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Entry
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- #203500 - ALKAPTONURIA; AKU
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- OMIM
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<p>
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<span class="h4">#203500</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/203500"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#history">History</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=ALKAPTONURIA" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=411&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1454/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/304" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/alkaptonuria" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=203500[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=56" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/54cc18e7-3251-4e49-9c30-7b80208325c8/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:9270" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/203500" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/OMIA001243/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:9270" 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>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:203500" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 360378009<br />
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<strong>ICD10CM:</strong> E70.29<br />
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<strong>ORPHA:</strong> 56<br />
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<strong>DO:</strong> 9270<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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203500
|
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</span>
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</span>
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</div>
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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ALKAPTONURIA; AKU
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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HOMOGENTISIC ACID OXIDASE DEFICIENCY
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
|
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</div>
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|
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</div>
|
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|
|
|
|
<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/3/585?start=-3&limit=10&highlight=585">
|
|
3q13.33
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Alkaptonuria
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/203500"> 203500 </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">
|
|
HGD
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607474"> 607474 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/203500" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/203500" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/203500" 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> Height </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Height loss secondary to spinal changes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859880&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859880</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Ears </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Pigmentation of the ear cartilage <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859881&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859881</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Pigmentation of the sclera <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859882&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859882</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007832" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007832</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007832" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007832</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">
|
|
|
|
- Aortic valve calcification <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/250978003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">250978003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0428791&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0428791</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004380" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004380</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004380" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004380</a>]</span><br /> -
|
|
Mitral valve calcification <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/473372009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">473372009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0919718&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0919718</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004382" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004382</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004382" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004382</a>]</span><br /> -
|
|
Coronary artery calcification <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/445512009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">445512009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1611184&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1611184</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001717" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001717</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001717" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001717</a>]</span><br /> -
|
|
Aortic dilatation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26660001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26660001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I71.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I71.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I77.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I77.81</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/447.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">447.7</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0265004&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265004</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004942" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004942</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004942" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004942</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> Internal Genitalia (Male) </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Ochronotic prostate stones <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859879&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859879</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Kidneys </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Urolithiasis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95566004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95566004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N20-N23" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N20-N23</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0451641&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0451641</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034368" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034368</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034368" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034368</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">
|
|
|
|
- Ochronotic pigmentation of fibrous tissues including cartilage, tendons, ligaments <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859883&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859883</a>]</span><br /> -
|
|
Ochronotic arthritis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39838007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39838007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268493&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268493</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030764" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030764</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030764" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030764</a>]</span><br /> -
|
|
Ochronotic arthropathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39838007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39838007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268493&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268493</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030764" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030764</a>]</span><br /> -
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Chronic joint pain <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859884&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859884</a>]</span><br />
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</span>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<em> Spine </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Back pain <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/161891005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">161891005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M54" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M54</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M54.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M54.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/724.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">724.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004604&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004604</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003418" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003418</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003418" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003418</a>]</span><br /> -
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Kyphosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/71311003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">71311003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/414564002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">414564002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413428007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413428007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M40.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M40.20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q76.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q76.41</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/737.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">737.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0265673&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265673</a>, <a href="https://bioportal.bioontology.org/search?q=C0022821&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022821</a>, <a href="https://bioportal.bioontology.org/search?q=C2115817&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2115817</a>, <a href="https://bioportal.bioontology.org/search?q=C0022822&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022822</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002808</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002808</a>]</span><br /> -
