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- #207900 - ARGININOSUCCINIC ACIDURIA
- OMIM
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<span class="h4">#207900</span>
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/207900"><strong>Clinical Synopsis</strong></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="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<div><a href="https://clinicaltrials.gov/search?cond=ARGININOSUCCINIC ACIDURIA" 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>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=459&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 style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1217/" title="Urea Cycle Disorders Overview" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Urea Cycle Disorders Overv…</a></div><div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK51784/" title="Argininosuccinate Lyase Deficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Argininosuccinate Lyase De…</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Citrullinemia.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG ACT Sheet</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Citrulline-Algorithm.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG Algorithm</a></div>
</div>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=23" 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>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/b0af9309-4287-42df-b030-8b5aea3a80b0/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:14755" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/207900" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:207900" 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>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 41013004<br />
<strong>ORPHA:</strong> 23<br />
<strong>DO:</strong> 14755<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
207900
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
ARGININOSUCCINIC ACIDURIA
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
ARGININOSUCCINASE DEFICIENCY<br />
ARGININOSUCCINATE LYASE DEFICIENCY<br />
ASL DEFICIENCY<br />
ARGININOSUCCINIC ACID LYASE DEFICIENCY
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/298?start=-3&limit=10&highlight=298">
7q11.21
</a>
</span>
</td>
<td>
<span class="mim-font">
Argininosuccinic aciduria
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/207900"> 207900 </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">
ASL
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608310"> 608310 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/207900" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<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/207900" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/207900" 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">
- Hepatic fibrosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/62484002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">62484002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K74.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K74.00</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K74.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K74.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239946&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239946</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001395" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001395</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001395" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001395</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 /> -
Elevated serum glutamic oxaloacetic transaminase (SGOT) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3150119&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3150119</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031956" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031956</a>]</span><br /> -
Elevated serum glutamic pyruvic transaminase (SGPT) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3150120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3150120</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">
- Poor feeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/299698007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">299698007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78164000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0576456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0576456</a>, <a href="https://bioportal.bioontology.org/search?q=C0232466&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232466</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span><br /> -
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 /> -
Vomiting <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422400008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422400008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/300359004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">300359004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249497008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249497008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042963&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042963</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Hair </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Trichorrhexis nodosa <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/238736006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">238736006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L67.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L67.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0263485&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0263485</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009886" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009886</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009886" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009886</a>]</span><br /> -
Dry brittle hair <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859734&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859734</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">
- Ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20262006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20262006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39384006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39384006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.84</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004134</a>, <a href="https://bioportal.bioontology.org/search?q=C1135207&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1135207</a>, <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0010867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010867</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br /> -
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 /> -
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 /> -
Cerebral edema <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/2032001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">2032001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G93.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G93.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/348.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">348.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0006114&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0006114</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002181" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002181</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002181" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002181</a>]</span><br /> -
Developmental delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
Mental retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a>, <a href="https://bioportal.bioontology.org/search?q=C0025362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Irritability <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55929007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55929007</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.22</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0022107&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022107</a>, <a href="https://bioportal.bioontology.org/search?q=C2700617&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2700617</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000737" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000737</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000737" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000737</a>]</span><br /> -
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 />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> METABOLIC FEATURES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Episodic ammonia intoxication <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839541</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001951" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001951</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001951" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001951</a>]</span><br /> -
Respiratory alkalosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111378004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111378004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002064&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002064</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001950" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001950</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001950" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001950</a>]</span><br /> -
Arginine deficiency <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859735&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859735</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005961" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005961</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005961" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005961</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- 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 /> -
High plasma citrulline (100-300 micromolar) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859731&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859731</a>]</span><br /> -
High plasma glutamine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839533&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839533</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003217" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003217</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003217" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003217</a>]</span><br /> -
Hepatic argininosuccinase deficiency <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859732&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859732</a>]</span><br /> -
Argininosuccinicaciduria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/41013004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">41013004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268547&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268547</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025630" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025630</a>]</span><br /> -
Elevated serum glutamic oxaloacetic transaminase (SGOT) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3150119&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3150119</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031956" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031956</a>]</span><br /> -
Elevated serum glutamic pyruvic transaminase (SGPT) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3150120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3150120</a>]</span><br /> -
Orotic aciduria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/47641009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">47641009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/124277009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">124277009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/69525003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">69525003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268130&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268130</a>, <a href="https://bioportal.bioontology.org/search?q=C0268128&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268128</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003218</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003218</a>]</span><br />
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- Onset in neonatal period or infancy<br /> -
Prevalence is estimated to be 1 in 150,000<br />
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- Caused by mutation in the argininosuccinate lyase gene (ASL, <a href="/entry/608310#0001">608310.0001</a>)<br />
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<p>A number sign (#) is used with this entry because of evidence that argininosuccinic aciduria is caused by homozygous or compound heterozygous mutation in the gene encoding argininosuccinate lyase (ASL; <a href="/entry/608310">608310</a>) on chromosome 7q11.</p>
