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<title>
Entry
- #276700 - TYROSINEMIA, TYPE I; TYRSN1
- OMIM
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<span class="h4">#276700</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/276700"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS276700"> <strong>Phenotypic Series</strong> </a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<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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<div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Tyrosine.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/Tyrosine-Normal-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=882" 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/b283bdf9-1d90-4727-90b3-528c2f79eb09/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
<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">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
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</a>
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</span>
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<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:0050726" 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/276700" 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><a href="https://omia.org/OMIA002078/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0050726" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<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:276700" 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>
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</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> 124536006, 410056006<br />
<strong>ORPHA:</strong> 882<br />
<strong>DO:</strong> 0050726<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>
276700
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
TYROSINEMIA, TYPE I; TYRSN1
</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">
HEPATORENAL TYROSINEMIA<br />
FUMARYLACETOACETASE DEFICIENCY<br />
FAH 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/15/442?start=-3&limit=10&highlight=442">
15q25.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Tyrosinemia, type I
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/276700"> 276700 </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">
FAH
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613871"> 613871 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/276700" 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>
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&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS276700" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/276700" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/276700" 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> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypertrophic cardiomyopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/195020003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">195020003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/233873004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">233873004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45227007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45227007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I42.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I42.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I42.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I42.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/425.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">425.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/425.11" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">425.11</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551472&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551472</a>, <a href="https://bioportal.bioontology.org/search?q=C0340425&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0340425</a>, <a href="https://bioportal.bioontology.org/search?q=C0007194&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007194</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001639</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> External Features </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Ascites <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/389026000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">389026000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R18" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R18</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R18.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R18.8</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003962&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003962</a>, <a href="https://bioportal.bioontology.org/search?q=C5441966&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5441966</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001541" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001541</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0030995" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030995</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001541" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001541</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Liver </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- 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 /> -
Acute liver failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197270009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197270009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162557&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162557</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006554" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006554</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006554" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006554</a>]</span><br /> -
Cirrhosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/19943007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">19943007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K74.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K74.60</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023890&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023890</a>, <a href="https://bioportal.bioontology.org/search?q=C1623038&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1623038</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001394</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001394</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Pancreas </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pancreatic islet-cell hypertrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0597167&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0597167</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004510</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004510</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spleen </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Splenomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16294009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16294009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038002&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038002</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</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">
- GI bleeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74474003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74474003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K92.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K92.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/578" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">578</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/578.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">578.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0017181&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017181</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002239" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002239</a>]</span><br /> -
Paralytic ileus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55525008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55525008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K56.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K56.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/560.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">560.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0030446&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030446</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002590" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002590</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002590" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002590</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Renal Fanconi syndrome <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/236466005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">236466005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/236468006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">236468006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/61598006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">61598006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857395&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857395</a>, <a href="https://bioportal.bioontology.org/search?q=C0341703&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0341703</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001994" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001994</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001994" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001994</a>]</span><br /> -
Renal failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42399005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42399005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N19</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/586" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">586</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0035078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035078</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span><br /> -
Glomerulosclerosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/82646005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">82646005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197661001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197661001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1417247&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1417247</a>, <a href="https://bioportal.bioontology.org/search?q=C0178664&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0178664</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000096" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000096</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000096" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000096</a>]</span><br /> -
Nephromegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/300444006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">300444006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0542518&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0542518</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000105" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000105</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000105" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000105</a>]</span><br /> -
Nephrocalcinosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48638002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48638002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027709&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027709</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000121" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000121</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000121" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000121</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Rickets <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/41345002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">41345002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E55.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0035579&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035579</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002748" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002748</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002748" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002748</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MUSCLE, SOFT TISSUES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Chronic weakness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806558&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806558</a>]</span><br />
</span>
</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">
- Episodic paralysis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/198030008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">198030008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G72.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G72.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/359.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">359.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1279412&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279412</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003768" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003768</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003768" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003768</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Peripheral Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Episodic peripheral neuropathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848695&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848695</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006949" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006949</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006949" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006949</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">
- Renal Fanconi syndrome <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/236466005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">236466005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/236468006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">236468006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/61598006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">61598006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857395&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857395</a>, <a href="https://bioportal.bioontology.org/search?q=C0341703&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0341703</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001994" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001994</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001994" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001994</a>]</span><br /> -
Hypophosphatemic rickets <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/66266003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">66266003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/72831007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">72831007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3536983&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3536983</a>, <a href="https://bioportal.bioontology.org/search?q=C1704375&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1704375</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004912" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004912</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004912" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004912</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Abnormal blood coagulation studies (prolonged PT and PTT) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848703&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848703</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001928" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001928</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEOPLASIA </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Hepatocellular carcinoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/109841003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">109841003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/187769009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">187769009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1186630006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1186630006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25370001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25370001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C22.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C22.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2239176&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2239176</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001402" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001402</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001402" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001402</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">
- Fumarylacetoacetate hydrolase (FAH) deficiency <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848698&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848698</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/410056006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">410056006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/124536006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">124536006</a>]</span><br /> -
Deficient hepatic 4-hydroxyphenylpyruvate dioxygenase <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848699&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848699</a>]</span><br /> -
Tyrosinemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56595005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56595005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271847005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271847005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/190694001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">190694001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E70.21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E70.21</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268483&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268483</a>, <a href="https://bioportal.bioontology.org/search?q=C0268486&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268486</a>, <a href="https://bioportal.bioontology.org/search?q=C1879362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1879362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003231" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003231</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003231" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003231</a>]</span><br /> -
Methioninemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43123004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43123004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E72.19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E72.19</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4048705&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4048705</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003235" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003235</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003235" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003235</a>]</span><br /> -
Elevated plasma and urine succinylacetone <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848700&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848700</a>]</span><br /> -
Elevated hepatic transaminases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235996&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235996</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002910" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002910</a>]</span><br /> -
Elevated alpha-fetoprotein <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235971&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235971</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006254</a>]</span><br /> -
Hypophosphatemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/4996001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">4996001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0595888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0595888</a>, <a href="https://bioportal.bioontology.org/search?q=C0085682&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085682</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002148" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002148</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002148" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002148</a>]</span><br /> -
Hypoglycemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237630007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237630007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271327008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271327008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302866003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302866003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1179458001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1179458001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E16.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E16.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/251.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">251.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020615&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020615</a>, <a href="https://bioportal.bioontology.org/search?q=C5767385&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5767385</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001943</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001943</a>]</span><br /> -
Elevated urinary delta-aminolevulinic acid <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848702&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848702</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003163" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003163</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003163" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003163</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- High incidence in Saguenay-Lac St. Jean region of the province of Quebec, Canada and northern Europe<br /> -
Unusual cabbage-like odor<br /> -
Symptoms highly variable - rapidly progressive course leading to hepatic failure versus acute hepatic crisis<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the fumarylacetoacetase gene (FAH, <a href="/entry/613871#0001">613871.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Tyrosinemia
- <a href="/phenotypicSeries/PS276700">PS276700</a>
- 3 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/899?start=-3&limit=10&highlight=899"> 12q24.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/276710"> Tyrosinemia, type III </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/276710"> 276710 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609695"> HPD </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609695"> 609695 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/442?start=-3&limit=10&highlight=442"> 15q25.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/276700"> Tyrosinemia, type I </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<a href="/entry/276700"> 276700 </a>
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<a href="/entry/613871"> FAH </a>
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<a href="/entry/613871"> 613871 </a>
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<a href="/geneMap/16/617?start=-3&limit=10&highlight=617"> 16q22.2 </a>
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<a href="/entry/276600"> Tyrosinemia, type II </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<a href="/entry/276600"> 276600 </a>
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<a href="/entry/613018"> TAT </a>
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<a href="/entry/613018"> 613018 </a>
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<p>A number sign (#) is used with this entry because tyrosinemia type I (TYRSN1) is caused by homozygous or compound heterozygous mutation in the FAH gene (<a href="/entry/613871">613871</a>), which encodes fumarylacetoacetate hydrolase, on chromosome 15q25.</p>
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<p>Hereditary tyrosinemia type I (TYRSN1) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase (FAH), the last enzyme of tyrosine degradation. The disorder is characterized by progressive liver disease and a secondary renal tubular dysfunction leading to hypophosphatemic rickets. Onset varies from infancy to adolescence. In the most acute form patients present with severe liver failure within weeks after birth, whereas rickets may be the major symptom in chronic tyrosinemia. Untreated, patients die from cirrhosis or hepatocellular carcinoma at a young age (summary by <a href="#5" class="mim-tip-reference" title="Bliksrud, Y. T., Brodtkorb, E., Andresen, P. A., van den Berg, I. E. T., Kvittingen, E. A. &lt;strong&gt;Tyrosinaemia type I--de novo mutation in liver tissue suppressing an inborn splicing defect.&lt;/strong&gt; J. Molec. Med. 83: 406-410, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15759101/&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;15759101&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00109-005-0648-2&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="15759101">Bliksrud et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15759101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Hereditary Tyrosinemia</em></strong></p><p>
Tyrosinemia type II (TYRSN2; <a href="/entry/276600">276600</a>), also known as Richner-Hanhart syndrome, is caused by mutation in the TAT gene (<a href="/entry/613018">613018</a>) on chromosome 16q22. Tyrosinemia type III (TYRNS3; <a href="/entry/276710">276710</a>) is caused by mutation in the HPD gene (<a href="/entry/609695">609695</a>) on chromosome 12q24.</p>
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<p>Among the children of first-cousin parents, <a href="#43" class="mim-tip-reference" title="Lelong, M., Alagille, D., Gentil, C. I., Colin, J., Le Tan, V., Gabilan, J. C. &lt;strong&gt;Cirrhose congenitale et familiale avec diabete phospho-gluco-amine, rachitisme vitamin D-resistant et tyrosinurie massive.&lt;/strong&gt; Rev. Franc. Etud. Clin. Biol. 8: 37-50, 1963."None>Lelong et al. (1963)</a> observed 2 sons with cirrhosis, Fanconi renotubular syndrome, and marked increase in plasma tyrosine. In the sib most extensively observed, hepatosplenomegaly was discovered at 3 months of age and rickets at 18 months. Malignant changes developed in the liver, and death from pulmonary metastases occurred shortly before his 5th birthday. The author suggested that the basic defect concerns an enzyme involved with tyrosine metabolism. Earlier, <a href="#23" class="mim-tip-reference" title="Himsworth, H. P. &lt;strong&gt;Lectures on the Liver and its Diseases. (2nd ed.)&lt;/strong&gt; Oxford: Blackwell (pub.) 1950."None>Himsworth (1950)</a> described a similar case. <a href="#72" class="mim-tip-reference" title="Zetterstrom, R. &lt;strong&gt;Tyrosinosis.&lt;/strong&gt; Ann. N.Y. Acad. Sci. 111: 220-226, 1963.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14085846/&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;14085846&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1749-6632.1963.tb36962.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="14085846">Zetterstrom (1963)</a> studied 7 cases coming from an isolated area of southwestern Sweden. <a href="#22" class="mim-tip-reference" title="Halvorsen, S., Pande, H., Loken, A. C., Gjessing, L. R. &lt;strong&gt;Tyrosinosis: a study of 6 cases.&lt;/strong&gt; Arch. Dis. Child. 41: 238-249, 1966.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5940613/&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;5940613&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.41.217.238&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="5940613">Halvorsen et al. (1966)</a> gave details on 6 cases from Norway. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14085846+5940613" 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="#52" class="mim-tip-reference" title="Perry, T. L., Hardwick, D. F., Dixon, G. H., Dolman, C. L., Hansen, S. &lt;strong&gt;Hypermethioninemia: a metabolic disorder associated with cirrhosis, islet cell hyperplasia, and renal tubular degeneration.&lt;/strong&gt; Pediatrics 36: 236-250, 1965.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14320034/&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;14320034&lt;/a&gt;]" pmid="14320034">Perry et al. (1965)</a> described 3 sibs (2 females and a male) in 1 sibship who died in the third month after an illness characterized by irritability and progressive somnolence, and terminally by a tendency to bleed and hypoglycemia. A peculiar odor was noted. Pathologic changes included hepatic cirrhosis, renal tubular dilatation, and pancreatic islet hypertrophy. Biochemical studies showed generalized amino aciduria, marked elevation of methionine in the serum, and a disproportionately high urinary excretion of methionine. Alpha-keto-gamma-methiolbutyric acid was present in the urine and may account for the peculiar odor. The hypertrophy of the islets of Langerhans was probably due to stimulation by methionine or one of its metabolites. It seems likely that the disorder in the patients of <a href="#52" class="mim-tip-reference" title="Perry, T. L., Hardwick, D. F., Dixon, G. H., Dolman, C. L., Hansen, S. &lt;strong&gt;Hypermethioninemia: a metabolic disorder associated with cirrhosis, islet cell hyperplasia, and renal tubular degeneration.&lt;/strong&gt; Pediatrics 36: 236-250, 1965.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14320034/&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;14320034&lt;/a&gt;]" pmid="14320034">Perry et al. (1965)</a> was tyrosinemia since hypermethioninemia occurs secondary to liver failure in that condition (<a href="#59" class="mim-tip-reference" title="Scriver, C. R., Larochelle, J., Silverberg, M. &lt;strong&gt;Hereditary tyrosinemia and tyrosyluria in a French-Canadian geographic isolate.&lt;/strong&gt; Am. J. Dis. Child. 113: 41-46, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6016174/&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;6016174&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archpedi.1967.02090160091008&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="6016174">Scriver et al., 1967</a>; <a href="#14" class="mim-tip-reference" title="Gaull, G. E., Rassin, D. K., Solomon, G. E., Harris, R. C., Sturman, J. A. &lt;strong&gt;Biochemical observations on so-called hereditary tyrosinemia.&lt;/strong&gt; Pediat. Res. 4: 337-344, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4393588/&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;4393588&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-197007000-00004&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="4393588">Gaull et al., 1970</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4393588+14320034+6016174" 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="Gentz, J., Jagenburg, R., Zetterstrom, R. &lt;strong&gt;Tyrosinemia.&lt;/strong&gt; J. Pediat. 66: 670-696, 1965.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14271358/&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;14271358&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(65)80002-6&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="14271358">Gentz et al. (1965)</a> described 7 patients in 4 families with multiple renal tubular defects like those of the de Toni-Debre-Fanconi syndrome, nodular cirrhosis of the liver, and impaired tyrosine metabolism. In the urine, p-hydroxyphenyllactic acid was excreted in unusually large amounts. A total lack of liver p-hydroxyphenylpyruvate oxidase activity was demonstrated. Tyrosine-alpha-ketoglutarate transaminase was normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14271358" 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="#59" class="mim-tip-reference" title="Scriver, C. R., Larochelle, J., Silverberg, M. &lt;strong&gt;Hereditary tyrosinemia and tyrosyluria in a French-Canadian geographic isolate.&lt;/strong&gt; Am. J. Dis. Child. 113: 41-46, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6016174/&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;6016174&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archpedi.1967.02090160091008&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="6016174">Scriver et al. (1967)</a> identified the disease in 35 French Canadian infants, of whom 16 were sibs (i.e., 2 or more in each of several families). Marked tyrosinemia and tyrosyluria were present. The urine contained parahydroxyphenylpyruvic acid (PHPPA) and lactic and acetic derivatives. Loading test with tyrosine and with PHPPA suggested deficient p-hydroxyphenylpyruvate oxidase activity, which was confirmed by assay of liver biopsy samples. In stage I, infants exhibit hepatic necrosis and hypermethioninemia. In stage II, nodular cirrhosis and chronic hepatic insufficiency without hypermethioninemia are found. In stage III, renal tubular damage (Baber syndrome), often with hypophosphatemic rickets, appears. Low tyrosine diet arrested progression of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6016174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Lindblad, B., Fallstrom, S. P., Hoyer, S., Nordborg, C., Solymar, L., Velander, H. &lt;strong&gt;Cardiomyopathy in fumarylacetoacetase deficiency (hereditary tyrosinaemia): a new feature of the disease.&lt;/strong&gt; J. Inherit. Metab. Dis. 10 (suppl. 2): 319-322, 1987."None>Lindblad et al. (1987)</a> suggested that cardiomyopathy, usually subclinical, is a frequent finding.</p><p><a href="#48" class="mim-tip-reference" title="Mitchell, G., Larochelle, J., Lambert, M., Michaud, J., Grenier, A., Ogier, H., Gautheir, M., Lacroix, J., Vanasse, M., Larbrisseau, A., Paradis, K., Weber, A., Lefevre, Y., Melancon, S., Dallaire, L. &lt;strong&gt;Neurologic crises in hereditary tyrosinemia.&lt;/strong&gt; New Eng. J. Med. 322: 432-437, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2153931/&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;2153931&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199002153220704&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="2153931">Mitchell et al. (1990)</a> pointed out the significance of neurologic crises in this disorder. They found that of 48 children with tyrosinemia identified on neonatal screening since 1970, 20 (42%) had neurologic crises that began at the mean age of 1 year and led to 104 hospital admissions. These abrupt episodes of peripheral neuropathy were characterized by severe pain with extensor hypertonia (in 75%), vomiting or paralytic ileus (69%), muscle weakness (29%), and self-mutilation (8%). In 8 children, mechanical ventilation was required because of paralysis and 14 of the 20 children died. Between crises, most survivors regained normal function. They could identify no reliable biochemical marker for the crises. Urinary excretion of delta-aminolevulinic acid, a neurotoxic intermediate of porphyrin biosynthesis, was elevated during both crises and asymptomatic periods. Electrophysiologic studies and neuromuscular biopsies showed axonal degeneration and secondary demyelination. Thus, they demonstrated that episodes of acute, severe, peripheral neuropathy are common in this disorder and resemble the crises of the neuropathic porphyrias. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2153931" 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>Fumarylacetoacetase Pseudodeficiency</em></strong></p><p>
<a href="#30" class="mim-tip-reference" title="Kvittingen, E. A., Borresen, A. L., Stokke, O., van der Hagen, C. B., Lie, S. O. &lt;strong&gt;Deficiency of fumarylacetoacetase without hereditary tyrosinemia.&lt;/strong&gt; Clin. Genet. 27: 550-554, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4017276/&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;4017276&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1985.tb02039.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="4017276">Kvittingen et al. (1985)</a> described a family that may have had a pseudodeficiency gene. Presumed homozygotes for this gene had levels of fumarylacetoacetase activity only slightly higher than those in patients with tyrosinemia. No clinical abnormalities were observed. <a href="#37" class="mim-tip-reference" title="Kvittingen, E. A., Rootwelt, H., van Dam, T., van Faassen, H., Berger, R. &lt;strong&gt;Hereditary tyrosinemia type I: lack of correlation between clinical findings and amount of immunoreactive fumarylacetoacetase protein.&lt;/strong&gt; Pediat. Res. 31: 43-46, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1594329/&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;1594329&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-199201000-00008&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="1594329">Kvittingen et al. (1992)</a> studied a healthy 41-year-old female homozygous for the pseudodeficiency gene and 3 tyrosinemia families in which one or both parents were compound heterozygotes for the tyrosinemia and pseudodeficiency genes. Only 2 of 7 patients with typical chronic tyrosinemia had definite immunoreactivity in fibroblasts when bovine fumarylacetoacetase antibodies were used; none of the patients with the acute type had detectable immunoreactive protein in fibroblast extracts. Twenty-eight patients with hereditary tyrosinemia of various clinical phenotypes were tested. The pseudodeficiency gene product gave almost no detectable immunoreactivity in fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4017276+1594329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#38" class="mim-tip-reference" title="La Du, B. N., Gjessing, L. R. &lt;strong&gt;Tyrosinosis and tyrosinemia.In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.) : The Metabolic Basis of Inherited Disease. (3rd ed.)&lt;/strong&gt; New York: McGraw-Hill (pub.) 1972. Pp. 256-267."None>La Du and Gjessing (1972)</a> discussed evidence against the hypothesis that tyrosinemia type I is a p-hydroxyphenylpyruvic acid oxidase deficiency. <a href="#45" class="mim-tip-reference" title="Lindblad, B., Lindstedt, S., Steen, G. &lt;strong&gt;On the enzymic defects in hereditary tyrosinemia.&lt;/strong&gt; Proc. Nat. Acad. Sci. 74: 4641-4645, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/270706/&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;270706&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.74.10.4641&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="270706">Lindblad et al. (1977)</a> suggested that the primary defect is in fumarylacetoacetase (<a href="https://enzyme.expasy.org/EC/3.7.1.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.7.1.2</a>), which leads to accumulation of succinylacetone and succinylacetoacetate. Porphobilinogen synthetase is inhibited by these substances and the authors suggested that the severe liver and kidney damage of tyrosinemia is caused by accumulation of tyrosine metabolites. A puzzling feature of hereditary tyrosinemia has been episodes similar to acute hepatic porphyria, with excretion of 5-aminolevulinic acid in the urine. The inhibition of porphobilinogen synthase explains this feature. Fumarylacetoacetase is the enzyme primarily deficient; deficiency of parahydroxyphenylpyruvate oxidase is secondary (<a href="#61" class="mim-tip-reference" title="Scriver, C. R. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Montreal, Quebec, Canada 2/15/1982."None>Scriver, 1982</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=270706" 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="#65" class="mim-tip-reference" title="Tanguay, R. M., Valet, J. P., Lescault, A., Duband, J. L., Laberge, C., Lettre, F., Plante, M. &lt;strong&gt;Different molecular basis for fumarylacetoacetate hydrolase deficiency in the two clinical forms of hereditary tyrosinemia (type I).&lt;/strong&gt; Am. J. Hum. Genet. 47: 308-316, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2378356/&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;2378356&lt;/a&gt;]" pmid="2378356">Tanguay et al. (1990)</a> concluded that the acute form of hereditary tyrosinemia has absence of FAH enzyme protein, whereas the chronic form has presence of immunoreactive enzyme protein. They quoted the work of others supporting these findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2378356" 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="#54" class="mim-tip-reference" title="Prieto-Alamo, M. J., Laval, F. &lt;strong&gt;Deficient DNA-ligase activity in the metabolic disease tyrosinemia type I.&lt;/strong&gt; Proc. Nat. Acad. Sci. 95: 12614-12618, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9770534/&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;9770534&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=9770534[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/10.1073/pnas.95.21.12614&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="9770534">Prieto-Alamo and Laval (1998)</a> noted that the defect in FAH in tyrosinemia type I results in accumulation of succinylacetone (SA), which reacts with amino acids and proteins to form stable adducts via Schiff base formation, lysine being the most reactive amino acid. Patients with this disorder surviving beyond infancy are at considerable risk for the development of hepatocellular carcinoma, and a high level of chromosomal breakage is observed in tyrosinemia cells, suggesting a defect in the processing of DNA. <a href="#54" class="mim-tip-reference" title="Prieto-Alamo, M. J., Laval, F. &lt;strong&gt;Deficient DNA-ligase activity in the metabolic disease tyrosinemia type I.&lt;/strong&gt; Proc. Nat. Acad. Sci. 95: 12614-12618, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9770534/&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;9770534&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=9770534[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/10.1073/pnas.95.21.12614&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="9770534">Prieto-Alamo and Laval (1998)</a> showed that the overall DNA-ligase activity is low in tyrosinemia cells (about 20% of normal) and that Okazaki fragments are rejoined at a reduced rate compared with normal fibroblasts. No mutation was found by sequencing the ligase I cDNA (LIG1; <a href="/entry/126391">126391</a>) from tyrosinemia cells, and the level of expression of the ligase I mRNA was similar in normal and tyrosinemia fibroblasts, suggesting the presence of a ligase inhibitor. SA was shown to inhibit in vitro the overall DNA-ligase activity present in normal cell extracts. The activity of purified T4 DNA-ligase, whose active site is also a lysine residue, was inhibited by SA in a dose-dependent manner. These results suggested that accumulation of SA reduces the overall ligase activity in tyrosinemia cells and indicated that metabolic errors may play a role in regulating enzymatic activities involved in DNA replication and repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9770534" 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="pathogenesis" class="mim-anchor"></a>
