HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME; HHHS
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- OMIM
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<p>
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<span class="h4">#238970</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/238970"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#otherFeatures">Other Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#diagnosis">Diagnosis</a>
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<li role="presentation" style="margin-left: 1em">
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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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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<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 class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div style="display: table-cell;">External Links</div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=770&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK97260/" 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://www.diseaseinfosearch.org/x/5413" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/ornithine-translocase-deficiency" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=238970[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=415" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0050720" 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/238970" 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/OMIA001290/" 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:0050720" 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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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:238970" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 30287008<br />
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<strong>ICD10CM:</strong> E72.4<br />
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<strong>ORPHA:</strong> 415<br />
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<strong>DO:</strong> 0050720<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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238970
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
|
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<span class="mim-font">
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HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME; HHHS
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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HHH SYNDROME; HHH<br />
|
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ORNITHINE TRANSLOCASE DEFICIENCY
|
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</span>
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</h4>
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</div>
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<div>
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<br />
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/13/124?start=-3&limit=10&highlight=124">
|
|
13q14.11
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/238970"> 238970 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
SLC25A15
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603861"> 603861 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/238970" 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">
|
|
<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/238970" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/238970" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- 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>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GROWTH </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Other </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Liver </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Liver dysfunction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/75183008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">75183008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0086565&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0086565</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001410" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001410</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002910" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002910</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001410" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001410</a>]</span><br /> -
|
|
Acute hepatitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/37871000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">37871000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/B17.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">B17.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0267797&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0267797</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0200119" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0200119</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0200119" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0200119</a>]</span><br /> -
|
|
Hepatomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80515008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80515008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019209&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019209</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Protein avoidance <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839531&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839531</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002038" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002038</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002038" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002038</a>]</span><br /> -
|
|
Episodic vomiting <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838993&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838993</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002572</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002572</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Psychomotor retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398991009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398991009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1144814003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1144814003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424230&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424230</a>, <a href="https://bioportal.bioontology.org/search?q=C5441816&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5441816</a>]</span><br /> -
|
|
Learning disabilities <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1855002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1855002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F81.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F81.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0751265&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0751265</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001328" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001328</a>]</span><br /> -
|
|
Mental retardation, variable <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859755&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859755</a>]</span> <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">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
|
|
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
|
|
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 /> -
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Coma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/371632003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">371632003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405809000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405809000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R40.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R40.20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R40.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R40.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.01</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0543874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0543874</a>, <a href="https://bioportal.bioontology.org/search?q=C3146279&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3146279</a>, <a href="https://bioportal.bioontology.org/search?q=C0009421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009421</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001259</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001259</a>]</span><br /> -
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Spastic paraparesis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/312444006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">312444006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0037771&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037771</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002313" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002313</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002313" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002313</a>]</span><br /> -
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Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
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Hyperreflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86854008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86854008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151889</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span><br /> -
