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Entry
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- #614820 - ALTERNATING HEMIPLEGIA OF CHILDHOOD 2; AHC2
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- OMIM
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<p>
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<span class="h4">#614820</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/614820"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS104290"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<span class="small">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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<div><a href="https://clinicaltrials.gov/search?cond=ALTERNATING HEMIPLEGIA OF CHILDHOOD" 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=748&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/NBK1115/" 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://medlineplus.gov/genetics/condition/alternating-hemiplegia-of-childhood" 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=614820[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=2131" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0050635" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/614820" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0050635" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<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>ORPHA:</strong> 2131<br />
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<strong>DO:</strong> 0050635<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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614820
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</span>
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</span>
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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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ALTERNATING HEMIPLEGIA OF CHILDHOOD 2; AHC2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="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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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/19/745?start=-3&limit=10&highlight=745">
|
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19q13.2
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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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Alternating hemiplegia of childhood 2
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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/614820"> 614820 </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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ATP1A3
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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/182350"> 182350 </a>
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</span>
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</td>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/614820" 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>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS104290" class="btn btn-info" role="button"> Phenotypic Series </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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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/614820" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/614820" 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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<div>
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<p />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small" style="margin: 5px">
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<div>
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<div>
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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>
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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 />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> HEAD & NECK </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<em> Eyes </em>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
|
|
|
|
- Abnormal extraocular movements <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103252009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103252009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0497202&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0497202</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000496" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000496</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000496" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000496</a>]</span><br /> -
|
|
Nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/563001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">563001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/379.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">379.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span><br />
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</span>
|
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</div>
|
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Respiratory disturbances <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4314646&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4314646</a>]</span><br />
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|
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</span>
|
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hemiplegia, episodic <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863061&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863061</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012194" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012194</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/50582007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">50582007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G81.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G81.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/342.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">342.9</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002301" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002301</a>]</span><br /> -
|
|
Quadriplegia, episodic <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1863062&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1863062</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0200072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0200072</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0200072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0200072</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11538006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11538006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G82.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G82.50</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G82.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G82.5</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/344.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">344.00</a>]</span><br /> -
|
|
Delayed psychomotor development <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
|
|
Intellectual disability <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
|
|
Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
|
|
Dysarthria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8011004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8011004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.13</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/784.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span><br /> -
|
|
Bulbar symptoms <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278184&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278184</a>]</span><br /> -
|
|
Choreoathetosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43105007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43105007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085583&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085583</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001266" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001266</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001266" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001266</a>]</span><br /> -