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<p>Argininosuccinic aciduria is an autosomal recessive disorder of the urea cycle. Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (<a href="/entry/311250">311250</a>), carbamyl phosphate synthetase deficiency (<a href="/entry/237300">237300</a>), argininosuccinate synthetase deficiency, or citrullinemia (<a href="/entry/215700">215700</a>), argininosuccinate lyase deficiency, and arginase deficiency (<a href="/entry/207800">207800</a>).</p><p><a href="#10" class="mim-tip-reference" title="Erez, A. &lt;strong&gt;Argininosuccinic aciduria: from a monogenic to a complex disorder.&lt;/strong&gt; Genet. Med. 15: 251-257, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23306800/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23306800&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2012.166&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23306800">Erez (2013)</a> reviewed argininosuccinic aciduria and progress in understanding it as a monogenic disorder that, like other inborn errors of metabolism, manifests as a multifactorial disorder at the phenotypic level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23306800" 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>Two forms of argininosuccinic aciduria have been recognized: an early-onset, or malignant, type and a late-onset type.</p><p>As originally described by <a href="#1" class="mim-tip-reference" title="Allan, J. D., Cusworth, D. C., Dent, C. E., Wilson, V. K. &lt;strong&gt;A disease, probably hereditary, characterized by severe mental deficiency and a constant gross abnormality of amino acid metabolism.&lt;/strong&gt; Lancet 271: 182-187, 1958. Note: Originally Volume I.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13503250/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13503250&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(58)90666-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13503250">Allan et al. (1958)</a>, onset of symptoms of argininosuccinic aciduria occurs in the first weeks of life. Features include mental and physical retardation, convulsions, episodic unconsciousness, liver enlargement, skin lesions, and dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red. <a href="#9" class="mim-tip-reference" title="Coryell, M. E., Hall, W. K., Thevaos, T. G., Welter, D. A., Gatz, A. J., Horton, B. F., Sisson, B. D., Looper, J. W., Jr., Farrow, R. T. &lt;strong&gt;Familial study of human enzyme defect, argininosuccinic aciduria.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 14: 307-312, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5836520/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5836520&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0006-291x(64)80001-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5836520">Coryell et al. (1964)</a> reported familial association of argininosuccinic aciduria. They noted that in the U.S., where arginine is probably supplied adequately by the usual diet, brittle hair may not occur as often as in Great Britain, where the average protein intake is less ample. <a href="#27" class="mim-tip-reference" title="Shih, V. E., Littlefield, J. W., Moser, H. W. &lt;strong&gt;Argininosuccinase deficiency in fibroblasts cultured from patients with argininosuccinic aciduria.&lt;/strong&gt; Biochem. Genet. 3: 81-83, 1969."None>Shih et al. (1969)</a> reported deficiency of argininosuccinase in cultured fibroblasts from patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13503250+5836520" 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="Lewis, P. D., Miller, A. L. &lt;strong&gt;Argininosuccinic aciduria: case report with neuropathological findings.&lt;/strong&gt; Brain 93: 413-422, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5422414/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5422414&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/93.2.413&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5422414">Lewis and Miller (1970)</a> described the neuropathologic changes in argininosuccinic aciduria. They noted that astrocyte transformation to Alzheimer type II glia may be a consistent feature of any form of hyperammonemia. Postmortem liver showed marked deficiency of argininosuccinate lyase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5422414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Asai, K., Ishii, S., Ohta, S., Furusho, K. &lt;strong&gt;Fatal hyperammonaemia in argininosuccinic aciduria following enflurane anaesthesia. (Letter)&lt;/strong&gt; Europ. J. Pediat. 157: 169-170, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9504797/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9504797&lt;/a&gt;]" pmid="9504797">Asai et al. (1998)</a> described fatal hyperammonemia in a child with argininosuccinic aciduria following enflurane anesthesia. The diagnosis of argininosuccinic aciduria had been made while the patient was hospitalized for febrile seizures at the age of 18 months. Plasma argininosuccinate was markedly elevated. Argininosuccinase activity was absent in her erythrocytes and was within the heterozygous range in both parents. Oral arginine supplementation and a low protein diet were started. At 13 years of age, the patient underwent an inguinal hernioplasty. The preoperative state was satisfactory except for hepatomegaly and mental retardation. All routine investigations were normal, including those for ammonia. During the second evening after operation, the patient became lethargic with frequent convulsions despite adequate levels of the 3 antiepileptics on which she had been maintained for many years. Despite intravenous hypertonic glucose and arginine supplementation, her ammonia level rose greatly and she became comatose. Despite repeated hemodialysis, she died on the sixth postoperative day. Hepatic findings were consistent with fatty changes. <a href="#3" class="mim-tip-reference" title="Asai, K., Ishii, S., Ohta, S., Furusho, K. &lt;strong&gt;Fatal hyperammonaemia in argininosuccinic aciduria following enflurane anaesthesia. (Letter)&lt;/strong&gt; Europ. J. Pediat. 157: 169-170, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9504797/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9504797&lt;/a&gt;]" pmid="9504797">Asai et al. (1998)</a> suggested that although it was tempting to conclude that only enflurane was directly responsible for the hyperammonemia in the patient and although this relationship was not proved beyond reasonable doubt, general anesthesia, including enflurane, should be avoided in patients with argininosuccinic aciduria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9504797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Kleijer, W. J., Garritsen, V. H., Linnebank, M., Mooyer, P., Huijmans, J. G. M., Mustonen, A., Simola, K. O. J., Arslan-Kirchner, M., Battini, R., Briones, P., Cardo, E., Mandel, H., Tschiedel, E., Wanders, R. J. A., Koch, H. G. &lt;strong&gt;Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in 5 unrelated families.&lt;/strong&gt; J. Inherit. Metab. Dis. 25: 399-410, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12408190/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12408190&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1020108002877&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12408190">Kleijer et al. (2002)</a> reported a biochemical variant of argininosuccinate lyase deficiency found in 5 individuals. In comparison to classic cases, the variant cases of argininosuccinate lyase deficiency were characterized by residual enzyme activity as measured by the incorporation of C-14-citrulline into proteins. The 5 patients of different ethnic backgrounds presented with relatively mild clinical symptoms, variable age of onset, marked argininosuccinic aciduria, and severe, but not complete, deficiency of argininosuccinate lyase. C14-citrulline incorporation into proteins, which is completely blocked in classic argininosuccinic aciduria, was only partially reduced in fibroblasts of these patients. All of these patients were found to have mutations in the ASL gene (see, e.g., <a href="/entry/608310#0004">608310.0004</a>-<a href="/entry/608310#0006">608310.0006</a>). The authors concluded that there are patients of different ethnic backgrounds who are characterized by residual activity of argininosuccinate lyase and who present with less severe clinical course. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12408190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Batshaw, M. L., Tuchman, M., Summar, M., Seminara, J., Members of the Urea Cycle Disorders Consortium. &lt;strong&gt;A longitudinal study of urea cycle disorders.&lt;/strong&gt; Molec. Genet. Metab. 113: 127-130, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25135652/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25135652&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2014.08.001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="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. Argininosuccinate lyase deficiency was found in 95 individuals (15.5%). The risk of mortality (neonatal plus late onset) was 6%. <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><p><a href="#14" class="mim-tip-reference" title="Kho, J., Tian, X., Wong, W.-T., Bertin, T., Jiang, M.-M., Chen, S., Jin, Z., Shchelochkov, O. A., Burrage, L. C., Reddy, A. K., Jiang, H., Abo-Zahrah, R., and 10 others. &lt;strong&gt;Argininosuccinate lyase deficiency causes an endothelial-dependent form of hypertension.&lt;/strong&gt; Am. J. Hum. Genet. 103: 276-287, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30075114/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30075114&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=30075114[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2018.07.008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30075114">Kho et al. (2018)</a> observed that among 8 children with ASLD, blood pressure values were significantly above the expected distribution from normal population values. The children were enrolled in a randomized clinical trial evaluating the effects of arginine therapy on hepatic function, and blood pressures were recorded daily over a 2-week period. Arginine therapy did not affect the blood pressure values. In vitro studies of human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from individuals with ASLD showed that loss of ASL in endothelial cells led to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) signaling, increased oxidative stress, and impaired angiogenesis. These results as well as observations in endothelial-specific Asl knockout mice (see ANIMAL MODEL) led <a href="#14" class="mim-tip-reference" title="Kho, J., Tian, X., Wong, W.-T., Bertin, T., Jiang, M.-M., Chen, S., Jin, Z., Shchelochkov, O. A., Burrage, L. C., Reddy, A. K., Jiang, H., Abo-Zahrah, R., and 10 others. &lt;strong&gt;Argininosuccinate lyase deficiency causes an endothelial-dependent form of hypertension.&lt;/strong&gt; Am. J. Hum. Genet. 103: 276-287, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30075114/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30075114&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=30075114[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2018.07.008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30075114">Kho et al. (2018)</a> to conclude that endothelial dysfunction is a primary driver of hypertension in ASLD, through the possible mechanisms of increased vascular tone and altered vascular structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30075114" 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="AlTassan, R., Bubshait, D., Imtiaz, F., Rahbeeni, Z. &lt;strong&gt;A retrospective biochemical, molecular, and neurocognitive review of Saudi patients with argininosuccinic aciduria.&lt;/strong&gt; Europ. J. Med. Genet. 61: 307-311, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29326055/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29326055&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ejmg.2018.01.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29326055">AlTassan et al. (2018)</a> described 54 Arab patients, aged 2 to 19 years, with argininosuccinic aciduria. Fifty of the patients were diagnosed during the neonatal period, 3 were diagnosed between 40 and 60 days of age, and one was diagnosed at 7 months of age. Hyperammonemia was present in 40 of the patients, and 23 patients were in a coma at presentation. Neurologic features, which were all reported in the first year of life, included seizures in 34 patients, hypotonia in 17 patients, and spasticity in 7 patients. Hepatomegaly was diagnosed in 29 patients, and elevated liver enzymes were seen in 41 patients. The frequency of hyperammonemic episodes in the patient cohort was variable, ranging between 0 and 8 episodes per year. All of the patients except 1 had at least 1 episode of elevated platelets. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29326055" 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="#34" class="mim-tip-reference" title="Zielonka, M., Garbade, S. F., Gleich, F., Okun, J. G., Nagamani, S. C. S., Gropman, A. L., Hoffmann, G. F., Kolker, S., Posset, R., Urea Cycle Disorders Consortium (UCDC), European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. &lt;strong&gt;From genotype to phenotype: early prediction of disease severity in argininosuccinic aciduria.&lt;/strong&gt; Hum. Mutat. 41: 946-960, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31943503/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31943503&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31943503[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.23983&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31943503">Zielonka et al. (2020)</a> compared molecular, clinical, and biochemical characteristics in 58 patients with argininosuccinic aciduria. Forty-two individual ASL gene mutations were identified in 42 different combinations in the 58 patients. The impact of each patient's ASL mutation combinations on gene expression, protein expression, and enzyme activity was determined in COS-7 cells transfected with plasmids encoding the mutant ASLs. Clinical features were then compared to residual enzymatic activities in the patients. Individuals with early-onset argininosuccinic aciduria showed lower ASL activities than patients with late-onset argininosuccinic aciduria. ASL enzyme activity was associated with the number of hyperammonemic episodes per year and maximum ammonia level during the most severe hyperammonemic decompensation. Patients with ASL activity below or equal to 24.3% performed worse on cognitive testing than individuals with ASL activity above 24.3%. Patients with ASL activity below or equal to 8.7% had more episodes of hepatocellular injury than patients with higher activity. The presence of movement disorders, abnormal muscular tone, and abnormal renal function was not associated with level of ASL enzyme activity. <a href="#34" class="mim-tip-reference" title="Zielonka, M., Garbade, S. F., Gleich, F., Okun, J. G., Nagamani, S. C. S., Gropman, A. L., Hoffmann, G. F., Kolker, S., Posset, R., Urea Cycle Disorders Consortium (UCDC), European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. &lt;strong&gt;From genotype to phenotype: early prediction of disease severity in argininosuccinic aciduria.&lt;/strong&gt; Hum. Mutat. 41: 946-960, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31943503/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31943503&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31943503[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.23983&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31943503">Zielonka et al. (2020)</a> concluded that determination of ASL enzymatic activity using the ASL-transfected COS-7 cell model can serve as an important marker of phenotypic severity in argininosuccinic aciduria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31943503" 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><strong><em>Prenatal Diagnosis</em></strong></p><p>