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Clonus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36649002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36649002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009024&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009024</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002169" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002169</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002169" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002169</a>]</span><br /> -
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Episodic confusion <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2673486&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2673486</a>]</span><br /> -
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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 /> -
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Myoclonic seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1208991001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1208991001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4317123&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4317123</a>, <a href="https://bioportal.bioontology.org/search?q=C0014550&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014550</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0032794" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0032794</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0032794" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0032794</a>]</span><br /> -
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Acute encephalopathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1306587&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1306587</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006846" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006846</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006846" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006846</a>]</span><br /> -
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Poor coordination <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0563243&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0563243</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002370" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002370</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002370" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002370</a>]</span><br /> -
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Buccolingofacial dyspraxia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2673487&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2673487</a>]</span><br /> -
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Pyramidal signs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14648003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14648003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234132&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234132</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span><br /> -
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Cortical atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/278849000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">278849000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551583&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551583</a>, <a href="https://bioportal.bioontology.org/search?q=C0235946&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235946</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002120</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002120</a>]</span><br /> -
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Subcortical white matter abnormalities (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0948163&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0948163</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002500" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002500</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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<span class="h5 mim-font">
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<em> Peripheral Nervous System </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Decreased vibration sense (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/130980003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">130980003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1295585&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1295585</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002495" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002495</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002495" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002495</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> HEMATOLOGY </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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- Coagulopathy due to liver dysfunction <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2673491&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2673491</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64779008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64779008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/362970003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">362970003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D68.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D68.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">286</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003256</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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- Hyperornithinemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/314467007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">314467007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/276426004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">276426004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/33985005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">33985005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0599035&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0599035</a>, <a href="https://bioportal.bioontology.org/search?q=C0018425&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018425</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012026" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012026</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012026" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012026</a>]</span><br /> -
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Hyperammonemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/9360008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">9360008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E72.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E72.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5574662&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5574662</a>, <a href="https://bioportal.bioontology.org/search?q=C0220994&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220994</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001987" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001987</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001987" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001987</a>]</span><br /> -
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Homocitrullinuria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2673490&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2673490</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034464" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034464</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034464" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034464</a>]</span><br />
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- Onset in first months or years of life<br /> -
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Phenotypic variability <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837514&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837514</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span><br /> -
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Increased prevalence in the French-Canadian population<br />
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- Caused by mutation in the solute carrier family 25 (mitochondrial carrier, ornithine transporter), member 15 gene (SLC25A15, <a href="/entry/603861#0001">603861.0001</a>)<br />
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<p>A number sign (#) is used with this entry because of evidence that the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (HHHS) is caused by homozygous mutation in the SLC25A15 gene (<a href="/entry/603861">603861</a>), which encodes the mitochondrial ornithine transporter, on chromosome 13q14.</p>