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Ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20262006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20262006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39384006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39384006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.84</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004134</a>, <a href="https://bioportal.bioontology.org/search?q=C1135207&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1135207</a>, <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0010867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010867</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br /> -
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Autonomic involvement <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3553789&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3553789</a>]</span><br /> -
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Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
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Status epilepticus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230456007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230456007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038220&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038220</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002133" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002133</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002133" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002133</a>]</span><br /> -
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Interictal neurologic impairment <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3553790&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3553790</a>]</span><br />
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</span>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Onset before 18 months of age<br /> -
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Variable severity and progression<br /> -
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Abrupt onset of episodes<br /> -
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Episodes may be triggered by physical or emotional stress<br /> -
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Flunarizine treatment may be beneficial<br /> -
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Most cases due to de novo mutation<br />
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</span>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the ATPase, Na+K+ transporting, alpha-3 polypeptide gene (ATP1A3, <a href="/entry/182350#0009">182350.0009</a>)<br />
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</span>
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</div>
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</div>
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small">
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<div class="row">
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<h5>
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Alternating hemiplegia of childhood
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- <a href="/phenotypicSeries/PS104290">PS104290</a>
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- 2 Entries
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</h5>
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</div>
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</div>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
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<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<thead>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Location</strong>
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</th>
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
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<strong>Phenotype</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Inheritance</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />mapping key</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />MIM number</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus<br />MIM number</strong>
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/1310?start=-3&limit=10&highlight=1310"> 1q23.2 </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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<a href="/entry/104290"> Alternating hemiplegia of childhood 1 </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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</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/104290"> 104290 </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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<a href="/entry/182340"> ATP1A2 </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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<a href="/entry/182340"> 182340 </a>
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</span>
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</td>
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</tr>
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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/19/745?start=-3&limit=10&highlight=745"> 19q13.2 </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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<a href="/entry/614820"> Alternating hemiplegia of childhood 2 </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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</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/614820"> 614820 </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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<a href="/entry/182350"> ATP1A3 </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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<a href="/entry/182350"> 182350 </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 class="text-right small">
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because alternating hemiplegia of childhood-2 (AHC2) is caused by heterozygous mutation in the ATP1A3 gene (<a href="/entry/182350">182350</a>) on chromosome 19q13.</p><p>Heterozygous mutation in the ATP1A3 gene can also cause 2 other neurologic disorders that share some clinical features: dystonia-12 (DYT12; <a href="/entry/128235">128235</a>) and CAPOS syndrome (CAPOS; <a href="/entry/601338">601338</a>).</p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Alternating hemiplegia of childhood is a rare syndrome characterized by infantile onset of episodic hemi-or quadriplegia. Most cases are accompanied by dystonic posturing, choreoathetoid movements, abnormal ocular movements, developmental delay, and progressive cognitive impairment (summary by <a href="#2" class="mim-tip-reference" title="Heinzen, E. L., Swoboda, K. J., Hitomi, Y., Gurrieri, F., Nicole, S., de Vries, B., Tiziano, F. D., Fontaine, B., Walley, N. M., Heavin, S., Panagiotakaki, E, European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium, and 33 others. <strong>De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.</strong> Nature Genet. 44: 1030-1034, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842232[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/10.1038/ng.2358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842232">Heinzen et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of alternating hemiplegia of childhood, see AHC1 (<a href="/entry/104290">104290</a>).</p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
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<strong>Clinical Features</strong>
|
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</span>
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</h4>
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</div>