<a href="#25" class="mim-tip-reference" title="Pijpers, L., Kleijer, W. J., Reuss, A., Jahoda, M. G. J., Los, F. J., Sachs, E. S., Wladimiroff, J. W. &lt;strong&gt;Transabdominal chorionic villus sampling in a multiple pregnancy at risk of argininosuccinic aciduria: a case report.&lt;/strong&gt; Am. J. Med. Genet. 36: 449-450, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2389802/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2389802&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320360415&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2389802">Pijpers et al. (1990)</a> established the diagnosis of argininosuccinic aciduria in both fetuses of a dizygotic pregnancy, using transabdominal chorionic villus sampling at 10 weeks' gestation. <a href="#16" class="mim-tip-reference" title="Kleijer, W. J., Garritsen, V. H., Linnebank, M., Mooyer, P., Huijmans, J. G. M., Mustonen, A., Simola, K. O. J., Arslan-Kirchner, M., Battini, R., Briones, P., Cardo, E., Mandel, H., Tschiedel, E., Wanders, R. J. A., Koch, H. G. &lt;strong&gt;Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in 5 unrelated families.&lt;/strong&gt; J. Inherit. Metab. Dis. 25: 399-410, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12408190/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12408190&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1020108002877&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12408190">Kleijer et al. (2002)</a> performed successful molecular prenatal diagnosis in 3 affected families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12408190+2389802" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Brusilow, S. W., Batshaw, M. L. &lt;strong&gt;Arginine therapy of argininosuccinase deficiency.&lt;/strong&gt; Lancet 313: 124-127, 1979. Note: Originally Volume I.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/84150/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;84150&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(79)90518-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="84150">Brusilow and Batshaw (1979)</a> reported success with arginine treatment in argininosuccinase deficiency. The treatment favors the formation of argininosuccinic acid (ASA); since ASA contains the 2 waste nitrogen atoms later excreted in urea in healthy persons, and since it has a renal clearance similar to the glomerular filtration rate, the authors reasoned that hyperammonemia might be relieved by arginine therapy, provided stoichiometric amounts of ornithine are available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=84150" 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="Kvedar, J. C., Baden, H. P., Baden, L. A., Shih, V. E., Kolodny, E. H. &lt;strong&gt;Dietary management reverses grooving and abnormal polarization of hair shafts in argininosuccinase deficiency.&lt;/strong&gt; Am. J. Med. Genet. 40: 211-213, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1897577/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1897577&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320400218&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1897577">Kvedar et al. (1991)</a> observed 'normalization' of hair shafts after patients were treated with a low protein, arginine-supplemented diet. <a href="#33" class="mim-tip-reference" title="Widhalm, K., Koch, S., Scheibenreiter, S., Knoll, E., Colombo, J. P., Bachmann, C., Thalhammer, O. &lt;strong&gt;Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy.&lt;/strong&gt; Pediatrics 89: 1182-1184, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1594374/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1594374&lt;/a&gt;]" pmid="1594374">Widhalm et al. (1992)</a> described a follow-up of 12 Austrian children detected since 1973 in a national neonate screening program. All were managed with a daily arginine supplement in conjunction with either a normal diet or a special diet in which protein intake was restricted. They found that early treatment of partial argininosuccinate lyase deficiency resulted in normal intellectual and psychomotor development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1897577+1594374" 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>Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea cycle disorder, and leads to deficiency of both ureagenesis and nitric oxide (NO) production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In an ASA subject with severe hypertension refractory to antihypertensive medications, <a href="#24" class="mim-tip-reference" title="Nagamani, S. C. S., Campeau, P. M., Shchelochkov, O. A., Premkumar, M. H., Guse, K., Brunetti-Pierri, N., Chen, Y., Sun, Q., Tang, Y., Palmer, D., Reddy, A. K., Li, L., and 9 others. &lt;strong&gt;Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria.&lt;/strong&gt; Am. J. Hum. Genet. 90: 836-846, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22541557/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22541557&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22541557[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2012.03.018&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22541557">Nagamani et al. (2012)</a> showed that monotherapy with NO supplements (isosorbide dinitrate) resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychologic parameters pertaining to verbal memory and nonverbal problem solving. <a href="#24" class="mim-tip-reference" title="Nagamani, S. C. S., Campeau, P. M., Shchelochkov, O. A., Premkumar, M. H., Guse, K., Brunetti-Pierri, N., Chen, Y., Sun, Q., Tang, Y., Palmer, D., Reddy, A. K., Li, L., and 9 others. &lt;strong&gt;Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria.&lt;/strong&gt; Am. J. Hum. Genet. 90: 836-846, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22541557/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22541557&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22541557[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2012.03.018&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22541557">Nagamani et al. (2012)</a> concluded that ASA, in addition to being a classical urea cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation, which should be investigated for the long-term treatment of this condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22541557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<strong>Inheritance</strong>
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<p>The transmission pattern of argininoscuccinate lyase deficiency in the family reported by <a href="#32" class="mim-tip-reference" title="Walker, D. C., McCloskey, D. A., Simard, L. R., McInnes, R. R. &lt;strong&gt;Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region.&lt;/strong&gt; Proc. Nat. Acad. Sci. 87: 9625-9629, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2263616/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2263616&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.87.24.9625&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2263616">Walker et al. (1990)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2263616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Early Identification of Complementation Groups</em></strong></p><p>
In study of 5 cell lines from patients with argininosuccinate lyase deficiency, <a href="#7" class="mim-tip-reference" title="Cathelineau, L., Pham Dinh, D., Briand, P., Kamoun, P. &lt;strong&gt;Studies on complementation in argininosuccinate synthetase and argininosuccinate lyase deficiencies in human fibroblasts.&lt;/strong&gt; Hum. Genet. 57: 282-284, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7250970/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7250970&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00278945&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7250970">Cathelineau et al. (1981)</a> observed 2 complementation groups. Since the restoration of activity was not total, the complementation was assumed to be intragenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7250970" 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="McInnes, R. R., Shih, V., Chilton, S. &lt;strong&gt;Interallelic complementation in an inborn error of metabolism: genetic heterogeneity in argininosuccinate lyase deficiency.&lt;/strong&gt; Proc. Nat. Acad. Sci. 81: 4480-4484, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6589607/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6589607&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.81.14.4480&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6589607">McInnes et al. (1984)</a> performed complementation analysis in a search for genetic heterogeneity in this disorder. In 20 of 28 fibroblast strains cultured from patients with ASL deficiency, partial complementation was observed, with 2- to 10-fold increases in lyase activity. The data suggested that all the mutants were affected at a single locus, which the authors suggested was the structural gene coding for that enzyme. <a href="#22" class="mim-tip-reference" title="McInnes, R. R., Shih, V., Chilton, S. &lt;strong&gt;Interallelic complementation in an inborn error of metabolism: genetic heterogeneity in argininosuccinate lyase deficiency.&lt;/strong&gt; Proc. Nat. Acad. Sci. 81: 4480-4484, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6589607/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6589607&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.81.14.4480&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6589607">McInnes et al. (1984)</a> presented a complementation map of the gene. The authors noted that there are few examples of interallelic complementation in human genetics: galactosemia (<a href="/entry/230400">230400</a>) and propionyl-CoA-carboxylase deficiency (<a href="/entry/606054">606054</a>) are among them. ASL is a homotetramer; in microorganisms, interallelic complementation has been found to be almost universal at loci coding for homomultimeric proteins. The same group (<a href="#28" class="mim-tip-reference" title="Simard, L., O&#x27;Brien, W. E., McInnes, R. R. &lt;strong&gt;Argininosuccinate lyase deficiency: evidence for heterogeneous structural gene mutations by immunoblotting.&lt;/strong&gt; Am. J. Hum. Genet. 39: 38-51, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3752080/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3752080&lt;/a&gt;]" pmid="3752080">Simard et al., 1986</a>) found differing levels of ASL cross-reactive material (CRM) in different fibroblast lines, suggesting the presence of multiple lyase mutant monomers and mutations underlying ASL deficiency. Many of these mutants were indistinguishable by clinical, enzymatic, or complementation analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3752080+6589607" 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 15 unrelated patients who were compound heterozygotes for mutations at the ASL locus, <a href="#21" class="mim-tip-reference" title="Linnebank, M., Tschiedel, E., Haberle, J., Linnebank, A., Willenbring, H., Kleijer, W. J., Koch, H. G. &lt;strong&gt;Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene.&lt;/strong&gt; Hum. Genet. 111: 350-359, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12384776/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12384776&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-002-0793-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12384776">Linnebank et al. (2002)</a> could find no evidence that interallelic complementation plays a major role for modifying biochemical phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12384776" 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>Disease-Causing Mutations</em></strong></p><p>