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<p>Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHHS) is an autosomal recessive, chronic and progressive disorder of the urea cycle with typical age of onset in early life. The acute phase is characterized by hyperammonemia accompanied by vomiting, ataxia, lethargy, confusion, and coma. Chronically, aversion to protein-rich foods, coagulation abnormalities, hypotonia, developmental delay, progressive encephalopathy with mental regression, and signs of motor dysfunction are present. About 95% of patients survive after diagnosis and therapy is established. However, in early adulthood most patients develop signs of pyramidal tract dysfunction (summary by <a href="#28" class="mim-tip-reference" title="Tessa, A., Fiermonte, G., Dionisi-Vici, C., Paradies, E., Baumgartner, M. R., Chien, Y.-H., Loguercio, C., de Baulny, H. O., Nassogne, M.-C., Schiff, M., Deodato, F., Parenti, G., and 12 others. <strong>Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study.</strong> Hum. Mutat. 30: 741-748, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19242930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19242930</a>] [<a href="https://doi.org/10.1002/humu.20930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19242930">Tessa et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19242930" 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="#24" class="mim-tip-reference" title="Shih, V. E., Efron, M. L., Moser, H. W. <strong>Hyperornithinemia, hyperammonemia, and homocitrullinemia: a new disorder of amino acid metabolism associated with myoclonic seizures and mental retardation.</strong> Am. J. Dis. Child. 117: 83-92, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5782534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5782534</a>]" pmid="5782534">Shih et al. (1969)</a> reported a child with mental retardation and myoclonic seizures associated with hyperornithinemia, hyperammonemia, and homocitrullinemia. The findings were consistent with an inherited disorder of amino acid metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5782534" 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="Rodes, M., Ribes, A., Pineda, M., Alvarez, L., Fabregas, I., Fernandez Alvarez, E., Coude, F. X., Grimber, G. <strong>A new family affected by the syndrome of hyperornithinaemia, hyperammonaemia and homocitrullinuria.</strong> J. Inherit. Metab. Dis. 10: 73-81, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3106719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3106719</a>] [<a href="https://doi.org/10.1007/BF01799492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3106719">Rodes et al. (1987)</a> reported a family in which 2 brothers and a sister were affected with HHH syndrome. One patient had progressive spastic paraparesis. At least 2 of the individuals voluntarily avoided a high protein diet. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3106719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Dionisi Vici, C., Bachmann, C., Gambarara, M., Colombo, J. P., Sabetta, G. <strong>Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: low creatine excretion and effect of citrulline, arginine, or ornithine supplement.</strong> Pediat. Res. 22: 364-367, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3116497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3116497</a>] [<a href="https://doi.org/10.1203/00006450-198709000-00025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3116497">Dionisi Vici et al. (1987)</a> found reports of 23 patients with HHH syndrome in the literature, only 1 of whom showed symptoms as a neonate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3116497" 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="#17" class="mim-tip-reference" title="Koike, R., Fujimori, K., Yuasa, T., Miyatake, T., Inoue, I., Saheki, T. <strong>Hyperornithinemia, hyperammonemia, and homocitrullinuria: case report and biochemical study.</strong> Neurology 37: 1813-1815, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3670619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3670619</a>] [<a href="https://doi.org/10.1212/wnl.37.11.1813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3670619">Koike et al. (1987)</a> reported Japanese brothers, aged 13 and 19 years, with HHH syndrome. The clinical picture included protein intolerance, mental retardation, seizures, and stuporous episodes. One patient had cerebellar ataxia, myoclonus, convulsive seizure, and muscular weakness in both legs. The older brother had refused to eat fish and meat, and had episodes of vomiting when fed a high-protein formula. Both brothers also had myoclonus epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3670619" 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="#20" class="mim-tip-reference" title="Nakajima, M., Ishii, S., Mito, T., Takeshita, K., Takashima, S., Takakura, H., Inoue, I., Saheki, T., Akiyoshi, H., Ichihara, K. <strong>Clinical, biochemical and ultrastructural study on the pathogenesis of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.</strong> Brain Dev. 10: 181-185, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3407856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3407856</a>] [<a href="https://doi.org/10.1016/s0387-7604(88)80025-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3407856">Nakajima et al. (1988)</a> reported a Japanese child, born of healthy first-cousin parents, with HHH syndrome. Development was delayed in late infancy, and spastic paraplegia was noted at the age of 3 years. The patient always avoided the intake of meat, milk, and eggs. At age 10, he had an episode of lethargy and hyperammonemia. Brain CT showed diffuse white matter low density and atrophy of the cerebellar vermis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3407856" 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="Tuchman, M., Knopman, D. S., Shih, V. E. <strong>Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.</strong> Arch. Neurol. 47: 1134-1137, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2222247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2222247</a>] [<a href="https://doi.org/10.1001/archneur.1990.00530100104022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2222247">Tuchman et al. (1990)</a> described this disorder in a 39-year-old man and his 42-year-old sister, both vegetarians, who had had episodic confusion for many years, but normal mental function between these episodes. Hyperammonemia was documented during an episode of confusion in the male sib but not in his sister. During therapy with citrulline and phenylbutyrate sodium, plasma ornithine levels increased in both patients, while plasma levels of glutamine and alanine decreased to normal. With therapy, their clinical conditions improved and no recurrent neurologic dysfunction was observed over a follow-up period of 20 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2222247" 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="#19" class="mim-tip-reference" title="Miyamoto, T., Kanazawa, N., Kato, S., Kawakami, M., Inoue, Y., Kuhara, T., Inoue, T., Takeshita, K., Tsujino, S. <strong>Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X.</strong> J. Hum. Genet. 46: 260-262, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11355015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11355015</a>] [<a href="https://doi.org/10.1007/s100380170075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11355015">Miyamoto et al. (2001)</a> reported a 52-year-old woman who had spastic gait and cerebellar signs, including dysmetria, dysdiadochokinesis, and scanning speech, since adolescence, but did not have mental retardation. She had spastic paraparesis of the arms since age 27. Hyperammonemia was noted at the age of 36 years, and a protein-restricted diet and kanamycin were prescribed. At age 37, she had surgery to elongate Achilles tendons in both legs. The diagnosis of HHH syndrome was made at the age of 52, on the basis of hyperornithinemia and homocitrullinuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11355015" 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="Salvi, S., Santorelli, F. M., Bertini, E., Boldrini, R., Meli, C., Donati, A., Burlina, A. B., Rizzo, C., Di Capua, M., Fariello, G., Dionisi-Vici, C. <strong>Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.</strong> Neurology 57: 911-914, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11552031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11552031</a>] [<a href="https://doi.org/10.1212/wnl.57.5.911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11552031">Salvi et al. (2001)</a> reported a follow-up on 8 Italian patients who had been diagnosed with HHH syndrome. Age at onset ranged from infancy to 18 years. The predominant neurologic finding was spastic paraparesis, seen in 5 patients. The remaining 3 patients showed signs of pyramidal dysfunction, which the authors suggested may progress to spastic paraparesis later in life. Mental retardation and clonic movements were variably present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11552031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Debray, F.-G., Lambert, M., Lemieux, B., Soucy, J. F., Drouin, R., Fenyves, D., Dube, J., Maranda, B., Laframboise, R., Mitchell, G. A. <strong>Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15.</strong> J. Med. Genet. 45: 759-764, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18978333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18978333</a>] [<a href="https://doi.org/10.1136/jmg.2008.059097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18978333">Debray et al. (2008)</a> reviewed the medical records of 16 French Canadian patients with HHH syndrome, 15 of whom were homozygous for the common F188del founder mutation in the SLC25A15 gene (<a href="/entry/603861#0001">603861.0001</a>). Six of the patients had previously been reported by <a href="#18" class="mim-tip-reference" title="Lemay, J. F., Lambert, M. A., Mitchell, G. A., Vanasse, M., Valle, D., Arbour, J. F., Dube, J., Flessas, J., Laberge, M., Lafleur, L., Orquin, J., Qureshi, I. A., Dery, R. <strong>Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of 6 patients.</strong> J. Pediat. 121: 725-730, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1432421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1432421</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)81900-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1432421">Lemay et al. (1992)</a>. The median age at presentation was 2.7 years (range, 3 months to 16 years). Common features included failure to thrive, developmental delay, liver dysfunction with secondary coagulation defects, hyperammonemia, hyperornithinemia, and abnormally increased liver enzymes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18978333+1432421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Batshaw, M. L., Tuchman, M., Summar, M., Seminara, J., Members of the Urea Cycle Disorders Consortium. <strong>A longitudinal study of urea cycle disorders.</strong> Molec. Genet. Metab. 113: 127-130, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25135652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25135652</a>] [<a href="https://doi.org/10.1016/j.ymgme.2014.08.