2511 lines
172 KiB
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2511 lines
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Entry
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- #611773 - ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS; HANAC
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- OMIM
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<p>
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<span class="h4">#611773</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/611773"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></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="#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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<a href="#creationDate"><strong>Creation Date</strong></a>
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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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</a>
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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><a href="https://clinicaltrials.gov/search?cond=ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS" 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=11037&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/NBK7046/" 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/7693" 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/hereditary-angiopathy-with-nephropathy-aneurysms-and-muscle-cramps-syndrome" 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=611773[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=73229" 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>
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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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<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> 702428000<br />
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<strong>ORPHA:</strong> 73229<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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611773
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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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ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS; HANAC
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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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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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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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<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/13/311?start=-3&limit=10&highlight=311">
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13q34
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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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Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps
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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/611773"> 611773 </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="Autosomal dominant">AD</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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</td>
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<td>
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<span class="mim-font">
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COL4A1
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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/120130"> 120130 </a>
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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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<div class="btn-group ">
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<a href="/clinicalSynopsis/611773" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<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')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/611773" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/611773" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<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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<p />
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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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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- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
|
|
|
|
|
|
|
|
|
|
<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> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Retinal arteriolar tortuosity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1231183003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1231183003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5779553&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5779553</a>, <a href="https://bioportal.bioontology.org/search?q=C5779554&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5779554</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001136" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001136</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001136" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001136</a>]</span><br /> -
|
|
Retinal hemorrhage <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28998008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28998008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H35.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H35.6</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H35.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H35.60</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/362.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">362.81</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0035317&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035317</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000573" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000573</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000573" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000573</a>]</span><br />
|
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|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
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|
|
|
|
|
|
</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">
|
|
|
|
- Arrhythmias, supraventricular <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/72654001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">72654001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0428974&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0428974</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005115" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005115</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Aneurysms of right internal carotid artery, intracranial segment <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278169&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278169</a>]</span><br /> -
|
|
Aneurysm of right middle cerebral artery, horizontal segment <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278170&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278170</a>]</span><br /> -
|
|