In a patient with ASL deficiency, born of a consanguineous mating, <a href="#32" class="mim-tip-reference" title="Walker, D. C., McCloskey, D. A., Simard, L. R., McInnes, R. R. &lt;strong&gt;Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region.&lt;/strong&gt; Proc. Nat. Acad. Sci. 87: 9625-9629, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2263616/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2263616&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.87.24.9625&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2263616">Walker et al. (1990)</a> identified a homozygous mutation in the ASL gene (<a href="/entry/608310#0001">608310.0001</a>). The residual activity of the mutant enzyme was about 1%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2263616" 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 27 unrelated patients with ASL deficiency, <a href="#21" class="mim-tip-reference" title="Linnebank, M., Tschiedel, E., Haberle, J., Linnebank, A., Willenbring, H., Kleijer, W. J., Koch, H. G. &lt;strong&gt;Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene.&lt;/strong&gt; Hum. Genet. 111: 350-359, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12384776/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12384776&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-002-0793-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12384776">Linnebank et al. (2002)</a> identified 23 different mutations, 19 novel, in the ASL gene. Fifteen of the 54 alleles had an IVS5+1G-A splice site mutation (<a href="/entry/608310#0003">608310.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12384776" 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 5 patients with a biochemical variant of ASL deficiency in which there was residual enzyme activity and mild clinical symptoms, <a href="#16" class="mim-tip-reference" title="Kleijer, W. J., Garritsen, V. H., Linnebank, M., Mooyer, P., Huijmans, J. G. M., Mustonen, A., Simola, K. O. J., Arslan-Kirchner, M., Battini, R., Briones, P., Cardo, E., Mandel, H., Tschiedel, E., Wanders, R. J. A., Koch, H. G. &lt;strong&gt;Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in 5 unrelated families.&lt;/strong&gt; J. Inherit. Metab. Dis. 25: 399-410, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12408190/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12408190&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1020108002877&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12408190">Kleijer et al. (2002)</a> identified several mutations in the ASL gene. R385C (<a href="/entry/608310#0004">608310.0004</a>), V178M (<a href="/entry/608310#0005">608310.0005</a>), and R379C (<a href="/entry/608310#0006">608310.0006</a>) were detected in homozygous states, whereas 1 patient was compound heterozygous for 2 known mutations, including Q286R (<a href="/entry/608310#0002">608310.0002</a>). Prenatal diagnosis was successfully performed in 3 of the families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12408190" 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="Trevisson, E., Salviati, L., Baldoin, M. C., Toldo, I., Casarin, A., Sacconi, S., Cesaro, L., Basso, G., Burlina, A. B. &lt;strong&gt;Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene.&lt;/strong&gt; Hum. Mutat. 28: 694-702, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17326097/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17326097&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20498&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17326097">Trevisson et al. (2007)</a> identified 16 different mutations in the ASL gene, including 14 novel mutations, in 12 Italian patients from 10 families with ASL deficiency. All patients tested, except 1, had less than 5% residual enzyme activity. Mutations were scattered throughout the gene, but there were no genotype/phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17326097" 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="AlTassan, R., Bubshait, D., Imtiaz, F., Rahbeeni, Z. &lt;strong&gt;A retrospective biochemical, molecular, and neurocognitive review of Saudi patients with argininosuccinic aciduria.&lt;/strong&gt; Europ. J. Med. Genet. 61: 307-311, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29326055/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29326055&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ejmg.2018.01.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29326055">AlTassan et al. (2018)</a> identified homozygous mutations in the ASL gene in 35 Arab patients with ASL deficiency, including 26 patients with the same nonsense mutation (Q354X; <a href="/entry/608310#0007">608310.0007</a>), 7 with an R186W missense mutation, and 2 with different splice site mutations. All of the patients had elevated plasma and urine argininosuccinic acid and plasma citrulline. Hyperammonemia episodes were observed to be more frequent in patients with the Q354X mutation compared to patients with the other mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29326055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="populationGenetics" class="mim-anchor"></a>
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<strong>Population Genetics</strong>
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<p>The prevalence of argininosuccinic aciduria is estimated to be 1 in 150,000 (<a href="#29" class="mim-tip-reference" title="Testai, F. D., Gorelick, P. B. &lt;strong&gt;Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders.&lt;/strong&gt; Arch. Neurol. 67: 148-153, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20142522/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20142522&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2009.333&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20142522">Testai and Gorelick, 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20142522" 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 endothelial-specific Asl conditional knockout mice, <a href="#14" class="mim-tip-reference" title="Kho, J., Tian, X., Wong, W.-T., Bertin, T., Jiang, M.-M., Chen, S., Jin, Z., Shchelochkov, O. A., Burrage, L. C., Reddy, A. K., Jiang, H., Abo-Zahrah, R., and 10 others. &lt;strong&gt;Argininosuccinate lyase deficiency causes an endothelial-dependent form of hypertension.&lt;/strong&gt; Am. J. Hum. Genet. 103: 276-287, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30075114/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30075114&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=30075114[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2018.07.008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30075114">Kho et al. (2018)</a> observed elevated blood pressure compared to wildtype littermates. Preconstricted aortic rings showed impaired acetylcholine-induced endothelial-dependent relaxation. Indicators of liver and kidney dysfunction in blood chemistry panels were normal. Treatment with sodium nitrite, a nitric oxide synthase (NOS)-dependent NO source, prevented the development of hypertension in Asl conditional knockout mice, demonstrating that systemic replacement can correct the cell-autonomous deficiency in endothelial cells. <a href="#14" class="mim-tip-reference" title="Kho, J., Tian, X., Wong, W.-T., Bertin, T., Jiang, M.-M., Chen, S., Jin, Z., Shchelochkov, O. A., Burrage, L. C., Reddy, A. K., Jiang, H., Abo-Zahrah, R., and 10 others. &lt;strong&gt;Argininosuccinate lyase deficiency causes an endothelial-dependent form of hypertension.&lt;/strong&gt; Am. J. Hum. Genet. 103: 276-287, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30075114/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30075114&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=30075114[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2018.07.008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30075114">Kho et al. (2018)</a> concluded that the results suggested that the development of hypertension in ASLD is endothelial-dependent and is driven at least in part by NO deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30075114" 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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<strong>See Also:</strong>
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<a href="#Bohles1978" class="mim-tip-reference" title="Bohles, H., Heid, H., Harms, D., Schmid, D., Fekl, W. &lt;strong&gt;Argininosuccinic aciduria: metabolic studies and effects of treatment with keto-analogues of essential amino acids.&lt;/strong&gt; Europ. J. Pediat. 128: 225-233, 1978.">Bohles et al. (1978)</a>; <a href="#Collins1980" class="mim-tip-reference" title="Collins, F. S., Summer, G. K., Schwartz, R. P., Parke, J. C., Jr. &lt;strong&gt;Neonatal argininosuccinic aciduria--survival after early diagnosis and dietary management.&lt;/strong&gt; J. Pediat. 96: 429-431, 1980.">Collins et al. (1980)</a>; <a href="#Fleisher1979" class="mim-tip-reference" title="Fleisher, L. D., Rassin, D. K., Desnick, R. J., Salwen, H. R., Rogers, P., Bean, M., Gaull, G. E. &lt;strong&gt;Argininosuccinic aciduria: prenatal studies in a family at risk.&lt;/strong&gt; Am. J. Hum. Genet. 31: 439-445, 1979.">Fleisher et al. (1979)</a>; <a href="#Glick1976" class="mim-tip-reference" title="Glick, N. R., Snodgrass, P. J., Schafer, I. A. &lt;strong&gt;Neonatal argininosuccinic aciduria with normal brain and kidney but absent liver argininosuccinate lyase activity.&lt;/strong&gt; Am. J. Hum. Genet. 28: 22-30, 1976.">Glick et al. (1976)</a>; <a href="#Goodman1973" class="mim-tip-reference" title="Goodman, S. I., Mace, J. W., Turner, B., Garrett, W. J. &lt;strong&gt;Antenatal diagnosis of argininosuccinic aciduria.&lt;/strong&gt; Clin. Genet. 4: 236-240, 1973.">Goodman et al. (1973)</a>; <a href="#Kint1968" class="mim-tip-reference" title="Kint, J. A., Carton, D. &lt;strong&gt;Deficient argininosuccinase activity in brain in argininosuccinicaciduria. (Letter)&lt;/strong&gt; Lancet 292: 635 only, 1968. Note: Originally Volume II.">Kint and Carton (1968)</a>; <a href="#Levin1961" class="mim-tip-reference" title="Levin, B., MacKay, H. M., Oberholzer, V. G. &lt;strong&gt;Argininosuccinic aciduria: an inborn error of amino acid metabolism.&lt;/strong&gt; Arch. Dis. Child. 36: 622-632, 1961.">Levin et al. (1961)</a>; <a href="#Levin1967" class="mim-tip-reference" title="Levin, B. &lt;strong&gt;Argininosuccinic aciduria.&lt;/strong&gt; Am. J. Dis. Child. 113: 162-165, 1967.">Levin (1967)</a>; <a href="#Moser1967" class="mim-tip-reference" title="Moser, H. W., Efron, M. L., Brown, H., Diamond, R., Neumann, C. G. &lt;strong&gt;Argininosuccinic aciduria: report of two cases and demonstration of intermittent elevation of blood ammonia.&lt;/strong&gt; Am. J. Med. 42: 9-26, 1967.">Moser et al. (1967)</a>; <a href="#Qureshi1978" class="mim-tip-reference" title="Qureshi, I. A., Letarte, J., Ouellet, R., Lemieux, B. &lt;strong&gt;Enzymologic and metabolic studies in two families affected by argininosuccinic aciduria.&lt;/strong&gt; Pediat. Res. 12: 256-262, 1978.">Qureshi et
al. (1978)</a>; <a href="#Van1976" class="mim-tip-reference" title="Van der Heiden, C., Gerards, L. J., van Biervliet, J. P. G. M., Desplanque, J., DeBree, P. K., Van Sprang, F. J., Wadman, S. K. &lt;strong&gt;Lethal neonatal argininosuccinate lyase deficiency in four children from one sibship.&lt;/strong&gt; Helv. Paediat. Acta 31: 407-417, 1976.">Van der Heiden et al. (1976)</a>
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<a id="references"class="mim-anchor"></a>
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<a id="1" class="mim-anchor"></a>
<a id="Allan1958" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Allan, J. D., Cusworth, D. C., Dent, C. E., Wilson, V. K.
<strong>A disease, probably hereditary, characterized by severe mental deficiency and a constant gross abnormality of amino acid metabolism.</strong>
Lancet 271: 182-187, 1958. Note: Originally Volume I.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13503250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13503250</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13503250" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0140-6736(58)90666-4" target="_blank">Full Text</a>]
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<a id="AlTassan2018" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
AlTassan, R., Bubshait, D., Imtiaz, F., Rahbeeni, Z.
<strong>A retrospective biochemical, molecular, and neurocognitive review of Saudi patients with argininosuccinic aciduria.</strong>
Europ. J. Med. Genet. 61: 307-311, 2018.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29326055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29326055</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29326055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ejmg.2018.01.007" target="_blank">Full Text</a>]
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<a id="Asai1998" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Asai, K., Ishii, S., Ohta, S., Furusho, K.
<strong>Fatal hyperammonaemia in argininosuccinic aciduria following enflurane anaesthesia. (Letter)</strong>
Europ. J. Pediat. 157: 169-170, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9504797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9504797</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9504797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="4" class="mim-anchor"></a>
<a id="Batshaw2014" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
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://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'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ymgme.2014.08.001" target="_blank">Full Text</a>]
</p>
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<a id="5" class="mim-anchor"></a>
<a id="Bohles1978" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bohles, H., Heid, H., Harms, D., Schmid, D., Fekl, W.
<strong>Argininosuccinic aciduria: metabolic studies and effects of treatment with keto-analogues of essential amino acids.</strong>
Europ. J. Pediat. 128: 225-233, 1978.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/668730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">668730</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=668730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00445607" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
<a id="Brusilow1979" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Brusilow, S. W., Batshaw, M. L.
<strong>Arginine therapy of argininosuccinase deficiency.</strong>
Lancet 313: 124-127, 1979. Note: Originally Volume I.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/84150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">84150</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=84150" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0140-6736(79)90518-x" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
<a id="Cathelineau1981" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Cathelineau, L., Pham Dinh, D., Briand, P., Kamoun, P.
<strong>Studies on complementation in argininosuccinate synthetase and argininosuccinate lyase deficiencies in human fibroblasts.</strong>
Hum. Genet. 57: 282-284, 1981.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7250970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7250970</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7250970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00278945" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
<a id="Collins1980" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Collins, F. S., Summer, G. K., Schwartz, R. P., Parke, J. C., Jr.