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Degeneration of intervertebral disks <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/77547008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">77547008</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/722.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">722.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0158266&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0158266</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008419</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008419</a>]</span><br /> -
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Fusion of vertebral bodies <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1835763&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1835763</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002948" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002948</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002948" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002948</a>]</span><br /> -
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Decreased lumbar flexion <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859886&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859886</a>]</span><br />
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</span>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<em> Feet </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Thickened Achilles tendon <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0919997&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0919997</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004690" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004690</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004690" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004690</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Increased plasma homogentisic acid (HGA) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859887&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859887</a>]</span><br /> -
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Increased urinary HGA <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859888</a>]</span><br /> -
|
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Decreased liver homogentisate 1,2-dioxygenase activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859889</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Urine turns dark on standing and alkalinization<br /> -
|
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Joint symptoms begin in third or fourth decade<br /> -
|
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Affects 1 in 250,000 to 1 million people worldwide<br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the homogentisate 1,2-dioxygenase gene (HGD, <a href="/entry/607474#0001">607474.0001</a>)<br />
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</span>
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</div>
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</div>
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</div>
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because alkaptonuria (AKU) is caused by homozygous or compound heterozygous mutation in the homogentisate 1,2-dioxygenase gene (HGD; <a href="/entry/607474">607474</a>) on chromosome 3q13.</p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Alkaptonuria is an autosomal recessive metabolic disorder characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of the cardiac valves (summary by <a href="#41" class="mim-tip-reference" title="Vilboux, T., Kayser, M., Introne, W., Suwannarat, P., Bernardini, I., Fischer, R., O'Brien, K., Kleta, R., Huizing, M., Gahl, W. A. <strong>Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria.</strong> Hum. Mutat. 30: 1611-1619, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19862842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19862842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19862842[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19862842">Vilboux et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19862842" 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>Alkaptonuria enjoys the historic distinction of being one of the first conditions in which mendelian recessive inheritance was proposed (by <a href="#14" class="mim-tip-reference" title="Garrod, A. E. <strong>The incidence of alkaptonuria: a study in chemical individuality.</strong> Lancet 160: 1616-1620, 1902. Note: Originally Volume II."None>Garrod, 1902</a>, on the suggestion of Bateson) and of being 1 of the 4 conditions in the charter group of inborn errors of metabolism. The manifestations are urine that turns dark on standing and alkalinization, black ochronotic pigmentation of cartilage and collagenous tissues, and arthritis, especially characteristic in the spine.</p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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</div>
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<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#9" class="mim-tip-reference" title="Cunningham, T. J., Roux, E., Lagier, R., Fallet, G. H. <strong>Rapidly progressive hip osteoarthrosis: an unusual presentation of ochronosis.</strong> Clin. Exp. Rheum. 7: 315-318, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2667832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2667832</a>]" pmid="2667832">Cunningham et al. (1989)</a> observed rapidly evolving osteoarthrosis of the right hip in a 65-year-old woman who had unusual stress after being forced to abandon a train as a result of a bomb threat and having to carry 2 heavy suitcases. <a href="#6" class="mim-tip-reference" title="Carrier, D. A., Harris, C. M. <strong>Bilateral hip and bilateral knee arthroplasties in a patient with ochronotic arthropathy.</strong> Orthop. Rev. 19: 1005-1009, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2270175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2270175</a>]" pmid="2270175">Carrier and Harris (1990)</a> reported the case of a 70-year-old man who underwent bilateral hip and knee total joint arthroplasties for the treatment of ochronotic arthropathy. <a href="#10" class="mim-tip-reference" title="Dereymaeker, L., Van Parijs, G., Bayart, M., Daenen, W., Lauwerijns, J., De Geest, H. <strong>Ochronosis and alkaptonuria: report of a new case with calcified aortic valve stenosis.</strong> Acta Cardiol. 45: 87-92, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2316305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2316305</a>]" pmid="2316305">Dereymaeker et al. (1990)</a> described a patient in whom calcified aortic valve disease secondary to ochronosis necessitated urgent aortic valve replacement. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2667832+2316305+2270175" 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>There are reports of urolithiasis in AKU patients in middle and late adulthood who have already developed the full clinical picture of the disorder (e.g., <a href="#35" class="mim-tip-reference" title="Sener, R. N. <strong>Prostatic and renal stones and unilateral obstruction of the urinary tract caused by ochronosis.</strong> Am. J. Roentgen. 158: 214-215, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1727353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1727353</a>] [<a href="https://doi.org/10.2214/ajr.158.1.1727353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1727353">Sener, 1992</a>). <a href="#44" class="mim-tip-reference" title="Zibolen, M., Srsnova, K., Srsen, S. <strong>Increased urolithiasis in patients with alkaptonuria in childhood. (Letter)</strong> Clin. Genet. 58: 79-80, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10945668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10945668</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2000.580115.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10945668">Zibolen et al. (2000)</a> emphasized the increased frequency of urolithiasis in AKU patients younger than 15 years. They reported 5 such patients, in one of whom the diagnosis of urolithiasis had been made at the age of 2 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1727353+10945668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Phornphutkul, C., Introne, W. J., Perry, M. B., Bernardini, I., Murphey, M. D., Fitzpatrick, D. L., Anderson, P. D., Huizing, M., Anikster, Y., Gerber, L. H., Gahl, W. A. <strong>Natural history of alkaptonuria.</strong> New Eng. J. Med. 347: 2111-2121, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12501223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12501223</a>] [<a href="https://doi.org/10.1056/NEJMoa021736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12501223">Phornphutkul et al. (2002)</a> provided a review of the natural history of alkaptonuria. They based the review on an evaluation of 58 patients with the disorder ranging in age from 4 to 80 years. They found that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity of disease began increasing after the age of 30 years, with a more rapid increase in men than in women. In the 58 patients reviewed by <a href="#29" class="mim-tip-reference" title="Phornphutkul, C., Introne, W. J., Perry, M. B., Bernardini, I., Murphey, M. D., Fitzpatrick, D. L., Anderson, P. D., Huizing, M., Anikster, Y., Gerber, L. H., Gahl, W. A. <strong>Natural history of alkaptonuria.</strong> New Eng. J. Med. 347: 2111-2121, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12501223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12501223</a>] [<a href="https://doi.org/10.1056/NEJMoa021736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12501223">Phornphutkul et al. (2002)</a>, kidney stones were documented in 13 male and 3 female patients. Of the 27 men who were 31 to 60 years old, 8 had prostate stones. The development of prostate stones was not associated with the development of kidney stones. Three patients, each over the age of 50 years, had undergone aortic valve replacement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12501223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Ranganath, L. R., Heseltine, T., Khedr, M., Fisher, M. F. <strong>Evaluating the aortic stenosis phenotype before and after the effect of homogentisic acid lowering therapy: analysis of a large cohort of eighty-one alkaptonuria patients.</strong> Molec. Genet. Metab. 133: 324-331, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34059444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34059444</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34059444">Ranganath et al. (2021)</a> examined the clinical phenotype, with a focus on aortic disease, in 81 individuals with alkaptonuria and a mean age of 48.6 years, 51 of whom received nitisinone treatment. The prevalence of aortic stenosis was 22.2% and the prevalence of aortic valve replacement was 6.2%. Aortic valve maximum velocity (Vmax) was found to be directly related to age, systolic blood pressure, serum homogentisic acid, ochronosis score, and alkaptonuria severity score index. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34059444" 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 AKU in the families reported by <a href="#12" class="mim-tip-reference" title="Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S. <strong>The molecular basis of alkaptonuria.