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<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#6" class="mim-tip-reference" title="Verret, S., Steele, J. C. <strong>Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy.</strong> Pediatrics 47: 675-680, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5089756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5089756</a>]" pmid="5089756">Verret and Steele (1971)</a> first characterized alternating hemiplegia in childhood as a distinct condition. They reported 8 patients, including 2 sibs, with the disorder. All had intermittent hemiparesis of variable severity beginning in infancy or early childhood. Episodes usually lasted minutes or hours, with a few patients having weakness for several days. Only 2 patients had intermittent seizures. Four patients had residual neurologic deficits including mental retardation and a movement disorder, such as dystonia and/or choreoathetosis. Attacks ceased spontaneously in 2 patients by age 4 years. EEG in all patients showed no constant focal abnormality or evidence of seizure activity. Some patients later developed headaches, and all had relatives with migraine headaches. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5089756" 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="Heinzen, E. L., Swoboda, K. J., Hitomi, Y., Gurrieri, F., Nicole, S., de Vries, B., Tiziano, F. D., Fontaine, B., Walley, N. M., Heavin, S., Panagiotakaki, E, European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium, and 33 others. <strong>De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.</strong> Nature Genet. 44: 1030-1034, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842232[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/10.1038/ng.2358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842232">Heinzen et al. (2012)</a> reported 82 patients with AHC2 confirmed by genetic analysis. Affected individuals had infantile onset of hemiplegic attacks, usually associated with episodes of quadriparesis, abnormal eye movements, autonomic signs, seizures, dystonia, ataxia, chorea, and developmental delay. Most cases occurred sporadically, but there was 1 family of Puerto Rican origin in which 4 affected individuals were described in detail. One child in this family had onset at 2 months of age of tonic stiffening and eye deviation, but without loss of consciousness. By age 1 year, he had episodes of flaccid hemiplegia alternating with dystonia. He also had generalized tonic-clonic seizures that stopped by age 5 years. Hemiplegic episodes lasted from 5 to 30 minutes, and EEG showed no abnormalities during episodes. In childhood, he showed permanent neurologic sequelae, including mild cognitive impairment, ataxia, chorea, and dysarthria. At age 16 years, he had episodic severe dystonia and parkinsonism several times per month. This patient's brother developed whole body stiffening at age 3 years. Typical spells rendered him mute and unable to ambulate. In childhood, he had mild cognitive impairment, behavioral abnormalities, hypotonia, ataxia, dysarthria, and chorea. Since childhood, the father had episodic hemiplegic spells since childhood, accompanied by tonic or dystonic stiffening and abnormal eye movements. He also had rare generalized seizures. At age 41 years, he had neurocognitive deficits, depression, and anxiety. The father's brother had onset of hemi- and quadriplegia since age 6 months. As an adult, he continued to have episodes of flaccidity or parkinsonism-like rigidity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842232" 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>Simultaneously and independently, <a href="#4" class="mim-tip-reference" title="Rosewich, H., Thiele, H., Ohlenbusch, A., Maschke, U., Altmuller, J., Frommolt, P., Zirn, B., Ebinger, F., Siemes, H., Nurnberg, P., Brockmann, K., Gartner, J. <strong>Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study.</strong> Lancet Neurol. 11: 764-773, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22850527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22850527</a>] [<a href="https://doi.org/10.1016/S1474-4422(12)70182-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22850527">Rosewich et al. (2012)</a> reported 24 unrelated patients with AHC2 confirmed by genetic analysis. The patients ranged in age from 8 to 35 years, and all except 1 had onset before age 7 months. Most patients presented with a dystonic episode, although a few presented with nystagmus or seizures. The patient with the latest onset presented with hemiplegic episodes at age 16 months. Additional variable paroxysmal features included abnormal ocular movements, bulbar symptoms, autonomic dysfunction, and respiratory disturbances. Nonparoxysmal features included delayed psychomotor development with intellectual disability, hypotonia, choreoathetosis, ataxia, and dysarthria. Patients had abrupt onset of dystonic episodes that could be triggered by physical or emotional stress, a rostrocaudal gradient of involvement, and prominent bulbar findings. <a href="#4" class="mim-tip-reference" title="Rosewich, H., Thiele, H., Ohlenbusch, A., Maschke, U., Altmuller, J., Frommolt, P., Zirn, B., Ebinger, F., Siemes, H., Nurnberg, P., Brockmann, K., Gartner, J. <strong>Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study.</strong> Lancet Neurol. 11: 764-773, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22850527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22850527</a>] [<a href="https://doi.org/10.1016/S1474-4422(12)70182-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22850527">Rosewich et al. (2012)</a> noted the clinical overlap between AHC2 and DYT12, and considered the disorders to be part of a phenotypic spectrum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22850527" 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="#7" class="mim-tip-reference" title="Yang, X., Gao, H., Zhang, J., Xu, X., Liu, X., Wu, X., Wei, L., Zhang, Y. <strong>ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients.</strong> PLoS One 9: e97274, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24842602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24842602</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24842602[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/10.1371/journal.pone.0097274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24842602">Yang et al. (2014)</a> reported 47 Chinese children with typical AHC. All patients had abnormal eye movement and hemiplegia. Up to 70.2% of the patients developed their first symptom before 4 months, and 40.4% before 2 months. Abnormal eye movement was the initial symptom in 57.4% of the patients at a median age as early as 2 months, making it the most common and earliest symptom of the disorder. All patients had developmental delay, but only some developed epilepsy. Treatment with flunarizine, a calcium channel blocker, reduced the severity, duration, or frequency of the hemiplegic attacks in 68.3% of the patients, but did not lead to complete cure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24842602" 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="#1" class="mim-tip-reference" title="Balestrini, S., Mikati, M. A., Alvarez-Garcia-Roves, R., Carboni, M. Hunanyan, A. S., Kherallah, B., McLean, M., Prange, L., De Grandis, E., Gagliardi, A., Pisciotta, L., Stagnaro, M., and 42 others. <strong>Cardiac phenotype in ATP1A3-related syndromes: a multicenter study.</strong> Neurology 95: e2866-e2879, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32913013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32913013</a>] [<a href="https://doi.org/10.1212/WNL.0000000000010794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32913013">Balestrini et al. (2020)</a> evaluated the cardiac phenotype in 110 patients with ATP1A3-related disorders, including 98 with AHC2, 9 with DYT12, and 3 with CAPOS; 22 of the AHC2 patients were previously reported, whereas all of the DYT12 and CAPOS patients were newly reported. Seizures were reported in 58 patients, status epilepticus in 21, and autonomic dysfunction in 60. Syncope, which was the only reported symptom related to cardiac function, was seen in 3 patients. Resting electrocardiograms were abnormal in 52 of 87 individuals with AHC2 who were tested, and serial electrocardiograms showed dynamic changes in 10 of 18 patients with AHC2 who were tested. Echocardiograms did not show structural abnormalities in any of the patients who were tested. Three patients with AHC2 underwent implantation of a cardiac loop recorder, and all 3 subsequently underwent implantation of an implantable cardiac defibrillator or a permanent pacemaker based on findings from the loop recorder records. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32913013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a study of 33 Japanese patients with AHC2 confirmed by genetic analysis, <a href="#5" class="mim-tip-reference" title="Sasaki, M., Ishii, A., Saito, Y., Morisada, N., Iijima, K., Takada, S., Araki, A., Tanabe, Y., Arai, H., Yamashita, S., Ohashi, T., Oda, Y., and 22 others. <strong>Genotype-phenotype correlations in alternating hemiplegia of childhood.