Raynaud phenomenon <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/266261006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">266261006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I73.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I73.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/443.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">443.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034735&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034735</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030880</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030880</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GENITOURINARY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Kidneys </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hematuria, microscopic <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197940006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197940006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/599.72" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">599.72</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239937&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239937</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002907" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002907</a>]</span><br /> -
|
|
Hematuria, gross (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197941005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197941005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R31.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R31.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/599.71" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">599.71</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0473237&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0473237</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012587" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012587</a>]</span><br /> -
|
|
Renal cysts <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/722223000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">722223000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3887499&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887499</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000107</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000107</a>]</span><br /> -
|
|
Renal failure, mild <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278162&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278162</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42399005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42399005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N19</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/586" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">586</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span><br /> -
|
|
Basement membrane alterations in Bowman capsule, tubules, and interstitial capillaries, with irregular thickening, splitting into multiple layers, and electron-lucent areas <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278163&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278163</a>]</span><br /> -
|
|
Glomerular basement membrane normal <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278164&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278164</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> Electron Microscopy </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Basement membrane duplications at dermoepidermal junction <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278165&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278165</a>]</span><br /> -
|
|
Dermal arteriole dissociation in vascular smooth muscle cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278166&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278166</a>]</span><br /> -
|
|
Basement membrane abnormally spread in vascular smooth muscle cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278167&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278167</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Nails </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Capillary tortuosity in nail beds <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278168</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
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- Muscle cramps <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45352006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45352006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55300003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55300003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M62.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M62.83</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/728.85" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">728.85</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0037763&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037763</a>, <a href="https://bioportal.bioontology.org/search?q=C0026821&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026821</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003394</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003394</a>]</span><br />
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<strong> NEUROLOGIC </strong>
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- Leukoencephalopathy, periventricular <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230769007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230769007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/P91.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">P91.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/779.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">779.7</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023529&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023529</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006970" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006970</a>]</span><br /> -
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Microvascular spaces, dilated <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278159&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278159</a>]</span><br /> -
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Cerebrovascular accident (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230690007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230690007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I63.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I63.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038454&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038454</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span><br />
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<strong> LABORATORY ABNORMALITIES </strong>
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- Creatine kinase, serum, elevated <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241005&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241005</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003236" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003236</a>]</span><br /> -
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Glomerular filtration rate, decreased <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/863929001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">863929001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0853068&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0853068</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012213" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012213</a>]</span><br />
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Caused by mutation in the collagen IV, alpha-1 polypeptide gene (COL4A1, <a href="/entry/120130#0007">120130.0007</a>)<br />
