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Entry
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- #300752 - PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED; XLEPP
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- OMIM
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<p>
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<span class="h4">#300752</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/300752"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS177000"> <strong>Phenotypic Series</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="#clinicalManagement">Clinical Management</a>
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<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</h4>
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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 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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</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=PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED" 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=23451&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/NBK121284/" 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/9183" 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/porphyria" 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=300752[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=443197" 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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<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:13270" 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/300752" 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://wormbase.org/resources/disease/DOID:13270" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</div>
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<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> 1197360001<br />
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<strong>ORPHA:</strong> 443197<br />
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<strong>DO:</strong> 13270<br />
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">ICD+</a>
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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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300752
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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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PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED; XLEPP
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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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PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT; XLDPP<br />
|
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ERYTHROHEPATIC PROTOPORPHYRIA, X-LINKED
|
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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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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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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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<a href="/geneMap/X/341?start=-3&limit=10&highlight=341">
|
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Xp11.21
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Protoporphyria, erythropoietic, X-linked
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/300752"> 300752 </a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked">XL</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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ALAS2
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/301300"> 301300 </a>
|
|
</span>
|
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</td>
|
|
</tr>
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</tbody>
|
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</table>
|
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</div>
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</div>
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<div>
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|
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<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/300752" 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>
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|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS177000" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
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|
|
<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/300752" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/300752" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- X-linked <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263934009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263934009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241764&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241764</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001417" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001417</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001417" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001417</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
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|
|
</div>
|
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|
|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Liver </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Abnormal liver function (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/75183008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">75183008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0086565&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0086565</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001410" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001410</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002910" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002910</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002910" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002910</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Biliary Tract </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Gallstones (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/235919008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">235919008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/266474003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">266474003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/256896000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">256896000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K80" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K80</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/574" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">574</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0008350&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008350</a>, <a