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<title>
Entry
- #223900 - NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE III; HSAN3
- OMIM
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<span class="h4">#223900</span>
<br />
<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/223900"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS162400"> <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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<li role="presentation" style="margin-left: 1em">
<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#history">History</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE III" 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.possumcore.com/nuxeo/nxdoc/default/53a868f2-a752-4e1d-a87c-4a6e60098084/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
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</a>
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</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:11589" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/223900" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://omia.org/results?search_type=advanced&omia_id=000312,001514" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:11589" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:223900" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
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</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 29159009<br />
<strong>ICD10CM:</strong> G90.1<br />
<strong>ORPHA:</strong> 1764<br />
<strong>DO:</strong> 11589<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
223900
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE III; HSAN3
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
HSAN III<br />
DYSAUTONOMIA, FAMILIAL; DYS; FD<br />
RILEY-DAY SYNDROME
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/397?start=-3&limit=10&highlight=397">
9q31.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Dysautonomia, familial
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/223900"> 223900 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
ELP1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603722"> 603722 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/223900" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
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</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS162400" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/223900" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/223900" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Poor growth <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837385&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837385</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001510</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001510</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Alacrima <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253215004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253215004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0344505&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344505</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000522" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000522</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000522" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000522</a>]</span><br /> -
Decreased corneal reflex <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103254005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103254005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008000</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008000</a>]</span><br /> -
Corneal ulceration <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91514001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91514001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H16.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H16.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H16.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H16.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/370.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">370.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/370.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">370.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0010043&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010043</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012804" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012804</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012804" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012804</a>]</span><br /> -
Pupillary contraction in response to methacholine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857166&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857166</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Mouth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Decreased or absent lingual fungiform papillae <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857167&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857167</a>]</span><br /> -
Decreased taste <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/697990000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">697990000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151934&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151934</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000224" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000224</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000224" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000224</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypertension, episodic <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857175&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857175</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000875" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000875</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38341003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38341003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/401-405.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">401-405.99</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/997.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">997.91</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span><br /> -
Postural hypotension without compensatory tachycardia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857176&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857176</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Recurrent infections due to aspiration <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806285&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806285</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004891</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004891</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/451991000124106" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">451991000124106</a>]</span><br /> -
Decreased sensitivity to hypoxemia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806286&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806286</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005947" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005947</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005947" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005947</a>]</span><br /> -
Breath-holding episodes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857174&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857174</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Feeding difficulties <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78164000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0232466&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232466</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span><br /> -
Poor oral coordination <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857164&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857164</a>]</span><br /> -
Gastroesophageal reflux <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/235595009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">235595009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/722884003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">722884003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/698065002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">698065002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K21</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K21.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K21.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/530.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">530.81</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3813607&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3813607</a>, <a href="https://bioportal.bioontology.org/search?q=C4317146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4317146</a>, <a href="https://bioportal.bioontology.org/search?q=C0017168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017168</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002020</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002020</a>]</span><br /> -