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<p>It had been postulated that the severe liver damage in tyrosinemia is the result of defective degradation of tyrosine. <a href="#27" class="mim-tip-reference" title="Hostetter, M. K., Levy, H. L., Winter, H. S., Knight, G. J., Haddow, J. E. &lt;strong&gt;Evidence for liver disease preceding amino acid abnormalities in hereditary tyrosinemia.&lt;/strong&gt; New Eng. J. Med. 308: 1265-1267, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6188953/&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;6188953&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198305263082105&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="6188953">Hostetter et al. (1983)</a> showed, however, that liver damage is prenatal in onset (as indicated by greatly elevated alpha-fetoprotein in cord blood) and that hypertyrosinemia developed only postnatally. Thus, therapy aimed at reduction of the elevated tyrosine level is unlikely to be of fundamental value. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6188953" 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><a href="#6" class="mim-tip-reference" title="De Braekeleer, M., Larochelle, J. &lt;strong&gt;Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenay-Lac-St-Jean.&lt;/strong&gt; Am. J. Hum. Genet. 47: 302-307, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2378355/&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;2378355&lt;/a&gt;]" pmid="2378355">De Braekeleer and Larochelle (1990)</a> estimated the prevalence of hereditary tyrosinemia at birth as 1/1,846 liveborn and the carrier rate as 1/20 inhabitants in the Saguenay-Lac-Saint-Jean region. The mean coefficient of inbreeding was only slightly elevated in the tyrosinemic group compared to a control group and was due to remote consanguinity. The mean kinship coefficient was 2.3 times higher in the tyrosinemic group than in the control group. This was interpreted as indicating founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2378355" 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="diagnosis" class="mim-anchor"></a>
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<p>Prenatal diagnosis of tyrosinemia is possible either by the detection of succinylacetone in the amniotic fluid (<a href="#12" class="mim-tip-reference" title="Gagne, R., Lescault, A., Grenier, A., Laberge, C., Melancon, S. B., Dallaire, L. &lt;strong&gt;Prenatal diagnosis of hereditary tyrosinaemia: measurement of succinylacetone in amniotic fluid.&lt;/strong&gt; Prenatal Diag. 2: 185-188, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7145846/&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;7145846&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/pd.1970020307&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="7145846">Gagne et al., 1982</a>) or by measurement of fumarylacetoacetase in cultured amniotic cells (<a href="#32" class="mim-tip-reference" title="Kvittingen, E. A., Halvorsen, S., Jellum, E. &lt;strong&gt;Deficient fumarylacetoacetate fumarylhydrolase activity in lymphocytes and fibroblasts from patients with hereditary tyrosinemia.&lt;/strong&gt; Pediat. Res. 17: 541-544, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6622096/&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;6622096&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-198307000-00005&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="6622096">Kvittingen et al., 1983</a>). <a href="#24" class="mim-tip-reference" title="Holme, E., Lindblad, B., Lindstedt, S. &lt;strong&gt;Possibilities for treatment and for early prenatal diagnosis of hereditary tyrosinaemia. (Letter)&lt;/strong&gt; Lancet 325: 527 only, 1985. Note: Originally Volume I.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2857895/&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;2857895&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(85)92132-4&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="2857895">Holme et al. (1985)</a> demonstrated the feasibility of enzymatic diagnosis in chorionic villus material. Also, they showed that normal red cells have fumarylacetoacetase activity. They proposed that studies of red cells permit rapid diagnosis and recognition of heterozygotes and that enzyme replacement by blood transfusion may help patients over acute metabolic crises and until such time as definitive therapy by orthotopic liver transplantation (<a href="#10" class="mim-tip-reference" title="Fisch, R. O., McCabe, E. R. B., Doeden, D., Koep, L. J., Kohlhoff, J. G., Silverman, A., Starzl, T. E. &lt;strong&gt;Homotransplantation of the liver in a patient with hepatoma and hereditary tyrosinemia.&lt;/strong&gt; J. Pediat. 93: 592-596, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/212542/&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;212542&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(78)80893-2&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="212542">Fisch et al., 1978</a>; <a href="#13" class="mim-tip-reference" title="Gartner, J. C., Zitelli, B. J., Malatack, J. J., Shaw, B. W., Iwatsuki, S., Starzl, T. E. &lt;strong&gt;Orthotopic liver transplantation in children: two-year experience with 47 patients.&lt;/strong&gt; Pediatrics 74: 140-145, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6377219/&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;6377219&lt;/a&gt;]" pmid="6377219">Gartner et al., 1984</a>) can be performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=212542+6622096+7145846+2857895+6377219" 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="#40" class="mim-tip-reference" title="Laberge, C., Grenier, A., Valet, J. P., Morissette, J. &lt;strong&gt;Fumarylacetoacetase measurement as a mass-screening procedure for hereditary tyrosinemia type I.&lt;/strong&gt; Am. J. Hum. Genet. 47: 325-328, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2378358/&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;2378358&lt;/a&gt;]" pmid="2378358">Laberge et al. (1990)</a> described an enzyme-linked immunosorbent assay (ELISA) to measure the deficient enzyme in dried blood spots in this disorder. As mean levels of blood tyrosine in newborn specimens have declined, probably as a result of dietary changes and early discharge from nurseries, the traditional approach to screening for tyrosinemia, which was based on the fluorometric determination of tyrosine on the first dried blood spot received by neonatal screening programs, has required replacement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2378358" 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>As an aid to early diagnosis for early institution of drug therapy, <a href="#25" class="mim-tip-reference" title="Holme, E., Lindstedt, S. &lt;strong&gt;Neonatal screen for hereditary tyrosinaemia type I. (Letter)&lt;/strong&gt; Lancet 340: 850 only, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1357267/&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;1357267&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(92)92724-t&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="1357267">Holme and Lindstedt (1992)</a> suggested a neonatal screening test based on the measurement of porphobilinogen synthase activity. Porphobilinogen synthase activity is always low in patients with tyrosinemia type I. <a href="#25" class="mim-tip-reference" title="Holme, E., Lindstedt, S. &lt;strong&gt;Neonatal screen for hereditary tyrosinaemia type I. (Letter)&lt;/strong&gt; Lancet 340: 850 only, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1357267/&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;1357267&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(92)92724-t&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="1357267">Holme and Lindstedt (1992)</a> were not aware of any drug used neonatally or of conditions that would interfere with the test or mimic porphobilinogen synthase activity to result in a false-normal test. Specificity of the test is not absolute because homozygous porphobilinogen synthase deficiency (<a href="/entry/125270">125270</a>) would be detected; in this disorder also, early diagnosis would presumably benefit the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1357267" 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="#64" class="mim-tip-reference" title="Tanguay, R. M., Phaneuf, D., Labelle, Y., Demers, S. &lt;strong&gt;Molecular cloning and expression of the c-DNA encoding the enzyme deficient in hereditary tyrosinemia: evidence for molecular heterogeneity. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 47 (suppl.): A168 only, 1990."None>Tanguay et al. (1990)</a> identified RFLPs for 4 restriction sites within the FAH gene and proposed the development of a carrier detection test by linkage analysis.</p>
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<strong>Clinical Management</strong>
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<p><a href="#7" class="mim-tip-reference" title="Dehner, L. P., Snover, D. C., Sharp, H. L., Ascher, N., Nakhleh, R., Day, D. L. &lt;strong&gt;Hereditary tyrosinemia type I (chronic form): pathologic findings in the liver.&lt;/strong&gt; Hum. Path. 20: 149-158, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2536631/&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;2536631&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0046-8177(89)90179-2&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="2536631">Dehner et al. (1989)</a> reviewed the pathologic findings in the liver on the basis of the findings in children undergoing liver transplant. They concluded that to preclude hepatocellular carcinoma, a liver replacement is necessary before the age of 2 years. In the view of <a href="#68" class="mim-tip-reference" title="van Spronsen, F. J., Berger, R., Smit, G. P. A., de Klerk, J. B. C., Duran, M., Bijleveld, C. M. A., van Faassen, H., Slooff, M. J. H., Heymans, H. S. A. &lt;strong&gt;Tyrosinaemia type I: orthotopic liver transplantation as the only definitive answer to a metabolic as well as an oncological problem.&lt;/strong&gt; J. Inherit. Metab. Dis. 12: 339-342, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2556611/&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;2556611&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF03335416&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="2556611">Van Spronsen et al. (1989)</a> also, orthotopic liver transplantation is the only definitive therapy for both the metabolic and the oncologic problem in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2556611+2536631" 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="#57" class="mim-tip-reference" title="Russo, P., O&#x27;Regan, S. &lt;strong&gt;Visceral pathology of hereditary tyrosinemia type I.&lt;/strong&gt; Am. J. Hum. Genet. 47: 317-324, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2378357/&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;2378357&lt;/a&gt;]" pmid="2378357">Russo and O'Regan (1990)</a> reviewed the pathologic findings in the liver and kidney. In the Hopital Sainte-Justine in Montreal, 16 patients had been evaluated for liver transplantation. Renal involvement was found to be 'more abnormal than expected.' The liver was transplanted in 7 patients of whom 2 also received kidney transplantation. Hepatocarcinoma was detected in 2 of 8 patients in whom the whole liver was examined. Of the 9 patients who did not receive transplants, 5 died; of the 7 transplant patients, 1 died in an instance of combined liver-kidney transplantation. The 6 patients who survived had normal liver function, normal growth, and no recurrence of neurologic crises on a normal diet. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2378357" 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="#62" class="mim-tip-reference" title="Sokal, E. M., Bustos, R., Van Hoof, F., Otte, J. B. &lt;strong&gt;Liver transplantation for hereditary tyrosinemia--early transplantation following the patient&#x27;s stabilization.&lt;/strong&gt; Transplantation 54: 937-939, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1440864/&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;1440864&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00007890-199211000-00035&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="1440864">Sokal et al. (1992)</a> recommended orthotopic liver transplantation at an early stage. The procedure was performed in 4 children under 1 year of age, within 5 months of presentation and diagnosis. During the pretransplant period, intensive medical support and restriction of dietary tyrosine was initiated to improve the patient's condition and promote weight gain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1440864" 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>As an alternative to liver transplantation, <a href="#46" class="mim-tip-reference" title="Lindstedt, S., Holme, E., Lock, E. A., Hjalmarson, O., Strandvik, B. &lt;strong&gt;Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase.&lt;/strong&gt; Lancet 340: 813-817, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1383656/&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;1383656&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(92)92685-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1383656">Lindstedt et al. (1992)</a> treated patients with type I tyrosinemia with a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPD; <a href="https://enzyme.expasy.org/EC/1.13.11.27" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 1.13.11.27</a>) to prevent the formation of maleylacetoacetate and fumarylacetoacetate and their saturated derivatives. The agent used in 1 acute and 4 subacute/chronic cases was 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Signs of improvement included decrease in several metabolites, correction of the almost complete inhibition of porphobilinogen synthase in erythrocytes, decrease in alpha-fetoprotein, improved liver and renotubular function, and regression of hepatic abnormalities by computed tomography. No side effects were encountered. Inhibition of 4-hydroxyphenylpyruvate dioxygenase may prevent the development of liver cirrhosis and abolish or diminish the risk of liver cancer. Furthermore, normalization of porphyrin synthesis should eliminate the risk of porphyric crises. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1383656" 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="#42" class="mim-tip-reference" title="Laine, J., Salo, M. K., Krogerus, L., Karkkainen, J., Wahlroos, O., Holmberg, C. &lt;strong&gt;The nephropathy of type I tyrosinemia after liver transplantation.&lt;/strong&gt; Pediat. Res. 37: 640-645, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7603784/&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;7603784&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-199505000-00015&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="7603784">Laine et al. (1995)</a> studied renal function after orthotopic liver transplantation and found that the patients had normal glomerular filtration rates but showed signs of tubular dysfunction 18 to 36 months after operation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7603784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Holme, E., Lindstedt, S. &lt;strong&gt;Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione).&lt;/strong&gt; J. Inherit. Metab. Dis. 21: 507-517, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9728331/&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;9728331&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1005410820201&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="9728331">Holme and Lindstedt (1998)</a> stated that since the first trial of NTBC treatment for type I tyrosinemia in 1991, over 220 patients had been treated by the drug using a protocol that included regular follow-up with reports of clinical and laboratory investigations. Only 10% of the patients had not responded clinically to NTBC treatment. In half of these patients, successful liver transplantation had been performed, which further reduced the mortality rate during infancy to 5%. The data indicated a decreased risk for early development of hepatocellular carcinoma in patients who started treatment at an early age. Of the 101 patients aged 2 to 8 years who had started NTBC treatment before 2 years of age, no patient developed cancer after 2 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9728331" 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="Bendadi, F., de Koning, T. J., Visser, G., Prinsen, H. C. M. T., de Sain, M. G. M., Verhoeven-Duif, N., Sinnema, G., van Spronsen, F. J., van Hasselt, P. M. &lt;strong&gt;Impaired cognitive functioning in patients with tyrosinemia type I receiving nitisinone.&lt;/strong&gt; J. Pediat. 164: 398-401, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24238861/&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;24238861&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.jpeds.2013.10.001&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="24238861">Bendadi et al. (2014)</a> evaluated cognitive functioning of 10 patients with tyrosinemia type I who were receiving treatment with NTBC and a protein-restricted diet. IQ scores of patients were significantly lower than scores among their unaffected sibs (71 vs 91, p = 0.008). Both verbal and performance scores showed significant differences. Repeated IQ measurements done at 2- to 3-year intervals in 5 patients showed a decline in average IQ over time. Lower IQ scores were associated with special education attendance. No significant association was observed between IQ score and plasma tyrosine or phenylalanine concentrations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24238861" 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="#58" class="mim-tip-reference" title="Schultz, M. J., Netzel, B. C., Singh R. H., Pino, G. B., Gavrilov, D. K., Oglesbee, D., Raymond, K. M., Rinaldo, P., Tortorelli, S., Smith, W. E., Matern, D. &lt;strong&gt;Laboratory monitoring of patients with hereditary tyrosinemia type I.&lt;/strong&gt; Molec. Genet. Metab. 130: 247-254, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32546364/&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;32546364&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2020.06.001&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="32546364">Schultz et al. (2020)</a> developed a liquid chromatography tandem mass spectrometry methodology to measure tyrosine, phenylalanine, methionine, NTBC, and succinylacetone across a wide range of relevant concentrations in dried whole blood spots. This assay enables measurement of metabolites that are important for treatment monitoring in tyrosinemia type I, with subsequent adjustment of the patient's treatment regimen, including optimization of NTBC dosing to keep succinylacetone levels in the normal range. The metabolites were shown to be stable in blood that was collected in a range of anticoagulants (including sodium heparin and EDTA) and across a range of storage conditions (including heated, ambient, frozen, and refrigerated), except that succinylacetone was substantially degraded after being stored in a heated environment. <a href="#58" class="mim-tip-reference" title="Schultz, M. J., Netzel, B. C., Singh R. H., Pino, G. B., Gavrilov, D. K., Oglesbee, D., Raymond, K. M., Rinaldo, P., Tortorelli, S., Smith, W. E., Matern, D. &lt;strong&gt;Laboratory monitoring of patients with hereditary tyrosinemia type I.