href="https://bioportal.bioontology.org/search?q=C0947622&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0947622</a>, <a href="https://bioportal.bioontology.org/search?q=C0242216&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242216</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001081" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001081</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001081" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001081</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Photosensitivity, severe <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849186&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849186</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007537" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007537</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/90128006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">90128006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000992" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000992</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEMATOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Iron deficiency <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35240004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35240004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/87522002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">87522002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E61.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E61.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D50</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D50.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">280</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/280.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">280.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162316&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162316</a>, <a href="https://bioportal.bioontology.org/search?q=C0240066&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240066</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001891</a>]</span><br /> -
|
|
Iron-deficiency anemia (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/87522002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">87522002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D50</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D50.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">280</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/280.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">280.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162316&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162316</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001891</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001891</a>]</span><br /> -
|
|
Increased erythrocyte zinc- and metal-free protoporphyrin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806658&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806658</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Onset in early childhood<br /> -
|
|
Some females with the mutation may be unaffected or mildly affected due to skewed X-chromosome inactivation<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the delta-aminolevulinate synthase 2 gene (ALAS2, <a href="/entry/301300#0015">301300.0015</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Protoporphyria, erythropoietic
|
|
- <a href="/phenotypicSeries/PS177000">PS177000</a>
|
|
- 3 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus<br />MIM number</strong>
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<a href="/geneMap/15/294?start=-3&limit=10&highlight=294"> 15q22.31 </a>
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<span class="mim-font">
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<a href="/entry/618015"> ?Protoporphyria, erythropoietic, 2 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/615611"> 615611 </a>
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<a href="/geneMap/18/206?start=-3&limit=10&highlight=206"> 18q21.31 </a>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/300752"> Protoporphyria, erythropoietic, X-linked </a>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/300752"> 300752 </a>
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<a href="/entry/301300"> 301300 </a>
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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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<p>A number sign (#) is used with this entry because of evidence that X-linked erythropoietic protoporphyria (XLEPP) is caused by gain-of-function mutations in the ALAS2 gene (<a href="/entry/301300">301300</a>) on chromosome Xp11.</p><p>Loss-of-function mutations in the ALAS2 gene cause X-linked sideroblastic anemia (<a href="/entry/300751">300751</a>).</p>
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<p>X-linked erythropoietic protoporphyria (XLEPP) is a metabolic disorder of heme biosynthesis characterized by onset in early childhood of severe photosensitivity associated with decreased iron stores and increased erythrocyte zinc- and metal-free protoporphyrin. Some patients may develop liver disease or gallstones (summary by <a href="#3" class="mim-tip-reference" title="Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H. <strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong> Hum. Molec. Genet. 22: 1280-1288, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23263862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23263862</a>] [<a href="https://doi.org/10.1093/hmg/dds531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23263862">Ducamp et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23263862" 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>For a discussion of genetic heterogeneity of erythropoietic protoporphyria, see EPP1 (<a href="/entry/177000">177000</a>).</p>