Vomiting crises <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857165&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857165</a>]</span><br /> -
Diarrhea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267060006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267060006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/62315008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">62315008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R19.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R19.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011991&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011991</a>, <a href="https://bioportal.bioontology.org/search?q=C2169706&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2169706</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span><br /> -
Constipation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14760008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14760008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/564.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/564.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009806&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009806</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Impaired renal function <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/723188008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">723188008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/236423003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">236423003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1565489&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1565489</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span><br /> -
Glomerulosclerosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/82646005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">82646005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197661001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197661001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1417247&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1417247</a>, <a href="https://bioportal.bioontology.org/search?q=C0178664&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0178664</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000096" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000096</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000096" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000096</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Neuropathic arthropathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/67536000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">67536000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/359554008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">359554008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M14.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M14.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/713.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">713.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003892&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003892</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002821" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002821</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002821" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002821</a>]</span><br />
</span>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spine </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Scoliosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/298382003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">298382003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20944008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20944008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111266001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111266001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M41.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0559260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0559260</a>, <a href="https://bioportal.bioontology.org/search?q=C0036439&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036439</a>, <a href="https://bioportal.bioontology.org/search?q=C0700208&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700208</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Erythematous skin blotching <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857170&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857170</a>]</span><br /> -
Hyperhidrosis, episodic <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857171&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857171</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001069" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001069</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001069" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001069</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/312230002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">312230002</a>]</span><br /> -
Acrocyanosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25003006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25003006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I73.89" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I73.89</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221347&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221347</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001063" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001063</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001063" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001063</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Peripheral Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
Decreased pain and temperature perception <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857154&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857154</a>]</span><br /> -
Decreased taste <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/697990000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">697990000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151934&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151934</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000224" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000224</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000224" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000224</a>]</span><br /> -
Vibratory loss occurs later <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857156&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857156</a>]</span><br /> -
Hyporeflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/835279003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">835279003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405946002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405946002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700078</a>, <a href="https://bioportal.bioontology.org/search?q=C0151888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151888</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001315</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>]</span><br /> -
Incoordination <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/281016006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">281016006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302289002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302289002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0520966&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0520966</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002311</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002311</a>]</span><br /> -
Prominent autonomic manifestations <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857157&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857157</a>]</span><br /> -
Intellect is unimpaired <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857158&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857158</a>]</span><br /> -
Hypoplastic sural nerve <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857159&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857159</a>]</span><br /> -
Decreased myelinated and unmyelinated small fibers <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857160&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857160</a>]</span><br /> -
Decreased large myelinated fibers <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857161&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857161</a>]</span><br /> -
Decreased neurons in spinal sympathetic ganglia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857162&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857162</a>]</span><br /> -