</strong> Neurology 82: 482-490, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24431296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24431296</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24431296">Sasaki et al. (2014)</a> observed that patients treated continuously with flunarizine did not show severe motor deterioration. Seven of 13 patients who discontinued the medication experienced either abrupt or stepwise severe motor deterioration. Eight patients with severe motor deterioration had not received flunarizine during the period of deterioration. <a href="#5" class="mim-tip-reference" title="Sasaki, M., Ishii, A., Saito, Y., Morisada, N., Iijima, K., Takada, S., Araki, A., Tanabe, Y., Arai, H., Yamashita, S., Ohashi, T., Oda, Y., and 22 others. <strong>Genotype-phenotype correlations in alternating hemiplegia of childhood.</strong> Neurology 82: 482-490, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24431296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24431296</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24431296">Sasaki et al. (2014)</a> recommended that flunarizine be continued in all patients with the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24431296" 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="#1" class="mim-tip-reference" title="Balestrini, S., Mikati, M. A., Alvarez-Garcia-Roves, R., Carboni, M. Hunanyan, A. S., Kherallah, B., McLean, M., Prange, L., De Grandis, E., Gagliardi, A., Pisciotta, L., Stagnaro, M., and 42 others. <strong>Cardiac phenotype in ATP1A3-related syndromes: a multicenter study.</strong> Neurology 95: e2866-e2879, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32913013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32913013</a>] [<a href="https://doi.org/10.1212/WNL.0000000000010794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32913013">Balestrini et al. (2020)</a> recommended that all individuals with the ATP1A3-related disorders AHC2, DYT12, and CAPOS undergo a baseline ECG, cardiac ultrasound, and Holter monitoring. They further recommended annual 12-lead ECGs for all patients, and additional studies (e.g., Holter monitoring) as needed based on patient symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32913013" 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 alternating hemiplegia of childhood-2 in the family reported by <a href="#2" class="mim-tip-reference" title="Heinzen, E. L., Swoboda, K. J., Hitomi, Y., Gurrieri, F., Nicole, S., de Vries, B., Tiziano, F. D., Fontaine, B., Walley, N. M., Heavin, S., Panagiotakaki, E, European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium, and 33 others. <strong>De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.</strong> Nature Genet. 44: 1030-1034, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842232[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/10.1038/ng.2358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842232">Heinzen et al. (2012)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 82 of 105 patients with alternating hemiplegia of childhood, <a href="#2" class="mim-tip-reference" title="Heinzen, E. L., Swoboda, K. J., Hitomi, Y., Gurrieri, F., Nicole, S., de Vries, B., Tiziano, F. D., Fontaine, B., Walley, N. M., Heavin, S., Panagiotakaki, E, European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium, and 33 others. <strong>De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.</strong> Nature Genet. 44: 1030-1034, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842232[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/10.1038/ng.2358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842232">Heinzen et al. (2012)</a> identified 19 different heterozygous mutations in the ATP1A3 gene (see, e.g., <a href="/entry/182350#0009">182350.0009</a>-<a href="/entry/182350#0012">182350.0012</a>). The first mutations were identified through exome sequencing of affected individuals. Thirteen of the 18 mutations observed in sporadic cases were confirmed to occur de novo in multiple cases. Since it was possible that some variants represented polymorphisms, <a href="#2" class="mim-tip-reference" title="Heinzen, E. L., Swoboda, K. J., Hitomi, Y., Gurrieri, F., Nicole, S., de Vries, B., Tiziano, F. D., Fontaine, B., Walley, N. M., Heavin, S., Panagiotakaki, E, European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium, and 33 others. <strong>De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.</strong> Nature Genet. 44: 1030-1034, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842232[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/10.1038/ng.2358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842232">Heinzen et al. (2012)</a> estimated that mutations in the ATP1A3 gene may be responsible for up to 74% of patients with sporadic, typical AHC. Several mutations were recurrent, and some occurred within hypermutable sequences. In vitro functional expression studies of several of the mutations showed that they caused reductions in protein activity without affecting the level of protein expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842232" 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>Simultaneously and independently, <a href="#4" class="mim-tip-reference" title="Rosewich, H., Thiele, H., Ohlenbusch, A., Maschke, U., Altmuller, J., Frommolt, P., Zirn, B., Ebinger, F., Siemes, H., Nurnberg, P., Brockmann, K., Gartner, J. <strong>Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study.</strong> Lancet Neurol. 11: 764-773, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22850527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22850527</a>] [<a href="https://doi.org/10.1016/S1474-4422(12)70182-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22850527">Rosewich et al. (2012)</a> identified de novo heterozygous mutations in the ATP1A3 gene (see, e.g., <a href="/entry/182350#0009">182350.0009</a>; <a href="/entry/182350#0010">182350.0010</a>; <a href="/entry/182350#0015">182350.0015</a>-<a href="/entry/182350#0017">182350.0017</a>) in 24 unrelated patients with AHC2. Mutations in the first 3 patients were found by whole-exome sequencing of 3 affected child-parent trios, and subsequent mutations were found by direct Sanger sequencing of the ATP1A3 gene in additional patients. There were 2 main recurrent mutations: D801N (<a href="/entry/182350#0009">182350.0009</a>) and E815K (<a href="/entry/182350#0010">182350.0010</a>), found in 9 (38%) and 7 (29%) patients, respectively, suggesting mutation hotspots. None of the mutations resulted in a truncated protein, although there was 1 splice site mutation (<a href="/entry/182350#0017">182350.0017</a>). Functional studies of the variants and studies of patients cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22850527" 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 45 (95.7%) of 47 Chinese children with typical AHC2, <a href="#7" class="mim-tip-reference" title="Yang, X., Gao, H., Zhang, J., Xu, X., Liu, X., Wu, X., Wei, L., Zhang, Y. <strong>ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients.</strong> PLoS One 9: e97274, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24842602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24842602</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24842602[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/10.1371/journal.pone.0097274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24842602">Yang et al. (2014)</a> identified 19 different heterozygous missense mutations in the ATP1A3 gene. Three mutation hotspots, D801N (<a href="/entry/182350#0009">182350.0009</a>), E815K (<a href="/entry/182350#0010">182350.0010</a>), and G947R (<a href="/entry/182350#0012">182350.0012</a> and <a href="/entry/182350#0013">182350.0013</a>), were detected in 14 (31.1%), 9 (20.0%), and 7 (15.6%) ATP1A3-positive patients, respectively. Except for 1 patient who had inherited a mutation from her affected mother, all patients from whom parental DNA was available were found to have de novo mutations. Heterozygous ATP1A3 mutations were also found in 4 additional Chinese patients with atypical AHC2 who had onset of the disorder after 18 months of age. The initial mutations were found by whole-exome sequencing of several patients, and the subsequent mutations were found by direct sequencing of the ATP1A3 gene in a larger cohort. Presence of the E815K mutation was associated with epilepsy. A review of published disease-associated ATP1A3 mutations suggested that mutations associated with AHC2 were predominantly located in the transmembrane domain. Molecular modeling of the variants identified 2 statistically significant molecular features, solvent accessibility and distance to metal ion, that distinguished disease-associated mutations from neutral variants. In vitro functional studies were not performed on any of the variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24842602" 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="#5" class="mim-tip-reference" title="Sasaki, M., Ishii, A., Saito, Y., Morisada, N., Iijima, K., Takada, S., Araki, A., Tanabe, Y., Arai, H., Yamashita, S., Ohashi, T., Oda, Y., and 22 others. <strong>Genotype-phenotype correlations in alternating hemiplegia of childhood.