</strong> Nature Genet. 14: 19-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782815</a>] [<a href="https://doi.org/10.1038/ng0996-19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782815">Fernandez-Canon et al. (1996)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782815" 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="#23" class="mim-tip-reference" title="Lustberg, T. J., Schulman, J. D., Seegmiller, J. E. <strong>Decreased binding of (14)C-homogentisic acid induced by ascorbic acid in connective tissues of rats with experimental alkaptonuria.</strong> Nature 228: 770-771, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5472968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5472968</a>] [<a href="https://doi.org/10.1038/228770a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5472968">Lustberg et al. (1970)</a> presented evidence that ascorbic acid in high doses decreases binding of C(14)-homogentisic acid (HGA) in connective tissues of rats with experimental alkaptonuria. Long-term therapy in young patients with alkaptonuria is indicated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5472968" 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="Wolff, J. A., Barshop, B., Nyhan, W. L., Leslie, J., Seegmiller, J. E., Gruber, H., Garst, M., Winter, S., Michals, K., Matalon, R. <strong>Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy.</strong> Pediat. Res. 26: 140-144, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2771520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2771520</a>] [<a href="https://doi.org/10.1203/00006450-198908000-00015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2771520">Wolff et al. (1989)</a> treated 2 adults and 3 infants with high doses of ascorbic acid and studied the effect on the excretion of homogentisic acid and its toxic oxidation product, benzoquinone acetic acid (BQA). The purpose was to determine whether concentrations in body fluids of the latter substance, the putative toxic metabolite in alkaptonuria, would be reduced. Indeed, disappearance of BQA from the urine was observed in adults, whereas the level of excretion of homogentisic acid did not change. This could have relevance to the pathogenesis of ochronotic arthritis. In 2 of the infants studied (a 4- and a 5-month-old), ascorbic acid may have doubled the amount of homogentisic acid in the urine, presumably through an effect on the immature p-hydroxyphenylpyruvic acid oxidase. Dietary reduction of the intake of tyrosine and phenylalanine substantially reduced the excretion of homogentisic acid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2771520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 48-year-old man in whom alkaptonuria had been diagnosed during infancy, <a href="#24" class="mim-tip-reference" title="Mayatepek, E., Kallas, K., Anninos, A., Muller, E. <strong>Effects of ascorbic acid and low-protein diet in alkaptonuria.</strong> Europ. J. Pediat. 157: 867-868, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9809834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9809834</a>] [<a href="https://doi.org/10.1007/s004310050956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9809834">Mayatepek et al. (1998)</a> studied the effects of 4 different therapeutic 1-month trials consisting of supplementation with ascorbic acid (1 g/day and 10 g/day) or a low-protein diet (0.3 g/kg/day and 1.3 g/kg/day). Administration of ascorbic acid in doses of 1 g/day or more resulted in a significant and constant decrease of urinary BQA, whereas the excretion of HGA could not be substantially reduced. Mild and severe dietary reduction of protein intake alone also substantially reduced the excretion of BQA, whereas the level of HGA excretion could not be drastically reduced. Such an extreme protein restriction would not, however, have been acceptable for a longer period of time. They concluded that supplementation of ascorbic acid in doses of 1 g/day represents a simple and rational treatment in patients with alkaptonuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9809834" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="La Du, B. N., Jr. <strong>Are we ready to try to cure alkaptonuria? (Editorial)</strong> Am. J. Hum. Genet. 62: 765-767, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529368</a>] [<a href="https://doi.org/10.1086/301810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529368">La Du (1998)</a> examined the question 'Are we ready to try to cure alkaptonuria?' He explored the possibilities and indicated that model animal systems, either those representing known spontaneous hereditary deficiencies of homogentisic acid or appropriate 'knockout' animals with created deficiencies of the enzyme, need to be tested before human trials are undertaken. He said that it is to be hoped that some, perhaps all, of the adverse effects of alkaptonuria can be prevented by new molecular therapeutic approaches; however, trading alkaptonuric problems for even more serious metabolic disturbances because of the pronounced toxicity of the later tyrosine metabolites is not an acceptable alternative. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529368" 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="Suzuki, Y., Oda, K., Yoshikawa, Y., Maeda, T., Suzuki, T. <strong>A novel therapeutic trial of homogentisic aciduria in a murine model of alkaptonuria.</strong> J. Hum. Genet. 44: 79-84, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10083729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10083729</a>] [<a href="https://doi.org/10.1007/s100380050114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10083729">Suzuki et al. (1999)</a> used 2(-2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) as a therapeutic agent for alkaptonuria. NTBC is a potent inhibitor of p-hydroxyphenylpyruvate dioxygenase, which catalyzes the formation of homogentisic acid from p-hydroxyphenylpyruvic acid, and had been used in the treatment of type I tyrosinemia (<a href="/entry/276700">276700</a>). In a murine model of alkaptonuria that had been created with ethylnitrosurea by <a href="#26" class="mim-tip-reference" title="Montagutelli, X., Lalouette, A., Coude, M., Kamoun, P., Forest, M., Guenet, J.-L. <strong>aku, a mutation of the mouse homologous to human alkaptonuria, maps to chromosome 16.</strong> Genomics 19: 9-11, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8188247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8188247</a>] [<a href="https://doi.org/10.1006/geno.1994.1004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8188247">Montagutelli et al. (1994)</a>, they observed a dose-dependent reduction in urinary output of homogentisic acid with administration of NTBC. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10083729+8188247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Phornphutkul, C., Introne, W. J., Perry, M. B., Bernardini, I., Murphey, M. D., Fitzpatrick, D. L., Anderson, P. D., Huizing, M., Anikster, Y., Gerber, L. H., Gahl, W. A. <strong>Natural history of alkaptonuria.</strong> New Eng. J. Med. 347: 2111-2121, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12501223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12501223</a>] [<a href="https://doi.org/10.1056/NEJMoa021736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12501223">Phornphutkul et al. (2002)</a> reported that, in a 51-year-old woman, urinary HGA excretion fell from 2.9 to 0.13 g per day after a 10-day course of nitisinone. In a 59-year-old woman, similar reductions were observed after 9 days of treatment. Plasma tyrosine levels in these patients rose, with no clinical signs or symptoms. They emphasized that the long-term safety and efficacy of this treatment requires further evaluation. Nitisinone is a triketone herbicide that inhibits 4-hydroxyphenylpyruvate dioxygenase by rapid, avid binding that is reversible. The agent had been approved by the FDA for the treatment of tyrosinemia type I. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12501223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Ranganath, L. R., Heseltine, T., Khedr, M., Fisher, M. F. <strong>Evaluating the aortic stenosis phenotype before and after the effect of homogentisic acid lowering therapy: analysis of a large cohort of eighty-one alkaptonuria patients.</strong> Molec. Genet. Metab. 133: 324-331, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34059444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34059444</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34059444">Ranganath et al. (2021)</a> found that nitisinone treatment in a cohort of 51 patients with alkaptonuria reduced serum homogentisic acid, urine homogentisic acid, ochronosis scores, and alkaptonuria severity score index. Nitisinone also decreased aortic valve maximum velocity (Vmax) over time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34059444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 6 Slovak pedigrees selected from a total of 191 alkaptonuria patients registered at the Institute of Clinical Genetics in Martin, Slovakia, <a href="#17" class="mim-tip-reference" title="Janocha, S., Wolz, W., Srsen, S., Srsnova, K., Montagutelli, X., Guenet, J.-L., Grimm, T., Kress, W., Muller, C. R. <strong>The human gene for alkaptonuria (AKU) maps to chromosome 3q.</strong> Genomics 19: 5-8, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8188241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8188241</a>] [<a href="https://doi.org/10.1006/geno.1994.1003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8188241">Janocha et al. (1994)</a> demonstrated linkage to microsatellite markers from proximal 3q. Markers on that chromosome were selected for study because of previously demonstrated homology of synteny with mouse chromosome 16. Independently, <a href="#30" class="mim-tip-reference" title="Pollak, M. R., Chou, Y.-H. W., Cerda, J. J., Steinmann, B., La Du, B. N., Seidman, J. G., Seidman, C. E. <strong>Homozygosity mapping of the gene for alkaptonuria to chromosome 3q2.</strong> Nature Genet. 5: 201-204, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8252048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8252048</a>] [<a href="https://doi.org/10.1038/ng1093-201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8252048">Pollak et al. (1993)</a> used homozygosity mapping to locate the alkaptonuria gene to 3q2 in a 16-cM region. They studied 2 consanguineous families with 4 affected children and 2 nonconsanguineous families which supported the linkage. They pointed out that <a href="#13" class="mim-tip-reference" title="Garnica, A. D., Cerda, J. J., Maenard, D., Preiser, H., Crane, K. <strong>Alcaptonuria and sucrase-isomaltase deficiency in three offspring of a consanguineous marriage.</strong> Acta Vitaminol. Enzymol. 3: 157-169, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7347488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7347488</a>]" pmid="7347488">Garnica et al. (1981)</a> described coinheritance of alkaptonuria and sucrase-isomaltase deficiency (<a href="/entry/222900">222900</a>), which maps to 3q25-q26. Furthermore, <a href="#38" class="mim-tip-reference" title="Steinmann, B., Gnehm, H. E., Rao, V. H., Kind, H. P., Prader, A. <strong>Neonatal severe primary hyperparathyroidism and alkaptonuria in a boy born to related parents with familial hypocalciuric hypercalcemia.