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<p>In a subgroup of families with FECH (<a href="/entry/612386">612386</a>) mutation-negative protoporphyria, <a href="#4" class="mim-tip-reference" title="Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H. <strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong> Am. J. Hum. Genet. 83: 408-414, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18760763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18760763">Whatley et al. (2008)</a> studied 8 families in which at least 1 member had acute photosensitivity clinically indistinguishable from that seen in autosomal recessive erythropoietic protoporphyria-1 (EPP1; <a href="/entry/177000">177000</a>). Four families were of western European ancestry, and the others were of Jewish, North African, Indo-Asian, and Sudanese ancestry. In these 8 families, both sexes were affected. Patients had neither anemia nor iron overload. Instead there was some evidence of diminished iron stores, particularly in males. Five patients (17%) had overt liver disease, which was more common in males (0.008), and 1 obligate carrier was asymptomatic. These families showed an apparent X-linked pattern of inheritance with an absence of father-to-son transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18760763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H. <strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong> Hum. Molec. Genet. 22: 1280-1288, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23263862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23263862</a>] [<a href="https://doi.org/10.1093/hmg/dds531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23263862">Ducamp et al. (2013)</a> reported 5 XLEPP patients from 4 unrelated families referred for a history of skin photosensitivity associated with increased levels of zinc- and metal-free protoporphyrin in erythrocytes. Two patients had elevated liver enzymes and 1 had gallstones. Most had evidence of iron deficiency, but only some patients had anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23263862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Brancaleoni, V., Balwani, M., Granata, F., Graziadei, G., Missineo, P., Fiorentino, V., Fustinoni, S., Cappellini, M. D., Naik, H., Desnick, R. J., Di Pierro, E. <strong>X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria.</strong> Clin. Genet. 89: 20-26, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25615817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25615817</a>] [<a href="https://doi.org/10.1111/cge.12562" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25615817">Brancaleoni et al. (2016)</a> reported 6 unrelated families of European descent with XLP confirmed by genetic analysis. Five of the families carried the common ALAS2 4-bp deletion (c.1706_1709delAGTG; <a href="/entry/301300#0015">301300.0015</a>). Among the families, there were 7 affected males with a hemizygous mutation and 10 females who had the mutation in the heterozygous state. In 1 family (family C), there was only 1 affected male who had a de novo mutation; his mother was not a carrier. There was heterogeneity among the females with the mutation: 2 were fully affected with photosensitivity from childhood and increased erythrocyte protoporphyrin IX (PPIX), 7 had later onset of symptoms and/or only mildly increased PPIX, and 1 was completely asymptomatic with normal laboratory values. X-chromosome inactivation studies on the females with mutations were consistent with the clinical and biochemical heterogeneity: the 2 photosensitive females had a skewed pattern with over 73% of the wildtype allele inactivated, the asymptomatic female had 88.4% inactivation of the mutant allele, and the 7 females with no or late-onset photosensitivity and/or mildly increased PPIX values had relatively balanced X-inactivation patterns with preferential expression of the wildtype ALAS2 allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25615817" 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="#1" class="mim-tip-reference" title="Balwani, M., Bonkovsky, H. L., Levy, C., Anderson, K. E., Bissell, D. M., Parker, C., Takahashi, F., Desnick, R. J., Belongie, K., Endeavor investigators. <strong>dersimelagon in erythropoietic protoporphyrias.</strong> New Eng. J. Med. 388: 1376-1385, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37043653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37043653</a>] [<a href="https://doi.org/10.1056/NEJMoa2208754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37043653">Balwani et al. (2023)</a> performed a phase 2 clinical trial in 93 patients with erythropoietic protoporphyria (<a href="/entry/177000">177000</a>) and 9 patients with X-linked protoporphyria aged 18 to 75 years who were randomly assigned in a 1:1:1 ratio to placebo or dersimelagon 100 mg or 300 mg once daily for 16 weeks. The primary endpoint was the change from baseline to 16 weeks in the time to first prodromal symptom associated with sunlight exposure. Daily sunlight exposure and symptoms were recorded in an electronic diary. Quality of life and safety were also assessed. Among enrollees, 90% completed the treatment period. There was a significant change in time to the first prodromal symptom compared with the placebo group for the 100 mg dersimelagon group (53.8 minutes, p = 0.008) and for the 300 gm dersimelagon group (62.5 minutes, p = 0.003). Quality of life improved in both treatment groups. The most common adverse events that occurred or worsened during treatment were nausea, freckles, headache, and skin hyperpigmentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37043653" 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 erythropoietic porphyria in the families reported by <a href="#4" class="mim-tip-reference" title="Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H. <strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong> Am. J. Hum. Genet. 83: 408-414, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18760763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18760763">Whatley et al. (2008)</a> was consistent with X-linked dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18760763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H. <strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong> Hum. Molec. Genet. 22: 1280-1288, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23263862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23263862</a>] [<a href="https://doi.org/10.1093/hmg/dds531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23263862">Ducamp et al. (2013)</a> reported a French girl with XLEPP whose mother was mildly affected and was demonstrated to be germline and somatic mosaic for an ALAS2 mutation (<a href="/entry/301300#0015">301300.0015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23263862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Brancaleoni, V., Balwani, M., Granata, F., Graziadei, G., Missineo, P., Fiorentino, V., Fustinoni, S., Cappellini, M. D., Naik, H., Desnick, R. J., Di Pierro, E. <strong>X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria.</strong> Clin. Genet. 89: 20-26, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25615817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25615817</a>] [<a href="https://doi.org/10.1111/cge.12562" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25615817">Brancaleoni et al. (2016)</a> determined that clinical and biochemical heterogeneity in females who are heterozygous for pathogenic ALAS2 mutations is associated with X-chromosome inactivation patterns. Females with full symptoms of the disorder tend to have a skewed pattern with most of the wildtype allele inactivated, whereas those without symptoms have most of the mutant allele inactivated. Those with intermediate or mild symptoms have relatively balanced X-inactivation patterns with preferential expression of the wildtype ALAS2 allele. The findings indicated that the disorder should be considered to have X-linked inheritance with penetrance and severity in females related to the level of X-chromosome inactivation, and that the term 'X-linked dominant' inheritance be discontinued. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25615817" 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 observation of apparent X linkage of EPP in 8 families prompted <a href="#4" class="mim-tip-reference" title="Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H. <strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong> Am. J. Hum. Genet. 83: 408-414, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18760763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18760763">Whatley et al. (2008)</a> to investigate 2 candidate genes on the X chromosome that are involved in heme formation, GATA1 (<a href="/entry/305371">305371</a>) and ALAS2 (<a href="/entry/301300">301300</a>). Protoporphyrin accumulation segregated with an X chromosome haplotype defined by microsatellite markers around ALAS2 in 3 families. Sequencing of genomic DNA identified 2 different deletions in the last exon (exon 11) of ALAS2. The frameshifts produced by these deletions led to replacement or deletion of the approximately 20 C-terminal amino acids of the ALAS2 enzyme. These mutations segregated with photosensitivity (lod score 7.8) and were absent from 129 unrelated EPP patients (106 with dominant EPP, 23 with FECH mutation-negative EPP), and 100 normal chromosomes. The delAGTG mutation (<a href="/entry/301300#0015">301300.0015</a>), present in 6 families, occurred on 5 different haplotypes, indicating that it had arisen on at least 5 separate occasions, whereas the 2 families with delAT (<a href="/entry/301300#0016">301300.0016</a>), both from southwest England, had the same background haplotype and may have come from a single extended family. The ALAS2 gene encodes erythroid-specific mitochondrial aminolevulinate synthase-2, which catalyzes the first committed step of heme biosynthesis. Expression studies showed that both deletions markedly increased ALAS2 activity and that some of the 5-aminolevulinate (ALA) that was produced was further metabolized to porphyrin. <a href="#4" class="mim-tip-reference" title="Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H. <strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong> Am. J. Hum. Genet. 83: 408-414, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18760763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18760763">Whatley et al. (2008)</a> concluded that deletions in ALAS2 cause a theretofore unrecognized X-linked protoporphyria that, in contrast to autosomal dominant porphyrias, has close to 100% penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18760763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 unrelated girls with X-linked dominant erythropoietic protoporphyria, <a href="#3" class="mim-tip-reference" title="Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H. <strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong> Hum. Molec. Genet. 22: 1280-1288, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23263862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23263862</a>] [<a href="https://doi.org/10.1093/hmg/dds531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23263862">Ducamp et al. (2013)</a> identified 3 different heterozygous mutations in the ALAS2 gene. One was recurrent (delAGTG; <a href="/entry/301300#0015">301300.0015</a>) and the other 2 were novel (<a href="/entry/301300#0019">301300.0019</a> and <a href="/entry/301300#0020">301300.0020</a>). All occurred in the last exon of the ALAS2 gene, and all were shown in vitro to result in increased ALAS2 catalytic activity, consistent with a gain of function. By generating a series of ALAS2 variants, <a href="#3" class="mim-tip-reference" title="Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H. <strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong> Hum. Molec. Genet. 22: 1280-1288, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23263862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23263862</a>] [<a href="https://doi.org/10.1093/hmg/dds531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23263862">Ducamp et al. (2013)</a> found that the 'gain-of-function domain' contains a minimum of 33 amino acids between residues 544 and 576 in the C terminus of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23263862" 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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Balwani, M., Bonkovsky, H. L., Levy, C., Anderson, K. E., Bissell, D. M., Parker, C., Takahashi, F., Desnick, R. J., Belongie, K., Endeavor investigators.
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<strong>dersimelagon in erythropoietic protoporphyrias.</strong>
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New Eng. J. Med. 388: 1376-1385, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37043653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37043653</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37043653" 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/10.1056/NEJMoa2208754" target="_blank">Full Text</a>]
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Brancaleoni, V., Balwani, M., Granata, F., Graziadei, G., Missineo, P., Fiorentino, V., Fustinoni, S., Cappellini, M. D., Naik, H., Desnick, R. J., Di Pierro, E.
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<strong>X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria.</strong>
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Clin. Genet. 89: 20-26, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25615817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25615817</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25615817" 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/10.1111/cge.12562" target="_blank">Full Text</a>]
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Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H.
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<strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong>
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Hum. Molec. Genet. 22: 1280-1288, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23263862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23263862</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23263862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H.
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<strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong>
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Am. J. Hum. Genet. 83: 408-414, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18760763[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=18760763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Ada Hamosh - updated : 01/24/2024