&lt;/strong&gt; Molec. Genet. Metab. 130: 247-254, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32546364/&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;32546364&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2020.06.001&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="32546364">Schultz et al. (2020)</a> concluded that this assay could enable home collection of blood specimens in patients with tyrosinemia type I, as well as serve as second tier assay to reduce false-positive newborn screening results in places that only assay for tyrosine on newborn screening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32546364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of TYRSN1 in the families reported by <a href="#19" class="mim-tip-reference" title="Grompe, M., St-Louis, M., Demers, S. I., Al-Dhalimy, M., Leclerc, B., Tanguay, R. M. &lt;strong&gt;A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I.&lt;/strong&gt; New. Eng. J. Med. 331: 353-357, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8028615/&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;8028615&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199408113310603&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="8028615">Grompe et al. (1994)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8028615" 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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<p><a href="#19" class="mim-tip-reference" title="Grompe, M., St-Louis, M., Demers, S. I., Al-Dhalimy, M., Leclerc, B., Tanguay, R. M. &lt;strong&gt;A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I.&lt;/strong&gt; New. Eng. J. Med. 331: 353-357, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8028615/&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;8028615&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199408113310603&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="8028615">Grompe et al. (1994)</a> found that 100% of patients with tyrosinemia type I from the Saguenay-Lac-Saint-Jean region of Quebec and 28% of TYRSN1 patients from other regions of the world carry a splice donor site mutation in intron 12 of the FAH gene (<a href="/entry/613871#0003">613871.0003</a>). Of 25 patients from the Saguenay-Lac-Saint-Jean region, 20 were homozygous. The frequency of carrier status, based on screening of blood spots from newborns, was about 1 per 25 in that region of Quebec and about 1 per 66 overall in Quebec. Using cDNA probes for the FAH gene, <a href="#8" class="mim-tip-reference" title="Demers, S. I., Phaneuf, D., Tanguay, R. M. &lt;strong&gt;Hereditary tyrosinemia type I: strong association with haplotype 6 in French Canadians permits simple carrier detection and prenatal diagnosis.&lt;/strong&gt; Am. J. Hum. Genet. 55: 327-333, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7913582/&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;7913582&lt;/a&gt;]" pmid="7913582">Demers et al. (1994)</a> identified 10 haplotypes with 5 RFLPs in 118 normal chromosomes from the French Canadian population. Among 29 children with hereditary tyrosinemia, haplotype 6 was found to be strongly associated with disease, at a frequency of 90% as compared with approximately 18% in 35 control individuals. This frequency increased to 96% in the 24 patients originating from the Saguenay-Lac-Saint-Jean region. Most patients were found to be homozygous for a specific haplotype in this population. Analysis of 24 tyrosinemia patients from 9 countries gave a frequency of approximately 52% for haplotype 6, suggesting a relatively high association worldwide. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8028615+7913582" 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="#35" class="mim-tip-reference" title="Kvittingen, E. A., Rootwelt, H., Berger, R., Brandtzaeg, P. &lt;strong&gt;Self-induced correction of the genetic defect in tyrosinemia type I.&lt;/strong&gt; J. Clin. Invest. 94: 1657-1661, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7929843/&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;7929843&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI117509&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="7929843">Kvittingen et al. (1994)</a> demonstrated a mosaic pattern of immunoreactive FAH protein in liver tissue from 15 of 18 tyrosinemia type I patients of various ethnic origins. One additional patient had variable levels of FAH enzyme activity in liver tissue. In 4 patients exhibiting mosaicism of FAH protein, analysis for the tyrosinemia-causing mutations was performed in immunonegative and immunopositive areas of liver tissue by restriction digestion analysis and direct DNA sequencing. In all 4 patients, the immunonegative liver tissue contained the FAH mutations demonstrated in fibroblasts of the patients. In the immunopositive nodules of regenerating liver tissue, one of the mutated alleles apparently had reverted to the normal genotype. This genetic correction was observed for 3 different tyrosinemia-causing mutations. In each case, a mutant AT nucleotide pair was reverted to a normal GC pair. One of the mutations that showed reversion was the splice site mutation described in <a href="/entry/613871#0003">613871.0003</a>. Another was the glu357-to-ter mutation due to a G-to-T transversion at nucleotide 1069, which is described in <a href="/entry/613871#0004">613871.0004</a>. In a compound heterozygous patient, the same mutation was reverted to wildtype in all 4 nodules investigated. A gene conversion event or mitotic recombination between homologous chromosomes could theoretically explain the appearance of a normal allele in a compound heterozygote. Two of the patients with reverted mutations, however, were homozygous for their mutations, and no pseudogenes for FAH, for contribution of wildtype sequences, are known. Early embryonic mutation with selective growth of the mutated cells could account for the mosaicism, but a high incidence of such an event would indicate a precipitating factor. Chemical mutagenesis, reverting the disease-causing mutation, could result from the metabolites accumulating in tyrosinemia. Even if the metabolites are not direct mutagens, the compounds are toxic and induce cell necrosis with a subsequent accelerated regeneration of hepatocytes. Rapidly replicating cells are generally prone to mutations. Reversion of the genetic defect resulting from accelerated cell regeneration should be sought in other genetic diseases in tissues with an induced, or naturally high, rate of cell replication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7929843" 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="Hahn, S. H., Krasnewich, D., Brantly, M., Kvittingen, E. A., Gahl, W. A. &lt;strong&gt;Heterozygosity for an exon 12 splicing mutation and a W234G missense mutation in an American child with chronic tyrosinemia type 1.&lt;/strong&gt; Hum. Mutat. 6: 66-73, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7550234/&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;7550234&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.1380060113&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="7550234">Hahn et al. (1995)</a> reviewed 7 previously reported mutations in tyrosinemia type I and added 2 more identified in a compound heterozygote. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550234" 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="#66" class="mim-tip-reference" title="Timmers, C., Grompe, M. &lt;strong&gt;Six novel mutations in the fumarylacetoacetate hydrolase gene of patients with hereditary tyrosinemia type I.&lt;/strong&gt; Hum. Mutat. 7: 367-369, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8723690/&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;8723690&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1996)7:4&lt;367::AID-HUMU14&gt;3.0.CO;2-0&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="8723690">Timmers and Grompe (1996)</a> reported 6 new mutations in the FAH gene in patients with hereditary tyrosinemia type I: 2 splice mutations, 3 missense mutations, and 1 nonsense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8723690" 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="#56" class="mim-tip-reference" title="Rootwelt, H., Hoie, K., Berger, R., Kvittingen, E. A. &lt;strong&gt;Fumarylacetoacetase mutations in tyrosinaemia type I.&lt;/strong&gt; Hum. Mutat. 7: 239-243, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8829657/&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;8829657&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1996)7:3&lt;239::AID-HUMU8&gt;3.0.CO;2-5&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="8829657">Rootwelt et al. (1996)</a> classified 62 hereditary tyrosinemia type I patients of various ethnic origins clinically into acute, chronic, or intermediate phenotypes and screened for the 14 published causal mutations in the FAH gene. Restriction analysis of PCR-amplified genomic DNA identified 74% of the mutated alleles. The IVS12+5G-A mutation (<a href="/entry/613871#0003">613871.0003</a>), which is predominant in French Canadian tyrosinemia type I patients, was the most common mutation being present in 32 alleles in patients from Europe, Pakistan, Turkey, and the United States. The IVS6-1G-T mutation (<a href="/entry/613871#0010">613871.0010</a>), encountered in 14 alleles, was common in central and western Europe. There was an apparent 'Scandinavian' 1009G-to-A combined splice and missense mutation (12 alleles), a 'Pakistani' 192G-to-T splice mutation (11 alleles), a 'Turkish' D233V mutation (6 alleles), and a 'Finnish' or northern European W262X (<a href="/entry/613871#0009">613871.0009</a>) mutation (7 alleles). <a href="#56" class="mim-tip-reference" title="Rootwelt, H., Hoie, K., Berger, R., Kvittingen, E. A. &lt;strong&gt;Fumarylacetoacetase mutations in tyrosinaemia type I.&lt;/strong&gt; Hum. Mutat. 7: 239-243, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8829657/&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;8829657&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1996)7:3&lt;239::AID-HUMU8&gt;3.0.CO;2-5&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="8829657">Rootwelt et al. (1996)</a> commented that some of the mutations seemed to predispose for acute and others for more chronic forms of tyrosinemia type I, although no clear-cut genotype/phenotype correlation could be established. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8829657" 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>According to the review of <a href="#63" class="mim-tip-reference" title="St-Louis, M., Tanguay, R. M. &lt;strong&gt;Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: overview.&lt;/strong&gt; Hum. Mutat. 9: 291-299, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9101289/&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;9101289&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1997)9:4&lt;291::AID-HUMU1&gt;3.0.CO;2-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9101289">St-Louis and Tanguay (1997)</a>, 26 mutations in the FAH gene had been reported in type I tyrosinemia. All consisted of single-base substitutions resulting in 16 amino acid replacements, 1 silent mutation causing a splicing defect, 5 nonsense codons, and 4 putative splicing defects. The mutations were spread over the entire FAH gene, with a particular clustering between amino acid residues 230 and 250. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9101289" 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="Arranz, J. A., Pinol, F., Kozak, L., Perez-Cerda, C., Cormand, B., Ugarte, M., Riudor, E. &lt;strong&gt;Splicing mutations, mainly IVS6-1(G-T), account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients.&lt;/strong&gt; Hum. Mutat. 20: 180-188, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12203990/&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;12203990&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10084&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="12203990">Arranz et al. (2002)</a> determined the FAH genotype in a group of 29 patients, most of them from the Mediterranean area, with hereditary tyrosinemia type I. They identified 7 novel mutations and 2 previously described mutations. At least one splice site mutation was found in 92.8% of patients, with IVS6-1G-T (<a href="/entry/613871#0010">613871.0010</a>) accounting for 58.9% of the total number of alleles. The group of patients with splice mutations showed heterogeneous phenotypic patterns ranging from the acute form, with severe liver malfunction, to chronic forms, with renal manifestations and slow progressive hepatic alterations. Despite the high prevalence of the IVS12+5G-A mutation (<a href="/entry/613871#0003">613871.0003</a>) in the northwestern European population, <a href="#2" class="mim-tip-reference" title="Arranz, J. A., Pinol, F., Kozak, L., Perez-Cerda, C., Cormand, B., Ugarte, M., Riudor, E. &lt;strong&gt;Splicing mutations, mainly IVS6-1(G-T), account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients.&lt;/strong&gt; Hum. Mutat. 20: 180-188, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12203990/&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;12203990&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10084&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="12203990">Arranz et al. (2002)</a> found only 2 patients with this mutation from the group of 29 patients. One patient, who was a double heterozygote for a nonsense and a frameshift mutation, showed an atypical clinical picture of hypotonia and repeated infections. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12203990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Bliksrud, Y. T., Brodtkorb, E., Andresen, P. A., van den Berg, I. E. T., Kvittingen, E. A. &lt;strong&gt;Tyrosinaemia type I--de novo mutation in liver tissue suppressing an inborn splicing defect.&lt;/strong&gt; J. Molec. Med. 83: 406-410, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15759101/&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;15759101&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00109-005-0648-2&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="15759101">Bliksrud et al. (2005)</a> described revertant mosaicism in a patient with type I tyrosinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15759101" 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>Fumarylacetoacetase Pseudodeficiency</em></strong></p><p>
<a href="#55" class="mim-tip-reference" title="Rootwelt, H., Brodtkorb, E., Kvittingen, E. A. &lt;strong&gt;Identification of a frequent pseudodeficiency mutation in the fumarylacetoacetase gene, with implications for diagnosis of tyrosinemia type I.&lt;/strong&gt; Am. J. Hum. Genet. 55: 1122-1127, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7977370/&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;7977370&lt;/a&gt;]" pmid="7977370">Rootwelt et al. (1994)</a> presented evidence for the existence of a 'pseudodeficiency' FAH allele. In an individual homozygous for pseudodeficiency of FAH and in 3 hereditary tyrosinemia type I families also carrying the pseudodeficiency allele, Western blotting of fibroblast extracts showed that the pseudodeficiency allele gave very little immunoreactive FAH protein, whereas Northern blot analysis revealed a normal amount of FAH mRNA. All the pseudodeficiency alleles were found to carry a 1021C-T transition, predicting an arg341-to-trp substitution (R341W; <a href="/entry/613871#0006">613871.0006</a>). Site-directed mutagenesis and expression in a rabbit reticulocyte lysate system demonstrated that the arg341-to-trp mutation gave reduced FAH activity and reduced amounts of the full-length protein. The normal and the mutated sequences could be distinguished by BsiEI restriction digestion of PCR products. Among 516 healthy volunteers of Norwegian origin, the R341W mutation was found in 2.2% of alleles. Testing for this specific mutation may solve the problem of prenatal diagnosis and carrier detection in families with compound heterozygote genotypes for type I tyrosinemia and pseudodeficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7977370" 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>Mice homozygous for an FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction. <a href="#18" class="mim-tip-reference" title="Grompe, M., Lindstedt, S., Al-Dhalimy, M., Kennaway, N. G., Papaconstantinou, J., Torres-Ramos, C. A., Ou, C.-N., Finegold, M. &lt;strong&gt;Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I.&lt;/strong&gt; Nature Genet. 10: 453-460, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7545495/&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;7545495&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0895-453&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="7545495">Grompe et al. (1995)</a> demonstrated that treatment of affected animals with NTBC abolished neonatal lethality, corrected liver function, and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged life span of affected animals resulted in a phenotype analogous to human tyrosinemia type I, including hepatocellular carcinoma. These animals will serve as a useful model for studies of the pathophysiology and treatment of hereditary tyrosinemia type I as well as hepatic cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7545495" 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 mice deficient in FAH through targeted disruption of the Fah gene, <a href="#50" class="mim-tip-reference" title="Overturf, K., Al-Dhalimy, M., Tanguay, R., Brantly, M., Ou, C.-N., Finegold, M., Grompe, M. &lt;strong&gt;Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I.&lt;/strong&gt; Nature Genet. 12: 266-273, 1996. Note: Erratum: Nature Genet. 12: 458 only, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8589717/&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;8589717&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0396-266&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="8589717">Overturf et al. (1996)</a> found that as few as 1,000 transplanted wildtype hepatocytes were able to repopulate mutant liver, demonstrating their strong competitive growth advantage. Mutant hepatocytes corrected in situ by retroviral gene transfer were also positively selected. In mutant animals treated by multiple retrovirus injections, more than 90% of hepatocytes became FAH positive and liver function was restored to normal. These studies were prompted by a number of observations including the finding that the livers of patients with hereditary tyrosinemia frequently contained discrete nodules with FAH enzyme activity, due to a somatic reversion event (<a href="#36" class="mim-tip-reference" title="Kvittingen, E. A., Rootwelt, H., Brandtzaeg, P., Bergan, A., Berger, R. &lt;strong&gt;Hereditary tyrosinemia type I: self-induced correction of the fumarylacetoacetase defect.&lt;/strong&gt; J. Clin. Invest. 91: 1816-1821, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8473520/&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;8473520&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI116393&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="8473520">Kvittingen et al., 1993</a>). <a href="#71" class="mim-tip-reference" title="Wilson, J. M. &lt;strong&gt;Round two for liver gene therapy.&lt;/strong&gt; Nature Genet. 12: 232-233, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8589710/&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;8589710&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0396-232&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="8589710">Wilson (1996)</a> commented on the significance of these results for the liver gene therapy for genetic diseases in general. He stated that, based on the encouraging data in the mouse model, it would seem reasonable to evaluate this approach in patients with hereditary tyrosinemia. A similar approach might be considered for other liver metabolic diseases in which genetically corrected hepatocytes would have a selective advantage over degenerating mutant cells. <a href="#71" class="mim-tip-reference" title="Wilson, J. M. &lt;strong&gt;Round two for liver gene therapy.&lt;/strong&gt; Nature Genet. 12: 232-233, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8589710/&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;8589710&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0396-232&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="8589710">Wilson (1996)</a> suggested that a useful extension of this approach might be to introduce into the vector a gene that confers upon the hepatocyte a selective advantage such as resistance to a hepatotoxic drug. This concept was being developed in bone marrow using the multidrug resistance (MDR) gene (<a href="/entry/171050">171050</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8473520+8589710+8589717" 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="#49" class="mim-tip-reference" title="Overturf, K., Al-Dhalimy, M., Ou, C. N., Finegold, M., Tanguay, R., Lieber, A., Kay, M., Grompe, M. &lt;strong&gt;Adenovirus-mediated gene therapy in a mouse model of hereditary tyrosinemia type I.