</strong> Helv. Paediat. Acta 39: 171-186, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6543841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6543841</a>]" pmid="6543841">Steinmann et al. (1984)</a> described coinheritance of neonatal severe hyperparathyroidism and alkaptonuria. The former condition is thought to be the recessive (i.e., homozygous) form of familial hypocalciuric hypercalcemia (<a href="/entry/145980">145980</a>), which maps to 3q21-q24. In the case reported by <a href="#38" class="mim-tip-reference" title="Steinmann, B., Gnehm, H. E., Rao, V. H., Kind, H. P., Prader, A. <strong>Neonatal severe primary hyperparathyroidism and alkaptonuria in a boy born to related parents with familial hypocalciuric hypercalcemia.</strong> Helv. Paediat. Acta 39: 171-186, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6543841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6543841</a>]" pmid="6543841">Steinmann et al. (1984)</a>, both parents, who were related, had familial hypocalciuric hypercalcemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6543841+8252048+8188241+7347488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In patients with alkaptonuria, <a href="#12" class="mim-tip-reference" title="Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S. <strong>The molecular basis of alkaptonuria.</strong> Nature Genet. 14: 19-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782815</a>] [<a href="https://doi.org/10.1038/ng0996-19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782815">Fernandez-Canon et al. (1996)</a> identified missense mutations in the homogentisate 1,2-dioxygenase gene that cosegregated with the disease (<a href="/entry/607474#0001">607474.0001</a>, <a href="/entry/607474#0002">607474.0002</a>), and provided biochemical evidence that at least one of these missense mutations is a loss-of-function mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782815" 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>Studying 4 alkaptonuria patients from Slovakia, where alkaptonuria has a notably high frequency, <a href="#15" class="mim-tip-reference" title="Gehrig, A., Schmidt, S. R., Muller, C. R., Srsen, S., Srsnova, K., Kress, W. <strong>Molecular defects in alkaptonuria.</strong> Cytogenet. Cell Genet. 76: 14-16, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9154114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9154114</a>] [<a href="https://doi.org/10.1159/000134501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9154114">Gehrig et al. (1997)</a> found 2 novel mutations in the HGD gene (<a href="/entry/607474#0003">607474.0003</a>, <a href="/entry/607474#0004">607474.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9154114" 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>Other mutations in the HGD gene were identified in patients with alkaptonuria by Beltran-Valero de Bernabe et al. (<a href="#4" class="mim-tip-reference" title="Beltran-Valero de Bernabe, D., Granadino, B., Chiarelli, I., Porfirio, B., Mayatepek, E., Aquaron, R., Moore, M. M., Festen, J. J. M., Sanmarti, R., Penalva, M. A., Rodriguez de Cordoba, S. <strong>Mutation and polymorphism analysis of the human homogentisate 1,2-dioxygenase gene in alkaptonuria patients.</strong> Am. J. Hum. Genet. 62: 776-784, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529363</a>] [<a href="https://doi.org/10.1086/301805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529363">1998</a>, <a href="#5" class="mim-tip-reference" title="Beltran-Valero de Bernabe, D., Peterson, P., Luopajarvi, K., Matintalo, P., Alho, A., Konttinen, Y., Krohn, K., Rodriguez de Cordoba, S., Ranki, A. <strong>Mutational analysis of the HGO gene in Finnish alkaptonuria patients.</strong> J. Med. Genet. 36: 922-923, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10594001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10594001</a>]" pmid="10594001">1999</a>), <a href="#27" class="mim-tip-reference" title="Muller, C. R., Fregin, A., Srsen, S., Srsnova, K., Halliger-Keller, B., Felbor, U., Seemanova, E., Kress, W. <strong>Allelic heterogeneity of alkaptonuria in Central Europe.</strong> Europ. J. Hum. Genet. 7: 645-651, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10482952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10482952</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10482952">Muller et al. (1999)</a>, <a href="#33" class="mim-tip-reference" title="Rodriguez, J. M., Timm, D. E., Titus, G. P., Bertran-Valero de Bernabe, D., Criado, O., Mueller, H. A., Rodriguez de Cordoba, S., Penalva, M. A. <strong>Structural and functional analysis of mutations in alkaptonuria.</strong> Hum. Molec. Genet. 9: 2341-2350, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001939</a>] [<a href="https://doi.org/10.1093/oxfordjournals.hmg.a018927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11001939">Rodriguez et al. (2000)</a>, <a href="#43" class="mim-tip-reference" title="Zatkova, A., Polakova, H., Micutkova, L., Zvarik, M., Bosak, V., Ferakova, E., Matusek, J., Ferak, V., Kadasi, L. <strong>Novel mutations in the homogentisate-1,2-dioxygenase gene identified in Slovak patients with alkaptonuria. (Letter)</strong> J. Med. Genet. 37: 539-542, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10970188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10970188</a>] [<a href="https://doi.org/10.1136/jmg.37.7.539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10970188">Zatkova et al. (2000)</a>, and <a href="#29" class="mim-tip-reference" title="Phornphutkul, C., Introne, W. J., Perry, M. B., Bernardini, I., Murphey, M. D., Fitzpatrick, D. L., Anderson, P. D., Huizing, M., Anikster, Y., Gerber, L. H., Gahl, W. A. <strong>Natural history of alkaptonuria.</strong> New Eng. J. Med. 347: 2111-2121, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12501223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12501223</a>] [<a href="https://doi.org/10.1056/NEJMoa021736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12501223">Phornphutkul et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10482952+11001939+10970188+9529363+10594001+12501223" 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 Turkey, <a href="#11" class="mim-tip-reference" title="Elcioglu, N. H., Aytug, A. F., Muller, C. R., Gurbuz, O., Ergun, T., Kotiloglu E., Elcioglu, M. <strong>Alkaptonuria caused by compound heterozygote mutations.</strong> Genet. Counsel. 14: 207-213, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12872815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12872815</a>]" pmid="12872815">Elcioglu et al. (2003)</a> described a 39-year-old male patient with typical features of alkaptonuria. In addition to the typical changes in the skin at many sites and in the pinnae and sclerae, there were grayish-blue longitudinal rigging of his fingernails and bluish-gray pigment deposition on the tympanic membrane. He was found to be compound heterozygous for 2 mutations in the HGD gene: gly270 to arg (G270R; <a href="/entry/607474#0011">607474.0011</a>) in exon 11 and 342delA (<a href="/entry/607474#0006">607474.0006</a>) in exon 3 leading to a frameshift after arg58 and a subsequent premature stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12872815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Vilboux, T., Kayser, M., Introne, W., Suwannarat, P., Bernardini, I., Fischer, R., O'Brien, K., Kleta, R., Huizing, M., Gahl, W. A. <strong>Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria.</strong> Hum. Mutat. 30: 1611-1619, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19862842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19862842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19862842[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19862842">Vilboux et al. (2009)</a> provided an extensive update of published HGD mutations associated with AKU and identified 52 variants in 93 additional patients. Twenty-two novel mutations were identified, yielding a total of 91 identified HGD variants associated with the disorder. Most of the variants occurred in exons 3, 6, 8, and 13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19862842" 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>Alkaptonuria was found to be unusually frequent in the Dominican Republic (<a href="#25" class="mim-tip-reference" title="Milch, R. A. <strong>Studies of alcaptonuria: inheritance of 47 cases in eight highly inter-related Dominican kindreds.</strong> Am. J. Hum. Genet. 12: 76-85, 1960.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17948450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17948450</a>]" pmid="17948450">Milch, 1960</a>) and in Slovakia (<a href="#7" class="mim-tip-reference" title="Cervenansky, J., Sitaj, S., Urbanek, T. <strong>Alkaptonuria and ochronosis.</strong> J. Bone Joint Surg. Am. 41: 1169-1182, 1959.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13849350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13849350</a>]" pmid="13849350">Cervenansky et al., 1959</a>). According to <a href="#28" class="mim-tip-reference" title="O'Brien, W. M., La Du, B. N., Bunim, J. J. <strong>Biochemical, pathologic and clinical aspects of alcaptonuria, achronosis and ochronotic arthropathy: review of world literature (1584-1962).</strong> Am. J. Med. 34: 813-838, 1963."None>O'Brien et al. (1963)</a>, more cases (126) had been reported from Czechoslovakia than anywhere else. From Germany 108 had been reported, and from the United States 90. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17948450+13849350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Vilboux, T., Kayser, M., Introne, W., Suwannarat, P., Bernardini, I., Fischer, R., O'Brien, K., Kleta, R., Huizing, M., Gahl, W. A. <strong>Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria.</strong> Hum. Mutat. 30: 1611-1619, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19862842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19862842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19862842[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19862842">Vilboux et al. (2009)</a> stated that alkaptonuria affects 1 in 250,000 to 1 million people worldwide <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19862842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In the course of an ethylnitrosourea mutation study, <a href="#16" class="mim-tip-reference" title="Guenet, J. L. <strong>Personal Communication.</strong> Paris, France 11/5/1990."None>Guenet (1990)</a> and his group detected a mutation for alkaptonuria in the mouse by the finding of black wood shavings in the mouse boxes. Affected mice showed high levels of urinary homogentisic acid without signs of ochronosis or arthritis. <a href="#26" class="mim-tip-reference" title="Montagutelli, X., Lalouette, A., Coude, M., Kamoun, P., Forest, M., Guenet, J.-L. <strong>aku, a mutation of the mouse homologous to human alkaptonuria, maps to chromosome 16.</strong> Genomics 19: 9-11, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8188247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8188247</a>] [<a href="https://doi.org/10.1006/geno.1994.1004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8188247">Montagutelli et al. (1994)</a> demonstrated that the locus, symbolized aku, maps to mouse chromosome 16 in a region of syntenic homology with human 3q. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8188247" 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="#39" class="mim-tip-reference" title="Stenn, F. F., Milgram, J. W., Lee, S. L., Weigand, R. J., Veis, A. <strong>Biochemical identification of homogentisic acid pigment in an ochronotic Egyptian mummy.</strong> Science 197: 566-568, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/327549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">327549</a>] [<a href="https://doi.org/10.1126/science.327549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="327549">Stenn et al. (1977)</a> provided evidence that the Egyptian mummy Harwa, dating from 1500 B.C., had alkaptonuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=327549" 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 phenocopy (a nongenetically produced phenotype resembling a gene-determined one) of alkaptonuria is provided by the ochronosis that develops after the prolonged use of carbolic acid dressings for chronic cutaneous ulcers (<a href="#3" class="mim-tip-reference" title="Beddard, A. P. <strong>Ochronosis associated with carboluria.</strong> Quart. J. Med. 3: 329-336, 1910."None>Beddard, 1910</a>; <a href="#2" class="mim-tip-reference" title="Beddard, A. P., Plumtre, C. M. <strong>A further note on ochronosis associated with carboluria.</strong> Quart. J. Med. 5: 505-508, 1912."None>Beddard and Plumtre, 1912</a>). Fortunately this is a thing of the past. Quinacrine (atabrine), after prolonged administration, also causes an ochronotic change with pigmentation in many of the same sites as in alkaptonuria, and probably with a comparable arthrosis (<a href="#22" class="mim-tip-reference" title="Ludwig, G. D., Toole, J. F., Wood, J. C. <strong>Ochronosis from quinacrine (atabrine).</strong> Ann. Intern. Med. 59: 378-384, 1963.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14065956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14065956</a>] [<a href="https://doi.org/10.7326/0003-4819-59-3-378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14065956">Ludwig et al., 1963</a>). <a href="#36" class="mim-tip-reference" title="Snider, R. L., Thiers, B. H. <strong>Exogenous ochronosis.</strong> J. Am. Acad. Derm. 28: 662-664, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8463477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8463477</a>] [<a href="https://doi.org/10.1016/s0190-9622(08)81794-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8463477">Snider and Thiers (1993)</a> described a case of exogenous ochronosis due to use of bleaching creams that contain hydroquinone by black women to lighten their complexion. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14065956+8463477" 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="#34" class="mim-tip-reference" title="Sandler, M., Karoum, F., Ruthven, C. R. J. <strong>Parkinsonism with alkaptonuria: a new syndrome? (Letter)</strong> Lancet 296: 770 only, 1970. Note: Originally Volume II."None>Sandler et al. (1970)</a> raised the question of whether parkinsonism occurs in increased frequency with alkaptonuria, either as a complication or as a syndromal entity separate from ordinary alkaptonuria.</p><p><a href="#29" class="mim-tip-reference" title="Phornphutkul, C., Introne, W. J., Perry, M. B., Bernardini, I., Murphey, M. D., Fitzpatrick, D. L., Anderson, P. D., Huizing, M., Anikster, Y., Gerber, L. H., Gahl, W. A. <strong>Natural history of alkaptonuria.</strong> New Eng. J. Med. 347: 2111-2121, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12501223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12501223</a>] [<a href="https://doi.org/10.1056/NEJMoa021736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12501223">Phornphutkul et al. (2002)</a> provided a review of the natural history of alkaptonuria in the year marking the one-hundredth anniversary of Garrod's description of the disease as the first disorder in humans found to conform to the principles of mendelian autosomal recessive inheritance (<a href="#14" class="mim-tip-reference" title="Garrod, A. E. <strong>The incidence of alkaptonuria: a study in chemical individuality.</strong> Lancet 160: 1616-1620, 1902. Note: Originally Volume II."None>Garrod, 1902</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12501223" 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="#Abe1960" class="mim-tip-reference" title="Abe, Y., Oshima, N., Hatanaka, R., Amako, T., Hirohata, R. <strong>Thirteen cases of alkaptonuria from one family tree with special reference to osteo-arthrosis alkaptonuria.</strong> J. Bone Joint Surg. Am. 42: 817-831, 1960.">Abe et al. (1960)</a>; <a href="#Christensen1983" class="mim-tip-reference" title="Christensen, K., Manthorpe, R. <strong>Alkaptonuria and ochronosis: a survey and 5 cases.</strong> Hum. Hered. 33: 140-144, 1983.">Christensen and Manthorpe (1983)</a>; <a href="#Knox1958" class="mim-tip-reference" title="Knox, A. E. <strong>Sir Archibald Garrod's 'inborn errors of metabolism.' II. Alkaptonuria.</strong> Am. J. Hum. Genet. 10: 95-124, 1958.">Knox (1958)</a>; <a href="#La1978" class="mim-tip-reference" title="La Du, B. N. <strong>Alcaptonuria.In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.) : The Metabolic Basis of Inherited Disease. (4th ed.)</strong> New York: McGraw-Hill (pub.) 1978. Pp. 268-282.">La
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Du (1978)</a>; <a href="#Levine1978" class="mim-tip-reference" title="Levine, H. D., Parisi, A. F., Holdsworth, D. E., Cohn, L. W. <strong>Aortic valve replacement for ochronosis of the aortic valve.</strong> Chest 74: 466-467, 1978.">Levine et al. (1978)</a>; <a href="#Reginato1972" class="mim-tip-reference" title="Reginato, A. J., Riera, M., Martinez, V. A., Ruiz, F. <strong>Alkaptonuria, ochronotic arthropathy and aortic stenosis.</strong> Rev. Med. Chile 100: 529-533, 1972.">Reginato et al. (1972)</a>; <a href="#Srsen1978" class="mim-tip-reference" title="Srsen, S., Cisarik, F., Pasztor, L., Harmecko, L. <strong>Alkaptonuria in the Trencin district of Czechoslovakia.</strong> Am. J. Med. Genet. 2: 159-166, 1978.">Srsen et al.
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Abe, Y., Oshima, N., Hatanaka, R., Amako, T., Hirohata, R.
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<strong>Thirteen cases of alkaptonuria from one family tree with special reference to osteo-arthrosis alkaptonuria.</strong>
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J. Bone Joint Surg. Am. 42: 817-831, 1960.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13848727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13848727</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13848727" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Beddard, A. P., Plumtre, C. M.
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<strong>A further note on ochronosis associated with carboluria.</strong>
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Quart. J. Med. 5: 505-508, 1912.
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Beddard, A. P.
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<strong>Ochronosis associated with carboluria.</strong>
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Quart. J. Med. 3: 329-336, 1910.
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Beltran-Valero de Bernabe, D., Granadino, B., Chiarelli, I., Porfirio, B., Mayatepek, E., Aquaron, R., Moore, M. M., Festen, J. J. M., Sanmarti, R., Penalva, M. A., Rodriguez de Cordoba, S.
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<strong>Mutation and polymorphism analysis of the human homogentisate 1,2-dioxygenase gene in alkaptonuria patients.</strong>
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Am. J. Hum. Genet. 62: 776-784, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529363</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/301805" target="_blank">Full Text</a>]
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Beltran-Valero de Bernabe, D., Peterson, P., Luopajarvi, K., Matintalo, P., Alho, A., Konttinen, Y., Krohn, K., Rodriguez de Cordoba, S., Ranki, A.
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<strong>Mutational analysis of the HGO gene in Finnish alkaptonuria patients.</strong>
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J. Med. Genet. 36: 922-923, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10594001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10594001</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10594001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Carrier, D. A., Harris, C. M.
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<strong>Bilateral hip and bilateral knee arthroplasties in a patient with ochronotic arthropathy.</strong>
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Orthop. Rev. 19: 1005-1009, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2270175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2270175</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2270175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Cervenansky, J., Sitaj, S., Urbanek, T.
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<strong>Alkaptonuria and ochronosis.</strong>
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J. Bone Joint Surg. Am. 41: 1169-1182, 1959.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13849350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13849350</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13849350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Christensen, K., Manthorpe, R.
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<strong>Alkaptonuria and ochronosis: a survey and 5 cases.</strong>
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Hum. Hered. 33: 140-144, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6862457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6862457</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6862457" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1159/000153365" target="_blank">Full Text</a>]
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Cunningham, T. J., Roux, E., Lagier, R., Fallet, G. H.
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<strong>Rapidly progressive hip osteoarthrosis: an unusual presentation of ochronosis.</strong>
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Clin. Exp. Rheum. 7: 315-318, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2667832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2667832</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2667832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Dereymaeker, L., Van Parijs, G., Bayart, M., Daenen, W., Lauwerijns, J., De Geest, H.
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<strong>Ochronosis and alkaptonuria: report of a new case with calcified aortic valve stenosis.</strong>
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Acta Cardiol. 45: 87-92, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2316305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2316305</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2316305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Elcioglu, N. H., Aytug, A. F., Muller, C. R., Gurbuz, O., Ergun, T., Kotiloglu E., Elcioglu, M.