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Cassandra L. Kniffin - updated : 04/24/2018<br>Cassandra L. Kniffin - updated : 8/8/2013
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carol : 06/19/2018<br>carol : 06/05/2018<br>carol : 04/26/2018<br>ckniffin : 04/24/2018<br>carol : 05/09/2017<br>joanna : 04/18/2014<br>carol : 8/14/2013<br>ckniffin : 8/8/2013<br>carol : 8/26/2011<br>alopez : 6/4/2010<br>alopez : 12/2/2008
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<span class="mim-font">
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<strong>#</strong> 300752
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<h3>
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PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED; XLEPP
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PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT; XLDPP<br />
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ERYTHROHEPATIC PROTOPORPHYRIA, X-LINKED
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<strong>SNOMEDCT:</strong> 1197360001;
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<strong>ORPHA:</strong> 443197;
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<strong>DO:</strong> 13270;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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Xp11.21
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<span class="mim-font">
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Protoporphyria, erythropoietic, X-linked
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300752
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X-linked
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<span class="mim-font">
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3
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ALAS2
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301300
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<p>A number sign (#) is used with this entry because of evidence that X-linked erythropoietic protoporphyria (XLEPP) is caused by gain-of-function mutations in the ALAS2 gene (301300) on chromosome Xp11.</p><p>Loss-of-function mutations in the ALAS2 gene cause X-linked sideroblastic anemia (300751).</p>
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<strong>Description</strong>
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<p>X-linked erythropoietic protoporphyria (XLEPP) is a metabolic disorder of heme biosynthesis characterized by onset in early childhood of severe photosensitivity associated with decreased iron stores and increased erythrocyte zinc- and metal-free protoporphyrin. Some patients may develop liver disease or gallstones (summary by Ducamp et al., 2013). </p><p>For a discussion of genetic heterogeneity of erythropoietic protoporphyria, see EPP1 (177000).</p>
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<strong>Clinical Features</strong>
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<p>In a subgroup of families with FECH (612386) mutation-negative protoporphyria, Whatley et al. (2008) studied 8 families in which at least 1 member had acute photosensitivity clinically indistinguishable from that seen in autosomal recessive erythropoietic protoporphyria-1 (EPP1; 177000). Four families were of western European ancestry, and the others were of Jewish, North African, Indo-Asian, and Sudanese ancestry. In these 8 families, both sexes were affected. Patients had neither anemia nor iron overload. Instead there was some evidence of diminished iron stores, particularly in males. Five patients (17%) had overt liver disease, which was more common in males (0.008), and 1 obligate carrier was asymptomatic. These families showed an apparent X-linked pattern of inheritance with an absence of father-to-son transmission. </p><p>Ducamp et al. (2013) reported 5 XLEPP patients from 4 unrelated families referred for a history of skin photosensitivity associated with increased levels of zinc- and metal-free protoporphyrin in erythrocytes. Two patients had elevated liver enzymes and 1 had gallstones. Most had evidence of iron deficiency, but only some patients had anemia. </p><p>Brancaleoni et al. (2016) reported 6 unrelated families of European descent with XLP confirmed by genetic analysis. Five of the families carried the common ALAS2 4-bp deletion (c.1706_1709delAGTG; 301300.0015). Among the families, there were 7 affected males with a hemizygous mutation and 10 females who had the mutation in the heterozygous state. In 1 family (family C), there was only 1 affected male who had a de novo mutation; his mother was not a carrier. There was heterogeneity among the females with the mutation: 2 were fully affected with photosensitivity from childhood and increased erythrocyte protoporphyrin IX (PPIX), 7 had later onset of symptoms and/or only mildly increased PPIX, and 1 was completely asymptomatic with normal laboratory values. X-chromosome inactivation studies on the females with mutations were consistent with the clinical and biochemical heterogeneity: the 2 photosensitive females had a skewed pattern with over 73% of the wildtype allele inactivated, the asymptomatic female had 88.4% inactivation of the mutant allele, and the 7 females with no or late-onset photosensitivity and/or mildly increased PPIX values had relatively balanced X-inactivation patterns with preferential expression of the wildtype ALAS2 allele. </p>
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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>Balwani et al. (2023) performed a phase 2 clinical trial in 93 patients with erythropoietic protoporphyria (177000) and 9 patients with X-linked protoporphyria aged 18 to 75 years who were randomly assigned in a 1:1:1 ratio to placebo or dersimelagon 100 mg or 300 mg once daily for 16 weeks. The primary endpoint was the change from baseline to 16 weeks in the time to first prodromal symptom associated with sunlight exposure. Daily sunlight exposure and symptoms were recorded in an electronic diary. Quality of life and safety were also assessed. Among enrollees, 90% completed the treatment period. There was a significant change in time to the first prodromal symptom compared with the placebo group for the 100 mg dersimelagon group (53.8 minutes, p = 0.008) and for the 300 gm dersimelagon group (62.5 minutes, p = 0.003). Quality of life improved in both treatment groups. The most common adverse events that occurred or worsened during treatment were nausea, freckles, headache, and skin hyperpigmentation. </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>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 erythropoietic porphyria in the families reported by Whatley et al. (2008) was consistent with X-linked dominant inheritance. </p><p>Ducamp et al. (2013) reported a French girl with XLEPP whose mother was mildly affected and was demonstrated to be germline and somatic mosaic for an ALAS2 mutation (301300.0015). </p><p>Brancaleoni et al. (2016) determined that