&lt;/strong&gt; Hum. Gene Ther. 8: 513-521, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9095403/&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;9095403&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1089/hum.1997.8.5-513&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="9095403">Overturf et al. (1997)</a> injected Fah-deficient mice with a first-generation adenoviral vector expressing the human FAH gene and followed them for up to 9 months. Nontreated FAH mutant control mice died within 6 weeks from fulminant liver failure, whereas FAH adenovirus-infected animals survived until sacrifice at 2 to 9 months. Hepatocellular cancer developed in 9 of 13 virus-treated animals. Immunohistochemical analysis revealed a mosaic of FAH-deficient and FAH-positive cells in all animals and liver function tests were improved compared to controls. Even mice harvested 9 months after viral infection had more than 50% FAH-positive cells. These results demonstrated a strong selective advantage of FAH-expressing cells in an FAH-deficient liver but also illustrated the danger of carcinomas arising from FAH-deficient hepatocytes in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9095403" 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>The 'albino lethal' mouse, first described by <a href="#17" class="mim-tip-reference" title="Gluecksohn-Waelsch, S. &lt;strong&gt;Genetic control of morphogenetic and biochemical differentiation: lethal albino deletions in the mouse.&lt;/strong&gt; Cell 16: 225-237, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/36985/&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;36985&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0092-8674(79)90001-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="36985">Gluecksohn-Waelsch (1979)</a>, has a large deletion on chromosome 7, including the albino locus and the Fah gene. Another Fah-deficient mouse was generated by targeted disruption of the Fah gene (<a href="#18" class="mim-tip-reference" title="Grompe, M., Lindstedt, S., Al-Dhalimy, M., Kennaway, N. G., Papaconstantinou, J., Torres-Ramos, C. A., Ou, C.-N., Finegold, M. &lt;strong&gt;Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I.&lt;/strong&gt; Nature Genet. 10: 453-460, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7545495/&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;7545495&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0895-453&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="7545495">Grompe et al., 1995</a>). <a href="#9" class="mim-tip-reference" title="Endo, F., Kubo, S., Awata, H., Kiwaki, K., Katoh, H., Kanegae, Y., Saito, I., Miyazaki, J., Yamamoto, T., Jakobs, C., Hattori, S., Matsuda, I. &lt;strong&gt;Complete rescue of lethal albino c14o5 mice by null mutation of 4-hydroxyphenylpyruvate-dioxygenase and induction of apoptosis of hepatocytes in these mice in vivo retrieval of the tyrosine catabolic pathway.&lt;/strong&gt; J. Biol. Chem. 272: 24426-24432, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9305902/&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;9305902&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.272.39.24426&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="9305902">Endo et al. (1997)</a> generated mice with disruption of both the Fah gene and the Hpd gene, which encodes 4-hydroxyphenylpyruvate dioxygenase at a step earlier in the metabolic pathway. This doubly mutant tyrosinemic mouse model showed apoptosis of hepatocytes and acute onset of liver failure after administration of homogentisic acid (HGA), the intermediate metabolite between the enzymes HPD and FAH (<a href="#29" class="mim-tip-reference" title="Kubo, S., Sun, M., Miyahara, M., Umeyama, K., Urakami, K., Yamamoto, T., Jakobs, C., Matsuda, I., Endo, F. &lt;strong&gt;Hepatocyte injury in tyrosinemia type 1 is induced by fumarylacetoacetate and is inhibited by caspase inhibitors.&lt;/strong&gt; Proc. Nat. Acad. Sci. 95: 9552-9557, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9689118/&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;9689118&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=9689118[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/10.1073/pnas.95.16.9552&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="9689118">Kubo et al., 1998</a>). Cytochrome c was released from mitochondria prior to liver failure in the double-mutant mice after administration of HGA. In a cell-free system, the addition of fumarylacetoacetate induced release of cytochrome c from the mitochondria. <a href="#29" class="mim-tip-reference" title="Kubo, S., Sun, M., Miyahara, M., Umeyama, K., Urakami, K., Yamamoto, T., Jakobs, C., Matsuda, I., Endo, F. &lt;strong&gt;Hepatocyte injury in tyrosinemia type 1 is induced by fumarylacetoacetate and is inhibited by caspase inhibitors.&lt;/strong&gt; Proc. Nat. Acad. Sci. 95: 9552-9557, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9689118/&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;9689118&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=9689118[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/10.1073/pnas.95.16.9552&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="9689118">Kubo et al. (1998)</a> also found that caspase inhibitors were highly effective in preventing the liver failure induced by HGA in the double-mutant mice. Therefore, fumarylacetoacetate apparently induces the release of cytochrome c, which in turn triggers activation of the caspase cascade in hepatocytes of subjects with hereditary tyrosinemia type I. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9305902+9689118+7545495+36985" 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>Mice homozygous for certain chromosome 7 deletions that include Fah die perinatally as a result of liver dysfunction and exhibit a complex syndrome characterized by structural abnormalities and alterations in gene expression in the liver and kidney. <a href="#1" class="mim-tip-reference" title="Aponte, J. L., Sega, G. A., Hauser, L. J., Dhar, M. S., Withrow, C. M., Carpenter, D. A., Rinchik, E. M., Culiat, C. T., Johnson, D. K. &lt;strong&gt;Point mutations in the murine fumarylacetoacetate hydrolase gene: animal models for the human genetic disorder hereditary tyrosinemia type 1.&lt;/strong&gt; Proc. Nat. Acad. Sci. 98: 641-645, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11209059/&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;11209059&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11209059[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/10.1073/pnas.98.2.641&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="11209059">Aponte et al. (2001)</a> showed that 2 independent, postnatally lethal mutations induced by N-ethyl-N-nitrosourea were alleles of Fah. One was a missense mutation in exon 6, and the other a splice mutation causing loss of exon 7, with subsequent frameshift in the resulting mRNA, and a severe reduction of Fah mRNA levels. Increased levels of the diagnostic metabolite succinylacetone in the urine of both mutants indicated that these mutations cause a decrease in Fah enzymatic activity. The mutants were proposed as mouse models for acute and chronic forms of human hepatorenal tyrosinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11209059" 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="#47" class="mim-tip-reference" title="Malpuech, G., Mattei, J. F., Gaulme, J., Palcoux, J. B., Lesec, G., Vanlieferinghen, P. &lt;strong&gt;Association, chez le meme sujet, d&#x27;une deletion du bras court du chromosome 4 (4p-) et d&#x27;un deficit complet en parahydroxyphenylpyruvate oxydase hepatique (tyrosinose).&lt;/strong&gt; J. Genet. Hum. 29: 455-461, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7328420/&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;7328420&lt;/a&gt;]" pmid="7328420">Malpuech et al. (1981)</a> described tyrosinemia in a child with partial monosomy 4p-. The parents were not consanguineous and were chromosomally normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7328420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Berube1989" class="mim-tip-reference" title="Berube, D., Phaneuf, D., Tanguay, R. M., Gagne, R. &lt;strong&gt;Assignment of the fumarylacetoacetate hydrolase gene to chromosome 15q23-15q25. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 51: 962 only, 1989.">Berube et al. (1989)</a>; <a href="#Fritzell1964" class="mim-tip-reference" title="Fritzell, S., Jagenburg, O. R., Schnurer, L. B. &lt;strong&gt;Familial cirrhosis of the liver, renal tubular defects with rickets and impaired tyrosine metabolism.&lt;/strong&gt; Acta Paediat. 53: 18-32, 1964.">Fritzell et al. (1964)</a>; <a href="#Gaull1968" class="mim-tip-reference" title="Gaull, G. E., Rassin, D. K., Sturman, J. A. &lt;strong&gt;Significance of hypermethioninaemia in acute tyrosinosis. (Letter)&lt;/strong&gt; Lancet 291: 1318-1319, 1968. Note: Originally Volume I.">Gaull et al. (1968)</a>; <a href="#Halvorsen1964" class="mim-tip-reference" title="Halvorsen, S., Gjessing, L. R. &lt;strong&gt;Studies of tyrosinosis. I. Effect of low-tyrosine and low-phenylalanine diet.&lt;/strong&gt; Brit. Med. J. 2: 1171-1173, 1964.">Halvorsen and Gjessing (1964)</a>; <a href="#Kang1970" class="mim-tip-reference" title="Kang, E. S., Gerald, P. S. &lt;strong&gt;Hereditary tyrosinemia and abnormal pyrrole metabolism: a patient with hereditary tyrosinemia is described who developed metabolic and clinical changes compatible with acute intermittent porphyria.&lt;/strong&gt; J. Pediat. 77: 397-406, 1970.">Kang and Gerald (1970)</a>; <a href="#Kvittingen1986" class="mim-tip-reference" title="Kvittingen, E. A., Jellum, E., Stokke, O., Flatmark, A., Bergan, A., Sodal, G., Halvorsen, S., Schrumpf, E., Gjone, E. &lt;strong&gt;Liver transplantation in a 23-year-old tyrosinaemia patient: effects on the renal tubular dysfunction.&lt;/strong&gt; J. Inherit. Metab. Dis. 9: 216-224, 1986.">Kvittingen et
al. (1986)</a>; <a href="#Kvittingen1986" class="mim-tip-reference" title="Kvittingen, E. A., Jellum, E., Stokke, O., Flatmark, A., Bergan, A., Sodal, G., Halvorsen, S., Schrumpf, E., Gjone, E. &lt;strong&gt;Liver transplantation in a 23-year-old tyrosinaemia patient: effects on the renal tubular dysfunction.&lt;/strong&gt; J. Inherit. Metab. Dis. 9: 216-224, 1986.">Kvittingen et al. (1986)</a>; <a href="#Kvittingen1981" class="mim-tip-reference" title="Kvittingen, E. A., Jellum, E., Stokke, O. &lt;strong&gt;Assay of fumarylacetoacetate fumarylhydrolase in human liver: deficient activity in a case of hereditary tyrosinemia.&lt;/strong&gt; Clin. Chim. Acta 115: 311-319, 1981.">Kvittingen et al. (1981)</a>; <a href="#La1967" class="mim-tip-reference" title="La Du, B. N. &lt;strong&gt;The enzymatic deficiency in tyrosinemia.&lt;/strong&gt; Am. J. Dis. Child. 113: 54-57, 1967.">La Du
(1967)</a>; <a href="#Laberge1969" class="mim-tip-reference" title="Laberge, C. &lt;strong&gt;Hereditary tyrosinemia in a French-Canadian isolate.&lt;/strong&gt; Am. J. Hum. Genet. 21: 36-45, 1969.">Laberge (1969)</a>; <a href="#Paradis1990" class="mim-tip-reference" title="Paradis, K., Weber, A., Seidman, E. G., Larochelle, J., Garel, L., Lenaerts, C., Roy, C. C. &lt;strong&gt;Liver transplantation for hereditary tyrosinemia: the Quebec experience.&lt;/strong&gt; Am. J. Hum. Genet. 47: 338-342, 1990.">Paradis et al. (1990)</a>; <a href="#Pettit1985" class="mim-tip-reference" title="Pettit, B. R., Kvittingen, E. A., Leonard, J. V. &lt;strong&gt;Early prenatal diagnosis of hereditary tyrosinaemia. (Letter)&lt;/strong&gt; Lancet 325: 1038 only, 1985. Note: Originally Volume I.">Pettit et al. (1985)</a>; <a href="#Scriver1967" class="mim-tip-reference" title="Scriver, C. R., Partington, M. W., Sass-Kortsak, A. &lt;strong&gt;Conference on hereditary tyrosinemia held at the Hospital for Sick Children.&lt;/strong&gt; Canad. Med. Assoc. J. 97: 1045-1100, 1967.">Scriver et al. (1967)</a>; <a href="#Tuchman1985" class="mim-tip-reference" title="Tuchman, M., Freese, D. K., Sharp, H. L., Whitley, C. B., Ramnaraine, M. L., Ulstrom, R. A., Najarian, J. S., Ascher, N., Buist, N. R. M., Terry, A. B. &lt;strong&gt;Persistent succinylacetone excretion after liver transplantation in a patient with hereditary tyrosinaemia type I.&lt;/strong&gt; J. Inherit. Metab. Dis. 8: 21-24, 1985.">Tuchman et al. (1985)</a>; <a href="#Weinberg1976" class="mim-tip-reference" title="Weinberg, A. G., Mize, C. E., Vorthen, H. G. &lt;strong&gt;Occurrence of hepatoma in chronic form of hereditary tyrosinemia.&lt;/strong&gt; J. Pediat. 88: 434-438, 1976.">Weinberg et al. (1976)</a>; <a href="#Whelan1974" class="mim-tip-reference" title="Whelan, D. T., Zannoni, V. G. &lt;strong&gt;Microassay of tyrosine-amino transferase and p-hydroxyphenylpyruvic acid oxidase in mammalian liver and patients with hereditary tyrosinemia.&lt;/strong&gt; Biochem. Med. 9: 19-31, 1974.">Whelan and Zannoni (1974)</a>
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[<a href="https://doi.org/10.1073/pnas.98.2.641" target="_blank">Full Text</a>]
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<strong>Splicing mutations, mainly IVS6-1(G-T), account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients.</strong>
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[<a href="https://doi.org/10.1002/humu.10084" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.jpeds.2013.10.001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00109-005-0648-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0046-8177(89)90179-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.272.39.24426" target="_blank">Full Text</a>]
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<strong>Homotransplantation of the liver in a patient with hepatoma and hereditary tyrosinemia.</strong>
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[<a href="https://doi.org/10.1016/s0022-3476(78)80893-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1651-2227.1964.tb07202.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/pd.1970020307" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-197007000-00004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(68)92343-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(65)80002-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(79)90001-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0895-453" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199408113310603" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380060113" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/bmj.2.5418.1171" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/adc.41.217.238" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(85)92132-4" target="_blank">Full Text</a>]
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<strong>Neonatal screen for hereditary tyrosinaemia type I. (Letter)</strong>
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[<a href="https://doi.org/10.1016/0140-6736(92)92724-t" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/a:1005410820201" target="_blank">Full Text</a>]
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<strong>Evidence for liver disease preceding amino acid abnormalities in hereditary tyrosinemia.</strong>
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[<a href="https://doi.org/10.1056/NEJM198305263082105" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(70)80006-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.95.16.9552" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1985.tb02039.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00496047" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-198307000-00005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01799465" target="_blank">Full Text</a>]
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Kvittingen, E. A., Jellum, E., Stokke, O.
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[<a href="https://doi.org/10.1016/0009-8981(81)90244-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI116393" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-199201000-00008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archpedi.1967.02090160104010" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.74.10.4641" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0140-6736(92)92685-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199002153220704" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1089/hum.1997.8.5-513" target="_blank">Full Text</a>]
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Overturf, K., Al-Dhalimy, M., Tanguay, R., Brantly, M., Ou, C.-N., Finegold, M., Grompe, M.
<strong>Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I.</strong>
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[<a href="https://doi.org/10.1038/ng0396-266" target="_blank">Full Text</a>]
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Paradis, K., Weber, A., Seidman, E. G., Larochelle, J., Garel, L., Lenaerts, C., Roy, C. C.
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Perry, T. L., Hardwick, D. F., Dixon, G. H., Dolman, C. L., Hansen, S.
<strong>Hypermethioninemia: a metabolic disorder associated with cirrhosis, islet cell hyperplasia, and renal tubular degeneration.</strong>
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Pettit, B. R., Kvittingen, E. A., Leonard, J. V.
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[<a href="https://doi.org/10.1016/s0140-6736(85)91633-2" target="_blank">Full Text</a>]
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<strong>Deficient DNA-ligase activity in the metabolic disease tyrosinemia type I.</strong>
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[<a href="https://doi.org/10.1073/pnas.95.21.12614" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)7:3&lt;239::AID-HUMU8&gt;3.0.CO;2-5" target="_blank">Full Text</a>]
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<strong>Visceral pathology of hereditary tyrosinemia type I.</strong>
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<p class="mim-text-font">
Schultz, M. J., Netzel, B. C., Singh R. H., Pino, G. B., Gavrilov, D. K., Oglesbee, D., Raymond, K. M., Rinaldo, P., Tortorelli, S., Smith, W. E., Matern, D.
<strong>Laboratory monitoring of patients with hereditary tyrosinemia type I.</strong>
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[<a href="https://doi.org/10.1016/j.ymgme.2020.06.001" target="_blank">Full Text</a>]
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<strong>Hereditary tyrosinemia and tyrosyluria in a French-Canadian geographic isolate.</strong>
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[<a href="https://doi.org/10.1001/archpedi.1967.02090160091008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00007890-199211000-00035" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:4&lt;291::AID-HUMU1&gt;3.0.CO;2-9" target="_blank">Full Text</a>]
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<strong>Molecular cloning and expression of the c-DNA encoding the enzyme deficient in hereditary tyrosinemia: evidence for molecular heterogeneity. (Abstract)</strong>
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<strong>Six novel mutations in the fumarylacetoacetate hydrolase gene of patients with hereditary tyrosinemia type I.</strong>
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)7:4&lt;367::AID-HUMU14&gt;3.0.CO;2-0" target="_blank">Full Text</a>]
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<p class="mim-text-font">
Tuchman, M., Freese, D. K., Sharp, H. L., Whitley, C. B., Ramnaraine, M. L., Ulstrom, R. A., Najarian, J. S., Ascher, N., Buist, N. R. M., Terry, A. B.
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[<a href="https://doi.org/10.1007/BF01805479" target="_blank">Full Text</a>]
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van Spronsen, F. J., Berger, R., Smit, G. P. A., de Klerk, J. B. C., Duran, M., Bijleveld, C. M. A., van Faassen, H., Slooff, M. J. H., Heymans, H. S. A.
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[<a href="https://doi.org/10.1007/BF03335416" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(76)80259-4" target="_blank">Full Text</a>]
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<strong>Microassay of tyrosine-amino transferase and p-hydroxyphenylpyruvic acid oxidase in mammalian liver and patients with hereditary tyrosinemia.</strong>
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[<a href="https://doi.org/10.1016/0006-2944(74)90079-9" target="_blank">Full Text</a>]
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<strong>Round two for liver gene therapy.</strong>
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[<a href="https://doi.org/10.1038/ng0396-232" target="_blank">Full Text</a>]
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<strong>Tyrosinosis.</strong>
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[<a href="https://doi.org/10.1111/j.1749-6632.1963.tb36962.x" target="_blank">Full Text</a>]
</p>
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Sonja A. Rasmussen - updated : 08/04/2022