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</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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<p>A number sign (#) is used with this entry because of evidence that hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) is caused by heterozygous mutation in the COL4A1 gene (<a href="/entry/120130">120130</a>) on chromosome 13q34.</p>
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<br />
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<strong>Clinical Features</strong>
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<p><a href="#6" class="mim-tip-reference" title="Plaisier, E., Alamowitch, S., Gribouval, O., Mougenot, B., Gaudric, A., Antignac, C., Roullet, E., Ronco, P. <strong>Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: a novel syndrome.</strong> Kidney Int. 67: 2354-2360, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15882279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15882279</a>] [<a href="https://doi.org/10.1111/j.1523-1755.2005.00341.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15882279">Plaisier et al. (2005)</a> described a 4-generation French Caucasian family presenting with autosomal dominant hematuria associated with extrarenal manifestations. All affected patients presented with association of renal involvement, retinal arterial tortuosities, and muscular contractures. Retinal arterial tortuosities were present bilaterally; affected family members also experienced episodes of superficial intraretinal hemorrhages with transient visual impairment which resolved spontaneously, without visual sequelae. Muscle contractures were painful and paroxysmal, lasting from a few seconds to minutes, and occasionally to a few hours. Three patients suffered from recurrent headaches, and one presented with a generalized seizure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15882279" 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="Gekeler, F., Shinoda, K., Junger, M., Bartz-Schmidt, K. U., Gelisken, F. <strong>Familial retinal arterial tortuosity associated with tortuosity in nail bed capillaries.</strong> Arch. Ophthal. 124: 1492-1494, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030722</a>] [<a href="https://doi.org/10.1001/archopht.124.10.1492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17030722">Gekeler et al. (2006)</a> reported a father and 2 daughters with retinal arterial tortuosity associated with tortuosity of nail bed capillaries. Only second- and third-order arteries were affected, whereas first-order arteries and the venous system were normal. Symptomatic retinal hemorrhage occasionally followed minor stress or trauma, but no leakage was seen on fluorescein angiography, and all 3 patients had good visual acuity. One of the daughters had an episode of transient microhematuria of unknown origin, and the father had a stroke with speech disturbances 8 years earlier but reported no residual adverse effects. No associated systemic disease was found in any of the 3 patients. <a href="#2" class="mim-tip-reference" title="Gekeler, F., Shinoda, K., Junger, M., Bartz-Schmidt, K. U., Gelisken, F. <strong>Familial retinal arterial tortuosity associated with tortuosity in nail bed capillaries.</strong> Arch. Ophthal. 124: 1492-1494, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030722</a>] [<a href="https://doi.org/10.1001/archopht.124.10.1492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17030722">Gekeler et al. (2006)</a> noted that the high degree of tortuosity of capillaries observed on nailfold capillaroscopy indicated systemic vascular pathology, but stated that the syndrome in these patients was distinct from that described by <a href="#6" class="mim-tip-reference" title="Plaisier, E., Alamowitch, S., Gribouval, O., Mougenot, B., Gaudric, A., Antignac, C., Roullet, E., Ronco, P. <strong>Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: a novel syndrome.</strong> Kidney Int. 67: 2354-2360, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15882279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15882279</a>] [<a href="https://doi.org/10.1111/j.1523-1755.2005.00341.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15882279">Plaisier et al. (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15882279+17030722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Plaisier, E., Gribouval, O., Alamowitch, S., Mougenot, B., Prost, C., Verpont, M. C., Marro, B., Desmettre, T., Cohen, S. Y., Roullet, E., Dracon, M., Fardeau, M., Van Agtmael, T., Kerjaschki, D., Antignac, C., Ronco, P. <strong>COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.</strong> New Eng. J. Med. 357: 2687-2695, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18160688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18160688</a>] [<a href="https://doi.org/10.1056/NEJMoa071906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18160688">Plaisier et al. (2007)</a> characterized the renal and extrarenal phenotypes of subjects from 3 families with autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps, including the one previously described by them (<a href="#6" class="mim-tip-reference" title="Plaisier, E., Alamowitch, S., Gribouval, O., Mougenot, B., Gaudric, A., Antignac, C., Roullet, E., Ronco, P. <strong>Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: a novel syndrome.</strong> Kidney Int. 67: 2354-2360, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15882279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15882279</a>] [<a href="https://doi.org/10.1111/j.1523-1755.2005.00341.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15882279">Plaisier et al., 2005</a>). <a href="#8" class="mim-tip-reference" title="Plaisier, E., Gribouval, O., Alamowitch, S., Mougenot, B., Prost, C., Verpont, M. C., Marro, B., Desmettre, T., Cohen, S. Y., Roullet, E., Dracon, M., Fardeau, M., Van Agtmael, T., Kerjaschki, D., Antignac, C., Ronco, P. <strong>COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.</strong> New Eng. J. Med. 357: 2687-2695, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18160688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18160688</a>] [<a href="https://doi.org/10.1056/NEJMoa071906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18160688">Plaisier et al. (2007)</a> proposed the acronym HANAC for this syndrome. The clinical renal manifestations of the HANAC syndrome in these families included hematuria and bilateral large cysts. Histologic analysis revealed complex basement membrane defects in kidney and skin. The systemic angiopathy of the HANAC syndrome appeared to affect both small vessels and large arteries. Muscle cramps occurred in 2 of the 3 families and affected members of all 3 showed elevated creatine kinase levels. Retinal arteriolar tortuosity leading to repeated retinal hemorrhages was a frequent finding. Microscopic hematuria occurred in most affected individuals and gross hematuria in some. Supraventricular cardiac arrhythmia and Raynaud phenomenon were also observed. Changes of leukoencephalopathy were found frequently on brain scans. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15882279+18160688" 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>Among 14 patients from 3 families with HANAC, <a href="#1" class="mim-tip-reference" title="Alamowitch, S., Plaisier, E., Favrole, P., Prost, C., Chen, Z., Van Agtmael, T., Marro, B., Ronco, P. <strong>Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome.</strong> Neurology 73: 1873-1882, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949034</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19949034[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/10.1212/WNL.0b013e3181c3fd12" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949034">Alamowitch et al. (2009)</a> found that only 2 had clinical cerebrovascular symptoms: a minor ischemic stroke at age 47 years and a small posttraumatic hemorrhage under anticoagulants at age 48 years. However, 8 of 9 adult patients studied using brain MRI and magnetic resonance angiography (MRA) were found to have cerebrovascular lesions, including 5 with intracranial aneurysms of the carotid siphon, and 7 with cerebral small vessel disease characterized by deep white matter changes (7 of 7), dilated perivascular spaces (5 of 7), and lacunar infarcts (4 of 7). None had hemiplegia, major stroke, or porencephaly. Skin biopsies of 3 patients showed alterations of basement membranes at the dermoepidermal junction associated with expansion of extracellular matrix between smooth vascular cells in the arteriolar wall, indicating a systemic vasculopathy. These imaging findings indicated that the cerebrovascular phenotype in HANAC includes both small vessel disease and large vessel disease, but with a low incidence of hemorrhagic stroke compared to other COL4A1-related disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19949034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Meuwissen, M. E. C., Halley, D. J. J., Smit, L. S., Lequin, M. H., Cobben, J. M., de Coo, R., van Harssel, J., Sallevelt, S., Woldringh, G., van der Knaap, M. S., de Vries, L. S., Mancini, G. M. S. <strong>The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature.</strong> Genet. Med. 17: 843-853, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25719457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25719457</a>] [<a href="https://doi.org/10.1038/gim.2014.210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25719457">Meuwissen et al. (2015)</a> reported the experience of the Erasmus University Medical Center in sequencing the COL4A1 and COL4A2 genes in 183 index patients, mostly with cerebral hemorrhage or porencephaly, between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). A review of the literature brought the total to 137 individuals with a COL4A1 mutation, 54 of whom had periventricular leukencephaly or small vessel disease and 53 had porencephaly. Sixteen had cerebral calcifications or microbleeds, and 15 had intracerebral hemorrhage. Twelve had cerebellar atrophy. Other brain MRI complications were rarer. Ophthalmologic findings included 29 with cataracts, 26 with retinal arteriol tortuosity, 10 with strabismus, and 10 with iris hypoplasia, as well as 9 with posterior embryotoxon. Renal cysts and hematuria were present in 4 patients each. Elevated creatine kinase was present in 25, and 18 had muscle cramps. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25719457" 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 HANAC in the families reported by <a href="#8" class="mim-tip-reference" title="Plaisier, E., Gribouval, O., Alamowitch, S., Mougenot, B., Prost, C., Verpont, M. C., Marro, B., Desmettre, T., Cohen, S. Y., Roullet, E., Dracon, M., Fardeau, M., Van Agtmael, T., Kerjaschki, D., Antignac, C., Ronco, P. <strong>COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.</strong> New Eng. J. Med. 357: 2687-2695, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18160688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18160688</a>] [<a href="https://doi.org/10.1056/NEJMoa071906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18160688">Plaisier et al. (2007)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18160688" 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>Because of reduced penetrance with possible modifying factors and variable phenotype, <a href="#5" class="mim-tip-reference" title="Meuwissen, M. E. C., Halley, D. J. J., Smit, L. S., Lequin, M. H., Cobben, J. M., de Coo, R., van Harssel, J., Sallevelt, S., Woldringh, G., van der Knaap, M. S., de Vries, L. S., Mancini, G. M. S. <strong>The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature.</strong> Genet. Med. 17: 843-853, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25719457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25719457</a>] [<a href="https://doi.org/10.1038/gim.2014.210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25719457">Meuwissen et al. (2015)</a> recommended initial workup in families with a COL4A1 or COL4A2 mutation, including neurologic, ophthalmologic, renal, and cardiac screening in mutation carriers and first-degree relatives with a 50% chance of harboring the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25719457" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Plaisier, E., Gribouval, O., Alamowitch, S., Mougenot, B., Prost, C., Verpont, M. C., Marro, B., Desmettre, T., Cohen, S. Y., Roullet, E., Dracon, M., Fardeau, M., Van Agtmael, T., Kerjaschki, D., Antignac, C., Ronco, P. <strong>COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.</strong> New Eng. J. Med. 357: 2687-2695, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18160688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18160688</a>] [<a href="https://doi.org/10.1056/NEJMoa071906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18160688">Plaisier et al. (2007)</a> performed linkage analysis in the original family described by them with HANAC, which showed that all affected subjects shared a common haplotype at the COL4A1-COL4A2 locus (<a href="/entry/120130">120130</a>, <a href="/entry/120090">120090</a>). Sequence analysis of COL4A1 cDNA from skin-fibroblast specimens from the subjects demonstrated a missense mutation in each of the 3 families converting glycine to another amino acid in exon 24 or exon 25 of the COL4A1 gene (<a href="/entry/120130#0007">120130.0007</a>, <a href="/entry/120130#0008">120130.0008</a>, <a href="/entry/120130#0009">120130.0009</a>). A suggestion by <a href="#8" class="mim-tip-reference" title="Plaisier, E., Gribouval, O., Alamowitch, S., Mougenot, B., Prost, C., Verpont, M. C., Marro, B., Desmettre, T., Cohen, S. Y., Roullet, E., Dracon, M., Fardeau, M., Van Agtmael, T., Kerjaschki, D., Antignac, C., Ronco, P. <strong>COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.</strong> New Eng. J. Med. 357: 2687-2695, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18160688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18160688</a>] [<a href="https://doi.org/10.1056/NEJMoa071906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18160688">Plaisier et al. (2007)</a> that the phenotype of the HANAC syndrome may be caused by dominant-negative effects of the mutations was supported by findings from several animal models (<a href="#4" class="mim-tip-reference" title="Gould, D. B., Phalan, F. C., Breedveld, G. J., van Mil, S. E., Smith, R. S., Schimenti, J. C., Aguglia, U., van der Knapp, M. S., Heutink, P., John, S. W. M. <strong>Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly.</strong> Science 308: 1167-1171, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15905400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15905400</a>] [<a href="https://doi.org/10.1126/science.1109418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15905400">Gould et al., 2005</a>; <a href="#3" class="mim-tip-reference" title="Gould, D. B., Marchant, J. K., Savinova, O. V., Smith, R. S., John, S. W. M. <strong>Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis.</strong> Hum. Molec. Genet. 16: 798-807, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17317786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17317786</a>] [<a href="https://doi.org/10.1093/hmg/ddm024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17317786">Gould et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18160688+15905400+17317786" 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 affected members of 3 families exhibiting key features of HANAC, 1 of which was previously reported by <a href="#2" class="mim-tip-reference" title="Gekeler, F., Shinoda, K., Junger, M., Bartz-Schmidt, K. U., Gelisken, F. <strong>Familial retinal arterial tortuosity associated with tortuosity in nail bed capillaries.