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25135652">Batshaw et al. (2014)</a> reported the results of an analysis of 614 patients with urea cycle disorders (UCDs) enrolled in the Urea Cycle Disorders Consortium's longitudinal study protocol. HHH syndrome occurred in 9 patients (1.5%), 8 of whom had a late-onset form. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25135652" 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="Hommes, F. A., Roesel, R. A., Metoki, K., Hartlage, P. L., Dyken, P. R. <strong>Studies on a case of HHH-syndrome (hyperammonemia, hyperornithinemia, homocitrullinuria).</strong> Neuropediatrics 17: 48-52, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3960284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3960284</a>] [<a href="https://doi.org/10.1055/s-2008-1052499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3960284">Hommes et al. (1986)</a> reported what they considered to be the twelfth documented case of HHH syndrome. They showed that the uptake of ornithine by the particulate fraction of the patient's fibroblasts was abnormally low, but still measurable. This suggested a partial impairment of uptake of ornithine by mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3960284" 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="Rodes, M., Ribes, A., Pineda, M., Alvarez, L., Fabregas, I., Fernandez Alvarez, E., Coude, F. X., Grimber, G. <strong>A new family affected by the syndrome of hyperornithinaemia, hyperammonaemia and homocitrullinuria.</strong> J. Inherit. Metab. Dis. 10: 73-81, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3106719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3106719</a>] [<a href="https://doi.org/10.1007/BF01799492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3106719">Rodes et al. (1987)</a> found that cultured skin fibroblasts derived from patients with HHH syndrome showed 6 times less incorporation of labeled ornithine into protein as compared to control cells. Further studies were consistent with a defect in the transport of ornithine into the mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3106719" 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="#17" class="mim-tip-reference" title="Koike, R., Fujimori, K., Yuasa, T., Miyatake, T., Inoue, I., Saheki, T. <strong>Hyperornithinemia, hyperammonemia, and homocitrullinuria: case report and biochemical study.</strong> Neurology 37: 1813-1815, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3670619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3670619</a>] [<a href="https://doi.org/10.1212/wnl.37.11.1813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3670619">Koike et al. (1987)</a> found that isolated liver mitochondria in a patient with HHH syndrome showed decreased ornithine transport and citrulline synthesis, but urea cycle enzymes and ornithine aminotransferase were normal. Ornithine metabolism was also decreased in cultured skin fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3670619" 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="#8" class="mim-tip-reference" title="Dionisi Vici, C., Bachmann, C., Gambarara, M., Colombo, J. P., Sabetta, G. <strong>Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: low creatine excretion and effect of citrulline, arginine, or ornithine supplement.</strong> Pediat. Res. 22: 364-367, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3116497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3116497</a>] [<a href="https://doi.org/10.1203/00006450-198709000-00025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3116497">Dionisi Vici et al. (1987)</a> reported 2 unrelated patients with neonatal onset of HHH syndrome. One of their patients also had deficiency of clotting factors VII (F7; <a href="/entry/613878">613878</a>) and X (F10; <a href="/entry/613872">613872</a>), both of which are linked to chromosome 13q. The same association had been described by <a href="#11" class="mim-tip-reference" title="Gatfield, P. D., Taller, E., Wolfe, D. M., Haust, M. D. <strong>Hyperornithinemia, hyperammonemia, and homocitrullinuria associated with decreased carbamyl phosphate synthetase I activity.</strong> Pediat. Res. 9: 488-497, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/166348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">166348</a>] [<a href="https://doi.org/10.1203/00006450-197505000-00006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="166348">Gatfield et al. (1975)</a> and by <a href="#26" class="mim-tip-reference" title="Simell, O., Mackenzie, S., Clow, C. L., Scriver, C. R. <strong>Ornithine loading did not prevent induced hyperammonemia in a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.</strong> Pediat. Res. 19: 1283-1287, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4080446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4080446</a>] [<a href="https://doi.org/10.1203/00006450-198512000-00016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4080446">Simell et al. (1985)</a>. <a href="#8" class="mim-tip-reference" title="Dionisi Vici, C., Bachmann, C., Gambarara, M., Colombo, J. P., Sabetta, G. <strong>Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: low creatine excretion and effect of citrulline, arginine, or ornithine supplement.</strong> Pediat. Res. 22: 364-367, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3116497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3116497</a>] [<a href="https://doi.org/10.1203/00006450-198709000-00025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3116497">Dionisi Vici et al. (1987)</a> suggested that the mutation responsible for the HHH syndrome is located on 13q. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3116497+4080446+166348" 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="#27" class="mim-tip-reference" title="Smith, L., Lambert, M. A., Brochu, P., Jasmin, G., Qureshi, I. A., Seidman, E. G. <strong>Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: presentation as acute liver disease with coagulopathy.</strong> J. Pediat. Gastroent. Nutr. 15: 431-436, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1469525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1469525</a>] [<a href="https://doi.org/10.1097/00005176-199211000-00011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1469525">Smith et al. (1992)</a>, who stated that over 30 patients had been described, reported a 5-year-old French-Canadian girl with HHH syndrome who presented a clinical picture suggesting hepatitis associated with coagulopathy, initially thought to be acute viral hepatitis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1469525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Lemay, J. F., Lambert, M. A., Mitchell, G. A., Vanasse, M., Valle, D., Arbour, J. F., Dube, J., Flessas, J., Laberge, M., Lafleur, L., Orquin, J., Qureshi, I. A., Dery, R. <strong>Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of 6 patients.</strong> J. Pediat. 121: 725-730, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1432421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1432421</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)81900-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1432421">Lemay et al. (1992)</a> described the clinical, electrophysiologic, ophthalmologic, and neuropsychologic features of 6 patients. Pyramidal signs, decreased vibration sense, buccofaciolingual dyspraxia, and learning difficulties or subnormal intelligence were found in most. Anomalies of peripheral nerve conduction velocity and of evoked potentials were common. In 1 patient, markedly abnormal white matter was demonstrated on cranial MRI. One patient had retinal depigmentation and chorioretinal thinning. Only 2 of the patients had had episodes of symptomatic hyperammonemia. The relationship of hyperammonemia to the chronic neuropsychologic problems of these patients was unclear. However, in a follow-up to these patients, <a href="#7" class="mim-tip-reference" title="Debray, F.-G., Lambert, M., Lemieux, B., Soucy, J. F., Drouin, R., Fenyves, D., Dube, J., Maranda, B., Laframboise, R., Mitchell, G. A. <strong>Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15.</strong> J. Med. Genet. 45: 759-764, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18978333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18978333</a>] [<a href="https://doi.org/10.1136/jmg.2008.059097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18978333">Debray et al. (2008)</a> noted that these patients showed no clinical signs of peripheral neuropathy. In addition, the patient with retinal depigmentation and chorioretinal thinning showed no deterioration and had normal visual function at age 22 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18978333+1432421" 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>Autosomal recessive inheritance was supported by the large Canadian pedigree of <a href="#11" class="mim-tip-reference" title="Gatfield, P. D., Taller, E., Wolfe, D. M., Haust, M. D. <strong>Hyperornithinemia, hyperammonemia, and homocitrullinuria associated with decreased carbamyl phosphate synthetase I activity.</strong> Pediat. Res. 9: 488-497, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/166348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">166348</a>] [<a href="https://doi.org/10.1203/00006450-197505000-00006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="166348">Gatfield et al. (1975)</a>, with 6 affected persons of both sexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=166348" 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="#6" class="mim-tip-reference" title="Chadefaux, B., Bonnefont, J. P., Rabier, D., Shih, V. E., Saudubray, J. M., Kamoun, P. <strong>Potential for the prenatal diagnosis of hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. (Letter)</strong> Am. J. Med. Genet. 