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Hilary J. Vernon - updated : 08/31/2020<br>Victor A. McKusick - updated : 10/12/2005<br>Victor A. McKusick - updated : 9/24/2002<br>George E. Tiller - updated : 1/22/2002<br>Victor A. McKusick - updated : 2/26/2001<br>Ada Hamosh - updated : 2/6/2001<br>Victor A. McKusick - updated : 6/7/1999<br>Victor A. McKusick - updated : 11/2/1998<br>Victor A. McKusick - updated : 10/14/1998<br>Victor A. McKusick - updated : 9/29/1998<br>Victor A. McKusick - updated : 6/23/1997
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Creation Date:
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Victor A. McKusick : 6/4/1986
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carol : 04/11/2024
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<strong>#</strong> 276700
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TYROSINEMIA, TYPE I; TYRSN1
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<em>Alternative titles; symbols</em>
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HEPATORENAL TYROSINEMIA<br />
FUMARYLACETOACETASE DEFICIENCY<br />
FAH DEFICIENCY
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<strong>SNOMEDCT:</strong> 124536006, 410056006; &nbsp;
<strong>ORPHA:</strong> 882; &nbsp;
<strong>DO:</strong> 0050726; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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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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15q25.1
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Tyrosinemia, type I
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276700
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Autosomal recessive
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3
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FAH
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613871
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because tyrosinemia type I (TYRSN1) is caused by homozygous or compound heterozygous mutation in the FAH gene (613871), which encodes fumarylacetoacetate hydrolase, on chromosome 15q25.</p>
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<strong>Description</strong>
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<p>Hereditary tyrosinemia type I (TYRSN1) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase (FAH), the last enzyme of tyrosine degradation. The disorder is characterized by progressive liver disease and a secondary renal tubular dysfunction leading to hypophosphatemic rickets. Onset varies from infancy to adolescence. In the most acute form patients present with severe liver failure within weeks after birth, whereas rickets may be the major symptom in chronic tyrosinemia. Untreated, patients die from cirrhosis or hepatocellular carcinoma at a young age (summary by Bliksrud et al., 2005). </p><p><strong><em>Genetic Heterogeneity of Hereditary Tyrosinemia</em></strong></p><p>
Tyrosinemia type II (TYRSN2; 276600), also known as Richner-Hanhart syndrome, is caused by mutation in the TAT gene (613018) on chromosome 16q22. Tyrosinemia type III (TYRNS3; 276710) is caused by mutation in the HPD gene (609695) on chromosome 12q24.</p>
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<strong>Clinical Features</strong>
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<p>Among the children of first-cousin parents, Lelong et al. (1963) observed 2 sons with cirrhosis, Fanconi renotubular syndrome, and marked increase in plasma tyrosine. In the sib most extensively observed, hepatosplenomegaly was discovered at 3 months of age and rickets at 18 months. Malignant changes developed in the liver, and death from pulmonary metastases occurred shortly before his 5th birthday. The author suggested that the basic defect concerns an enzyme involved with tyrosine metabolism. Earlier, Himsworth (1950) described a similar case. Zetterstrom (1963) studied 7 cases coming from an isolated area of southwestern Sweden. Halvorsen et al. (1966) gave details on 6 cases from Norway. </p><p>Perry et al. (1965) described 3 sibs (2 females and a male) in 1 sibship who died in the third month after an illness characterized by irritability and progressive somnolence, and terminally by a tendency to bleed and hypoglycemia. A peculiar odor was noted. Pathologic changes included hepatic cirrhosis, renal tubular dilatation, and pancreatic islet hypertrophy. Biochemical studies showed generalized amino aciduria, marked elevation of methionine in the serum, and a disproportionately high urinary excretion of methionine. Alpha-keto-gamma-methiolbutyric acid was present in the urine and may account for the peculiar odor. The hypertrophy of the islets of Langerhans was probably due to stimulation by methionine or one of its metabolites. It seems likely that the disorder in the patients of Perry et al. (1965) was tyrosinemia since hypermethioninemia occurs secondary to liver failure in that condition (Scriver et al., 1967; Gaull et al., 1970). </p><p>Gentz et al. (1965) described 7 patients in 4 families with multiple renal tubular defects like those of the de Toni-Debre-Fanconi syndrome, nodular cirrhosis of the liver, and impaired tyrosine metabolism. In the urine, p-hydroxyphenyllactic acid was excreted in unusually large amounts. A total lack of liver p-hydroxyphenylpyruvate oxidase activity was demonstrated. Tyrosine-alpha-ketoglutarate transaminase was normal. </p><p>Scriver et al. (1967) identified the disease in 35 French Canadian infants, of whom 16 were sibs (i.e., 2 or more in each of several families). Marked tyrosinemia and tyrosyluria were present. The urine contained parahydroxyphenylpyruvic acid (PHPPA) and lactic and acetic derivatives. Loading test with tyrosine and with PHPPA suggested deficient p-hydroxyphenylpyruvate oxidase activity, which was confirmed by assay of liver biopsy samples. In stage I, infants exhibit hepatic necrosis and hypermethioninemia. In stage II, nodular cirrhosis and chronic hepatic insufficiency without hypermethioninemia are found. In stage III, renal tubular damage (Baber syndrome), often with hypophosphatemic rickets, appears. Low tyrosine diet arrested progression of the disease. </p><p>Lindblad et al. (1987) suggested that cardiomyopathy, usually subclinical, is a frequent finding.</p><p>Mitchell et al. (1990) pointed out the significance of neurologic crises in this disorder. They found that of 48 children with tyrosinemia identified on neonatal screening since 1970, 20 (42%) had neurologic crises that began at the mean age of 1 year and led to 104 hospital admissions. These abrupt episodes of peripheral neuropathy were characterized by severe pain with extensor hypertonia (in 75%), vomiting or paralytic ileus (69%), muscle weakness (29%), and self-mutilation (8%). In 8 children, mechanical ventilation was required because of paralysis and 14 of the 20 children died. Between crises, most survivors regained normal function. They could identify no reliable biochemical marker for the crises. Urinary excretion of delta-aminolevulinic acid, a neurotoxic intermediate of porphyrin biosynthesis, was elevated during both crises and asymptomatic periods. Electrophysiologic studies and neuromuscular biopsies showed axonal degeneration and secondary demyelination. Thus, they demonstrated that episodes of acute, severe, peripheral neuropathy are common in this disorder and resemble the crises of the neuropathic porphyrias. </p><p><strong><em>Fumarylacetoacetase Pseudodeficiency</em></strong></p><p>
Kvittingen et al. (1985) described a family that may have had a pseudodeficiency gene. Presumed homozygotes for this gene had levels of fumarylacetoacetase activity only slightly higher than those in patients with tyrosinemia. No clinical abnormalities were observed. Kvittingen et al. (1992) studied a healthy 41-year-old female homozygous for the pseudodeficiency gene and 3 tyrosinemia families in which one or both parents were compound heterozygotes for the tyrosinemia and pseudodeficiency genes. Only 2 of 7 patients with typical chronic tyrosinemia had definite immunoreactivity in fibroblasts when bovine fumarylacetoacetase antibodies were used; none of the patients with the acute type had detectable immunoreactive protein in fibroblast extracts. Twenty-eight patients with hereditary tyrosinemia of various clinical phenotypes were tested. The pseudodeficiency gene product gave almost no detectable immunoreactivity in fibroblasts. </p>
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<strong>Biochemical Features</strong>
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<p>La Du and Gjessing (1972) discussed evidence against the hypothesis that tyrosinemia type I is a p-hydroxyphenylpyruvic acid oxidase deficiency. Lindblad et al. (1977) suggested that the primary defect is in fumarylacetoacetase (EC 3.7.1.2), which leads to accumulation of succinylacetone and succinylacetoacetate. Porphobilinogen synthetase is inhibited by these substances and the authors suggested that the severe liver and kidney damage of tyrosinemia is caused by accumulation of tyrosine metabolites. A puzzling feature of hereditary tyrosinemia has been episodes similar to acute hepatic porphyria, with excretion of 5-aminolevulinic acid in the urine. The inhibition of porphobilinogen synthase explains this feature. Fumarylacetoacetase is the enzyme primarily deficient; deficiency of parahydroxyphenylpyruvate oxidase is secondary (Scriver, 1982). </p><p>Tanguay et al. (1990) concluded that the acute form of hereditary tyrosinemia has absence of FAH enzyme protein, whereas the chronic form has presence of immunoreactive enzyme protein. They quoted the work of others supporting these findings. </p><p>Prieto-Alamo and Laval (1998) noted that the defect in FAH in tyrosinemia type I results in accumulation of succinylacetone (SA), which reacts with amino acids and proteins to form stable adducts via Schiff base formation, lysine being the most reactive amino acid. Patients with this disorder surviving beyond infancy are at considerable risk for the development of hepatocellular carcinoma, and a high level of chromosomal breakage is observed in tyrosinemia cells, suggesting a defect in the processing of DNA. Prieto-Alamo and Laval (1998) showed that the overall DNA-ligase activity is low in tyrosinemia cells (about 20% of normal) and that Okazaki fragments are rejoined at a reduced rate compared with normal fibroblasts. No mutation was found by sequencing the ligase I cDNA (LIG1; 126391) from tyrosinemia cells, and the level of expression of the ligase I mRNA was similar in normal and tyrosinemia fibroblasts, suggesting the presence of a ligase inhibitor. SA was shown to inhibit in vitro the overall DNA-ligase activity present in normal cell extracts. The activity of purified T4 DNA-ligase, whose active site is also a lysine residue, was inhibited by SA in a dose-dependent manner. These results suggested that accumulation of SA reduces the overall ligase activity in tyrosinemia cells and indicated that metabolic errors may play a role in regulating enzymatic activities involved in DNA replication and repair. </p>
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<strong>Pathogenesis</strong>
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<p>It had been postulated that the severe liver damage in tyrosinemia is the result of defective degradation of tyrosine. Hostetter et al. (1983) showed, however, that liver damage is prenatal in onset (as indicated by greatly elevated alpha-fetoprotein in cord blood) and that hypertyrosinemia developed only postnatally. Thus, therapy aimed at reduction of the elevated tyrosine level is unlikely to be of fundamental value. </p>
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<strong>Population Genetics</strong>
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<p>De Braekeleer and Larochelle (1990) estimated the prevalence of hereditary tyrosinemia at birth as 1/1,846 liveborn and the carrier rate as 1/20 inhabitants in the Saguenay-Lac-Saint-Jean region. The mean coefficient of inbreeding was only slightly elevated in the tyrosinemic group compared to a control group and was due to remote consanguinity. The mean kinship coefficient was 2.3 times higher in the tyrosinemic group than in the control group. This was interpreted as indicating founder effect. </p>
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<strong>Diagnosis</strong>
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<p>Prenatal diagnosis of tyrosinemia is possible either by the detection of succinylacetone in the amniotic fluid (Gagne et al., 1982) or by measurement of fumarylacetoacetase in cultured amniotic cells (Kvittingen et al., 1983). Holme et al. (1985) demonstrated the feasibility of enzymatic diagnosis in chorionic villus material. Also, they showed that normal red cells have fumarylacetoacetase activity. They proposed that studies of red cells permit rapid diagnosis and recognition of heterozygotes and that enzyme replacement by blood transfusion may help patients over acute metabolic crises and until such time as definitive therapy by orthotopic liver transplantation (Fisch et al., 1978; Gartner et al., 1984) can be performed. </p><p>Laberge et al. (1990) described an enzyme-linked immunosorbent assay (ELISA) to measure the deficient enzyme in dried blood spots in this disorder. As mean levels of blood tyrosine in newborn specimens have declined, probably as a result of dietary changes and early discharge from nurseries, the traditional approach to screening for tyrosinemia, which was based on the fluorometric determination of tyrosine on the first dried blood spot received by neonatal screening programs, has required replacement. </p><p>As an aid to early diagnosis for early institution of drug therapy, Holme and Lindstedt (1992) suggested a neonatal screening test based on the measurement of porphobilinogen synthase activity. Porphobilinogen synthase activity is always low in patients with tyrosinemia type I. Holme and Lindstedt (1992) were not aware of any drug used neonatally or of conditions that would interfere with the test or mimic porphobilinogen synthase activity to result in a false-normal test. Specificity of the test is not absolute because homozygous porphobilinogen synthase deficiency (125270) would be detected; in this disorder also, early diagnosis would presumably benefit the patients. </p><p>Tanguay et al. (1990) identified RFLPs for 4 restriction sites within the FAH gene and proposed the development of a carrier detection test by linkage analysis.</p>
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<strong>Clinical Management</strong>
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<p>Dehner et al. (1989) reviewed the pathologic findings in the liver on the basis of the findings in children undergoing liver transplant. They concluded that to preclude hepatocellular carcinoma, a liver replacement is necessary before the age of 2 years. In the view of Van Spronsen et al. (1989) also, orthotopic liver transplantation is the only definitive therapy for both the metabolic and the oncologic problem in this disorder. </p><p>Russo and O'Regan (1990) reviewed the pathologic findings in the liver and kidney. In the Hopital Sainte-Justine in Montreal, 16 patients had been evaluated for liver transplantation. Renal involvement was found to be 'more abnormal than expected.' The liver was transplanted in 7 patients of whom 2 also received kidney transplantation. Hepatocarcinoma was detected in 2 of 8 patients in whom the whole liver was examined. Of the 9 patients who did not receive transplants, 5 died; of the 7 transplant patients, 1 died in an instance of combined liver-kidney transplantation. The 6 patients who survived had normal liver function, normal growth, and no recurrence of neurologic crises on a normal diet. </p><p>Sokal et al. (1992) recommended orthotopic liver transplantation at an early stage. The procedure was performed in 4 children under 1 year of age, within 5 months of presentation and diagnosis. During the pretransplant period, intensive medical support and restriction of dietary tyrosine was initiated to improve the patient's condition and promote weight gain. </p><p>As an alternative to liver transplantation, Lindstedt et al. (1992) treated patients with type I tyrosinemia with a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPD; EC 1.13.11.27) to prevent the formation of maleylacetoacetate and fumarylacetoacetate and their saturated derivatives. The agent used in 1 acute and 4 subacute/chronic cases was 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Signs of improvement included decrease in several metabolites, correction of the almost complete inhibition of porphobilinogen synthase in erythrocytes, decrease in alpha-fetoprotein, improved liver and renotubular function, and regression of hepatic abnormalities by computed tomography. No side effects were encountered. Inhibition of 4-hydroxyphenylpyruvate dioxygenase may prevent the development of liver cirrhosis and abolish or diminish the risk of liver cancer. Furthermore, normalization of porphyrin synthesis should eliminate the risk of porphyric crises. </p><p>Laine et al. (1995) studied renal function after orthotopic liver transplantation and found that the patients had normal glomerular filtration rates but showed signs of tubular dysfunction 18 to 36 months after operation. </p><p>Holme and Lindstedt (1998) stated that since the first trial of NTBC treatment for type I tyrosinemia in 1991, over 220 patients had been treated by the drug using a protocol that included regular follow-up with reports of clinical and laboratory investigations. Only 10% of the patients had not responded clinically to NTBC treatment. In half of these patients, successful liver transplantation had been performed, which further reduced the mortality rate during infancy to 5%. The data indicated a decreased risk for early development of hepatocellular carcinoma in patients who started treatment at an early age. Of the 101 patients aged 2 to 8 years who had started NTBC treatment before 2 years of age, no patient developed cancer after 2 years of age. </p><p>Bendadi et al. (2014) evaluated cognitive functioning of 10 patients with tyrosinemia type I who were receiving treatment with NTBC and a protein-restricted diet. IQ scores of patients were significantly lower than scores among their unaffected sibs (71 vs 91, p = 0.008). Both verbal and performance scores showed significant differences. Repeated IQ measurements done at 2- to 3-year intervals in 5 patients showed a decline in average IQ over time. Lower IQ scores were associated with special education attendance. No significant association was observed between IQ score and plasma tyrosine or phenylalanine concentrations. </p><p>Schultz et al. (2020) developed a liquid chromatography tandem mass spectrometry methodology to measure tyrosine, phenylalanine, methionine, NTBC, and succinylacetone across a wide range of relevant concentrations in dried whole blood spots. This assay enables measurement of metabolites that are important for treatment monitoring in tyrosinemia type I, with subsequent adjustment of the patient's treatment regimen, including optimization of NTBC dosing to keep succinylacetone levels in the normal range. The metabolites were shown to be stable in blood that was collected in a range of anticoagulants (including sodium heparin and EDTA) and across a range of storage conditions (including heated, ambient, frozen, and refrigerated), except that succinylacetone was substantially degraded after being stored in a heated environment. Schultz et al. (2020) concluded that this assay could enable home collection of blood specimens in patients with tyrosinemia type I, as well as serve as second tier assay to reduce false-positive newborn screening results in places that only assay for tyrosine on newborn screening. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of TYRSN1 in the families reported by Grompe et al. (1994) was consistent with autosomal recessive inheritance. </p>
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<strong>Molecular Genetics</strong>