<strong>Neonatal argininosuccinic aciduria--survival after early diagnosis and dietary management.</strong>
J. Pediat. 96: 429-431, 1980.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7359236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7359236</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7359236" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(80)80688-3" target="_blank">Full Text</a>]
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<a id="Coryell1964" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Coryell, M. E., Hall, W. K., Thevaos, T. G., Welter, D. A., Gatz, A. J., Horton, B. F., Sisson, B. D., Looper, J. W., Jr., Farrow, R. T.
<strong>Familial study of human enzyme defect, argininosuccinic aciduria.</strong>
Biochem. Biophys. Res. Commun. 14: 307-312, 1964.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5836520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5836520</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5836520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0006-291x(64)80001-2" target="_blank">Full Text</a>]
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<a id="Erez2013" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Erez, A.
<strong>Argininosuccinic aciduria: from a monogenic to a complex disorder.</strong>
Genet. Med. 15: 251-257, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23306800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23306800</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23306800" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/gim.2012.166" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
<a id="Fleisher1979" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Fleisher, L. D., Rassin, D. K., Desnick, R. J., Salwen, H. R., Rogers, P., Bean, M., Gaull, G. E.
<strong>Argininosuccinic aciduria: prenatal studies in a family at risk.</strong>
Am. J. Hum. Genet. 31: 439-445, 1979.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/484552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">484552</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=484552" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="12" class="mim-anchor"></a>
<a id="Glick1976" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Glick, N. R., Snodgrass, P. J., Schafer, I. A.
<strong>Neonatal argininosuccinic aciduria with normal brain and kidney but absent liver argininosuccinate lyase activity.</strong>
Am. J. Hum. Genet. 28: 22-30, 1976.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/174426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">174426</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=174426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="13" class="mim-anchor"></a>
<a id="Goodman1973" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Goodman, S. I., Mace, J. W., Turner, B., Garrett, W. J.
<strong>Antenatal diagnosis of argininosuccinic aciduria.</strong>
Clin. Genet. 4: 236-240, 1973.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4765206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4765206</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4765206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.1973.tb01148.x" target="_blank">Full Text</a>]
</p>
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<a id="14" class="mim-anchor"></a>
<a id="Kho2018" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kho, J., Tian, X., Wong, W.-T., Bertin, T., Jiang, M.-M., Chen, S., Jin, Z., Shchelochkov, O. A., Burrage, L. C., Reddy, A. K., Jiang, H., Abo-Zahrah, R., and 10 others.
<strong>Argininosuccinate lyase deficiency causes an endothelial-dependent form of hypertension.</strong>
Am. J. Hum. Genet. 103: 276-287, 2018.
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[<a href="https://doi.org/10.1016/j.ajhg.2018.07.008" target="_blank">Full Text</a>]
</p>
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<a id="15" class="mim-anchor"></a>
<a id="Kint1968" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kint, J. A., Carton, D.
<strong>Deficient argininosuccinase activity in brain in argininosuccinicaciduria. (Letter)</strong>
Lancet 292: 635 only, 1968. Note: Originally Volume II.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4175179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4175179</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4175179" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0140-6736(68)90724-1" target="_blank">Full Text</a>]
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<a id="Kleijer2002" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kleijer, W. J., Garritsen, V. H., Linnebank, M., Mooyer, P., Huijmans, J. G. M., Mustonen, A., Simola, K. O. J., Arslan-Kirchner, M., Battini, R., Briones, P., Cardo, E., Mandel, H., Tschiedel, E., Wanders, R. J. A., Koch, H. G.
<strong>Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in 5 unrelated families.</strong>
J. Inherit. Metab. Dis. 25: 399-410, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12408190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12408190</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12408190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1023/a:1020108002877" target="_blank">Full Text</a>]
</p>
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<a id="17" class="mim-anchor"></a>
<a id="Kvedar1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kvedar, J. C., Baden, H. P., Baden, L. A., Shih, V. E., Kolodny, E. H.
<strong>Dietary management reverses grooving and abnormal polarization of hair shafts in argininosuccinase deficiency.</strong>
Am. J. Med. Genet. 40: 211-213, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1897577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1897577</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1897577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320400218" target="_blank">Full Text</a>]
</p>
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<a id="18" class="mim-anchor"></a>
<a id="Levin1961" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Levin, B., MacKay, H. M., Oberholzer, V. G.
<strong>Argininosuccinic aciduria: an inborn error of amino acid metabolism.</strong>
Arch. Dis. Child. 36: 622-632, 1961.
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[<a href="https://doi.org/10.1136/adc.36.190.622" target="_blank">Full Text</a>]
</p>
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<a id="19" class="mim-anchor"></a>
<a id="Levin1967" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Levin, B.
<strong>Argininosuccinic aciduria.</strong>
Am. J. Dis. Child. 113: 162-165, 1967.
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</p>
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<a id="20" class="mim-anchor"></a>
<a id="Lewis1970" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lewis, P. D., Miller, A. L.
<strong>Argininosuccinic aciduria: case report with neuropathological findings.</strong>
Brain 93: 413-422, 1970.
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[<a href="https://doi.org/10.1093/brain/93.2.413" target="_blank">Full Text</a>]
</p>
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<a id="21" class="mim-anchor"></a>
<a id="Linnebank2002" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Linnebank, M., Tschiedel, E., Haberle, J., Linnebank, A., Willenbring, H., Kleijer, W. J., Koch, H. G.
<strong>Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene.</strong>
Hum. Genet. 111: 350-359, 2002.
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[<a href="https://doi.org/10.1007/s00439-002-0793-4" target="_blank">Full Text</a>]
</p>
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<a id="22" class="mim-anchor"></a>
<a id="McInnes1984" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
McInnes, R. R., Shih, V., Chilton, S.
<strong>Interallelic complementation in an inborn error of metabolism: genetic heterogeneity in argininosuccinate lyase deficiency.</strong>
Proc. Nat. Acad. Sci. 81: 4480-4484, 1984.
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[<a href="https://doi.org/10.1073/pnas.81.14.4480" target="_blank">Full Text</a>]
</p>
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<a id="23" class="mim-anchor"></a>
<a id="Moser1967" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Moser, H. W., Efron, M. L., Brown, H., Diamond, R., Neumann, C. G.
<strong>Argininosuccinic aciduria: report of two cases and demonstration of intermittent elevation of blood ammonia.</strong>
Am. J. Med. 42: 9-26, 1967.
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[<a href="https://doi.org/10.1016/0002-9343(67)90003-4" target="_blank">Full Text</a>]
</p>
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<a id="Nagamani2012" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Nagamani, S. C. S., Campeau, P. M., Shchelochkov, O. A., Premkumar, M. H., Guse, K., Brunetti-Pierri, N., Chen, Y., Sun, Q., Tang, Y., Palmer, D., Reddy, A. K., Li, L., and 9 others.
<strong>Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria.</strong>
Am. J. Hum. Genet. 90: 836-846, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22541557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22541557</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22541557[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22541557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ajhg.2012.03.018" target="_blank">Full Text</a>]
</p>
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<a id="25" class="mim-anchor"></a>
<a id="Pijpers1990" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Pijpers, L., Kleijer, W. J., Reuss, A., Jahoda, M. G. J., Los, F. J., Sachs, E. S., Wladimiroff, J. W.
<strong>Transabdominal chorionic villus sampling in a multiple pregnancy at risk of argininosuccinic aciduria: a case report.</strong>
Am. J. Med. Genet. 36: 449-450, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2389802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2389802</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2389802" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320360415" target="_blank">Full Text</a>]
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<a id="26" class="mim-anchor"></a>
<a id="Qureshi1978" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Qureshi, I. A., Letarte, J., Ouellet, R., Lemieux, B.
<strong>Enzymologic and metabolic studies in two families affected by argininosuccinic aciduria.</strong>
Pediat. Res. 12: 256-262, 1978.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/652408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">652408</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=652408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1203/00006450-197804000-00002" target="_blank">Full Text</a>]
</p>
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<a id="27" class="mim-anchor"></a>
<a id="Shih1969" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Shih, V. E., Littlefield, J. W., Moser, H. W.
<strong>Argininosuccinase deficiency in fibroblasts cultured from patients with argininosuccinic aciduria.</strong>
Biochem. Genet. 3: 81-83, 1969.
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<a id="Simard1986" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Simard, L., O'Brien, W. E., McInnes, R. R.
<strong>Argininosuccinate lyase deficiency: evidence for heterogeneous structural gene mutations by immunoblotting.</strong>
Am. J. Hum. Genet. 39: 38-51, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3752080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3752080</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3752080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="29" class="mim-anchor"></a>
<a id="Testai2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Testai, F. D., Gorelick, P. B.
<strong>Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders.</strong>
Arch. Neurol. 67: 148-153, 2010.
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[<a href="https://doi.org/10.1001/archneurol.2009.333" target="_blank">Full Text</a>]
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<a id="30" class="mim-anchor"></a>
<a id="Trevisson2007" class="mim-anchor"></a>
<div class="">
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Trevisson, E., Salviati, L., Baldoin, M. C., Toldo, I., Casarin, A., Sacconi, S., Cesaro, L., Basso, G., Burlina, A. B.
<strong>Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene.</strong>
Hum. Mutat. 28: 694-702, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17326097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17326097</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17326097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/humu.20498" target="_blank">Full Text</a>]
</p>
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<a id="31" class="mim-anchor"></a>
<a id="Van der Heiden1976" class="mim-anchor"></a>
<div class="">
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Van der Heiden, C., Gerards, L. J., van Biervliet, J. P. G. M., Desplanque, J., DeBree, P. K., Van Sprang, F. J., Wadman, S. K.
<strong>Lethal neonatal argininosuccinate lyase deficiency in four children from one sibship.</strong>
Helv. Paediat. Acta 31: 407-417, 1976.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1017984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1017984</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1017984" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="32" class="mim-anchor"></a>
<a id="Walker1990" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Walker, D. C., McCloskey, D. A., Simard, L. R., McInnes, R. R.