32: 264 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2929667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2929667</a>] [<a href="https://doi.org/10.1002/ajmg.1320320228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2929667">Chadefaux et al. (1989)</a> suggested that the first-trimester diagnosis of HHHS can be achieved by study of the incorporation of (14)C-ornithine into proteins of chorionic villi. They referred to a case of untreated HHH syndrome in the mother being associated with a mentally retarded offspring. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2929667" 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="#25" class="mim-tip-reference" title="Shih, V. E., Laframboise, R., Mandell, R., Pichette, J. <strong>Neonatal form of the hyperornithinaemia, hyperammonaemia, and homocitrullinuria (HHH) syndrome and prenatal diagnosis.</strong> Prenatal Diag. 12: 717-723, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1438066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1438066</a>] [<a href="https://doi.org/10.1002/pd.1970120905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1438066">Shih et al. (1992)</a> described neonatal death in the HHH syndrome and successful prenatal diagnosis of the disorder in a subsequent pregnancy in this family. Thus, the severity ranges from minimal neurologic dysfunction in adulthood (<a href="#29" class="mim-tip-reference" title="Tuchman, M., Knopman, D. S., Shih, V. E. <strong>Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.</strong> Arch. Neurol. 47: 1134-1137, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2222247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2222247</a>] [<a href="https://doi.org/10.1001/archneur.1990.00530100104022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2222247">Tuchman et al., 1990</a>) to neonatal death. Diagnostic of the condition in amniotic cells was the combination of normal OAT activity and the inability of the cells to utilize ornithine. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2222247+1438066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In the first case of HHH syndrome reported from Norway, <a href="#12" class="mim-tip-reference" title="Gjessing, L. R., Lunde, H. A., Undrum, T., Broch, H., Alme, A., Lie, S. O. <strong>A new patient with hyperornithinaemia, hyperammonaemia and homocitrullinuria treated early with low protein diet.</strong> J. Inherit. Metab. Dis. 9: 186-192, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3091924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3091924</a>] [<a href="https://doi.org/10.1007/BF01799457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3091924">Gjessing et al. (1986)</a> found that a low protein diet initiated early in life permitted normal development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3091924" 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="Rodes, M., Ribes, A., Pineda, M., Alvarez, L., Fabregas, I., Fernandez Alvarez, E., Coude, F. X., Grimber, G. <strong>A new family affected by the syndrome of hyperornithinaemia, hyperammonaemia and homocitrullinuria.</strong> J. Inherit. Metab. Dis. 10: 73-81, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3106719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3106719</a>] [<a href="https://doi.org/10.1007/BF01799492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3106719">Rodes et al. (1987)</a> found that ornithine supplementation and restricted protein intake appeared to be useful in treatment of HHH syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3106719" 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="#30" class="mim-tip-reference" title="Wong, P., Lessick, M., Kang, S., Nelson, M. <strong>Maternal hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A14 only, 1989."None>Wong et al. (1989)</a> treated a woman with this disorder during pregnancy with lactulose and arginine to reduce blood ammonia. A normal offspring resulted, who developed normally and showed a full-scale IQ of 130 at age 5 years.</p>
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<p>Among 11 patients with the HHH syndrome, <a href="#3" class="mim-tip-reference" title="Camacho, J. A., Obie, C., Biery, B., Goodman, B. K., Hu, C.-A., Almashanu, S., Steel, G., Casey, R., Lambert, M., Mitchell, G. A., Valle, D. <strong>Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter.</strong> Nature Genet. 22: 151-158, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369256</a>] [<a href="https://doi.org/10.1038/9658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10369256">Camacho et al. (1999)</a> identified 2 mutations in the ORNT1 gene (see, e.g., F188del; <a href="/entry/603861#0001">603861.0001</a> and E180K; <a href="/entry/603861#0002">603861.0002</a>), and a larger deletion. The F188del mutation accounted for 19 of 20 possible mutant ORNT1 alleles among French Canadian patients, consistent with a founder effect in that population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369256" 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 Japanese patients with HHH syndrome, <a href="#19" class="mim-tip-reference" title="Miyamoto, T., Kanazawa, N., Kato, S., Kawakami, M., Inoue, Y., Kuhara, T., Inoue, T., Takeshita, K., Tsujino, S. <strong>Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X.</strong> J. Hum. Genet. 46: 260-262, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11355015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11355015</a>] [<a href="https://doi.org/10.1007/s100380170075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11355015">Miyamoto et al. (2001)</a> identified a homozygous mutation in the SLC25A15 gene (R179X; <a href="/entry/603861#0003">603861.0003</a>) substitution. One of the patients had previously been reported by <a href="#20" class="mim-tip-reference" title="Nakajima, M., Ishii, S., Mito, T., Takeshita, K., Takashima, S., Takakura, H., Inoue, I., Saheki, T., Akiyoshi, H., Ichihara, K. <strong>Clinical, biochemical and ultrastructural study on the pathogenesis of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.</strong> Brain Dev. 10: 181-185, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3407856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3407856</a>] [<a href="https://doi.org/10.1016/s0387-7604(88)80025-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3407856">Nakajima et al. (1988)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11355015+3407856" 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 Italian patients with HHH syndrome, <a href="#23" class="mim-tip-reference" title="Salvi, S., Santorelli, F. M., Bertini, E., Boldrini, R., Meli, C., Donati, A., Burlina, A. B., Rizzo, C., Di Capua, M., Fariello, G., Dionisi-Vici, C. <strong>Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.</strong> Neurology 57: 911-914, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11552031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11552031</a>] [<a href="https://doi.org/10.1212/wnl.57.5.911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11552031">Salvi et al. (2001)</a> identified 9 different mutations in the SLC25A15 gene, 7 of which were novel (see, e.g., <a href="/entry/603861#0004">603861.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11552031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Debray, F.-G., Lambert, M., Lemieux, B., Soucy, J. F., Drouin, R., Fenyves, D., Dube, J., Maranda, B., Laframboise, R., Mitchell, G. A. <strong>Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15.</strong> J. Med. Genet. 45: 759-764, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18978333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18978333</a>] [<a href="https://doi.org/10.1136/jmg.2008.059097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18978333">Debray et al. (2008)</a> noted that 22 different mutations of the SLC25A15 gene had been described in 49 patients from 31 unrelated families with HHH syndrome to date. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18978333" 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 16 patients from 13 unrelated families with HHH syndrome, <a href="#28" class="mim-tip-reference" title="Tessa, A., Fiermonte, G., Dionisi-Vici, C., Paradies, E., Baumgartner, M. R., Chien, Y.-H., Loguercio, C., de Baulny, H. O., Nassogne, M.-C., Schiff, M., Deodato, F., Parenti, G., and 12 others. <strong>Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study.</strong> Hum. Mutat. 30: 741-748, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19242930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19242930</a>] [<a href="https://doi.org/10.1002/humu.20930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19242930">Tessa et al. (2009)</a> identified 13 different mutations in the SLC25A15 gene, including 11 novel mutations (see, e.g., <a href="/entry/603861#0003">603861.0003</a>; <a href="/entry/603861#0006">603861.0006</a>-<a href="/entry/603861#0008">603861.0008</a>). In vitro functional expression assays showed mutant proteins with decreased transport activity between 4 and 19% of control values. There were no apparent genotype/phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19242930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Modifiers</em></strong></p><p>