</strong> Arch. Ophthal. 124: 1492-1494, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030722</a>] [<a href="https://doi.org/10.1001/archopht.124.10.1492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17030722">Gekeler et al. (2006)</a>, <a href="#7" class="mim-tip-reference" title="Plaisier, E., Chen, Z., Gekeler, F., Benhassine, S., Dahan, K., Marro, B., Alamowitch, S., Paques, M., Ronco, P. <strong>Novel COL4A1 mutations associated with HANAC syndrome: a role for triple helical CB3(IV) domain.</strong> Am. J. Med. Genet. 152A: 2550-2555, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20818663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20818663</a>] [<a href="https://doi.org/10.1002/ajmg.a.33659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20818663">Plaisier et al. (2010)</a> identified 3 different heterozygous missense mutations in the COL4A1 gene (<a href="/entry/120130#0012">120130.0012</a>-<a href="/entry/120130#0014">120130.0014</a>). <a href="#7" class="mim-tip-reference" title="Plaisier, E., Chen, Z., Gekeler, F., Benhassine, S., Dahan, K., Marro, B., Alamowitch, S., Paques, M., Ronco, P. <strong>Novel COL4A1 mutations associated with HANAC syndrome: a role for triple helical CB3(IV) domain.</strong> Am. J. Med. Genet. 152A: 2550-2555, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20818663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20818663</a>] [<a href="https://doi.org/10.1002/ajmg.a.33659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20818663">Plaisier et al. (2010)</a> stated that age of examination could account for the partial penetrance or variable severity of several symptoms, and concluded that these results confirmed HANAC as a distinct clinical entity among the COL4A1-related disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20818663+17030722" 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="#9" class="mim-tip-reference" title="Van Agtmael, T., Bailey, M. A., Schlotzer-Schrehardt, U., Craigie, E., Jackson, I. J., Brownstein, D. G., Megson, I. L., Mullins, J. J. <strong>Col4a1 mutation in mice causes defects in vascular function and low blood pressure associated with reduced red blood cell volume.</strong> Hum. Molec. Genet. 19: 1119-1128, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20056676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20056676</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20056676[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/10.1093/hmg/ddp584" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20056676">Van Agtmael et al. (2010)</a> showed that animals with a Col4a1 missense mutation (Col4a1+/Raw) display focal detachment of the endothelium from the media and age-dependent defects in vascular function including a reduced response to norepinephrine. Age-dependent hypersensitivity to acetylcholine was abolished by inhibition of nitric oxide synthase (NOS) activity, indicating that Col4a1 mutations affected vasorelaxation mediated by endothelium-derived nitric oxide. These defects were associated with a reduction in basal NOS activity and the development of heightened nitric oxide sensitivity of the smooth muscle. The vascular function defects were physiologically relevant as they maintained, in part, the hypotension in mutant animals, which was primarily associated with a reduced red blood cell volume due to a reduction in red blood cell number, rather than defects in kidney function. The deposition of collagen type IV in the basement membrane was defective, and the mutation was found to lead to activation of the unfolded protein response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20056676" 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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Alamowitch, S., Plaisier, E., Favrole, P., Prost, C., Chen, Z., Van Agtmael, T., Marro, B., Ronco, P.
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<strong>Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome.</strong>
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Neurology 73: 1873-1882, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949034</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19949034[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=19949034" 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/10.1212/WNL.0b013e3181c3fd12" target="_blank">Full Text</a>]
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<strong>Familial retinal arterial tortuosity associated with tortuosity in nail bed capillaries.</strong>
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Arch. Ophthal. 124: 1492-1494, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030722</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17030722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis.</strong>
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Hum. Molec. Genet. 16: 798-807, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17317786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17317786</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17317786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly.</strong>
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Science 308: 1167-1171, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15905400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15905400</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15905400" 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.1109418" target="_blank">Full Text</a>]
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<a id="Meuwissen2015" class="mim-anchor"></a>
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Meuwissen, M. E. C., Halley, D. J. J., Smit, L. S., Lequin, M. H., Cobben, J. M., de Coo, R., van Harssel, J., Sallevelt, S., Woldringh, G., van der Knaap, M. S., de Vries, L. S., Mancini, G. M. S.
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<strong>The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature.</strong>
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Genet. Med. 17: 843-853, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25719457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25719457</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25719457" 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/gim.2014.210" target="_blank">Full Text</a>]
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<a id="Plaisier2005" class="mim-anchor"></a>
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Plaisier, E., Alamowitch, S., Gribouval, O., Mougenot, B., Gaudric, A., Antignac, C., Roullet, E., Ronco, P.
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<strong>Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: a novel syndrome.</strong>
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Kidney Int. 67: 2354-2360, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15882279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15882279</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15882279" 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/j.1523-1755.2005.00341.x" target="_blank">Full Text</a>]
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<a id="Plaisier2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Plaisier, E., Chen, Z., Gekeler, F., Benhassine, S., Dahan, K., Marro, B., Alamowitch, S., Paques, M., Ronco, P.