<strong>Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region.</strong>
Proc. Nat. Acad. Sci. 87: 9625-9629, 1990.
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[<a href="https://doi.org/10.1073/pnas.87.24.9625" target="_blank">Full Text</a>]
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<a id="Widhalm1992" class="mim-anchor"></a>
<div class="">
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Widhalm, K., Koch, S., Scheibenreiter, S., Knoll, E., Colombo, J. P., Bachmann, C., Thalhammer, O.
<strong>Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy.</strong>
Pediatrics 89: 1182-1184, 1992.
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<a id="34" class="mim-anchor"></a>
<a id="Zielonka2020" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zielonka, M., Garbade, S. F., Gleich, F., Okun, J. G., Nagamani, S. C. S., Gropman, A. L., Hoffmann, G. F., Kolker, S., Posset, R., Urea Cycle Disorders Consortium (UCDC), European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group.
<strong>From genotype to phenotype: early prediction of disease severity in argininosuccinic aciduria.</strong>
Hum. Mutat. 41: 946-960, 2020.
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[<a href="https://doi.org/10.1002/humu.23983" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 11/22/2021
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Ada Hamosh - updated : 09/05/2018<br>Ada Hamosh - updated : 1/8/2015<br>Ada Hamosh - updated : 5/1/2013<br>Ada Hamosh - updated : 7/25/2012<br>Cassandra L. Kniffin - updated : 10/11/2010<br>Cassandra L. Kniffin - updated : 8/20/2007<br>Cassandra L. Kniffin - reorganized : 12/4/2003<br>Ada Hamosh - updated : 10/7/2003<br>Victor A. McKusick - updated : 11/13/2002<br>Victor A. McKusick - updated : 5/3/1999<br>Victor A. McKusick - updated : 11/2/1998
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Victor A. McKusick : 6/23/1986
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alopez : 04/04/2024
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<h3>
<span class="mim-font">
<strong>#</strong> 207900
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<span class="mim-font">
ARGININOSUCCINIC ACIDURIA
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<span class="mim-font">
<em>Alternative titles; symbols</em>
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<span class="mim-font">
ARGININOSUCCINASE DEFICIENCY<br />
ARGININOSUCCINATE LYASE DEFICIENCY<br />
ASL DEFICIENCY<br />
ARGININOSUCCINIC ACID LYASE DEFICIENCY
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<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 41013004; &nbsp;
<strong>ORPHA:</strong> 23; &nbsp;
<strong>DO:</strong> 14755; &nbsp;
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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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<td>
<span class="mim-font">
7q11.21
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Argininosuccinic aciduria
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207900
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Autosomal recessive
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3
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ASL
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<span class="mim-font">
608310
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that argininosuccinic aciduria is caused by homozygous or compound heterozygous mutation in the gene encoding argininosuccinate lyase (ASL; 608310) on chromosome 7q11.</p>
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<strong>Description</strong>
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<p>Argininosuccinic aciduria is an autosomal recessive disorder of the urea cycle. Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (311250), carbamyl phosphate synthetase deficiency (237300), argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency, and arginase deficiency (207800).</p><p>Erez (2013) reviewed argininosuccinic aciduria and progress in understanding it as a monogenic disorder that, like other inborn errors of metabolism, manifests as a multifactorial disorder at the phenotypic level. </p>
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<strong>Clinical Features</strong>
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<p>Two forms of argininosuccinic aciduria have been recognized: an early-onset, or malignant, type and a late-onset type.</p><p>As originally described by Allan et al. (1958), onset of symptoms of argininosuccinic aciduria occurs in the first weeks of life. Features include mental and physical retardation, convulsions, episodic unconsciousness, liver enlargement, skin lesions, and dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red. Coryell et al. (1964) reported familial association of argininosuccinic aciduria. They noted that in the U.S., where arginine is probably supplied adequately by the usual diet, brittle hair may not occur as often as in Great Britain, where the average protein intake is less ample. Shih et al. (1969) reported deficiency of argininosuccinase in cultured fibroblasts from patients. </p><p>Lewis and Miller (1970) described the neuropathologic changes in argininosuccinic aciduria. They noted that astrocyte transformation to Alzheimer type II glia may be a consistent feature of any form of hyperammonemia. Postmortem liver showed marked deficiency of argininosuccinate lyase. </p><p>Asai et al. (1998) described fatal hyperammonemia in a child with argininosuccinic aciduria following enflurane anesthesia. The diagnosis of argininosuccinic aciduria had been made while the patient was hospitalized for febrile seizures at the age of 18 months. Plasma argininosuccinate was markedly elevated. Argininosuccinase activity was absent in her erythrocytes and was within the heterozygous range in both parents. Oral arginine supplementation and a low protein diet were started. At 13 years of age, the patient underwent an inguinal hernioplasty. The preoperative state was satisfactory except for hepatomegaly and mental retardation. All routine investigations were normal, including those for ammonia. During the second evening after operation, the patient became lethargic with frequent convulsions despite adequate levels of the 3 antiepileptics on which she had been maintained for many years. Despite intravenous hypertonic glucose and arginine supplementation, her ammonia level rose greatly and she became comatose. Despite repeated hemodialysis, she died on the sixth postoperative day. Hepatic findings were consistent with fatty changes. Asai et al. (1998) suggested that although it was tempting to conclude that only enflurane was directly responsible for the hyperammonemia in the patient and although this relationship was not proved beyond reasonable doubt, general anesthesia, including enflurane, should be avoided in patients with argininosuccinic aciduria. </p><p>Kleijer et al. (2002) reported a biochemical variant of argininosuccinate lyase deficiency found in 5 individuals. In comparison to classic cases, the variant cases of argininosuccinate lyase deficiency were characterized by residual enzyme activity as measured by the incorporation of C-14-citrulline into proteins. The 5 patients of different ethnic backgrounds presented with relatively mild clinical symptoms, variable age of onset, marked argininosuccinic aciduria, and severe, but not complete, deficiency of argininosuccinate lyase. C14-citrulline incorporation into proteins, which is completely blocked in classic argininosuccinic aciduria, was only partially reduced in fibroblasts of these patients. All of these patients were found to have mutations in the ASL gene (see, e.g., 608310.0004-608310.0006). The authors concluded that there are patients of different ethnic backgrounds who are characterized by residual activity of argininosuccinate lyase and who present with less severe clinical course. </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. Argininosuccinate lyase deficiency was found in 95 individuals (15.5%). The risk of mortality (neonatal plus late onset) was 6%. </p><p>Kho et al. (2018) observed that among 8 children with ASLD, blood pressure values were significantly above the expected distribution from normal population values. The children were enrolled in a randomized clinical trial evaluating the effects of arginine therapy on hepatic function, and blood pressures were recorded daily over a 2-week period. Arginine therapy did not affect the blood pressure values. In vitro studies of human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from individuals with ASLD showed that loss of ASL in endothelial cells led to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) signaling, increased oxidative stress, and impaired angiogenesis. These results as well as observations in endothelial-specific Asl knockout mice (see ANIMAL MODEL) led Kho et al. (2018) to conclude that endothelial dysfunction is a primary driver of hypertension in ASLD, through the possible mechanisms of increased vascular tone and altered vascular structure. </p><p>AlTassan et al. (2018) described 54 Arab patients, aged 2 to 19 years, with argininosuccinic aciduria. Fifty of the patients were diagnosed during the neonatal period, 3 were diagnosed between 40 and 60 days of age, and one was diagnosed at 7 months of age. Hyperammonemia was present in 40 of the patients, and 23 patients were in a coma at presentation. Neurologic features, which were all reported in the first year of life, included seizures in 34 patients, hypotonia in 17 patients, and spasticity in 7 patients. Hepatomegaly was diagnosed in 29 patients, and elevated liver enzymes were seen in 41 patients. The frequency of hyperammonemic episodes in the patient cohort was variable, ranging between 0 and 8 episodes per year. All of the patients except 1 had at least 1 episode of elevated platelets. </p>
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<strong>Biochemical Features</strong>
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<p>Zielonka et al. (2020) compared molecular, clinical, and biochemical characteristics in 58 patients with argininosuccinic aciduria. Forty-two individual ASL gene mutations were identified in 42 different combinations in the 58 patients. The impact of each patient's ASL mutation combinations on gene expression, protein expression, and enzyme activity was determined in COS-7 cells transfected with plasmids encoding the mutant ASLs. Clinical features were then compared to residual enzymatic activities in the patients. Individuals with early-onset argininosuccinic aciduria showed lower ASL activities than patients with late-onset argininosuccinic aciduria. ASL enzyme activity was associated with the number of hyperammonemic episodes per year and maximum ammonia level during the most severe hyperammonemic decompensation. Patients with ASL activity below or equal to 24.3% performed worse on cognitive testing than individuals with ASL activity above 24.3%. Patients with ASL activity below or equal to 8.7% had more episodes of hepatocellular injury than patients with higher activity. The presence of movement disorders, abnormal muscular tone, and abnormal renal function was not associated with level of ASL enzyme activity. Zielonka et al. (2020) concluded that determination of ASL enzymatic activity using the ASL-transfected COS-7 cell model can serve as an important marker of phenotypic severity in argininosuccinic aciduria. </p>