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<a href="#4" class="mim-tip-reference" title="Camacho, J. A., Rioseco-Camacho, N., Andrade, D., Porter, J., Kong, J. <strong>Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder.</strong> Molec. Genet. Metab. 79: 257-271, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12948741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12948741</a>] [<a href="https://doi.org/10.1016/s1096-7192(03)00105-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12948741">Camacho et al. (2003)</a> identified ORNT2 (SLC25A2; <a href="/entry/608157">608157</a>), an intronless gene encoding a protein 88% identical to ORNT1. ORNT2 targets to mitochondria and is expressed in human liver, pancreas, kidney, and cultured fibroblasts from control and HHH patients. When ORNT2 was overexpressed transiently in cultured fibroblasts from HHH patients, it rescued the deficient ornithine metabolism in those cells. <a href="#4" class="mim-tip-reference" title="Camacho, J. A., Rioseco-Camacho, N., Andrade, D., Porter, J., Kong, J. <strong>Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder.</strong> Molec. Genet. Metab. 79: 257-271, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12948741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12948741</a>] [<a href="https://doi.org/10.1016/s1096-7192(03)00105-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12948741">Camacho et al. (2003)</a> suggested that expression of ORNT2 may in part be responsible for the milder phenotype in HHH patients secondary to a gene redundancy effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12948741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Camacho, J. A., Mardach, R., Rioseco-Camacho, N., Ruiz-Pesini, E., Derbeneva, O., Andrade, D., Zaldivar, F., Qu, Y., Cederbaum, S. D. <strong>Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.</strong> Pediat. Res. 60: 423-429, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16940241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16940241</a>] [<a href="https://doi.org/10.1203/01.pdr.0000238301.25938.f5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16940241">Camacho et al. (2006)</a> identified a homozygous mutation in the SLC25A15 gene (T32R; <a href="/entry/603861#0009">603861.0009</a>) in 5 affected members of 2 related families of Mexican descent with HHH syndrome. Overexpression studies showed that the mutant protein targeted normally to the mitochondrial and retained some residual activity. However, basal ornithine transport of primary untransfected patient fibroblasts showed loss of function; the observations were important, since they showed a discordance between the clinical and cellular phenotype in patients with HHH syndrome. The patients showed phenotypic variability, with 1 patient in particular having neurologic involvement, including poor school performance, low IQ (55), dysarthria, hyperreflexia, and cortical atrophy on MRI. This patient died from complications of hyperammonemic encephalopathy. The other patients had mild learning disabilities, but no neurologic deficits. Two patients with the mildest defects were found to be carriers for a gain of function val181-to-gly (V181G) polymorphism in the ORNT2 gene, whereas the members of the family who had the patient with the more severe phenotype had the wildtype val181 ORNT2 variant. The mitochondrial haplotypes of the 2 families also differed. <a href="#2" class="mim-tip-reference" title="Camacho, J. A., Mardach, R., Rioseco-Camacho, N., Ruiz-Pesini, E., Derbeneva, O., Andrade, D., Zaldivar, F., Qu, Y., Cederbaum, S. D. <strong>Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.</strong> Pediat. Res. 60: 423-429, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16940241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16940241</a>] [<a href="https://doi.org/10.1203/01.pdr.0000238301.25938.f5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16940241">Camacho et al. (2006)</a> suggested that the genotype of HHH patients cannot predict the clinical course of the disease, and that other modifying factors, such as gene redundancy or mitochondrial background may further influence the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16940241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Camacho, J. A., Rioseco-Camacho, N. <strong>The human and mouse SLC25A29 mitochondrial transporters rescue the deficient ornithine metabolism in fibroblasts of patients with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.</strong> Pediat. Res. 66: 35-41, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19287344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19287344</a>] [<a href="https://doi.org/10.1203/PDR.0b013e3181a283c1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19287344">Camacho and Rioseco-Camacho (2009)</a> found that mouse and human SLC25A29 (<a href="/entry/615064">615064</a>), a mitochondrial carnitine/acylcarnitine transporter, rescued defective ornithine metabolism in skin fibroblasts cultured from patients with HHH syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19287344" 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="#Eller1982" class="mim-tip-reference" title="Eller, A. G., Scott, D. F., Carter, A. L., Hommes, F. A. <strong>The synthesis of homocitrulline in the HHH-syndrome. (Abstract)</strong> Am. J. Hum. Genet. 34: 50A only, 1982.">Eller et al. (1982)</a>; <a href="#Fell1974" class="mim-tip-reference" title="Fell, V., Pollitt, R. J., Sampson, G. A., Wright, T. <strong>Ornithinemia, hyperammonemia, and homocitrullinuria: a disease associated with mental retardation and possibly caused by defective mitochondrial transport.</strong> Am. J. Dis. Child. 127: 752-756, 1974.">Fell et al. (1974)</a>; <a href="#Gray1982" class="mim-tip-reference" title="Gray, R. G. F., Hill, S. E., Pollitt, R. J. <strong>Reduced ornithine catabolism in cultured fibroblasts and phytohaemagglutinin-stimulated lymphocytes from a patient with hyperornithinaemia, hyperammonaemia and homocitrullinuria.</strong> Clin. Chim. Acta 118: 141-148, 1982.">Gray et al. (1982)</a>; <a href="#Gray1983" class="mim-tip-reference" title="Gray, R. G. F., Hill, S. E., Pollitt, R. J. <strong>Studies on the pathway from ornithine to proline in cultured skin fibroblasts with reference to the defect in hyperornithinaemia with hyperammonaemia and homocitrullinuria.</strong> J. Inherit. Metab. Dis. 6: 143-148, 1983.">Gray et
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al. (1983)</a>; <a href="#Haust1987" class="mim-tip-reference" title="Haust, M. D., Gordon, B. A. <strong>Possible pathogenetic mechanism in hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.</strong> Birth Defects Orig. Art. Ser. 23: 17-45, 1987.">Haust and Gordon (1987)</a>; <a href="#Oyanagi1983" class="mim-tip-reference" title="Oyanagi, K., Tsuchiyama, A., Itakura, Y., Sogawa, H., Wagatsuma, K., Nakao, T., Sakamoto, S., Yachi, A. <strong>The mechanism of hyperammonaemia and hyperornithinaemia in the syndrome of hyperornithinaemia, hyperammonaemia with homocitrullinuria.</strong> J. Inherit. Metab. Dis. 6: 133-134, 1983.">Oyanagi et al. (1983)</a>
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[<a href="https://doi.org/10.1203/01.pdr.0000238301.25938.f5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/9658" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1096-7192(03)00105-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/PDR.0b013e3181a283c1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320320228" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.059097" target="_blank">Full Text</a>]
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<a id="Dionisi Vici1987" class="mim-anchor"></a>
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Dionisi Vici, C., Bachmann, C., Gambarara, M., Colombo, J. P., Sabetta, G.
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<strong>Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: low creatine excretion and effect of citrulline, arginine, or ornithine supplement.</strong>
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[<a href="https://doi.org/10.1203/00006450-198709000-00025" target="_blank">Full Text</a>]
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Eller, A. G., Scott, D. F., Carter, A. L., Hommes, F. A.
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<strong>The synthesis of homocitrulline in the HHH-syndrome. (Abstract)</strong>
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Fell, V., Pollitt, R. J., Sampson, G. A., Wright, T.
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<strong>Ornithinemia, hyperammonemia, and homocitrullinuria: a disease associated with mental retardation and possibly caused by defective mitochondrial transport.</strong>
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[<a href="https://doi.org/10.1001/archpedi.1974.02110240138023" target="_blank">Full Text</a>]
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Gatfield, P. D., Taller, E., Wolfe, D. M., Haust, M. D.
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[<a href="https://doi.org/10.1203/00006450-197505000-00006" target="_blank">Full Text</a>]
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<strong>A new patient with hyperornithinaemia, hyperammonaemia and homocitrullinuria treated early with low protein diet.</strong>
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[<a href="https://doi.org/10.1007/BF01799457" target="_blank">Full Text</a>]
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<a id="Gray1982" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gray, R. G. F., Hill, S. E., Pollitt, R. J.
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<strong>Reduced ornithine catabolism in cultured fibroblasts and phytohaemagglutinin-stimulated lymphocytes from a patient with hyperornithinaemia, hyperammonaemia and homocitrullinuria.</strong>
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Clin. Chim. Acta 118: 141-148, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6120052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6120052</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6120052" 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/10.1016/0009-8981(82)90001-8" target="_blank">Full Text</a>]
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<a id="Gray1983" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gray, R. G. F., Hill, S. E., Pollitt, R. J.
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<strong>Studies on the pathway from ornithine to proline in cultured skin fibroblasts with reference to the defect in hyperornithinaemia with hyperammonaemia and homocitrullinuria.</strong>