Decreased neurons in dorsal root ganglia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857163&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857163</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Emotional lability <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18963009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18963009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R45.86" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R45.86</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085633&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085633</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000712</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000712</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> METABOLIC FEATURES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Fever, episodic <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/77957000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">77957000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0277799&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0277799</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R50.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.60</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001945" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001945</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Azotemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/445009001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">445009001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/445646001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">445646001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0554309&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0554309</a>, <a href="https://bioportal.bioontology.org/search?q=C0242528&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242528</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002157" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002157</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002157" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002157</a>]</span><br /> -
Increased blood urea nitrogen (BUN) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151539&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151539</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003138" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003138</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003138" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003138</a>]</span><br /> -
Increased serum creatinine <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/166717003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">166717003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700225&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700225</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003259</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003259</a>]</span><br /> -
Absent axonal flare response after intradermal histamine injection <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857168</a>]</span><br /> -
Increased sensitivity to adrenergic and cholinergic agents <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857169&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857169</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset at birth <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836142&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836142</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003577" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003577</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003577" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003577</a>]</span><br /> -
Progressive disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span><br /> -
Increased prevalence in persons of Ashkenazi Jewish descent<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the elongator complex protein 1 gene (ELP1, <a href="/entry/603722#0001">603722.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Hereditary sensory and autonomic neuropathy
- <a href="/phenotypicSeries/PS162400">PS162400</a>
- 16 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/949?start=-3&limit=10&highlight=949"> 1p13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608654"> Neuropathy, hereditary sensory and autonomic, type V </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608654"> 608654 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162030"> NGF </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162030"> 162030 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/1269?start=-3&limit=10&highlight=1269"> 1q23.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/256800"> Insensitivity to pain, congenital, with anhidrosis </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/256800"> 256800 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191315"> NTRK1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191315"> 191315 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/1177?start=-3&limit=10&highlight=1177"> 2q37.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614213"> Neuropathy, hereditary sensory, type IIC </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614213"> 614213 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601255"> KIF1A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601255"> 601255 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/104?start=-3&limit=10&highlight=104"> 3p24-p22 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608088"> Neuropathy, hereditary sensory, type IB </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608088"> 608088 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608088"> HSN1B </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608088"> 608088 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/183?start=-3&limit=10&highlight=183"> 3p22.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615548"> Neuropathy, hereditary sensory and autonomic, type VII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615548"> 615548 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604385"> SCN11A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604385"> 604385 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/5/67?start=-3&limit=10&highlight=67"> 5p15.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613115"> Neuropathy, hereditary sensory and autonomic, type IIB </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613115"> 613115 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613114"> RETREG1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613114"> 613114 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/611?start=-3&limit=10&highlight=611"> 6p12.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614653"> Neuropathy, hereditary sensory and autonomic, type VI </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614653"> 614653 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/113810"> DST </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/113810"> 113810 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/301?start=-3&limit=10&highlight=301"> 9q22.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162400"> Neuropathy, hereditary sensory and autonomic, type IA </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162400"> 162400 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605712"> SPTLC1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605712"> 605712 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/397?start=-3&limit=10&highlight=397"> 9q31.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/223900"> Dysautonomia, familial </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/223900"> 223900 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603722"> ELP1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603722"> 603722 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/579?start=-3&limit=10&highlight=579"> 9q34.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616488"> Neuropathy, hereditary sensory and autonomic, type VIII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616488"> 616488 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616458"> PRDM12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616458"> 616458 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/528?start=-3&limit=10&highlight=528"> 11q13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615632"> Neuropathy, hereditary sensory, type IF </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615632"> 615632 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609369"> ATL3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609369"> 609369 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/10?start=-3&limit=10&highlight=10"> 12p13.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/201300"> Neuropathy, hereditary sensory and autonomic, type II </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/201300"> 201300 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605232"> WNK1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605232"> 605232 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/225?start=-3&limit=10&highlight=225"> 14q22.