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<strong>Diagnosis</strong>
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<p><strong><em>Prenatal Diagnosis</em></strong></p><p>
Pijpers et al. (1990) established the diagnosis of argininosuccinic aciduria in both fetuses of a dizygotic pregnancy, using transabdominal chorionic villus sampling at 10 weeks' gestation. Kleijer et al. (2002) performed successful molecular prenatal diagnosis in 3 affected families. </p>
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<strong>Clinical Management</strong>
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<p>Brusilow and Batshaw (1979) reported success with arginine treatment in argininosuccinase deficiency. The treatment favors the formation of argininosuccinic acid (ASA); since ASA contains the 2 waste nitrogen atoms later excreted in urea in healthy persons, and since it has a renal clearance similar to the glomerular filtration rate, the authors reasoned that hyperammonemia might be relieved by arginine therapy, provided stoichiometric amounts of ornithine are available. </p><p>Kvedar et al. (1991) observed 'normalization' of hair shafts after patients were treated with a low protein, arginine-supplemented diet. Widhalm et al. (1992) described a follow-up of 12 Austrian children detected since 1973 in a national neonate screening program. All were managed with a daily arginine supplement in conjunction with either a normal diet or a special diet in which protein intake was restricted. They found that early treatment of partial argininosuccinate lyase deficiency resulted in normal intellectual and psychomotor development. </p><p>Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea cycle disorder, and leads to deficiency of both ureagenesis and nitric oxide (NO) production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In an ASA subject with severe hypertension refractory to antihypertensive medications, Nagamani et al. (2012) showed that monotherapy with NO supplements (isosorbide dinitrate) resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychologic parameters pertaining to verbal memory and nonverbal problem solving. Nagamani et al. (2012) concluded that ASA, in addition to being a classical urea cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation, which should be investigated for the long-term treatment of this condition. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of argininoscuccinate lyase deficiency in the family reported by Walker et al. (1990) was consistent with autosomal recessive inheritance. </p>
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<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
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<p><strong><em>Early Identification of Complementation Groups</em></strong></p><p>
In study of 5 cell lines from patients with argininosuccinate lyase deficiency, Cathelineau et al. (1981) observed 2 complementation groups. Since the restoration of activity was not total, the complementation was assumed to be intragenic. </p><p>McInnes et al. (1984) performed complementation analysis in a search for genetic heterogeneity in this disorder. In 20 of 28 fibroblast strains cultured from patients with ASL deficiency, partial complementation was observed, with 2- to 10-fold increases in lyase activity. The data suggested that all the mutants were affected at a single locus, which the authors suggested was the structural gene coding for that enzyme. McInnes et al. (1984) presented a complementation map of the gene. The authors noted that there are few examples of interallelic complementation in human genetics: galactosemia (230400) and propionyl-CoA-carboxylase deficiency (606054) are among them. ASL is a homotetramer; in microorganisms, interallelic complementation has been found to be almost universal at loci coding for homomultimeric proteins. The same group (Simard et al., 1986) found differing levels of ASL cross-reactive material (CRM) in different fibroblast lines, suggesting the presence of multiple lyase mutant monomers and mutations underlying ASL deficiency. Many of these mutants were indistinguishable by clinical, enzymatic, or complementation analysis. </p><p>In 15 unrelated patients who were compound heterozygotes for mutations at the ASL locus, Linnebank et al. (2002) could find no evidence that interallelic complementation plays a major role for modifying biochemical phenotypes. </p><p><strong><em>Disease-Causing Mutations</em></strong></p><p>
In a patient with ASL deficiency, born of a consanguineous mating, Walker et al. (1990) identified a homozygous mutation in the ASL gene (608310.0001). The residual activity of the mutant enzyme was about 1%. </p><p>In 27 unrelated patients with ASL deficiency, Linnebank et al. (2002) identified 23 different mutations, 19 novel, in the ASL gene. Fifteen of the 54 alleles had an IVS5+1G-A splice site mutation (608310.0003). </p><p>In 5 patients with a biochemical variant of ASL deficiency in which there was residual enzyme activity and mild clinical symptoms, Kleijer et al. (2002) identified several mutations in the ASL gene. R385C (608310.0004), V178M (608310.0005), and R379C (608310.0006) were detected in homozygous states, whereas 1 patient was compound heterozygous for 2 known mutations, including Q286R (608310.0002). Prenatal diagnosis was successfully performed in 3 of the families. </p><p>Trevisson et al. (2007) identified 16 different mutations in the ASL gene, including 14 novel mutations, in 12 Italian patients from 10 families with ASL deficiency. All patients tested, except 1, had less than 5% residual enzyme activity. Mutations were scattered throughout the gene, but there were no genotype/phenotype correlations. </p><p>AlTassan et al. (2018) identified homozygous mutations in the ASL gene in 35 Arab patients with ASL deficiency, including 26 patients with the same nonsense mutation (Q354X; 608310.0007), 7 with an R186W missense mutation, and 2 with different splice site mutations. All of the patients had elevated plasma and urine argininosuccinic acid and plasma citrulline. Hyperammonemia episodes were observed to be more frequent in patients with the Q354X mutation compared to patients with the other mutations. </p>
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<strong>Population Genetics</strong>
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<p>The prevalence of argininosuccinic aciduria is estimated to be 1 in 150,000 (Testai and Gorelick, 2010). </p>
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<strong>Animal Model</strong>
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<p>In endothelial-specific Asl conditional knockout mice, Kho et al. (2018) observed elevated blood pressure compared to wildtype littermates. Preconstricted aortic rings showed impaired acetylcholine-induced endothelial-dependent relaxation. Indicators of liver and kidney dysfunction in blood chemistry panels were normal. Treatment with sodium nitrite, a nitric oxide synthase (NOS)-dependent NO source, prevented the development of hypertension in Asl conditional knockout mice, demonstrating that systemic replacement can correct the cell-autonomous deficiency in endothelial cells. Kho et al. (2018) concluded that the results suggested that the development of hypertension in ASLD is endothelial-dependent and is driven at least in part by NO deficiency. </p>
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<h4>
<span class="mim-font">
<strong>See Also:</strong>
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<span class="mim-text-font">
Bohles et al. (1978); Collins et al. (1980); Fleisher et al. (1979);
Glick et al. (1976); Goodman et al. (1973); Kint and Carton (1968);
Levin et al. (1961); Levin (1967); Moser et al. (1967); Qureshi et
al. (1978); Van der Heiden et al. (1976)
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<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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<ol>
<li>
<p class="mim-text-font">
Allan, J. D., Cusworth, D. C., Dent, C. E., Wilson, V. K.
<strong>A disease, probably hereditary, characterized by severe mental deficiency and a constant gross abnormality of amino acid metabolism.</strong>
Lancet 271: 182-187, 1958. Note: Originally Volume I.
[PubMed: 13503250]
[Full Text: https://doi.org/10.1016/s0140-6736(58)90666-4]
</p>
</li>
<li>
<p class="mim-text-font">
AlTassan, R., Bubshait, D., Imtiaz, F., Rahbeeni, Z.
<strong>A retrospective biochemical, molecular, and neurocognitive review of Saudi patients with argininosuccinic aciduria.</strong>
Europ. J. Med. Genet. 61: 307-311, 2018.
[PubMed: 29326055]
[Full Text: https://doi.org/10.1016/j.ejmg.2018.01.007]
</p>
</li>
<li>
<p class="mim-text-font">
Asai, K., Ishii, S., Ohta, S., Furusho, K.
<strong>Fatal hyperammonaemia in argininosuccinic aciduria following enflurane anaesthesia. (Letter)</strong>
Europ. J. Pediat. 157: 169-170, 1998.
[PubMed: 9504797]
</p>
</li>
<li>
<p class="mim-text-font">
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: 25135652]
[Full Text: https://doi.org/10.1016/j.ymgme.2014.08.001]
</p>
</li>
<li>
<p class="mim-text-font">
Bohles, H., Heid, H., Harms, D., Schmid, D., Fekl, W.
<strong>Argininosuccinic aciduria: metabolic studies and effects of treatment with keto-analogues of essential amino acids.</strong>
Europ. J. Pediat. 128: 225-233, 1978.
[PubMed: 668730]
[Full Text: https://doi.org/10.1007/BF00445607]
</p>
</li>
<li>
<p class="mim-text-font">
Brusilow, S. W., Batshaw, M. L.
<strong>Arginine therapy of argininosuccinase deficiency.</strong>
Lancet 313: 124-127, 1979. Note: Originally Volume I.
[PubMed: 84150]
[Full Text: https://doi.org/10.1016/s0140-6736(79)90518-x]
</p>
</li>
<li>
<p class="mim-text-font">
Cathelineau, L., Pham Dinh, D., Briand, P., Kamoun, P.
<strong>Studies on complementation in argininosuccinate synthetase and argininosuccinate lyase deficiencies in human fibroblasts.</strong>
Hum. Genet. 57: 282-284, 1981.
[PubMed: 7250970]
[Full Text: https://doi.org/10.1007/BF00278945]
</p>
</li>
<li>
<p class="mim-text-font">
Collins, F. S., Summer, G. K., Schwartz, R. P., Parke, J. C., Jr.
<strong>Neonatal argininosuccinic aciduria--survival after early diagnosis and dietary management.</strong>
J. Pediat. 96: 429-431, 1980.
[PubMed: 7359236]
[Full Text: https://doi.org/10.1016/s0022-3476(80)80688-3]
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</li>
<li>
<p class="mim-text-font">
Coryell, M. E., Hall, W. K., Thevaos, T. G., Welter, D. A., Gatz, A. J., Horton, B. F., Sisson, B. D., Looper, J. W., Jr., Farrow, R. T.
<strong>Familial study of human enzyme defect, argininosuccinic aciduria.</strong>
Biochem. Biophys. Res. Commun. 14: 307-312, 1964.
[PubMed: 5836520]
[Full Text: https://doi.org/10.1016/s0006-291x(64)80001-2]
</p>
</li>
<li>
<p class="mim-text-font">
Erez, A.
<strong>Argininosuccinic aciduria: from a monogenic to a complex disorder.</strong>
Genet. Med. 15: 251-257, 2013.