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<strong>Alkaptonuria caused by compound heterozygote mutations.</strong>
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Genet. Counsel. 14: 207-213, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12872815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12872815</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12872815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S.
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<strong>The molecular basis of alkaptonuria.</strong>
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Nature Genet. 14: 19-24, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782815</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0996-19" target="_blank">Full Text</a>]
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<a id="33" class="mim-anchor"></a>
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<a id="Rodriguez2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rodriguez, J. M., Timm, D. E., Titus, G. P., Bertran-Valero de Bernabe, D., Criado, O., Mueller, H. A., Rodriguez de Cordoba, S., Penalva, M. A.
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<strong>Structural and functional analysis of mutations in alkaptonuria.</strong>
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Hum. Molec. Genet. 9: 2341-2350, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001939</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001939" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/oxfordjournals.hmg.a018927" target="_blank">Full Text</a>]
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<a id="34" class="mim-anchor"></a>
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<a id="Sandler1970" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sandler, M., Karoum, F., Ruthven, C. R. J.
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<strong>Parkinsonism with alkaptonuria: a new syndrome? (Letter)</strong>
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Lancet 296: 770 only, 1970. Note: Originally Volume II.
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<a id="Sener1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sener, R. N.
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<strong>Prostatic and renal stones and unilateral obstruction of the urinary tract caused by ochronosis.</strong>
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Am. J. Roentgen. 158: 214-215, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1727353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1727353</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1727353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.2214/ajr.158.1.1727353" target="_blank">Full Text</a>]
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<a id="Snider1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Snider, R. L., Thiers, B. H.
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<strong>Exogenous ochronosis.</strong>
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J. Am. Acad. Derm. 28: 662-664, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8463477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8463477</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8463477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0190-9622(08)81794-x" target="_blank">Full Text</a>]
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<a id="37" class="mim-anchor"></a>
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<a id="Srsen1978" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Srsen, S., Cisarik, F., Pasztor, L., Harmecko, L.
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<strong>Alkaptonuria in the Trencin district of Czechoslovakia.</strong>
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Am. J. Med. Genet. 2: 159-166, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/263435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">263435</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=263435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320020207" target="_blank">Full Text</a>]
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<a id="Steinmann1984" class="mim-anchor"></a>
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<p class="mim-text-font">
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Steinmann, B., Gnehm, H. E., Rao, V. H., Kind, H. P., Prader, A.
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<strong>Neonatal severe primary hyperparathyroidism and alkaptonuria in a boy born to related parents with familial hypocalciuric hypercalcemia.</strong>
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Helv. Paediat. Acta 39: 171-186, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6543841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6543841</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6543841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Stenn, F. F., Milgram, J. W., Lee, S. L., Weigand, R. J., Veis, A.
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<strong>Biochemical identification of homogentisic acid pigment in an ochronotic Egyptian mummy.</strong>
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Science 197: 566-568, 1977.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/327549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">327549</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=327549" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.327549" target="_blank">Full Text</a>]
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<a id="Suzuki1999" class="mim-anchor"></a>
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Suzuki, Y., Oda, K., Yoshikawa, Y., Maeda, T., Suzuki, T.
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<strong>A novel therapeutic trial of homogentisic aciduria in a murine model of alkaptonuria.</strong>
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J. Hum. Genet. 44: 79-84, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10083729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10083729</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10083729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s100380050114" target="_blank">Full Text</a>]
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<a id="Vilboux2009" class="mim-anchor"></a>
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Vilboux, T., Kayser, M., Introne, W., Suwannarat, P., Bernardini, I., Fischer, R., O'Brien, K., Kleta, R., Huizing, M., Gahl, W. A.
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<strong>Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria.</strong>
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Hum. Mutat. 30: 1611-1619, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19862842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19862842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19862842[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19862842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.21120" target="_blank">Full Text</a>]
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<a id="Wolff1989" class="mim-anchor"></a>
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Wolff, J. A., Barshop, B., Nyhan, W. L., Leslie, J., Seegmiller, J. E., Gruber, H., Garst, M., Winter, S., Michals, K., Matalon, R.
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<strong>Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy.</strong>
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Pediat. Res. 26: 140-144, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2771520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2771520</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2771520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1203/00006450-198908000-00015" target="_blank">Full Text</a>]
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<a id="Zatkova2000" class="mim-anchor"></a>
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Zatkova, A., Polakova, H., Micutkova, L., Zvarik, M., Bosak, V., Ferakova, E., Matusek, J., Ferak, V., Kadasi, L.
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<strong>Novel mutations in the homogentisate-1,2-dioxygenase gene identified in Slovak patients with alkaptonuria. (Letter)</strong>
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J. Med. Genet. 37: 539-542, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10970188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10970188</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10970188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.37.7.539" target="_blank">Full Text</a>]
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<a id="Zibolen2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zibolen, M., Srsnova, K., Srsen, S.
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<strong>Increased urolithiasis in patients with alkaptonuria in childhood. (Letter)</strong>
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Clin. Genet. 58: 79-80, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10945668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10945668</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10945668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1034/j.1399-0004.2000.580115.x" target="_blank">Full Text</a>]
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<br />
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 09/09/2021
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 4/21/2014<br>Victor A. McKusick - updated : 9/12/2003<br>Cassandra L. Kniffin - reorganized : 1/16/2003<br>Victor A. McKusick - updated : 1/8/2003<br>Michael J. Wright - updated : 7/24/2001<br>George E. Tiller - updated : 12/14/2000<br>Victor A. McKusick - updated : 9/1/2000<br>Michael J. Wright - updated : 4/14/2000<br>Victor A. McKusick - updated : 11/8/1999<br>Victor A. McKusick - updated : 4/22/1999<br>Victor A. McKusick - updated : 4/12/1999<br>Victor A. McKusick - updated : 3/1/1999<br>Victor A. McKusick - updated : 1/20/1999<br>Victor A. McKusick - updated : 9/3/1998<br>Victor A. McKusick - updated : 5/14/1998<br>Victor A. McKusick - updated : 6/19/1997<br>Victor A. McKusick - updated : 4/15/1997