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<strong>Novel COL4A1 mutations associated with HANAC syndrome: a role for triple helical CB3(IV) domain.</strong>
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Am. J. Med. Genet. 152A: 2550-2555, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20818663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20818663</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20818663" 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.a.33659" target="_blank">Full Text</a>]
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<a id="Plaisier2007" class="mim-anchor"></a>
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Plaisier, E., Gribouval, O., Alamowitch, S., Mougenot, B., Prost, C., Verpont, M. C., Marro, B., Desmettre, T., Cohen, S. Y., Roullet, E., Dracon, M., Fardeau, M., Van Agtmael, T., Kerjaschki, D., Antignac, C., Ronco, P.
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<strong>COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.</strong>
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New Eng. J. Med. 357: 2687-2695, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18160688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18160688</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18160688" 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/NEJMoa071906" target="_blank">Full Text</a>]
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<a id="Van Agtmael2010" class="mim-anchor"></a>
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<div class="">
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Van Agtmael, T., Bailey, M. A., Schlotzer-Schrehardt, U., Craigie, E., Jackson, I. J., Brownstein, D. G., Megson, I. L., Mullins, J. J.
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<strong>Col4a1 mutation in mice causes defects in vascular function and low blood pressure associated with reduced red blood cell volume.</strong>
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Hum. Molec. Genet. 19: 1119-1128, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20056676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20056676</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20056676[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=20056676" 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/hmg/ddp584" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Ada Hamosh - updated : 02/08/2016
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George E. Tiller - updated : 11/10/2011<br>Cassandra L. Kniffin - updated : 1/28/2011<br>Marla J. F. O'Neill - updated : 12/16/2010
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Victor A. McKusick : 2/7/2008
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alopez : 09/20/2023
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carol : 03/21/2019<br>alopez : 02/08/2016<br>carol : 7/29/2014<br>alopez : 11/17/2011<br>terry : 11/10/2011<br>wwang : 2/18/2011<br>ckniffin : 1/28/2011<br>alopez : 12/17/2010<br>terry : 12/16/2010<br>terry : 6/6/2008<br>alopez : 2/7/2008
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<strong>#</strong> 611773
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ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS; HANAC
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<strong>SNOMEDCT:</strong> 702428000;
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<strong>ORPHA:</strong> 73229;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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13q34
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Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps
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<span class="mim-font">
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611773
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Autosomal dominant
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<span class="mim-font">
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3
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COL4A1
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<span class="mim-font">
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120130
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<p>A number sign (#) is used with this entry because of evidence that hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) is caused by heterozygous mutation in the COL4A1 gene (120130) on chromosome 13q34.</p>
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<strong>Clinical Features</strong>
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<p>Plaisier et al. (2005) described a 4-generation French Caucasian family presenting with autosomal dominant hematuria associated with extrarenal manifestations. All affected patients presented with association of renal involvement, retinal arterial tortuosities, and muscular contractures. Retinal arterial tortuosities were present bilaterally; affected family members also experienced episodes of superficial intraretinal hemorrhages with transient visual impairment which resolved spontaneously, without visual sequelae. Muscle contractures were painful and paroxysmal, lasting from a few seconds to minutes, and occasionally to a few hours. Three patients suffered from recurrent headaches, and one presented with a generalized seizure. </p><p>Gekeler et al. (2006) reported a father and 2 daughters with retinal arterial tortuosity associated with tortuosity of nail bed capillaries. Only second- and third-order arteries were affected, whereas first-order arteries and the venous system were normal. Symptomatic retinal hemorrhage occasionally followed minor stress or trauma, but no leakage was seen on fluorescein angiography, and all 3 patients had good visual acuity. One of the daughters had an episode of transient microhematuria of unknown origin, and the father had a stroke with speech disturbances 8 years earlier but reported no residual adverse effects. No associated systemic disease was found in any of the 3 patients. Gekeler et al. (2006) noted that the high degree of tortuosity of capillaries observed on nailfold capillaroscopy indicated systemic vascular pathology, but stated that the syndrome in these patients was distinct from that described by Plaisier et al. (2005). </p><p>Plaisier et al. (2007) characterized the renal and extrarenal