[PubMed: 23306800]
[Full Text: https://doi.org/10.1038/gim.2012.166]
</p>
</li>
<li>
<p class="mim-text-font">
Fleisher, L. D., Rassin, D. K., Desnick, R. J., Salwen, H. R., Rogers, P., Bean, M., Gaull, G. E.
<strong>Argininosuccinic aciduria: prenatal studies in a family at risk.</strong>
Am. J. Hum. Genet. 31: 439-445, 1979.
[PubMed: 484552]
</p>
</li>
<li>
<p class="mim-text-font">
Glick, N. R., Snodgrass, P. J., Schafer, I. A.
<strong>Neonatal argininosuccinic aciduria with normal brain and kidney but absent liver argininosuccinate lyase activity.</strong>
Am. J. Hum. Genet. 28: 22-30, 1976.
[PubMed: 174426]
</p>
</li>
<li>
<p class="mim-text-font">
Goodman, S. I., Mace, J. W., Turner, B., Garrett, W. J.
<strong>Antenatal diagnosis of argininosuccinic aciduria.</strong>
Clin. Genet. 4: 236-240, 1973.
[PubMed: 4765206]
[Full Text: https://doi.org/10.1111/j.1399-0004.1973.tb01148.x]
</p>
</li>
<li>
<p class="mim-text-font">
Kho, J., Tian, X., Wong, W.-T., Bertin, T., Jiang, M.-M., Chen, S., Jin, Z., Shchelochkov, O. A., Burrage, L. C., Reddy, A. K., Jiang, H., Abo-Zahrah, R., and 10 others.
<strong>Argininosuccinate lyase deficiency causes an endothelial-dependent form of hypertension.</strong>
Am. J. Hum. Genet. 103: 276-287, 2018.
[PubMed: 30075114]
[Full Text: https://doi.org/10.1016/j.ajhg.2018.07.008]
</p>
</li>
<li>
<p class="mim-text-font">
Kint, J. A., Carton, D.
<strong>Deficient argininosuccinase activity in brain in argininosuccinicaciduria. (Letter)</strong>
Lancet 292: 635 only, 1968. Note: Originally Volume II.
[PubMed: 4175179]
[Full Text: https://doi.org/10.1016/s0140-6736(68)90724-1]
</p>
</li>
<li>
<p class="mim-text-font">
Kleijer, W. J., Garritsen, V. H., Linnebank, M., Mooyer, P., Huijmans, J. G. M., Mustonen, A., Simola, K. O. J., Arslan-Kirchner, M., Battini, R., Briones, P., Cardo, E., Mandel, H., Tschiedel, E., Wanders, R. J. A., Koch, H. G.
<strong>Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in 5 unrelated families.</strong>
J. Inherit. Metab. Dis. 25: 399-410, 2002.
[PubMed: 12408190]
[Full Text: https://doi.org/10.1023/a:1020108002877]
</p>
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<p class="mim-text-font">
Kvedar, J. C., Baden, H. P., Baden, L. A., Shih, V. E., Kolodny, E. H.
<strong>Dietary management reverses grooving and abnormal polarization of hair shafts in argininosuccinase deficiency.</strong>
Am. J. Med. Genet. 40: 211-213, 1991.
[PubMed: 1897577]
[Full Text: https://doi.org/10.1002/ajmg.1320400218]
</p>
</li>
<li>
<p class="mim-text-font">
Levin, B., MacKay, H. M., Oberholzer, V. G.
<strong>Argininosuccinic aciduria: an inborn error of amino acid metabolism.</strong>
Arch. Dis. Child. 36: 622-632, 1961.
[PubMed: 14464548]
[Full Text: https://doi.org/10.1136/adc.36.190.622]
</p>
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<li>
<p class="mim-text-font">
Levin, B.
<strong>Argininosuccinic aciduria.</strong>
Am. J. Dis. Child. 113: 162-165, 1967.
[PubMed: 6015896]
</p>
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<li>
<p class="mim-text-font">
Lewis, P. D., Miller, A. L.
<strong>Argininosuccinic aciduria: case report with neuropathological findings.</strong>
Brain 93: 413-422, 1970.
[PubMed: 5422414]
[Full Text: https://doi.org/10.1093/brain/93.2.413]
</p>
</li>
<li>
<p class="mim-text-font">
Linnebank, M., Tschiedel, E., Haberle, J., Linnebank, A., Willenbring, H., Kleijer, W. J., Koch, H. G.
<strong>Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene.</strong>
Hum. Genet. 111: 350-359, 2002.
[PubMed: 12384776]
[Full Text: https://doi.org/10.1007/s00439-002-0793-4]
</p>
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<li>
<p class="mim-text-font">
McInnes, R. R., Shih, V., Chilton, S.
<strong>Interallelic complementation in an inborn error of metabolism: genetic heterogeneity in argininosuccinate lyase deficiency.</strong>
Proc. Nat. Acad. Sci. 81: 4480-4484, 1984.
[PubMed: 6589607]
[Full Text: https://doi.org/10.1073/pnas.81.14.4480]
</p>
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<p class="mim-text-font">
Moser, H. W., Efron, M. L., Brown, H., Diamond, R., Neumann, C. G.
<strong>Argininosuccinic aciduria: report of two cases and demonstration of intermittent elevation of blood ammonia.</strong>
Am. J. Med. 42: 9-26, 1967.
[PubMed: 6016480]
[Full Text: https://doi.org/10.1016/0002-9343(67)90003-4]
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Nagamani, S. C. S., Campeau, P. M., Shchelochkov, O. A., Premkumar, M. H., Guse, K., Brunetti-Pierri, N., Chen, Y., Sun, Q., Tang, Y., Palmer, D., Reddy, A. K., Li, L., and 9 others.
<strong>Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria.</strong>
Am. J. Hum. Genet. 90: 836-846, 2012.
[PubMed: 22541557]
[Full Text: https://doi.org/10.1016/j.ajhg.2012.03.018]
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Pijpers, L., Kleijer, W. J., Reuss, A., Jahoda, M. G. J., Los, F. J., Sachs, E. S., Wladimiroff, J. W.
<strong>Transabdominal chorionic villus sampling in a multiple pregnancy at risk of argininosuccinic aciduria: a case report.</strong>
Am. J. Med. Genet. 36: 449-450, 1990.
[PubMed: 2389802]
[Full Text: https://doi.org/10.1002/ajmg.1320360415]
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Qureshi, I. A., Letarte, J., Ouellet, R., Lemieux, B.
<strong>Enzymologic and metabolic studies in two families affected by argininosuccinic aciduria.</strong>
Pediat. Res. 12: 256-262, 1978.
[PubMed: 652408]
[Full Text: https://doi.org/10.1203/00006450-197804000-00002]
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Shih, V. E., Littlefield, J. W., Moser, H. W.
<strong>Argininosuccinase deficiency in fibroblasts cultured from patients with argininosuccinic aciduria.</strong>
Biochem. Genet. 3: 81-83, 1969.
</p>
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<li>
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Simard, L., O'Brien, W. E., McInnes, R. R.
<strong>Argininosuccinate lyase deficiency: evidence for heterogeneous structural gene mutations by immunoblotting.</strong>
Am. J. Hum. Genet. 39: 38-51, 1986.
[PubMed: 3752080]
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Testai, F. D., Gorelick, P. B.
<strong>Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders.</strong>
Arch. Neurol. 67: 148-153, 2010.
[PubMed: 20142522]
[Full Text: https://doi.org/10.1001/archneurol.2009.333]
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Trevisson, E., Salviati, L., Baldoin, M. C., Toldo, I., Casarin, A., Sacconi, S., Cesaro, L., Basso, G., Burlina, A. B.
<strong>Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene.</strong>
Hum. Mutat. 28: 694-702, 2007.
[PubMed: 17326097]
[Full Text: https://doi.org/10.1002/humu.20498]
</p>
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Van der Heiden, C., Gerards, L. J., van Biervliet, J. P. G. M., Desplanque, J., DeBree, P. K., Van Sprang, F. J., Wadman, S. K.
<strong>Lethal neonatal argininosuccinate lyase deficiency in four children from one sibship.</strong>
Helv. Paediat. Acta 31: 407-417, 1976.
[PubMed: 1017984]
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Walker, D. C., McCloskey, D. A., Simard, L. R., McInnes, R. R.
<strong>Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region.</strong>
Proc. Nat. Acad. Sci. 87: 9625-9629, 1990.
[PubMed: 2263616]
[Full Text: https://doi.org/10.1073/pnas.87.24.9625]
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Widhalm, K., Koch, S., Scheibenreiter, S., Knoll, E., Colombo, J. P., Bachmann, C., Thalhammer, O.
<strong>Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy.</strong>
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[PubMed: 1594374]
</p>
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Zielonka, M., Garbade, S. F., Gleich, F., Okun, J. G., Nagamani, S. C. S., Gropman, A. L., Hoffmann, G. F., Kolker, S., Posset, R., Urea Cycle Disorders Consortium (UCDC), European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group.
<strong>From genotype to phenotype: early prediction of disease severity in argininosuccinic aciduria.</strong>
Hum. Mutat. 41: 946-960, 2020.
[PubMed: 31943503]
[Full Text: https://doi.org/10.1002/humu.23983]
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Hilary J. Vernon - updated : 11/22/2021<br>Ada Hamosh - updated : 09/05/2018<br>Ada Hamosh - updated : 1/8/2015<br>Ada Hamosh - updated : 5/1/2013<br>Ada Hamosh - updated : 7/25/2012<br>Cassandra L. Kniffin - updated : 10/11/2010<br>Cassandra L. Kniffin - updated : 8/20/2007<br>Cassandra L. Kniffin - reorganized : 12/4/2003<br>Ada Hamosh - updated : 10/7/2003<br>Victor A. McKusick - updated : 11/13/2002<br>Victor A. McKusick - updated : 5/3/1999<br>Victor A. McKusick - updated : 11/2/1998
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