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J. Inherit. Metab. Dis. 6: 143-148, 1983.
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[<a href="https://doi.org/10.1007/BF02310868" target="_blank">Full Text</a>]
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<a id="Haust1987" class="mim-anchor"></a>
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Haust, M. D., Gordon, B. A.
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<strong>Possible pathogenetic mechanism in hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.</strong>
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Birth Defects Orig. Art. Ser. 23: 17-45, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3580547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3580547</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3580547" 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-2008-1052499" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.37.11.1813" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0387-7604(88)80025-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01800748" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01799492" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.57.5.911" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/pd.1970120905" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-198512000-00016" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00005176-199211000-00011" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1990.00530100104022" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 03/11/2020
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<span class="mim-text-font">
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Ada Hamosh - updated : 1/8/2015<br>Patricia A. Hartz - updated : 1/30/2013<br>Cassandra L. Kniffin - updated : 10/19/2009<br>Cassandra L. Kniffin - updated : 8/18/2009<br>Cassandra L. Kniffin - updated : 12/18/2008<br>Ada Hamosh - updated : 10/9/2003<br>Cassandra L. Kniffin - updated : 7/10/2003<br>Victor A. McKusick - updated : 5/26/1999
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Victor A. McKusick : 6/3/1986
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 03/11/2020
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carol : 06/01/2016<br>alopez : 1/8/2015<br>mgross : 1/31/2013<br>mgross : 1/31/2013<br>terry : 1/30/2013<br>carol : 4/11/2011<br>carol : 4/8/2011<br>wwang : 11/12/2009<br>ckniffin : 10/19/2009<br>wwang : 9/4/2009<br>ckniffin : 8/18/2009<br>wwang : 7/29/2009<br>wwang : 2/5/2009<br>ckniffin : 12/18/2008<br>alopez : 10/9/2003<br>terry : 10/9/2003<br>carol : 7/14/2003<br>ckniffin : 7/10/2003<br>psherman : 7/29/1999<br>alopez : 6/4/1999<br>alopez : 6/1/1999<br>alopez : 5/27/1999<br>alopez : 5/27/1999<br>terry : 5/26/1999<br>terry : 3/8/1999<br>davew : 7/26/1994<br>jason : 6/16/1994<br>mimadm : 4/1/1994<br>carol : 2/18/1993<br>carol : 2/17/1993<br>carol : 1/12/1993
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<span class="mim-font">
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<strong>#</strong> 238970
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HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME; HHHS
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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HHH SYNDROME; HHH<br />
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ORNITHINE TRANSLOCASE DEFICIENCY
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<strong>SNOMEDCT:</strong> 30287008;
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<strong>ICD10CM:</strong> E72.4;
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<strong>ORPHA:</strong> 415;
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<strong>DO:</strong> 0050720;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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13q14.11
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<span class="mim-font">
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Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome
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<span class="mim-font">
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238970
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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SLC25A15
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603861
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (HHHS) is caused by homozygous mutation in the SLC25A15 gene (603861), which encodes the mitochondrial ornithine transporter, on chromosome 13q14.</p>
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<strong>Description</strong>
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<p>Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHHS) is an autosomal recessive, chronic and progressive disorder of the urea cycle with typical age of onset in early life. The acute phase is characterized by hyperammonemia accompanied by vomiting, ataxia, lethargy, confusion, and coma. Chronically, aversion to protein-rich foods, coagulation abnormalities, hypotonia, developmental delay, progressive encephalopathy with mental regression, and signs of motor dysfunction are present. About 95% of patients survive after diagnosis and therapy is established. However, in early adulthood most patients develop signs of pyramidal tract dysfunction (summary by Tessa et al., 2009). </p>
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<strong>Clinical Features</strong>
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<p>Shih et al. (1969) reported a child with mental retardation and myoclonic seizures associated with hyperornithinemia, hyperammonemia, and homocitrullinemia. The findings were consistent with an inherited disorder of amino acid metabolism. </p><p>Rodes et al. (1987) reported a family in which 2 brothers and a sister were affected with HHH syndrome. One patient had progressive spastic paraparesis. At least 2 of the individuals voluntarily avoided a high protein diet. </p><p>Dionisi Vici et al. (1987) found reports of 23 patients with HHH syndrome in the literature, only 1 of whom showed symptoms as a neonate. </p><p>Koike et al. (1987) reported Japanese brothers, aged 13 and 19 years, with HHH syndrome. The clinical picture included protein intolerance, mental retardation, seizures, and stuporous episodes. One patient had cerebellar ataxia, myoclonus, convulsive seizure, and muscular weakness in both legs. The older brother had refused to eat fish and meat, and had episodes of vomiting when fed a high-protein formula. Both brothers also had myoclonus epilepsy. </p><p>Nakajima et al. (1988) reported a Japanese child, born of healthy first-cousin parents, with HHH syndrome. Development was delayed in late infancy, and spastic paraplegia was noted at the age of 3 years. The patient always avoided the intake of meat, milk, and eggs. At age 10, he had an episode of lethargy and hyperammonemia. Brain CT showed diffuse white matter low density and atrophy of the cerebellar vermis. </p><p>Tuchman et al. (1990) described this disorder in a 39-year-old man and his 42-year-old sister, both vegetarians, who had had episodic confusion for many years, but normal mental function between these episodes. Hyperammonemia was documented during an episode of confusion in the male sib but not in his sister. During therapy with citrulline and phenylbutyrate sodium, plasma ornithine levels increased in both patients, while plasma levels of glutamine and alanine decreased to normal. With therapy, their clinical conditions improved and no recurrent neurologic dysfunction was observed over a follow-up period of 20 months. </p><p>Miyamoto et al. (2001) reported a 52-year-old woman who had spastic gait and cerebellar signs, including dysmetria, dysdiadochokinesis, and scanning speech, since adolescence, but did not have mental retardation. She had spastic paraparesis of the arms since age 27. Hyperammonemia was noted at the age of 36 years, and a protein-restricted diet and kanamycin were prescribed. At age 37, she had surgery to elongate Achilles tendons in both legs. The diagnosis of HHH syndrome was made at the age of 52, on the basis of hyperornithinemia and homocitrullinuria. </p><p>Salvi et al. (2001) reported a follow-up on 8 Italian patients who had been diagnosed with HHH syndrome. Age at onset ranged from infancy to 18 years. The predominant neurologic finding was spastic paraparesis, seen in 5 patients. The remaining 3 patients showed signs of pyramidal dysfunction, which the authors suggested may progress to spastic paraparesis later in life. Mental retardation and clonic movements were variably present. </p><p>Debray et al. (2008) reviewed the medical records of 16 French Canadian patients with HHH syndrome, 15 of whom were homozygous for the common F188del founder mutation in the SLC25A15 gene (603861.0001). Six of the patients had previously been reported by Lemay et al. (1992). The median age at presentation was 2.7 years (range, 3 months to 16 years). Common features included failure to thrive, developmental delay, liver dysfunction with secondary coagulation defects, hyperammonemia, hyperornithinemia, and abnormally increased liver enzymes. </p><p>Batshaw et al. (2014) reported the results of an analysis of 614 patients with urea cycle disorders (UCDs) enrolled in the Urea Cycle Disorders Consortium's longitudinal study protocol. HHH syndrome occurred in 9 patients (1.5%), 8 of whom had a late-onset form. </p>
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<strong>Biochemical Features</strong>