</strong> Neurology 82: 482-490, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24431296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24431296</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24431296">Sasaki et al. (2014)</a> identified a heterozygous E815K mutation and a heterozygous D801N mutation in the ATP1A3 gene in 12 (36%) and 10 (30%) of 33 Japanese patients with AHC2, respectively. Eleven additional patients from the cohort had other missense mutations in the ATP1A3 gene. All mutations occurred de novo. A comparison of the phenotype indicated that patients with the E815K mutation had a significantly more severe disease course than did those with the D801N mutation or other missense mutations. Patients with the E815K mutation had neonatal onset of abnormal ocular movements or seizures and showed very slow early development; none was able to control head movements before 6 months of age, and none achieved independent walking, even as teenagers and young adults. All patients with the E815K mutation experienced both status epilepticus and respiratory paralysis. Five of these patients experienced severe deterioration: 4 had discontinued flunarizine before the deterioration and 1 had never been treated with flunarizine. Most patients with the D801N mutation had onset between 4 and 10 months of age and slow early development, but they achieved head control by 6 months of age; 7 of the 10 could walk independently. Only some patients had status epilepticus (2 patients) or respiratory paralysis (3 patients); none showed severe motor deterioration. All 10 patients were treated with flunarizine; 4 had discontinued the medication but did not show severe motor deterioration. The 11 patients with other mutations had features most similar to those with the D801N mutation, although 3 of these patients who discontinued flunarizine treatment showed permanent severe deterioration following status epilepticus. <a href="#5" class="mim-tip-reference" title="Sasaki, M., Ishii, A., Saito, Y., Morisada, N., Iijima, K., Takada, S., Araki, A., Tanabe, Y., Arai, H., Yamashita, S., Ohashi, T., Oda, Y., and 22 others. <strong>Genotype-phenotype correlations in alternating hemiplegia of childhood.</strong> Neurology 82: 482-490, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24431296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24431296</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24431296">Sasaki et al. (2014)</a> concluded that the E815K mutation was associated with the most severe phenotype and that the D801N mutation may result in a moderate to mild phenotype, although they acknowledged that the sample size was relatively small. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24431296" 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>Using a formulated questionnaire, <a href="#3" class="mim-tip-reference" title="Panagiotakaki, E., De Grandis, E., Stagnaro, M., Heinzen, E. L., Fons, C., Sisodiya, S., de Vries, B., Goubau, C., Weckhuysen, S., Kemlink, D., Scheffer, I., Lesca, G., and 24 others. <strong>Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood--a study of 155 patients.</strong> Orphanet J. Rare Dis. 10: 123, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26410222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26410222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26410222[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/10.1186/s13023-015-0335-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26410222">Panagiotakaki et al. (2015)</a> assessed clinical data from 155 patients with AHC, including 132 confirmed to have ATP1A3 mutations by genetic analysis. Among those with AHC2, the most frequent mutations were D801N (in 43%), E815K (in 16%), and G947R (<a href="/entry/182350#0012">182350.0012</a> and <a href="/entry/182350#0013">182350.0013</a>, which were considered together) (in 11%). E815K was associated with a severe phenotype, with greater intellectual and motor disability; D801N appeared to confer a milder phenotype; and G947R correlated with the most favorable prognosis. For those with epilepsy, the age at seizure onset was earlier for patients with the E815K or G947R mutations than for those with the D801N mutation. Several mutational clusters within the gene were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26410222" 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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Balestrini, S., Mikati, M. A., Alvarez-Garcia-Roves, R., Carboni, M. Hunanyan, A. S., Kherallah, B., McLean, M., Prange, L., De Grandis, E., Gagliardi, A., Pisciotta, L., Stagnaro, M., and 42 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32913013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32913013</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32913013" 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.0000000000010794" target="_blank">Full Text</a>]
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Heinzen, E. L., Swoboda, K. J., Hitomi, Y., Gurrieri, F., Nicole, S., de Vries, B., Tiziano, F. D., Fontaine, B., Walley, N. M., Heavin, S., Panagiotakaki, E, European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium, and 33 others.
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<strong>De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842232[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=22842232" 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/ng.2358" target="_blank">Full Text</a>]
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Panagiotakaki, E., De Grandis, E., Stagnaro, M., Heinzen, E. L., Fons, C., Sisodiya, S., de Vries, B., Goubau, C., Weckhuysen, S., Kemlink, D., Scheffer, I., Lesca, G., and 24 others.
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<strong>Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood--a study of 155 patients.</strong>
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Orphanet J. Rare Dis. 10: 123, 2015. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26410222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26410222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26410222[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=26410222" 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/10.1186/s13023-015-0335-5" target="_blank">Full Text</a>]
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Rosewich, H., Thiele, H., Ohlenbusch, A., Maschke, U., Altmuller, J., Frommolt, P., Zirn, B., Ebinger, F., Siemes, H., Nurnberg, P., Brockmann, K., Gartner, J.
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<strong>Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study.</strong>
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Lancet Neurol. 11: 764-773, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22850527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22850527</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22850527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/S1474-4422(12)70182-5" target="_blank">Full Text</a>]
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Sasaki, M., Ishii, A., Saito, Y., Morisada, N., Iijima, K., Takada, S., Araki, A., Tanabe, Y., Arai, H., Yamashita, S., Ohashi, T., Oda, Y., and 22 others.
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<strong>Genotype-phenotype correlations in alternating hemiplegia of childhood.</strong>
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Neurology 82: 482-490, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24431296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24431296</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24431296" 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.0000000000000102" target="_blank">Full Text</a>]
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Verret, S., Steele, J. C.
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<strong>Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy.</strong>
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Pediatrics 47: 675-680, 1971.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5089756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5089756</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5089756" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Yang, X., Gao, H., Zhang, J., Xu, X., Liu, X., Wu, X., Wei, L., Zhang, Y.