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<p>Grompe et al. (1994) found that 100% of patients with tyrosinemia type I from the Saguenay-Lac-Saint-Jean region of Quebec and 28% of TYRSN1 patients from other regions of the world carry a splice donor site mutation in intron 12 of the FAH gene (613871.0003). Of 25 patients from the Saguenay-Lac-Saint-Jean region, 20 were homozygous. The frequency of carrier status, based on screening of blood spots from newborns, was about 1 per 25 in that region of Quebec and about 1 per 66 overall in Quebec. Using cDNA probes for the FAH gene, Demers et al. (1994) identified 10 haplotypes with 5 RFLPs in 118 normal chromosomes from the French Canadian population. Among 29 children with hereditary tyrosinemia, haplotype 6 was found to be strongly associated with disease, at a frequency of 90% as compared with approximately 18% in 35 control individuals. This frequency increased to 96% in the 24 patients originating from the Saguenay-Lac-Saint-Jean region. Most patients were found to be homozygous for a specific haplotype in this population. Analysis of 24 tyrosinemia patients from 9 countries gave a frequency of approximately 52% for haplotype 6, suggesting a relatively high association worldwide. </p><p>Kvittingen et al. (1994) demonstrated a mosaic pattern of immunoreactive FAH protein in liver tissue from 15 of 18 tyrosinemia type I patients of various ethnic origins. One additional patient had variable levels of FAH enzyme activity in liver tissue. In 4 patients exhibiting mosaicism of FAH protein, analysis for the tyrosinemia-causing mutations was performed in immunonegative and immunopositive areas of liver tissue by restriction digestion analysis and direct DNA sequencing. In all 4 patients, the immunonegative liver tissue contained the FAH mutations demonstrated in fibroblasts of the patients. In the immunopositive nodules of regenerating liver tissue, one of the mutated alleles apparently had reverted to the normal genotype. This genetic correction was observed for 3 different tyrosinemia-causing mutations. In each case, a mutant AT nucleotide pair was reverted to a normal GC pair. One of the mutations that showed reversion was the splice site mutation described in 613871.0003. Another was the glu357-to-ter mutation due to a G-to-T transversion at nucleotide 1069, which is described in 613871.0004. In a compound heterozygous patient, the same mutation was reverted to wildtype in all 4 nodules investigated. A gene conversion event or mitotic recombination between homologous chromosomes could theoretically explain the appearance of a normal allele in a compound heterozygote. Two of the patients with reverted mutations, however, were homozygous for their mutations, and no pseudogenes for FAH, for contribution of wildtype sequences, are known. Early embryonic mutation with selective growth of the mutated cells could account for the mosaicism, but a high incidence of such an event would indicate a precipitating factor. Chemical mutagenesis, reverting the disease-causing mutation, could result from the metabolites accumulating in tyrosinemia. Even if the metabolites are not direct mutagens, the compounds are toxic and induce cell necrosis with a subsequent accelerated regeneration of hepatocytes. Rapidly replicating cells are generally prone to mutations. Reversion of the genetic defect resulting from accelerated cell regeneration should be sought in other genetic diseases in tissues with an induced, or naturally high, rate of cell replication. </p><p>Hahn et al. (1995) reviewed 7 previously reported mutations in tyrosinemia type I and added 2 more identified in a compound heterozygote. </p><p>Timmers and Grompe (1996) reported 6 new mutations in the FAH gene in patients with hereditary tyrosinemia type I: 2 splice mutations, 3 missense mutations, and 1 nonsense mutation. </p><p>Rootwelt et al. (1996) classified 62 hereditary tyrosinemia type I patients of various ethnic origins clinically into acute, chronic, or intermediate phenotypes and screened for the 14 published causal mutations in the FAH gene. Restriction analysis of PCR-amplified genomic DNA identified 74% of the mutated alleles. The IVS12+5G-A mutation (613871.0003), which is predominant in French Canadian tyrosinemia type I patients, was the most common mutation being present in 32 alleles in patients from Europe, Pakistan, Turkey, and the United States. The IVS6-1G-T mutation (613871.0010), encountered in 14 alleles, was common in central and western Europe. There was an apparent 'Scandinavian' 1009G-to-A combined splice and missense mutation (12 alleles), a 'Pakistani' 192G-to-T splice mutation (11 alleles), a 'Turkish' D233V mutation (6 alleles), and a 'Finnish' or northern European W262X (613871.0009) mutation (7 alleles). Rootwelt et al. (1996) commented that some of the mutations seemed to predispose for acute and others for more chronic forms of tyrosinemia type I, although no clear-cut genotype/phenotype correlation could be established. </p><p>According to the review of St-Louis and Tanguay (1997), 26 mutations in the FAH gene had been reported in type I tyrosinemia. All consisted of single-base substitutions resulting in 16 amino acid replacements, 1 silent mutation causing a splicing defect, 5 nonsense codons, and 4 putative splicing defects. The mutations were spread over the entire FAH gene, with a particular clustering between amino acid residues 230 and 250. </p><p>Arranz et al. (2002) determined the FAH genotype in a group of 29 patients, most of them from the Mediterranean area, with hereditary tyrosinemia type I. They identified 7 novel mutations and 2 previously described mutations. At least one splice site mutation was found in 92.8% of patients, with IVS6-1G-T (613871.0010) accounting for 58.9% of the total number of alleles. The group of patients with splice mutations showed heterogeneous phenotypic patterns ranging from the acute form, with severe liver malfunction, to chronic forms, with renal manifestations and slow progressive hepatic alterations. Despite the high prevalence of the IVS12+5G-A mutation (613871.0003) in the northwestern European population, Arranz et al. (2002) found only 2 patients with this mutation from the group of 29 patients. One patient, who was a double heterozygote for a nonsense and a frameshift mutation, showed an atypical clinical picture of hypotonia and repeated infections. </p><p>Bliksrud et al. (2005) described revertant mosaicism in a patient with type I tyrosinemia. </p><p><strong><em>Fumarylacetoacetase Pseudodeficiency</em></strong></p><p>
Rootwelt et al. (1994) presented evidence for the existence of a 'pseudodeficiency' FAH allele. In an individual homozygous for pseudodeficiency of FAH and in 3 hereditary tyrosinemia type I families also carrying the pseudodeficiency allele, Western blotting of fibroblast extracts showed that the pseudodeficiency allele gave very little immunoreactive FAH protein, whereas Northern blot analysis revealed a normal amount of FAH mRNA. All the pseudodeficiency alleles were found to carry a 1021C-T transition, predicting an arg341-to-trp substitution (R341W; 613871.0006). Site-directed mutagenesis and expression in a rabbit reticulocyte lysate system demonstrated that the arg341-to-trp mutation gave reduced FAH activity and reduced amounts of the full-length protein. The normal and the mutated sequences could be distinguished by BsiEI restriction digestion of PCR products. Among 516 healthy volunteers of Norwegian origin, the R341W mutation was found in 2.2% of alleles. Testing for this specific mutation may solve the problem of prenatal diagnosis and carrier detection in families with compound heterozygote genotypes for type I tyrosinemia and pseudodeficiency. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Mice homozygous for an FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction. Grompe et al. (1995) demonstrated that treatment of affected animals with NTBC abolished neonatal lethality, corrected liver function, and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged life span of affected animals resulted in a phenotype analogous to human tyrosinemia type I, including hepatocellular carcinoma. These animals will serve as a useful model for studies of the pathophysiology and treatment of hereditary tyrosinemia type I as well as hepatic cancer. </p><p>In mice deficient in FAH through targeted disruption of the Fah gene, Overturf et al. (1996) found that as few as 1,000 transplanted wildtype hepatocytes were able to repopulate mutant liver, demonstrating their strong competitive growth advantage. Mutant hepatocytes corrected in situ by retroviral gene transfer were also positively selected. In mutant animals treated by multiple retrovirus injections, more than 90% of hepatocytes became FAH positive and liver function was restored to normal. These studies were prompted by a number of observations including the finding that the livers of patients with hereditary tyrosinemia frequently contained discrete nodules with FAH enzyme activity, due to a somatic reversion event (Kvittingen et al., 1993). Wilson (1996) commented on the significance of these results for the liver gene therapy for genetic diseases in general. He stated that, based on the encouraging data in the mouse model, it would seem reasonable to evaluate this approach in patients with hereditary tyrosinemia. A similar approach might be considered for other liver metabolic diseases in which genetically corrected hepatocytes would have a selective advantage over degenerating mutant cells. Wilson (1996) suggested that a useful extension of this approach might be to introduce into the vector a gene that confers upon the hepatocyte a selective advantage such as resistance to a hepatotoxic drug. This concept was being developed in bone marrow using the multidrug resistance (MDR) gene (171050). </p><p>Overturf et al. (1997) injected Fah-deficient mice with a first-generation adenoviral vector expressing the human FAH gene and followed them for up to 9 months. Nontreated FAH mutant control mice died within 6 weeks from fulminant liver failure, whereas FAH adenovirus-infected animals survived until sacrifice at 2 to 9 months. Hepatocellular cancer developed in 9 of 13 virus-treated animals. Immunohistochemical analysis revealed a mosaic of FAH-deficient and FAH-positive cells in all animals and liver function tests were improved compared to controls. Even mice harvested 9 months after viral infection had more than 50% FAH-positive cells. These results demonstrated a strong selective advantage of FAH-expressing cells in an FAH-deficient liver but also illustrated the danger of carcinomas arising from FAH-deficient hepatocytes in this disorder. </p><p>The 'albino lethal' mouse, first described by Gluecksohn-Waelsch (1979), has a large deletion on chromosome 7, including the albino locus and the Fah gene. Another Fah-deficient mouse was generated by targeted disruption of the Fah gene (Grompe et al., 1995). Endo et al. (1997) generated mice with disruption of both the Fah gene and the Hpd gene, which encodes 4-hydroxyphenylpyruvate dioxygenase at a step earlier in the metabolic pathway. This doubly mutant tyrosinemic mouse model showed apoptosis of hepatocytes and acute onset of liver failure after administration of homogentisic acid (HGA), the intermediate metabolite between the enzymes HPD and FAH (Kubo et al., 1998). Cytochrome c was released from mitochondria prior to liver failure in the double-mutant mice after administration of HGA. In a cell-free system, the addition of fumarylacetoacetate induced release of cytochrome c from the mitochondria. Kubo et al. (1998) also found that caspase inhibitors were highly effective in preventing the liver failure induced by HGA in the double-mutant mice. Therefore, fumarylacetoacetate apparently induces the release of cytochrome c, which in turn triggers activation of the caspase cascade in hepatocytes of subjects with hereditary tyrosinemia type I. </p><p>Mice homozygous for certain chromosome 7 deletions that include Fah die perinatally as a result of liver dysfunction and exhibit a complex syndrome characterized by structural abnormalities and alterations in gene expression in the liver and kidney. Aponte et al. (2001) showed that 2 independent, postnatally lethal mutations induced by N-ethyl-N-nitrosourea were alleles of Fah. One was a missense mutation in exon 6, and the other a splice mutation causing loss of exon 7, with subsequent frameshift in the resulting mRNA, and a severe reduction of Fah mRNA levels. Increased levels of the diagnostic metabolite succinylacetone in the urine of both mutants indicated that these mutations cause a decrease in Fah enzymatic activity. The mutants were proposed as mouse models for acute and chronic forms of human hepatorenal tyrosinemia. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Malpuech et al. (1981) described tyrosinemia in a child with partial monosomy 4p-. The parents were not consanguineous and were chromosomally normal. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Berube et al. (1989); Fritzell et al. (1964); Gaull et al. (1968);
Halvorsen and Gjessing (1964); Kang and Gerald (1970); Kvittingen et
al. (1986); Kvittingen et al. (1986); Kvittingen et al. (1981); La Du
(1967); Laberge (1969); Paradis et al. (1990); Pettit et al. (1985);
Scriver et al. (1967); Tuchman et al. (1985); Weinberg et al. (1976);
Whelan and Zannoni (1974)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
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<p class="mim-text-font">
Aponte, J. L., Sega, G. A., Hauser, L. J., Dhar, M. S., Withrow, C. M., Carpenter, D. A., Rinchik, E. M., Culiat, C. T., Johnson, D. K.
<strong>Point mutations in the murine fumarylacetoacetate hydrolase gene: animal models for the human genetic disorder hereditary tyrosinemia type 1.</strong>
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</p>
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<p class="mim-text-font">
Arranz, J. A., Pinol, F., Kozak, L., Perez-Cerda, C., Cormand, B., Ugarte, M., Riudor, E.
<strong>Splicing mutations, mainly IVS6-1(G-T), account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients.</strong>
Hum. Mutat. 20: 180-188, 2002.
[PubMed: 12203990]
[Full Text: https://doi.org/10.1002/humu.10084]
</p>
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Bendadi, F., de Koning, T. J., Visser, G., Prinsen, H. C. M. T., de Sain, M. G. M., Verhoeven-Duif, N., Sinnema, G., van Spronsen, F. J., van Hasselt, P. M.
<strong>Impaired cognitive functioning in patients with tyrosinemia type I receiving nitisinone.</strong>
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Berube, D., Phaneuf, D., Tanguay, R. M., Gagne, R.
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Endo, F., Kubo, S., Awata, H., Kiwaki, K., Katoh, H., Kanegae, Y., Saito, I., Miyazaki, J., Yamamoto, T., Jakobs, C., Hattori, S., Matsuda, I.
<strong>Complete rescue of lethal albino c14o5 mice by null mutation of 4-hydroxyphenylpyruvate-dioxygenase and induction of apoptosis of hepatocytes in these mice in vivo retrieval of the tyrosine catabolic pathway.</strong>
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[Full Text: https://doi.org/10.1074/jbc.272.39.24426]
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Fisch, R. O., McCabe, E. R. B., Doeden, D., Koep, L. J., Kohlhoff, J. G., Silverman, A., Starzl, T. E.
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J. Pediat. 93: 592-596, 1978.
[PubMed: 212542]
[Full Text: https://doi.org/10.1016/s0022-3476(78)80893-2]
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Fritzell, S., Jagenburg, O. R., Schnurer, L. B.
<strong>Familial cirrhosis of the liver, renal tubular defects with rickets and impaired tyrosine metabolism.</strong>
Acta Paediat. 53: 18-32, 1964.
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[Full Text: https://doi.org/10.1111/j.1651-2227.1964.tb07202.x]
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Gagne, R., Lescault, A., Grenier, A., Laberge, C., Melancon, S. B., Dallaire, L.
<strong>Prenatal diagnosis of hereditary tyrosinaemia: measurement of succinylacetone in amniotic fluid.</strong>
Prenatal Diag. 2: 185-188, 1982.
[PubMed: 7145846]
[Full Text: https://doi.org/10.1002/pd.1970020307]
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Gartner, J. C., Zitelli, B. J., Malatack, J. J., Shaw, B. W., Iwatsuki, S., Starzl, T. E.
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Pediatrics 74: 140-145, 1984.
[PubMed: 6377219]
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Gaull, G. E., Rassin, D. K., Solomon, G. E., Harris, R. C., Sturman, J. A.
<strong>Biochemical observations on so-called hereditary tyrosinemia.</strong>
Pediat. Res. 4: 337-344, 1970.
[PubMed: 4393588]
[Full Text: https://doi.org/10.1203/00006450-197007000-00004]
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<p class="mim-text-font">
Gaull, G. E., Rassin, D. K., Sturman, J. A.
<strong>Significance of hypermethioninaemia in acute tyrosinosis. (Letter)</strong>
Lancet 291: 1318-1319, 1968. Note: Originally Volume I.
[PubMed: 4172182]
[Full Text: https://doi.org/10.1016/s0140-6736(68)92343-x]
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<p class="mim-text-font">
Gentz, J., Jagenburg, R., Zetterstrom, R.
<strong>Tyrosinemia.</strong>
J. Pediat. 66: 670-696, 1965.
[PubMed: 14271358]
[Full Text: https://doi.org/10.1016/s0022-3476(65)80002-6]
</p>
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<li>
<p class="mim-text-font">
Gluecksohn-Waelsch, S.
<strong>Genetic control of morphogenetic and biochemical differentiation: lethal albino deletions in the mouse.</strong>
Cell 16: 225-237, 1979.
[PubMed: 36985]
[Full Text: https://doi.org/10.1016/0092-8674(79)90001-1]
</p>
</li>
<li>
<p class="mim-text-font">
Grompe, M., Lindstedt, S., Al-Dhalimy, M., Kennaway, N. G., Papaconstantinou, J., Torres-Ramos, C. A., Ou, C.-N., Finegold, M.
<strong>Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I.</strong>
Nature Genet. 10: 453-460, 1995.
[PubMed: 7545495]
[Full Text: https://doi.org/10.1038/ng0895-453]
</p>
</li>
<li>
<p class="mim-text-font">
Grompe, M., St-Louis, M., Demers, S. I., Al-Dhalimy, M., Leclerc, B., Tanguay, R. M.
<strong>A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I.</strong>
New. Eng. J. Med. 331: 353-357, 1994.
[PubMed: 8028615]
[Full Text: https://doi.org/10.1056/NEJM199408113310603]
</p>
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<p class="mim-text-font">
Hahn, S. H., Krasnewich, D., Brantly, M., Kvittingen, E. A., Gahl, W. A.
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[PubMed: 7550234]
[Full Text: https://doi.org/10.1002/humu.1380060113]
</p>
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<p class="mim-text-font">
Halvorsen, S., Gjessing, L. R.
<strong>Studies of tyrosinosis. I. Effect of low-tyrosine and low-phenylalanine diet.</strong>
Brit. Med. J. 2: 1171-1173, 1964.
[PubMed: 14190487]
[Full Text: https://doi.org/10.1136/bmj.2.5418.1171]
</p>
</li>
<li>
<p class="mim-text-font">
Halvorsen, S., Pande, H., Loken, A. C., Gjessing, L. R.
<strong>Tyrosinosis: a study of 6 cases.</strong>
Arch. Dis. Child. 41: 238-249, 1966.
[PubMed: 5940613]
[Full Text: https://doi.org/10.1136/adc.41.217.238]
</p>
</li>
<li>
<p class="mim-text-font">
Himsworth, H. P.
<strong>Lectures on the Liver and its Diseases. (2nd ed.)</strong>
Oxford: Blackwell (pub.) 1950.
</p>
</li>
<li>
<p class="mim-text-font">
Holme, E., Lindblad, B., Lindstedt, S.
<strong>Possibilities for treatment and for early prenatal diagnosis of hereditary tyrosinaemia. (Letter)</strong>
Lancet 325: 527 only, 1985. Note: Originally Volume I.
[PubMed: 2857895]
[Full Text: https://doi.org/10.1016/s0140-6736(85)92132-4]
</p>
</li>
<li>
<p class="mim-text-font">
Holme, E., Lindstedt, S.
<strong>Neonatal screen for hereditary tyrosinaemia type I. (Letter)</strong>
Lancet 340: 850 only, 1992.
[PubMed: 1357267]
[Full Text: https://doi.org/10.1016/0140-6736(92)92724-t]
</p>
</li>
<li>
<p class="mim-text-font">
Holme, E., Lindstedt, S.
<strong>Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione).</strong>
J. Inherit. Metab. Dis. 21: 507-517, 1998.
[PubMed: 9728331]
[Full Text: https://doi.org/10.1023/a:1005410820201]
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<li>
<p class="mim-text-font">
Hostetter, M. K., Levy, H. L., Winter, H. S., Knight, G. J., Haddow, J. E.
<strong>Evidence for liver disease preceding amino acid abnormalities in hereditary tyrosinemia.</strong>
New Eng. J. Med. 308: 1265-1267, 1983.
[PubMed: 6188953]
[Full Text: https://doi.org/10.1056/NEJM198305263082105]
</p>
</li>
<li>
<p class="mim-text-font">
Kang, E. S., Gerald, P. S.
<strong>Hereditary tyrosinemia and abnormal pyrrole metabolism: a patient with hereditary tyrosinemia is described who developed metabolic and clinical changes compatible with acute intermittent porphyria.</strong>
J. Pediat. 77: 397-406, 1970.
[PubMed: 5502089]
[Full Text: https://doi.org/10.1016/s0022-3476(70)80006-3]
</p>
</li>
<li>
<p class="mim-text-font">
Kubo, S., Sun, M., Miyahara, M., Umeyama, K., Urakami, K., Yamamoto, T., Jakobs, C., Matsuda, I., Endo, F.
<strong>Hepatocyte injury in tyrosinemia type 1 is induced by fumarylacetoacetate and is inhibited by caspase inhibitors.</strong>
Proc. Nat. Acad. Sci. 95: 9552-9557, 1998.
[PubMed: 9689118]
[Full Text: https://doi.org/10.1073/pnas.95.16.9552]
</p>
</li>
<li>
<p class="mim-text-font">
Kvittingen, E. A., Borresen, A. L., Stokke, O., van der Hagen, C. B., Lie, S. O.
<strong>Deficiency of fumarylacetoacetase without hereditary tyrosinemia.</strong>
Clin. Genet. 27: 550-554, 1985.
[PubMed: 4017276]
[Full Text: https://doi.org/10.1111/j.1399-0004.1985.tb02039.x]
</p>
</li>
<li>
<p class="mim-text-font">
Kvittingen, E. A., Guibaud, P. P., Divry, P., Mandon, G., Rolland, M. O., Domenichini, Y., Jakobs, C., Christensen, E.
<strong>Prenatal diagnosis of hereditary tyrosinaemia type I by determination of fumarylacetoacetase in chorionic villus material. (Letter)</strong>
Europ. J. Pediat. 144: 597-598, 1986.
[PubMed: 3709578]
[Full Text: https://doi.org/10.1007/BF00496047]
</p>
</li>
<li>
<p class="mim-text-font">
Kvittingen, E. A., Halvorsen, S., Jellum, E.