phenotypes of subjects from 3 families with autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps, including the one previously described by them (Plaisier et al., 2005). Plaisier et al. (2007) proposed the acronym HANAC for this syndrome. The clinical renal manifestations of the HANAC syndrome in these families included hematuria and bilateral large cysts. Histologic analysis revealed complex basement membrane defects in kidney and skin. The systemic angiopathy of the HANAC syndrome appeared to affect both small vessels and large arteries. Muscle cramps occurred in 2 of the 3 families and affected members of all 3 showed elevated creatine kinase levels. Retinal arteriolar tortuosity leading to repeated retinal hemorrhages was a frequent finding. Microscopic hematuria occurred in most affected individuals and gross hematuria in some. Supraventricular cardiac arrhythmia and Raynaud phenomenon were also observed. Changes of leukoencephalopathy were found frequently on brain scans. </p><p>Among 14 patients from 3 families with HANAC, Alamowitch et al. (2009) found that only 2 had clinical cerebrovascular symptoms: a minor ischemic stroke at age 47 years and a small posttraumatic hemorrhage under anticoagulants at age 48 years. However, 8 of 9 adult patients studied using brain MRI and magnetic resonance angiography (MRA) were found to have cerebrovascular lesions, including 5 with intracranial aneurysms of the carotid siphon, and 7 with cerebral small vessel disease characterized by deep white matter changes (7 of 7), dilated perivascular spaces (5 of 7), and lacunar infarcts (4 of 7). None had hemiplegia, major stroke, or porencephaly. Skin biopsies of 3 patients showed alterations of basement membranes at the dermoepidermal junction associated with expansion of extracellular matrix between smooth vascular cells in the arteriolar wall, indicating a systemic vasculopathy. These imaging findings indicated that the cerebrovascular phenotype in HANAC includes both small vessel disease and large vessel disease, but with a low incidence of hemorrhagic stroke compared to other COL4A1-related disorders. </p><p>Meuwissen et al. (2015) reported the experience of the Erasmus University Medical Center in sequencing the COL4A1 and COL4A2 genes in 183 index patients, mostly with cerebral hemorrhage or porencephaly, between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). A review of the literature brought the total to 137 individuals with a COL4A1 mutation, 54 of whom had periventricular leukencephaly or small vessel disease and 53 had porencephaly. Sixteen had cerebral calcifications or microbleeds, and 15 had intracerebral hemorrhage. Twelve had cerebellar atrophy. Other brain MRI complications were rarer. Ophthalmologic findings included 29 with cataracts, 26 with retinal arteriol tortuosity, 10 with strabismus, and 10 with iris hypoplasia, as well as 9 with posterior embryotoxon. Renal cysts and hematuria were present in 4 patients each. Elevated creatine kinase was present in 25, and 18 had muscle cramps. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of HANAC in the families reported by Plaisier et al. (2007) was consistent with autosomal dominant inheritance. </p>
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<strong>Clinical Management</strong>
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<p>Because of reduced penetrance with possible modifying factors and variable phenotype, Meuwissen et al. (2015) recommended initial workup in families with a COL4A1 or COL4A2 mutation, including neurologic, ophthalmologic, renal, and cardiac screening in mutation carriers and first-degree relatives with a 50% chance of harboring the mutation. </p>
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<strong>Molecular Genetics</strong>
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<p>Plaisier et al. (2007) performed linkage analysis in the original family described by them with HANAC, which showed that all affected subjects shared a common haplotype at the COL4A1-COL4A2 locus (120130, 120090). Sequence analysis of COL4A1 cDNA from skin-fibroblast specimens from the subjects demonstrated a missense mutation in each of the 3 families converting glycine to another amino acid in exon 24 or exon 25 of the COL4A1 gene (120130.0007, 120130.0008, 120130.0009). A suggestion by Plaisier et al. (2007) that the phenotype of the HANAC syndrome may be caused by dominant-negative effects of the mutations was supported by findings from several animal models (Gould et al., 2005; Gould et al., 2007). </p><p>In affected members of 3 families exhibiting key features of HANAC, 1 of which was previously reported by Gekeler et al. (2006), Plaisier et al. (2010) identified 3 different heterozygous missense mutations in the COL4A1 gene (120130.0012-120130.0014). Plaisier et al. (2010) stated that age of examination could account for the partial penetrance or variable severity of several symptoms, and concluded that these results confirmed HANAC as a distinct clinical entity among the COL4A1-related disorders. </p><p>Van Agtmael et al. (2010) showed that animals with a Col4a1 missense mutation (Col4a1+/Raw) display focal detachment of the endothelium from the media and age-dependent defects in vascular function including a reduced response to norepinephrine. Age-dependent hypersensitivity to acetylcholine was abolished by inhibition of nitric oxide synthase (NOS) activity, indicating that Col4a1 mutations affected vasorelaxation mediated by endothelium-derived nitric oxide. These defects were associated with a reduction in basal NOS activity and the development of heightened nitric oxide sensitivity of the smooth muscle. The vascular function defects were physiologically relevant as they maintained, in part, the hypotension in mutant animals, which was primarily associated with a reduced red blood cell volume due to a reduction in red blood cell number, rather than defects in kidney function. The deposition of collagen type IV in the basement membrane was defective, and the mutation was found to lead to activation of the unfolded protein response. </p>
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<strong>REFERENCES</strong>
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Alamowitch, S., Plaisier, E., Favrole, P., Prost, C., Chen, Z., Van Agtmael, T., Marro, B., Ronco, P.