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<strong>ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients.</strong>
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PLoS One 9: e97274, 2014. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24842602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24842602</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24842602[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=24842602" 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/10.1371/journal.pone.0097274" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 02/01/2021
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Cassandra L. Kniffin - updated : 4/13/2016<br>Cassandra L. Kniffin - updated : 2/25/2015<br>Cassandra L. Kniffin - updated : 6/30/2014
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carol : 02/01/2021<br>carol : 03/20/2019<br>carol : 08/01/2017<br>carol : 04/14/2016<br>ckniffin : 4/13/2016<br>carol : 3/3/2015<br>mcolton : 2/25/2015<br>ckniffin : 2/25/2015<br>alopez : 9/29/2014<br>ckniffin : 9/29/2014<br>alopez : 7/3/2014<br>ckniffin : 6/30/2014<br>carol : 9/14/2012<br>terry : 9/13/2012<br>ckniffin : 9/13/2012
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<strong>#</strong> 614820
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ALTERNATING HEMIPLEGIA OF CHILDHOOD 2; AHC2
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<strong>ORPHA:</strong> 2131;
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<strong>DO:</strong> 0050635;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus <br /> MIM number
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19q13.2
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Alternating hemiplegia of childhood 2
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614820
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Autosomal dominant
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3
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ATP1A3
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182350
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<p>A number sign (#) is used with this entry because alternating hemiplegia of childhood-2 (AHC2) is caused by heterozygous mutation in the ATP1A3 gene (182350) on chromosome 19q13.</p><p>Heterozygous mutation in the ATP1A3 gene can also cause 2 other neurologic disorders that share some clinical features: dystonia-12 (DYT12; 128235) and CAPOS syndrome (CAPOS; 601338).</p>
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<strong>Description</strong>
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<p>Alternating hemiplegia of childhood is a rare syndrome characterized by infantile onset of episodic hemi-or quadriplegia. Most cases are accompanied by dystonic posturing, choreoathetoid movements, abnormal ocular movements, developmental delay, and progressive cognitive impairment (summary by Heinzen et al., 2012). </p><p>For a discussion of genetic heterogeneity of alternating hemiplegia of childhood, see AHC1 (104290).</p>
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<strong>Clinical Features</strong>
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<p>Verret and Steele (1971) first characterized alternating hemiplegia in childhood as a distinct condition. They reported 8 patients, including 2 sibs, with the disorder. All had intermittent hemiparesis of variable severity beginning in infancy or early childhood. Episodes usually lasted minutes or hours, with a few patients having weakness for several days. Only 2 patients had intermittent seizures. Four patients had residual neurologic deficits including mental retardation and a movement disorder, such as dystonia and/or choreoathetosis. Attacks ceased spontaneously in 2 patients by age 4 years. EEG in all patients showed no constant focal abnormality or evidence of seizure activity. Some patients later developed headaches, and all had relatives with migraine headaches. </p><p>Heinzen et al. (2012) reported 82 patients with AHC2 confirmed by genetic analysis. Affected individuals had infantile onset of hemiplegic attacks, usually associated with episodes of quadriparesis, abnormal eye movements, autonomic signs, seizures, dystonia, ataxia, chorea, and developmental delay. Most cases occurred sporadically, but there was 1 family of Puerto Rican origin in which 4 affected individuals were described in detail. One child in this family had onset at 2 months of age of tonic stiffening and eye deviation, but without loss of consciousness. By age 1 year, he had episodes of flaccid hemiplegia alternating with dystonia. He also had generalized tonic-clonic seizures that stopped by age 5 years. Hemiplegic episodes lasted from 5 to 30 minutes, and EEG showed no abnormalities during episodes. In childhood, he showed permanent neurologic sequelae, including mild cognitive impairment, ataxia, chorea, and dysarthria. At age 16 years, he had episodic severe dystonia and parkinsonism several times per month. This patient's brother developed whole body stiffening at age 3 years. Typical spells rendered him mute and unable to ambulate. In childhood, he had mild cognitive impairment, behavioral abnormalities, hypotonia, ataxia, dysarthria, and chorea. Since childhood, the father had episodic hemiplegic spells since childhood, accompanied by tonic or dystonic stiffening and abnormal eye movements. He also had rare generalized seizures. At age 41 years, he had neurocognitive deficits, depression, and anxiety. The father's brother had onset of hemi- and quadriplegia since age 6 months. As an adult, he continued to have episodes of flaccidity or parkinsonism-like rigidity. </p><p>Simultaneously and independently, Rosewich et al. (2012) reported 24 unrelated patients with AHC2 confirmed by genetic analysis. The patients ranged in age from 8 to 35 years, and all except 1 had onset before age 7 months. Most patients presented with a dystonic episode, although a few presented with nystagmus or seizures. The patient with the latest onset presented with hemiplegic episodes at age 16 months. Additional variable paroxysmal features included abnormal ocular movements, bulbar symptoms, autonomic dysfunction, and respiratory disturbances. Nonparoxysmal features included delayed psychomotor development with intellectual disability, hypotonia, choreoathetosis, ataxia, and dysarthria. Patients had abrupt onset of dystonic episodes that could be triggered by physical or emotional stress, a rostrocaudal gradient of involvement, and prominent bulbar findings. Rosewich et al. (2012) noted the clinical overlap between AHC2 and DYT12, and considered the disorders to be part of a phenotypic spectrum. </p><p>Yang et al. (2014) reported 47 Chinese children with typical AHC. All patients had abnormal eye movement and hemiplegia. Up to 70.2% of the patients developed