<strong>Deficient fumarylacetoacetate fumarylhydrolase activity in lymphocytes and fibroblasts from patients with hereditary tyrosinemia.</strong>
Pediat. Res. 17: 541-544, 1983.
[PubMed: 6622096]
[Full Text: https://doi.org/10.1203/00006450-198307000-00005]
</p>
</li>
<li>
<p class="mim-text-font">
Kvittingen, E. A., Jellum, E., Stokke, O., Flatmark, A., Bergan, A., Sodal, G., Halvorsen, S., Schrumpf, E., Gjone, E.
<strong>Liver transplantation in a 23-year-old tyrosinaemia patient: effects on the renal tubular dysfunction.</strong>
J. Inherit. Metab. Dis. 9: 216-224, 1986.
[PubMed: 3091928]
[Full Text: https://doi.org/10.1007/BF01799465]
</p>
</li>
<li>
<p class="mim-text-font">
Kvittingen, E. A., Jellum, E., Stokke, O.
<strong>Assay of fumarylacetoacetate fumarylhydrolase in human liver: deficient activity in a case of hereditary tyrosinemia.</strong>
Clin. Chim. Acta 115: 311-319, 1981.
[PubMed: 7296877]
[Full Text: https://doi.org/10.1016/0009-8981(81)90244-8]
</p>
</li>
<li>
<p class="mim-text-font">
Kvittingen, E. A., Rootwelt, H., Berger, R., Brandtzaeg, P.
<strong>Self-induced correction of the genetic defect in tyrosinemia type I.</strong>
J. Clin. Invest. 94: 1657-1661, 1994.
[PubMed: 7929843]
[Full Text: https://doi.org/10.1172/JCI117509]
</p>
</li>
<li>
<p class="mim-text-font">
Kvittingen, E. A., Rootwelt, H., Brandtzaeg, P., Bergan, A., Berger, R.
<strong>Hereditary tyrosinemia type I: self-induced correction of the fumarylacetoacetase defect.</strong>
J. Clin. Invest. 91: 1816-1821, 1993.
[PubMed: 8473520]
[Full Text: https://doi.org/10.1172/JCI116393]
</p>
</li>
<li>
<p class="mim-text-font">
Kvittingen, E. A., Rootwelt, H., van Dam, T., van Faassen, H., Berger, R.
<strong>Hereditary tyrosinemia type I: lack of correlation between clinical findings and amount of immunoreactive fumarylacetoacetase protein.</strong>
Pediat. Res. 31: 43-46, 1992.
[PubMed: 1594329]
[Full Text: https://doi.org/10.1203/00006450-199201000-00008]
</p>
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<li>
<p class="mim-text-font">
La Du, B. N., Gjessing, L. R.
<strong>Tyrosinosis and tyrosinemia.In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.) : The Metabolic Basis of Inherited Disease. (3rd ed.)</strong>
New York: McGraw-Hill (pub.) 1972. Pp. 256-267.
</p>
</li>
<li>
<p class="mim-text-font">
La Du, B. N.
<strong>The enzymatic deficiency in tyrosinemia.</strong>
Am. J. Dis. Child. 113: 54-57, 1967.
[PubMed: 4380967]
[Full Text: https://doi.org/10.1001/archpedi.1967.02090160104010]
</p>
</li>
<li>
<p class="mim-text-font">
Laberge, C., Grenier, A., Valet, J. P., Morissette, J.
<strong>Fumarylacetoacetase measurement as a mass-screening procedure for hereditary tyrosinemia type I.</strong>
Am. J. Hum. Genet. 47: 325-328, 1990.
[PubMed: 2378358]
</p>
</li>
<li>
<p class="mim-text-font">
Laberge, C.
<strong>Hereditary tyrosinemia in a French-Canadian isolate.</strong>
Am. J. Hum. Genet. 21: 36-45, 1969.
[PubMed: 5763606]
</p>
</li>
<li>
<p class="mim-text-font">
Laine, J., Salo, M. K., Krogerus, L., Karkkainen, J., Wahlroos, O., Holmberg, C.
<strong>The nephropathy of type I tyrosinemia after liver transplantation.</strong>
Pediat. Res. 37: 640-645, 1995.
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[Full Text: https://doi.org/10.1203/00006450-199505000-00015]
</p>
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<li>
<p class="mim-text-font">
Lelong, M., Alagille, D., Gentil, C. I., Colin, J., Le Tan, V., Gabilan, J. C.
<strong>Cirrhose congenitale et familiale avec diabete phospho-gluco-amine, rachitisme vitamin D-resistant et tyrosinurie massive.</strong>
Rev. Franc. Etud. Clin. Biol. 8: 37-50, 1963.
</p>
</li>
<li>
<p class="mim-text-font">
Lindblad, B., Fallstrom, S. P., Hoyer, S., Nordborg, C., Solymar, L., Velander, H.
<strong>Cardiomyopathy in fumarylacetoacetase deficiency (hereditary tyrosinaemia): a new feature of the disease.</strong>
J. Inherit. Metab. Dis. 10 (suppl. 2): 319-322, 1987.
</p>
</li>
<li>
<p class="mim-text-font">
Lindblad, B., Lindstedt, S., Steen, G.
<strong>On the enzymic defects in hereditary tyrosinemia.</strong>
Proc. Nat. Acad. Sci. 74: 4641-4645, 1977.
[PubMed: 270706]
[Full Text: https://doi.org/10.1073/pnas.74.10.4641]
</p>
</li>
<li>
<p class="mim-text-font">
Lindstedt, S., Holme, E., Lock, E. A., Hjalmarson, O., Strandvik, B.
<strong>Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase.</strong>
Lancet 340: 813-817, 1992.
[PubMed: 1383656]
[Full Text: https://doi.org/10.1016/0140-6736(92)92685-9]
</p>
</li>
<li>
<p class="mim-text-font">
Malpuech, G., Mattei, J. F., Gaulme, J., Palcoux, J. B., Lesec, G., Vanlieferinghen, P.
<strong>Association, chez le meme sujet, d&#x27;une deletion du bras court du chromosome 4 (4p-) et d&#x27;un deficit complet en parahydroxyphenylpyruvate oxydase hepatique (tyrosinose).</strong>
J. Genet. Hum. 29: 455-461, 1981.
[PubMed: 7328420]
</p>
</li>
<li>
<p class="mim-text-font">
Mitchell, G., Larochelle, J., Lambert, M., Michaud, J., Grenier, A., Ogier, H., Gautheir, M., Lacroix, J., Vanasse, M., Larbrisseau, A., Paradis, K., Weber, A., Lefevre, Y., Melancon, S., Dallaire, L.
<strong>Neurologic crises in hereditary tyrosinemia.</strong>
New Eng. J. Med. 322: 432-437, 1990.
[PubMed: 2153931]
[Full Text: https://doi.org/10.1056/NEJM199002153220704]
</p>
</li>
<li>
<p class="mim-text-font">
Overturf, K., Al-Dhalimy, M., Ou, C. N., Finegold, M., Tanguay, R., Lieber, A., Kay, M., Grompe, M.
<strong>Adenovirus-mediated gene therapy in a mouse model of hereditary tyrosinemia type I.</strong>
Hum. Gene Ther. 8: 513-521, 1997.
[PubMed: 9095403]
[Full Text: https://doi.org/10.1089/hum.1997.8.5-513]
</p>
</li>
<li>
<p class="mim-text-font">
Overturf, K., Al-Dhalimy, M., Tanguay, R., Brantly, M., Ou, C.-N., Finegold, M., Grompe, M.
<strong>Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I.</strong>
Nature Genet. 12: 266-273, 1996. Note: Erratum: Nature Genet. 12: 458 only, 1996.
[PubMed: 8589717]
[Full Text: https://doi.org/10.1038/ng0396-266]
</p>
</li>
<li>
<p class="mim-text-font">
Paradis, K., Weber, A., Seidman, E. G., Larochelle, J., Garel, L., Lenaerts, C., Roy, C. C.
<strong>Liver transplantation for hereditary tyrosinemia: the Quebec experience.</strong>
Am. J. Hum. Genet. 47: 338-342, 1990.
[PubMed: 2378360]
</p>
</li>
<li>
<p class="mim-text-font">
Perry, T. L., Hardwick, D. F., Dixon, G. H., Dolman, C. L., Hansen, S.
<strong>Hypermethioninemia: a metabolic disorder associated with cirrhosis, islet cell hyperplasia, and renal tubular degeneration.</strong>
Pediatrics 36: 236-250, 1965.
[PubMed: 14320034]
</p>
</li>
<li>
<p class="mim-text-font">
Pettit, B. R., Kvittingen, E. A., Leonard, J. V.
<strong>Early prenatal diagnosis of hereditary tyrosinaemia. (Letter)</strong>
Lancet 325: 1038 only, 1985. Note: Originally Volume I.
[PubMed: 2859481]
[Full Text: https://doi.org/10.1016/s0140-6736(85)91633-2]
</p>
</li>
<li>
<p class="mim-text-font">
Prieto-Alamo, M. J., Laval, F.
<strong>Deficient DNA-ligase activity in the metabolic disease tyrosinemia type I.</strong>
Proc. Nat. Acad. Sci. 95: 12614-12618, 1998.
[PubMed: 9770534]
[Full Text: https://doi.org/10.1073/pnas.95.21.12614]
</p>
</li>
<li>
<p class="mim-text-font">
Rootwelt, H., Brodtkorb, E., Kvittingen, E. A.
<strong>Identification of a frequent pseudodeficiency mutation in the fumarylacetoacetase gene, with implications for diagnosis of tyrosinemia type I.</strong>
Am. J. Hum. Genet. 55: 1122-1127, 1994.
[PubMed: 7977370]
</p>
</li>
<li>
<p class="mim-text-font">
Rootwelt, H., Hoie, K., Berger, R., Kvittingen, E. A.
<strong>Fumarylacetoacetase mutations in tyrosinaemia type I.</strong>
Hum. Mutat. 7: 239-243, 1996.
[PubMed: 8829657]
[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)7:3&lt;239::AID-HUMU8&gt;3.0.CO;2-5]
</p>
</li>
<li>
<p class="mim-text-font">
Russo, P., O'Regan, S.
<strong>Visceral pathology of hereditary tyrosinemia type I.</strong>
Am. J. Hum. Genet. 47: 317-324, 1990.
[PubMed: 2378357]
</p>
</li>
<li>
<p class="mim-text-font">
Schultz, M. J., Netzel, B. C., Singh R. H., Pino, G. B., Gavrilov, D. K., Oglesbee, D., Raymond, K. M., Rinaldo, P., Tortorelli, S., Smith, W. E., Matern, D.
<strong>Laboratory monitoring of patients with hereditary tyrosinemia type I.</strong>
Molec. Genet. Metab. 130: 247-254, 2020.
[PubMed: 32546364]
[Full Text: https://doi.org/10.1016/j.ymgme.2020.06.001]
</p>
</li>
<li>
<p class="mim-text-font">
Scriver, C. R., Larochelle, J., Silverberg, M.
<strong>Hereditary tyrosinemia and tyrosyluria in a French-Canadian geographic isolate.</strong>
Am. J. Dis. Child. 113: 41-46, 1967.
[PubMed: 6016174]
[Full Text: https://doi.org/10.1001/archpedi.1967.02090160091008]
</p>
</li>
<li>
<p class="mim-text-font">
Scriver, C. R., Partington, M. W., Sass-Kortsak, A.
<strong>Conference on hereditary tyrosinemia held at the Hospital for Sick Children.</strong>
Canad. Med. Assoc. J. 97: 1045-1100, 1967.
</p>
</li>
<li>
<p class="mim-text-font">
Scriver, C. R.
<strong>Personal Communication.</strong>
Montreal, Quebec, Canada 2/15/1982.
</p>
</li>
<li>
<p class="mim-text-font">
Sokal, E. M., Bustos, R., Van Hoof, F., Otte, J. B.
<strong>Liver transplantation for hereditary tyrosinemia--early transplantation following the patient&#x27;s stabilization.</strong>
Transplantation 54: 937-939, 1992.
[PubMed: 1440864]
[Full Text: https://doi.org/10.1097/00007890-199211000-00035]
</p>
</li>
<li>
<p class="mim-text-font">
St-Louis, M., Tanguay, R. M.
<strong>Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: overview.</strong>
Hum. Mutat. 9: 291-299, 1997.
[PubMed: 9101289]
[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)9:4&lt;291::AID-HUMU1&gt;3.0.CO;2-9]
</p>
</li>
<li>
<p class="mim-text-font">
Tanguay, R. M., Phaneuf, D., Labelle, Y., Demers, S.
<strong>Molecular cloning and expression of the c-DNA encoding the enzyme deficient in hereditary tyrosinemia: evidence for molecular heterogeneity. (Abstract)</strong>
Am. J. Hum. Genet. 47 (suppl.): A168 only, 1990.
</p>
</li>
<li>
<p class="mim-text-font">
Tanguay, R. M., Valet, J. P., Lescault, A., Duband, J. L., Laberge, C., Lettre, F., Plante, M.
<strong>Different molecular basis for fumarylacetoacetate hydrolase deficiency in the two clinical forms of hereditary tyrosinemia (type I).</strong>
Am. J. Hum. Genet. 47: 308-316, 1990.
[PubMed: 2378356]
</p>
</li>
<li>
<p class="mim-text-font">
Timmers, C., Grompe, M.
<strong>Six novel mutations in the fumarylacetoacetate hydrolase gene of patients with hereditary tyrosinemia type I.</strong>
Hum. Mutat. 7: 367-369, 1996.
[PubMed: 8723690]
[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)7:4&lt;367::AID-HUMU14&gt;3.0.CO;2-0]
</p>
</li>
<li>
<p class="mim-text-font">
Tuchman, M., Freese, D. K., Sharp, H. L., Whitley, C. B., Ramnaraine, M. L., Ulstrom, R. A., Najarian, J. S., Ascher, N., Buist, N. R. M., Terry, A. B.
<strong>Persistent succinylacetone excretion after liver transplantation in a patient with hereditary tyrosinaemia type I.</strong>
J. Inherit. Metab. Dis. 8: 21-24, 1985.
[PubMed: 2581063]
[Full Text: https://doi.org/10.1007/BF01805479]
</p>
</li>
<li>
<p class="mim-text-font">
van Spronsen, F. J., Berger, R., Smit, G. P. A., de Klerk, J. B. C., Duran, M., Bijleveld, C. M. A., van Faassen, H., Slooff, M. J. H., Heymans, H. S. A.
<strong>Tyrosinaemia type I: orthotopic liver transplantation as the only definitive answer to a metabolic as well as an oncological problem.</strong>
J. Inherit. Metab. Dis. 12: 339-342, 1989.
[PubMed: 2556611]
[Full Text: https://doi.org/10.1007/BF03335416]
</p>
</li>
<li>
<p class="mim-text-font">
Weinberg, A. G., Mize, C. E., Vorthen, H. G.
<strong>Occurrence of hepatoma in chronic form of hereditary tyrosinemia.</strong>
J. Pediat. 88: 434-438, 1976.
[PubMed: 173827]
[Full Text: https://doi.org/10.1016/s0022-3476(76)80259-4]
</p>
</li>
<li>
<p class="mim-text-font">
Whelan, D. T., Zannoni, V. G.
<strong>Microassay of tyrosine-amino transferase and p-hydroxyphenylpyruvic acid oxidase in mammalian liver and patients with hereditary tyrosinemia.</strong>
Biochem. Med. 9: 19-31, 1974.
[PubMed: 4150247]
[Full Text: https://doi.org/10.1016/0006-2944(74)90079-9]
</p>
</li>
<li>
<p class="mim-text-font">
Wilson, J. M.
<strong>Round two for liver gene therapy.</strong>
Nature Genet. 12: 232-233, 1996.
[PubMed: 8589710]
[Full Text: https://doi.org/10.1038/ng0396-232]
</p>
</li>
<li>
<p class="mim-text-font">
Zetterstrom, R.
<strong>Tyrosinosis.</strong>
Ann. N.Y. Acad. Sci. 111: 220-226, 1963.
[PubMed: 14085846]
[Full Text: https://doi.org/10.1111/j.1749-6632.1963.tb36962.x]
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