clinical and biochemical heterogeneity in females who are heterozygous for pathogenic ALAS2 mutations is associated with X-chromosome inactivation patterns. Females with full symptoms of the disorder tend to have a skewed pattern with most of the wildtype allele inactivated, whereas those without symptoms have most of the mutant allele inactivated. Those with intermediate or mild symptoms have relatively balanced X-inactivation patterns with preferential expression of the wildtype ALAS2 allele. The findings indicated that the disorder should be considered to have X-linked inheritance with penetrance and severity in females related to the level of X-chromosome inactivation, and that the term 'X-linked dominant' inheritance be discontinued. </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>The observation of apparent X linkage of EPP in 8 families prompted Whatley et al. (2008) to investigate 2 candidate genes on the X chromosome that are involved in heme formation, GATA1 (305371) and ALAS2 (301300). Protoporphyrin accumulation segregated with an X chromosome haplotype defined by microsatellite markers around ALAS2 in 3 families. Sequencing of genomic DNA identified 2 different deletions in the last exon (exon 11) of ALAS2. The frameshifts produced by these deletions led to replacement or deletion of the approximately 20 C-terminal amino acids of the ALAS2 enzyme. These mutations segregated with photosensitivity (lod score 7.8) and were absent from 129 unrelated EPP patients (106 with dominant EPP, 23 with FECH mutation-negative EPP), and 100 normal chromosomes. The delAGTG mutation (301300.0015), present in 6 families, occurred on 5 different haplotypes, indicating that it had arisen on at least 5 separate occasions, whereas the 2 families with delAT (301300.0016), both from southwest England, had the same background haplotype and may have come from a single extended family. The ALAS2 gene encodes erythroid-specific mitochondrial aminolevulinate synthase-2, which catalyzes the first committed step of heme biosynthesis. Expression studies showed that both deletions markedly increased ALAS2 activity and that some of the 5-aminolevulinate (ALA) that was produced was further metabolized to porphyrin. Whatley et al. (2008) concluded that deletions in ALAS2 cause a theretofore unrecognized X-linked protoporphyria that, in contrast to autosomal dominant porphyrias, has close to 100% penetrance. </p><p>In 4 unrelated girls with X-linked dominant erythropoietic protoporphyria, Ducamp et al. (2013) identified 3 different heterozygous mutations in the ALAS2 gene. One was recurrent (delAGTG; 301300.0015) and the other 2 were novel (301300.0019 and 301300.0020). All occurred in the last exon of the ALAS2 gene, and all were shown in vitro to result in increased ALAS2 catalytic activity, consistent with a gain of function. By generating a series of ALAS2 variants, Ducamp et al. (2013) found that the 'gain-of-function domain' contains a minimum of 33 amino acids between residues 544 and 576 in the C terminus of the protein. </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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<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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<ol>
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<p class="mim-text-font">
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Balwani, M., Bonkovsky, H. L., Levy, C., Anderson, K. E., Bissell, D. M., Parker, C., Takahashi, F., Desnick, R. J., Belongie, K., Endeavor investigators.
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<strong>dersimelagon in erythropoietic protoporphyrias.</strong>
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New Eng. J. Med. 388: 1376-1385, 2023.
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[PubMed: 37043653]
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[Full Text: https://doi.org/10.1056/NEJMoa2208754]
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Brancaleoni, V., Balwani, M., Granata, F., Graziadei, G., Missineo, P., Fiorentino, V., Fustinoni, S., Cappellini, M. D., Naik, H., Desnick, R. J., Di Pierro, E.
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<strong>X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria.</strong>
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Clin. Genet. 89: 20-26, 2016.
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[PubMed: 25615817]
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[Full Text: https://doi.org/10.1111/cge.12562]
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<li>
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Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H.
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<strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong>
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Hum. Molec. Genet. 22: 1280-1288, 2013.
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[PubMed: 23263862]
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[Full Text: https://doi.org/10.1093/hmg/dds531]
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</li>
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<li>
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<p class="mim-text-font">
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Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H.
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<strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong>
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Am. J. Hum. Genet. 83: 408-414, 2008.
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[PubMed: 18760763]
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[Full Text: https://doi.org/10.1016/j.ajhg.2008.08.003]
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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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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Ada Hamosh - updated : 01/24/2024<br>Cassandra L. Kniffin - updated : 04/24/2018<br>Cassandra L. Kniffin - updated : 8/8/2013
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<span class="text-nowrap mim-text-font">
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Creation Date:
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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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Ada Hamosh : 12/2/2008
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Edit History:
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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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alopez : 01/24/2024<br>carol : 06/19/2018<br>carol : 06/05/2018<br>carol : 04/26/2018<br>ckniffin : 04/24/2018<br>carol : 05/09/2017<br>joanna : 04/18/2014<br>carol : 8/14/2013<br>ckniffin : 8/8/2013<br>carol : 8/26/2011<br>alopez : 6/4/2010<br>alopez : 12/2/2008
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