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 6/2/1986
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alopez : 04/27/2023
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carol : 09/09/2021<br>carol : 05/29/2019<br>carol : 07/09/2016<br>carol : 4/22/2014<br>mcolton : 4/21/2014<br>ckniffin : 4/21/2014<br>terry : 1/13/2011<br>terry : 2/10/2009<br>cwells : 9/12/2003<br>carol : 1/16/2003<br>ckniffin : 1/14/2003<br>cwells : 1/9/2003<br>tkritzer : 1/8/2003<br>alopez : 8/2/2001<br>alopez : 8/2/2001<br>terry : 7/24/2001<br>cwells : 2/21/2001<br>cwells : 1/18/2001<br>cwells : 1/16/2001<br>terry : 12/14/2000<br>terry : 9/1/2000<br>alopez : 4/14/2000<br>terry : 4/14/2000<br>alopez : 11/12/1999<br>terry : 11/8/1999<br>mgross : 5/6/1999<br>mgross : 5/3/1999<br>mgross : 4/26/1999<br>terry : 4/22/1999<br>carol : 4/13/1999<br>terry : 4/12/1999<br>terry : 3/1/1999<br>carol : 1/29/1999<br>terry : 1/20/1999<br>alopez : 9/8/1998<br>terry : 9/3/1998<br>alopez : 5/19/1998<br>terry : 5/14/1998<br>mark : 6/19/1997<br>jenny : 4/15/1997<br>terry : 4/10/1997<br>mark : 9/3/1996<br>randy : 8/31/1996<br>terry : 8/31/1996<br>mimadm : 11/12/1995<br>carol : 1/19/1995<br>davew : 8/19/1994<br>warfield : 4/14/1994<br>carol : 12/13/1993<br>carol : 10/27/1993
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<strong>#</strong> 203500
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<h3>
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ALKAPTONURIA; AKU
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<h4>
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<span class="mim-font">
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HOMOGENTISIC ACID OXIDASE DEFICIENCY
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</span>
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</h4>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 360378009;
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<strong>ICD10CM:</strong> E70.29;
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<strong>ORPHA:</strong> 56;
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<strong>DO:</strong> 9270;
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</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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3q13.33
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</span>
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</td>
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<td>
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<span class="mim-font">
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Alkaptonuria
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</span>
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</td>
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<td>
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<span class="mim-font">
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203500
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
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HGD
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</span>
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</td>
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<td>
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<span class="mim-font">
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607474
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because alkaptonuria (AKU) is caused by homozygous or compound heterozygous mutation in the homogentisate 1,2-dioxygenase gene (HGD; 607474) on chromosome 3q13.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Alkaptonuria is an autosomal recessive metabolic disorder characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of the cardiac valves (summary by Vilboux et al., 2009). </p><p>Alkaptonuria enjoys the historic distinction of being one of the first conditions in which mendelian recessive inheritance was proposed (by Garrod, 1902, on the suggestion of Bateson) and of being 1 of the 4 conditions in the charter group of inborn errors of metabolism. The manifestations are urine that turns dark on standing and alkalinization, black ochronotic pigmentation of cartilage and collagenous tissues, and arthritis, especially characteristic in the spine.</p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cunningham et al. (1989) observed rapidly evolving osteoarthrosis of the right hip in a 65-year-old woman who had unusual stress after being forced to abandon a train as a result of a bomb threat and having to carry 2 heavy suitcases. Carrier and Harris (1990) reported the case of a 70-year-old man who underwent bilateral hip and knee total joint arthroplasties for the treatment of ochronotic arthropathy. Dereymaeker et al. (1990) described a patient in whom calcified aortic valve disease secondary to ochronosis necessitated urgent aortic valve replacement. </p><p>There are reports of urolithiasis in AKU patients in middle and late adulthood who have already developed the full clinical picture of the disorder (e.g., Sener, 1992). Zibolen et al. (2000) emphasized the increased frequency of urolithiasis in AKU patients younger than 15 years. They reported 5 such patients, in one of whom the diagnosis of urolithiasis had been made at the age of 2 years. </p><p>Phornphutkul et al. (2002) provided a review of the natural history of alkaptonuria. They based the review on an evaluation of 58 patients with the disorder ranging in age from 4 to 80 years. They found that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity of disease began increasing after the age of 30 years, with a more rapid increase in men than in women. In the 58 patients reviewed by Phornphutkul et al. (2002), kidney stones were documented in 13 male and 3 female patients. Of the 27 men who were 31 to 60 years old, 8 had prostate stones. The development of prostate stones was not associated with the development of kidney stones. Three patients, each over the age of 50 years, had undergone aortic valve replacement. </p><p>Ranganath et al. (2021) examined the clinical phenotype, with a focus on aortic disease, in 81 individuals with alkaptonuria and a mean age of 48.6 years, 51 of whom received nitisinone treatment. The prevalence of aortic stenosis was 22.2% and the prevalence of aortic valve replacement was 6.2%. Aortic valve maximum velocity (Vmax) was found to be directly related to age, systolic blood pressure, serum homogentisic acid, ochronosis score, and alkaptonuria severity score index. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Inheritance</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The transmission pattern of AKU in the families reported by Fernandez-Canon et al. (1996) was consistent with autosomal recessive inheritance. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Management</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lustberg et al. (1970) presented evidence that ascorbic acid in high doses decreases binding of C(14)-homogentisic acid (HGA) in connective tissues of rats with experimental alkaptonuria. Long-term therapy in young patients with alkaptonuria is indicated. </p><p>Wolff et al. (1989) treated 2 adults and 3 infants with high doses of ascorbic acid and studied the effect on the excretion of homogentisic acid and its toxic oxidation product, benzoquinone acetic acid (BQA). The purpose was to determine whether concentrations in body fluids of the latter substance, the putative toxic metabolite in alkaptonuria, would be reduced. Indeed, disappearance of BQA from the urine was observed in adults, whereas the level of excretion of homogentisic acid did not change. This could have relevance to the pathogenesis of ochronotic arthritis. In 2 of the infants studied (a 4- and a 5-month-old), ascorbic acid may have doubled the amount of homogentisic acid in the urine, presumably through an effect on the immature p-hydroxyphenylpyruvic acid oxidase. Dietary reduction of the intake of tyrosine and phenylalanine substantially reduced the excretion of homogentisic acid. </p><p>In a 48-year-old man in whom alkaptonuria had been diagnosed during infancy, Mayatepek et al. (1998) studied the effects of 4 different therapeutic 1-month trials consisting of supplementation with ascorbic acid (1 g/day and 10 g/day) or a low-protein diet (0.3 g/kg/day and 1.3 g/kg/day). Administration of ascorbic acid in doses of 1 g/day or more resulted in a significant and constant decrease of urinary BQA, whereas the excretion of HGA could not be substantially reduced. Mild and severe dietary reduction of protein intake alone also substantially reduced the excretion of BQA, whereas the level of HGA excretion could not be drastically reduced. Such an extreme protein restriction would not, however, have been acceptable for a longer period of time. They concluded that supplementation of ascorbic acid in doses of 1 g/day represents a simple and rational treatment in patients with alkaptonuria. </p><p>La Du (1998) examined the question 'Are we ready to try to cure alkaptonuria?' He explored the possibilities and indicated that model animal systems, either those representing known spontaneous hereditary deficiencies of homogentisic acid or appropriate 'knockout' animals with created deficiencies of the enzyme, need to be tested before human trials are undertaken. He said that it is to be hoped that some, perhaps all, of the adverse effects of alkaptonuria can be prevented by new molecular therapeutic approaches; however, trading alkaptonuric problems for even more serious metabolic disturbances because of the pronounced toxicity of the later tyrosine metabolites is not an acceptable alternative. </p><p>Suzuki et al. (1999) used 2(-2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) as a therapeutic agent for alkaptonuria. NTBC is a potent inhibitor of p-hydroxyphenylpyruvate dioxygenase, which catalyzes the formation of homogentisic acid from p-hydroxyphenylpyruvic acid, and had been used in the treatment of type I tyrosinemia (276700). In a murine model of alkaptonuria that had been created with ethylnitrosurea by Montagutelli et al. (1994), they observed a dose-dependent reduction in urinary output of homogentisic acid with administration of NTBC. </p><p>Phornphutkul et al. (2002) reported that, in a 51-year-old woman, urinary HGA excretion fell from 2.9 to 0.13 g per day after a 10-day course of nitisinone. In a 59-year-old woman, similar reductions were observed after 9 days of treatment. Plasma tyrosine levels in these patients rose, with no clinical signs or symptoms. They emphasized that the long-term safety and efficacy of this treatment requires further evaluation. Nitisinone is a triketone herbicide that inhibits 4-hydroxyphenylpyruvate dioxygenase by rapid, avid binding that is reversible. The agent had been approved by the FDA for the treatment of tyrosinemia type I. </p><p>Ranganath et al. (2021) found that nitisinone treatment in a cohort of 51 patients with alkaptonuria reduced serum homogentisic acid, urine homogentisic acid, ochronosis scores, and alkaptonuria severity score index. Nitisinone also decreased aortic valve maximum velocity (Vmax) over time. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 6 Slovak pedigrees selected from a total of 191 alkaptonuria patients registered at the Institute of Clinical Genetics in Martin, Slovakia, Janocha et al. (1994) demonstrated linkage to microsatellite markers from proximal 3q. Markers on that chromosome were selected for study because of previously demonstrated homology of synteny with mouse chromosome 16. Independently, Pollak et al. (1993) used homozygosity mapping to locate the alkaptonuria gene to 3q2 in a 16-cM region. They studied 2 consanguineous families with 4 affected children and 2 nonconsanguineous families which supported the linkage. They pointed out that Garnica et al. (1981) described coinheritance of alkaptonuria and sucrase-isomaltase deficiency (222900), which maps to 3q25-q26. Furthermore, Steinmann et al. (1984) described coinheritance of neonatal severe hyperparathyroidism and alkaptonuria. The former condition is thought to be the recessive (i.e., homozygous) form of familial hypocalciuric hypercalcemia (145980), which maps to 3q21-q24. In the case reported by Steinmann et al. (1984), both parents, who were related, had familial hypocalciuric hypercalcemia. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In patients with alkaptonuria, Fernandez-Canon et al. (1996) identified missense mutations in the homogentisate 1,2-dioxygenase gene that cosegregated with the disease (607474.0001, 607474.0002), and provided biochemical evidence that at least one of these missense mutations is a loss-of-function mutation. </p><p>Studying 4 alkaptonuria patients from Slovakia, where alkaptonuria has a notably high frequency, Gehrig et al. (1997) found 2 novel mutations in the HGD gene (607474.0003, 607474.0004). </p><p>Other mutations in the HGD gene were identified in patients with alkaptonuria by Beltran-Valero de Bernabe et al. (1998, 1999), Muller et al. (1999), Rodriguez et al. (2000), Zatkova et al. (2000), and Phornphutkul et al. (2002). </p><p>In Turkey, Elcioglu et al. (2003) described a 39-year-old male patient with typical features of alkaptonuria. In addition to the typical changes in the skin at many sites and in the pinnae and sclerae, there were grayish-blue longitudinal rigging of his fingernails and bluish-gray pigment deposition on the tympanic membrane. He was found to be compound heterozygous for 2 mutations in the HGD gene: gly270 to arg (G270R; 607474.0011) in exon 11 and 342delA (607474.0006) in exon 3 leading to a frameshift after arg58 and a subsequent premature stop codon. </p><p>Vilboux et al. (2009) provided an extensive update of published HGD mutations associated with AKU and identified 52 variants in 93 additional patients. Twenty-two novel mutations were identified, yielding a total of 91 identified HGD variants associated with the disorder. Most of the variants occurred in exons 3, 6, 8, and 13. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Alkaptonuria was found to be unusually frequent in the Dominican Republic (Milch, 1960) and in Slovakia (Cervenansky et al., 1959). According to O'Brien et al. (1963), more cases (126) had been reported from Czechoslovakia than anywhere else. From Germany 108 had been reported, and from the United States 90. </p><p>Vilboux et al. (2009) stated that alkaptonuria affects 1 in 250,000 to 1 million people worldwide </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In the course of an ethylnitrosourea mutation study, Guenet (1990) and his group detected a mutation for alkaptonuria in the mouse by the finding of black wood shavings in the mouse boxes. Affected mice showed high levels of urinary homogentisic acid without signs of ochronosis or arthritis. Montagutelli et al. (1994) demonstrated that the locus, symbolized aku, maps to mouse chromosome 16 in a region of syntenic homology with human 3q. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Stenn et al. (1977) provided evidence that the Egyptian mummy Harwa, dating from 1500 B.C., had alkaptonuria. </p><p>A phenocopy (a nongenetically produced phenotype resembling a gene-determined one) of alkaptonuria is provided by the ochronosis that develops after the prolonged use of carbolic acid dressings for chronic cutaneous ulcers (Beddard, 1910; Beddard and Plumtre, 1912). Fortunately this is a thing of the past. Quinacrine (atabrine), after prolonged administration, also causes an ochronotic change with pigmentation in many of the same sites as in alkaptonuria, and probably with a comparable arthrosis (Ludwig et al., 1963). Snider and Thiers (1993) described a case of exogenous ochronosis due to use of bleaching creams that contain hydroquinone by black women to lighten their complexion. </p><p>Sandler et al. (1970) raised the question of whether parkinsonism occurs in increased frequency with alkaptonuria, either as a complication or as a syndromal entity separate from ordinary alkaptonuria.</p><p>Phornphutkul et al. (2002) provided a review of the natural history of alkaptonuria in the year marking the one-hundredth anniversary of Garrod's description of the disease as the first disorder in humans found to conform to the principles of mendelian autosomal recessive inheritance (Garrod, 1902). </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Abe et al. (1960); Christensen and Manthorpe (1983); Knox (1958); La
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Du (1978); Levine et al. (1978); Reginato et al. (1972); Srsen et al.
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(1978)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Abe, Y., Oshima, N., Hatanaka, R., Amako, T., Hirohata, R.
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<strong>Thirteen cases of alkaptonuria from one family tree with special reference to osteo-arthrosis alkaptonuria.</strong>
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J. Bone Joint Surg. Am. 42: 817-831, 1960.
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[PubMed: 13848727]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Beddard, A. P., Plumtre, C. M.
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<strong>A further note on ochronosis associated with carboluria.</strong>
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Quart. J. Med. 5: 505-508, 1912.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Beddard, A. P.
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<strong>Ochronosis associated with carboluria.</strong>
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Quart. J. Med. 3: 329-336, 1910.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Beltran-Valero de Bernabe, D., Granadino, B., Chiarelli, I., Porfirio, B., Mayatepek, E., Aquaron, R., Moore, M. M., Festen, J. J. M., Sanmarti, R., Penalva, M. A., Rodriguez de Cordoba, S.
|
|
<strong>Mutation and polymorphism analysis of the human homogentisate 1,2-dioxygenase gene in alkaptonuria patients.</strong>
|
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Am. J. Hum. Genet. 62: 776-784, 1998.
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[PubMed: 9529363]
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[Full Text: https://doi.org/10.1086/301805]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Beltran-Valero de Bernabe, D., Peterson, P., Luopajarvi, K., Matintalo, P., Alho, A., Konttinen, Y., Krohn, K., Rodriguez de Cordoba, S., Ranki, A.
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<strong>Mutational analysis of the HGO gene in Finnish alkaptonuria patients.</strong>
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J. Med. Genet. 36: 922-923, 1999.
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[PubMed: 10594001]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Carrier, D. A., Harris, C. M.
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<strong>Bilateral hip and bilateral knee arthroplasties in a patient with ochronotic arthropathy.</strong>
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Orthop. Rev. 19: 1005-1009, 1990.
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[PubMed: 2270175]
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[Full Text: https://doi.org/10.1034/j.1399-0004.2000.580115.x]
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Hilary J. Vernon - updated : 09/09/2021<br>Cassandra L. Kniffin - updated : 4/21/2014<br>Victor A. McKusick - updated : 9/12/2003<br>Cassandra L. Kniffin - reorganized : 1/16/2003<br>Victor A. McKusick - updated : 1/8/2003<br>Michael J. Wright - updated : 7/24/2001<br>George E. Tiller - updated : 12/14/2000<br>Victor A. McKusick - updated : 9/1/2000<br>Michael J. Wright - updated : 4/14/2000<br>Victor A. McKusick - updated : 11/8/1999<br>Victor A. McKusick - updated : 4/22/1999<br>Victor A. McKusick - updated : 4/12/1999<br>Victor A. McKusick - updated : 3/1/1999<br>Victor A. McKusick - updated : 1/20/1999<br>Victor A. McKusick - updated : 9/3/1998<br>Victor A. McKusick - updated : 5/14/1998<br>Victor A. McKusick - updated : 6/19/1997<br>Victor A. McKusick - updated : 4/15/1997
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Victor A. McKusick : 6/2/1986
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