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<p>Hommes et al. (1986) reported what they considered to be the twelfth documented case of HHH syndrome. They showed that the uptake of ornithine by the particulate fraction of the patient's fibroblasts was abnormally low, but still measurable. This suggested a partial impairment of uptake of ornithine by mitochondria. </p><p>Rodes et al. (1987) found that cultured skin fibroblasts derived from patients with HHH syndrome showed 6 times less incorporation of labeled ornithine into protein as compared to control cells. Further studies were consistent with a defect in the transport of ornithine into the mitochondria. </p><p>Koike et al. (1987) found that isolated liver mitochondria in a patient with HHH syndrome showed decreased ornithine transport and citrulline synthesis, but urea cycle enzymes and ornithine aminotransferase were normal. Ornithine metabolism was also decreased in cultured skin fibroblasts. </p>
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<strong>Other Features</strong>
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<p>Dionisi Vici et al. (1987) reported 2 unrelated patients with neonatal onset of HHH syndrome. One of their patients also had deficiency of clotting factors VII (F7; 613878) and X (F10; 613872), both of which are linked to chromosome 13q. The same association had been described by Gatfield et al. (1975) and by Simell et al. (1985). Dionisi Vici et al. (1987) suggested that the mutation responsible for the HHH syndrome is located on 13q. </p><p>Smith et al. (1992), who stated that over 30 patients had been described, reported a 5-year-old French-Canadian girl with HHH syndrome who presented a clinical picture suggesting hepatitis associated with coagulopathy, initially thought to be acute viral hepatitis. </p><p>Lemay et al. (1992) described the clinical, electrophysiologic, ophthalmologic, and neuropsychologic features of 6 patients. Pyramidal signs, decreased vibration sense, buccofaciolingual dyspraxia, and learning difficulties or subnormal intelligence were found in most. Anomalies of peripheral nerve conduction velocity and of evoked potentials were common. In 1 patient, markedly abnormal white matter was demonstrated on cranial MRI. One patient had retinal depigmentation and chorioretinal thinning. Only 2 of the patients had had episodes of symptomatic hyperammonemia. The relationship of hyperammonemia to the chronic neuropsychologic problems of these patients was unclear. However, in a follow-up to these patients, Debray et al. (2008) noted that these patients showed no clinical signs of peripheral neuropathy. In addition, the patient with retinal depigmentation and chorioretinal thinning showed no deterioration and had normal visual function at age 22 years. </p>
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<strong>Inheritance</strong>
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<p>Autosomal recessive inheritance was supported by the large Canadian pedigree of Gatfield et al. (1975), with 6 affected persons of both sexes. </p>
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<strong>Diagnosis</strong>
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<p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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Chadefaux et al. (1989) suggested that the first-trimester diagnosis of HHHS can be achieved by study of the incorporation of (14)C-ornithine into proteins of chorionic villi. They referred to a case of untreated HHH syndrome in the mother being associated with a mentally retarded offspring. </p><p>Shih et al. (1992) described neonatal death in the HHH syndrome and successful prenatal diagnosis of the disorder in a subsequent pregnancy in this family. Thus, the severity ranges from minimal neurologic dysfunction in adulthood (Tuchman et al., 1990) to neonatal death. Diagnostic of the condition in amniotic cells was the combination of normal OAT activity and the inability of the cells to utilize ornithine. </p>
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<strong>Clinical Management</strong>
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<p>In the first case of HHH syndrome reported from Norway, Gjessing et al. (1986) found that a low protein diet initiated early in life permitted normal development. </p><p>Rodes et al. (1987) found that ornithine supplementation and restricted protein intake appeared to be useful in treatment of HHH syndrome. </p><p>Wong et al. (1989) treated a woman with this disorder during pregnancy with lactulose and arginine to reduce blood ammonia. A normal offspring resulted, who developed normally and showed a full-scale IQ of 130 at age 5 years.</p>
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<strong>Molecular Genetics</strong>
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<p>Among 11 patients with the HHH syndrome, Camacho et al. (1999) identified 2 mutations in the ORNT1 gene (see, e.g., F188del; 603861.0001 and E180K; 603861.0002), and a larger deletion. The F188del mutation accounted for 19 of 20 possible mutant ORNT1 alleles among French Canadian patients, consistent with a founder effect in that population. </p><p>In 2 unrelated Japanese patients with HHH syndrome, Miyamoto et al. (2001) identified a homozygous mutation in the SLC25A15 gene (R179X; 603861.0003) substitution. One of the patients had previously been reported by Nakajima et al. (1988). </p><p>In 8 Italian patients with HHH syndrome, Salvi et al. (2001) identified 9 different mutations in the SLC25A15 gene, 7 of which were novel (see, e.g., 603861.0004). </p><p>Debray et al. (2008) noted that 22 different mutations of the SLC25A15 gene had been described in 49 patients from 31 unrelated families with HHH syndrome to date. </p><p>In 16 patients from 13 unrelated families with HHH syndrome, Tessa et al. (2009) identified 13 different mutations in the SLC25A15 gene, including 11 novel mutations (see, e.g., 603861.0003; 603861.0006-603861.0008). In vitro functional expression assays showed mutant proteins with decreased transport activity between 4 and 19% of control values. There were no apparent genotype/phenotype correlations. </p><p><strong><em>Genetic Modifiers</em></strong></p><p>
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Camacho et al. (2003) identified ORNT2 (SLC25A2; 608157), an intronless gene encoding a protein 88% identical to ORNT1. ORNT2 targets to mitochondria and is expressed in human liver, pancreas, kidney, and cultured fibroblasts from control and HHH patients. When ORNT2 was overexpressed transiently in cultured fibroblasts from HHH patients, it rescued the deficient ornithine metabolism in those cells. Camacho et al. (2003) suggested that expression of ORNT2 may in part be responsible for the milder phenotype in HHH patients secondary to a gene redundancy effect. </p><p>Camacho et al. (2006) identified a homozygous mutation in the SLC25A15 gene (T32R; 603861.0009) in 5 affected members of 2 related families of Mexican descent with HHH syndrome. Overexpression studies showed that the mutant protein targeted normally to the mitochondrial and retained some residual activity. However, basal ornithine transport of primary untransfected patient fibroblasts showed loss of function; the observations were important, since they showed a discordance between the clinical and cellular phenotype in patients with HHH syndrome. The patients showed phenotypic variability, with 1 patient in particular having neurologic involvement, including poor school performance, low IQ (55), dysarthria, hyperreflexia, and cortical atrophy on MRI. This patient died from complications of hyperammonemic encephalopathy. The other patients had mild learning disabilities, but no neurologic deficits. Two patients with the mildest defects were found to be carriers for a gain of function val181-to-gly (V181G) polymorphism in the ORNT2 gene, whereas the members of the family who had the patient with the more severe phenotype had the wildtype val181 ORNT2 variant. The mitochondrial haplotypes of the 2 families also differed. Camacho et al. (2006) suggested that the genotype of HHH patients cannot predict the clinical course of the disease, and that other modifying factors, such as gene redundancy or mitochondrial background may further influence the phenotype. </p><p>Camacho and Rioseco-Camacho (2009) found that mouse and human SLC25A29 (615064), a mitochondrial carnitine/acylcarnitine transporter, rescued defective ornithine metabolism in skin fibroblasts cultured from patients with HHH syndrome. </p>
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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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Eller et al. (1982); Fell et al. (1974); Gray et al. (1982); Gray et
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al. (1983); Haust and Gordon (1987); Oyanagi et al. (1983)
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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<div>
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<p />
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<p class="mim-text-font">
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Batshaw, M. L., Tuchman, M., Summar, M., Seminara, J., Members of the Urea Cycle Disorders Consortium.
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<strong>A longitudinal study of urea cycle disorders.</strong>
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Molec. Genet. Metab. 113: 127-130, 2014.
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[PubMed: 25135652]
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[Full Text: https://doi.org/10.1016/j.ymgme.2014.08.001]
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<span class="text-nowrap mim-text-font">
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 03/11/2020<br>Ada Hamosh - updated : 1/8/2015<br>Patricia A. Hartz - updated : 1/30/2013<br>Cassandra L. Kniffin - updated : 10/19/2009<br>Cassandra L. Kniffin - updated : 8/18/2009<br>Cassandra L. Kniffin - updated : 12/18/2008<br>Ada Hamosh - updated : 10/9/2003<br>Cassandra L. Kniffin - updated : 7/10/2003<br>Victor A. McKusick - updated : 5/26/1999
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 6/3/1986
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