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<strong>Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome.</strong>
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Neurology 73: 1873-1882, 2009.
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[PubMed: 19949034]
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[Full Text: https://doi.org/10.1212/WNL.0b013e3181c3fd12]
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Gekeler, F., Shinoda, K., Junger, M., Bartz-Schmidt, K. U., Gelisken, F.
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<strong>Familial retinal arterial tortuosity associated with tortuosity in nail bed capillaries.</strong>
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Arch. Ophthal. 124: 1492-1494, 2006.
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[PubMed: 17030722]
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[Full Text: https://doi.org/10.1001/archopht.124.10.1492]
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Gould, D. B., Marchant, J. K., Savinova, O. V., Smith, R. S., John, S. W. M.
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<strong>Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis.</strong>
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Hum. Molec. Genet. 16: 798-807, 2007.
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[PubMed: 17317786]
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[Full Text: https://doi.org/10.1093/hmg/ddm024]
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Gould, D. B., Phalan, F. C., Breedveld, G. J., van Mil, S. E., Smith, R. S., Schimenti, J. C., Aguglia, U., van der Knapp, M. S., Heutink, P., John, S. W. M.
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<strong>Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly.</strong>
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Science 308: 1167-1171, 2005.
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[PubMed: 15905400]
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[Full Text: https://doi.org/10.1126/science.1109418]
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Meuwissen, M. E. C., Halley, D. J. J., Smit, L. S., Lequin, M. H., Cobben, J. M., de Coo, R., van Harssel, J., Sallevelt, S., Woldringh, G., van der Knaap, M. S., de Vries, L. S., Mancini, G. M. S.
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<strong>The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature.</strong>
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Genet. Med. 17: 843-853, 2015.
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[PubMed: 25719457]
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[Full Text: https://doi.org/10.1038/gim.2014.210]
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Plaisier, E., Alamowitch, S., Gribouval, O., Mougenot, B., Gaudric, A., Antignac, C., Roullet, E., Ronco, P.
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<strong>Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: a novel syndrome.</strong>
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Kidney Int. 67: 2354-2360, 2005.
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[PubMed: 15882279]
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[Full Text: https://doi.org/10.1111/j.1523-1755.2005.00341.x]
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Plaisier, E., Chen, Z., Gekeler, F., Benhassine, S., Dahan, K., Marro, B., Alamowitch, S., Paques, M., Ronco, P.
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<strong>Novel COL4A1 mutations associated with HANAC syndrome: a role for triple helical CB3(IV) domain.</strong>
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Am. J. Med. Genet. 152A: 2550-2555, 2010.
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[PubMed: 20818663]
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[Full Text: https://doi.org/10.1002/ajmg.a.33659]
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Plaisier, E., Gribouval, O., Alamowitch, S., Mougenot, B., Prost, C., Verpont, M. C., Marro, B., Desmettre, T., Cohen, S. Y., Roullet, E., Dracon, M., Fardeau, M., Van Agtmael, T., Kerjaschki, D., Antignac, C., Ronco, P.
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<strong>COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.</strong>
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New Eng. J. Med. 357: 2687-2695, 2007.
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[PubMed: 18160688]
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[Full Text: https://doi.org/10.1056/NEJMoa071906]
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Van Agtmael, T., Bailey, M. A., Schlotzer-Schrehardt, U., Craigie, E., Jackson, I. J., Brownstein, D. G., Megson, I. L., Mullins, J. J.
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<strong>Col4a1 mutation in mice causes defects in vascular function and low blood pressure associated with reduced red blood cell volume.</strong>
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Hum. Molec. Genet. 19: 1119-1128, 2010.
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[PubMed: 20056676]
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[Full Text: https://doi.org/10.1093/hmg/ddp584]
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