their first symptom before 4 months, and 40.4% before 2 months. Abnormal eye movement was the initial symptom in 57.4% of the patients at a median age as early as 2 months, making it the most common and earliest symptom of the disorder. All patients had developmental delay, but only some developed epilepsy. Treatment with flunarizine, a calcium channel blocker, reduced the severity, duration, or frequency of the hemiplegic attacks in 68.3% of the patients, but did not lead to complete cure. </p><p>Balestrini et al. (2020) evaluated the cardiac phenotype in 110 patients with ATP1A3-related disorders, including 98 with AHC2, 9 with DYT12, and 3 with CAPOS; 22 of the AHC2 patients were previously reported, whereas all of the DYT12 and CAPOS patients were newly reported. Seizures were reported in 58 patients, status epilepticus in 21, and autonomic dysfunction in 60. Syncope, which was the only reported symptom related to cardiac function, was seen in 3 patients. Resting electrocardiograms were abnormal in 52 of 87 individuals with AHC2 who were tested, and serial electrocardiograms showed dynamic changes in 10 of 18 patients with AHC2 who were tested. Echocardiograms did not show structural abnormalities in any of the patients who were tested. Three patients with AHC2 underwent implantation of a cardiac loop recorder, and all 3 subsequently underwent implantation of an implantable cardiac defibrillator or a permanent pacemaker based on findings from the loop recorder records. </p>
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<strong>Clinical Management</strong>
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<p>In a study of 33 Japanese patients with AHC2 confirmed by genetic analysis, Sasaki et al. (2014) observed that patients treated continuously with flunarizine did not show severe motor deterioration. Seven of 13 patients who discontinued the medication experienced either abrupt or stepwise severe motor deterioration. Eight patients with severe motor deterioration had not received flunarizine during the period of deterioration. Sasaki et al. (2014) recommended that flunarizine be continued in all patients with the disorder. </p><p>Balestrini et al. (2020) recommended that all individuals with the ATP1A3-related disorders AHC2, DYT12, and CAPOS undergo a baseline ECG, cardiac ultrasound, and Holter monitoring. They further recommended annual 12-lead ECGs for all patients, and additional studies (e.g., Holter monitoring) as needed based on patient symptoms. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of alternating hemiplegia of childhood-2 in the family reported by Heinzen et al. (2012) was consistent with autosomal dominant inheritance. </p>
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<strong>Molecular Genetics</strong>
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<p>In 82 of 105 patients with alternating hemiplegia of childhood, Heinzen et al. (2012) identified 19 different heterozygous mutations in the ATP1A3 gene (see, e.g., 182350.0009-182350.0012). The first mutations were identified through exome sequencing of affected individuals. Thirteen of the 18 mutations observed in sporadic cases were confirmed to occur de novo in multiple cases. Since it was possible that some variants represented polymorphisms, Heinzen et al. (2012) estimated that mutations in the ATP1A3 gene may be responsible for up to 74% of patients with sporadic, typical AHC. Several mutations were recurrent, and some occurred within hypermutable sequences. In vitro functional expression studies of several of the mutations showed that they caused reductions in protein activity without affecting the level of protein expression. </p><p>Simultaneously and independently, Rosewich et al. (2012) identified de novo heterozygous mutations in the ATP1A3 gene (see, e.g., 182350.0009; 182350.0010; 182350.0015-182350.0017) in 24 unrelated patients with AHC2. Mutations in the first 3 patients were found by whole-exome sequencing of 3 affected child-parent trios, and subsequent mutations were found by direct Sanger sequencing of the ATP1A3 gene in additional patients. There were 2 main recurrent mutations: D801N (182350.0009) and E815K (182350.0010), found in 9 (38%) and 7 (29%) patients, respectively, suggesting mutation hotspots. None of the mutations resulted in a truncated protein, although there was 1 splice site mutation (182350.0017). Functional studies of the variants and studies of patients cells were not performed. </p><p>In 45 (95.7%) of 47 Chinese children with typical AHC2, Yang et al. (2014) identified 19 different heterozygous missense mutations in the ATP1A3 gene. Three mutation hotspots, D801N (182350.0009), E815K (182350.0010), and G947R (182350.0012 and 182350.0013), were detected in 14 (31.1%), 9 (20.0%), and 7 (15.6%) ATP1A3-positive patients, respectively. Except for 1 patient who had inherited a mutation from her affected mother, all patients from whom parental DNA was available were found to have de novo mutations. Heterozygous ATP1A3 mutations were also found in 4 additional Chinese patients with atypical AHC2 who had onset of the disorder after 18 months of age. The initial mutations were found by whole-exome sequencing of several patients, and the subsequent mutations were found by direct sequencing of the ATP1A3 gene in a larger cohort. Presence of the E815K mutation was associated with epilepsy. A review of published disease-associated ATP1A3 mutations suggested that mutations associated with AHC2 were predominantly located in the transmembrane domain. Molecular modeling of the variants identified 2 statistically significant molecular features, solvent accessibility and distance to metal ion, that distinguished disease-associated mutations from neutral variants. In vitro functional studies were not performed on any of the variants. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Sasaki et al. (2014) identified a heterozygous E815K mutation and a heterozygous D801N mutation in the ATP1A3 gene in 12 (36%) and 10 (30%) of 33 Japanese patients with AHC2, respectively. Eleven additional patients from the cohort had other missense mutations in the ATP1A3 gene. All mutations occurred de novo. A comparison of the phenotype indicated that patients with the E815K mutation had a significantly more severe disease course than did those with the D801N mutation or other missense mutations. Patients with the E815K mutation had neonatal onset of abnormal ocular movements or seizures and showed very slow early development; none was able to control head movements before 6 months of age, and none achieved independent walking, even as teenagers and young adults. All patients with the E815K mutation experienced both status epilepticus and respiratory paralysis. Five of these patients experienced severe deterioration: 4 had discontinued flunarizine before the deterioration and 1 had never been treated with flunarizine. Most patients with the D801N mutation had onset between 4 and 10 months of age and slow early development, but they achieved head control by 6 months of age; 7 of the 10 could walk independently. Only some patients had status epilepticus (2 patients) or respiratory paralysis (3 patients); none showed severe motor deterioration. All 10 patients were treated with flunarizine; 4 had discontinued the medication but did not show severe motor deterioration. The 11 patients with other mutations had features most similar to those with the D801N mutation, although 3 of these patients who discontinued flunarizine treatment showed permanent severe deterioration following status epilepticus. Sasaki et al. (2014) concluded that the E815K mutation was associated with the most severe phenotype and that the D801N mutation may result in a moderate to mild phenotype, although they acknowledged that the sample size was relatively small. </p><p>Using a formulated questionnaire, Panagiotakaki et al. (2015) assessed clinical data from 155 patients with AHC, including 132 confirmed to have ATP1A3 mutations by genetic analysis. Among those with AHC2, the most frequent mutations were D801N (in 43%), E815K (in 16%), and G947R (182350.0012 and 182350.0013, which were considered together) (in 11%). E815K was associated with a severe phenotype, with greater intellectual and motor disability; D801N appeared to confer a milder phenotype; and G947R correlated with the most favorable prognosis. For those with epilepsy, the age at seizure onset was earlier for patients with the E815K or G947R mutations than for those with the D801N mutation. Several mutational clusters within the gene were identified. </p>
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<strong>REFERENCES</strong>
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</h4>
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<p />
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<p class="mim-text-font">
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Balestrini, S., Mikati, M. A., Alvarez-Garcia-Roves, R., Carboni, M. Hunanyan, A. S., Kherallah, B., McLean, M., Prange, L., De Grandis, E., Gagliardi, A., Pisciotta, L., Stagnaro, M., and 42 others.
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<strong>Cardiac phenotype in ATP1A3-related syndromes: a multicenter study.</strong>
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Neurology 95: e2866-e2879, 2020.
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[PubMed: 32913013]
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[Full Text: https://doi.org/10.1212/WNL.0000000000010794]
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</li>
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<li>
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Heinzen, E. L., Swoboda, K. J., Hitomi, Y., Gurrieri, F., Nicole, S., de Vries, B., Tiziano, F. D., Fontaine, B., Walley, N. M., Heavin, S., Panagiotakaki, E, European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium, and 33 others.
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<strong>De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.</strong>
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Nature Genet. 44: 1030-1034, 2012.
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[PubMed: 22842232]
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[Full Text: https://doi.org/10.1038/ng.2358]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Panagiotakaki, E., De Grandis, E., Stagnaro, M., Heinzen, E. L., Fons, C., Sisodiya, S., de Vries, B., Goubau, C., Weckhuysen, S., Kemlink, D., Scheffer, I., Lesca, G., and 24 others.
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<strong>Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood--a study of 155 patients.</strong>
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Orphanet J. Rare Dis. 10: 123, 2015. Note: Electronic Article.
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[PubMed: 26410222]
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[Full Text: https://doi.org/10.1186/s13023-015-0335-5]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Rosewich, H., Thiele, H., Ohlenbusch, A., Maschke, U., Altmuller, J., Frommolt, P., Zirn, B., Ebinger, F., Siemes, H., Nurnberg, P., Brockmann, K., Gartner, J.
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<strong>Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study.</strong>
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Lancet Neurol. 11: 764-773, 2012.
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[PubMed: 22850527]
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[Full Text: https://doi.org/10.1016/S1474-4422(12)70182-5]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Sasaki, M., Ishii, A., Saito, Y., Morisada, N., Iijima, K., Takada, S., Araki, A., Tanabe, Y., Arai, H., Yamashita, S., Ohashi, T., Oda, Y., and 22 others.
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<strong>Genotype-phenotype correlations in alternating hemiplegia of childhood.</strong>
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Neurology 82: 482-490, 2014.
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[PubMed: 24431296]
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[Full Text: https://doi.org/10.1212/WNL.0000000000000102]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Verret, S., Steele, J. C.
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<strong>Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy.</strong>
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Pediatrics 47: 675-680, 1971.
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[PubMed: 5089756]
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</p>
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<li>
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<p class="mim-text-font">
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Yang, X., Gao, H., Zhang, J., Xu, X., Liu, X., Wu, X., Wei, L., Zhang, Y.
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<strong>ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients.</strong>
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PLoS One 9: e97274, 2014. Note: Electronic Article.
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[PubMed: 24842602]
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[Full Text: https://doi.org/10.1371/journal.pone.0097274]
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Hilary J. Vernon - updated : 02/01/2021<br>Cassandra L. Kniffin - updated : 4/13/2016<br>Cassandra L. Kniffin - updated : 2/25/2015<br>Cassandra L. Kniffin - updated : 6/30/2014
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Cassandra L. Kniffin : 9/13/2012
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