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613708"> Neuropathy, hereditary sensory, type ID </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613708"> 613708 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606439"> ATL1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606439"> 606439 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/419?start=-3&limit=10&highlight=419"> 14q24.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613640"> Neuropathy, hereditary sensory and autonomic, type IC </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613640"> 613640 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605713"> SPTLC2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605713"> 605713 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/564?start=-3&limit=10&highlight=564"> 14q32.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615031"> Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615031"> 615031 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615000"> TECPR2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615000"> 615000 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/260?start=-3&limit=10&highlight=260"> 19p13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614116"> Neuropathy, hereditary sensory, type IE </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614116"> 614116 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/126375"> DNMT1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/126375"> 126375 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
<div class="text-right small">
<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="text" class="mim-anchor"></a>
<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon &lt;span class='glyphicon glyphicon-plus-sign'&gt;&lt;/span&gt at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
<strong>TEXT</strong>
</span>
</span>
</h4>
<div id="mimTextFold" class="collapse in ">
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because hereditary sensory and autonomic neuropathy type III (HSAN3), or familial dysautonomia (FD), is caused by homozygous or compound heterozygous mutation in the IKBKAP gene (ELP1; <a href="/entry/603722">603722</a>) on chromosome 9q31.</p>
</span>
<div>
<br />
</div>
</div>
<div>
<a id="description" class="mim-anchor"></a>
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<div id="mimDescriptionFold" class="collapse in ">
<span class="mim-text-font">
<p>Hereditary sensory and autonomic neuropathy type III (HSAN3) is an autosomal recessive neurodegenerative disorder with onset soon after birth. Affected individuals show progressive symptoms resulting from depletion of sensory proprioceptive and autonomic neurons. Features include gastrointestinal dysfunction, gastroesophageal reflux, vomiting crises, recurrent pneumonia, seizures, gait abnormalities with loss of ambulation, kyphoscoliosis, postural hypotension, hypertension crises, absence of fungiform papillae on the tongue, decreased deep tendon reflexes, defective lacrimation, and impaired pain and temperature perception. The disorder is inevitably fatal, with only 50% of patients reaching 40 years of age. HSAN3 has a high carrier frequency in the Ashkenazi Jewish population (summary by <a href="#36" class="mim-tip-reference" title="Morini, E., Dietrich, P., Salani, M., Downs, H. M., Wojtkiewicz, G. R., Alli, S., Brenner, A., Nilbratt, M., LeClair, J. W., Oaklander, A. L., Slaugenhaupt, S. A., Dragatsis, I. &lt;strong&gt;Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia.&lt;/strong&gt; Hum. Molec. Genet. 25: 1116-1128, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26769677/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26769677&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddv634&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26769677">Morini et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26769677" 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 hereditary sensory and autonomic neuropathy, see HSAN1 (<a href="/entry/162400">162400</a>).</p>
</span>
<div>
<br />
</div>
</div>
<div>
<a id="clinicalFeatures" class="mim-anchor"></a>
<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Clinical Features</strong>
</span>
</h4>
</div>
<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
<span class="mim-text-font">
<p><a href="#48" class="mim-tip-reference" title="Riley, C. M., Day, R. L., Greeley, D. M., Langford, W. S. &lt;strong&gt;Central autonomic dysfunction with defective lacrimation: report of five cases.&lt;/strong&gt; Pediatrics 3: 468-478, 1949.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18118947/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18118947&lt;/a&gt;]" pmid="18118947">Riley et al. (1949)</a> first described this disorder in 5 Jewish patients with autonomic dysfunction and defective lacrimation. Other features included episodic hypertension, hyperhidrosis, cyclic vomiting, and skin blotching. <a href="#56" class="mim-tip-reference" title="Smith, A. A., Dancis, J. &lt;strong&gt;Response to intradermal histamine in familial dysautonomia: a diagnostic test.&lt;/strong&gt; J. Pediat. 63: 889-894, 1963.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14071043/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14071043&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(63)80219-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14071043">Smith and Dancis (1963)</a> noted the lack of an axon flare after intradermal histamine, and <a href="#57" class="mim-tip-reference" title="Smith, A. A., Farbman, A., Dancis, J. &lt;strong&gt;Absence of taste-bud papillae in familial dysautonomia.&lt;/strong&gt; Science 147: 1040-1041, 1965.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14245781/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14245781&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.147.3661.1040&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14245781">Smith et al. (1965)</a> noted the absence of fungiform papillae on the tongue. These authors also described Ashkenazi Jewish heritage and decreased deep tendon reflexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14245781+18118947+14071043" 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 an extensive review of 210 children with familial dysautonomia from 172 families, <a href="#15" class="mim-tip-reference" title="Brunt, P. W., McKusick, V. A. &lt;strong&gt;Familial dysautonomia: a report of genetic and clinical studies, with a review of the literature.&lt;/strong&gt; Medicine 49: 343-374, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4322121/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4322121&lt;/a&gt;]" pmid="4322121">Brunt and McKusick (1970)</a> concluded that FD is an autosomal recessive disorder occurring almost exclusively in persons of Ashkenazi Jewish descent. Common features included alacrima, absence of lingual fungiform papillae with impaired taste, vasomotor instability, hypoactive or absent deep tendon reflexes, and relative indifference to pain and temperature. Patients showed incoordination, and neuropathic joints and scoliosis were often seen. Although emotional instability occurred, intellect was unimpaired. Patients also showed increased sensitivity to adrenergic and cholinergic agents, suggesting functional autonomic denervation. <a href="#6" class="mim-tip-reference" title="Axelrod, F. B., Iyer, K., Fish, I., Pearson, J., Sein, M. E., Spielholz, N. &lt;strong&gt;Progressive sensory loss in familial dysautonomia.&lt;/strong&gt; Pediatrics 67: 517-522, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7254974/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7254974&lt;/a&gt;]" pmid="7254974">Axelrod et al. (1981)</a> demonstrated clinical variability in sensory impairment among 75 patients with FD. Older patients tended to have increased dysfunction in pain sensation, joint position and Romberg sign, and vibratory sense. Testing after a 5-year interval showed significant worsening with increased age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7254974+4322121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Pearson, J., Gallo, G., Gluck, M., Axelrod, F. &lt;strong&gt;Renal disease in familial dysautonomia.&lt;/strong&gt; Kidney Int. 17: 102-112, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7374014/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7374014&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ki.1980.12&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7374014">Pearson et al. (1980)</a> demonstrated glomerulosclerosis in 10 or 13 autopsied and biopsied patients with familial dysautonomia. Sympathetic nerve terminals could not be identified in renal vessels from the patients, whereas they were demonstrated in controls. In a review of 79 patients, elevated serum creatinine (32% of patients) and blood urea nitrogen (76% of patients) were found, and an association was found between hypotension and renal dysfunction. <a href="#44" class="mim-tip-reference" title="Pearson, J., Gallo, G., Gluck, M., Axelrod, F. &lt;strong&gt;Renal disease in familial dysautonomia.&lt;/strong&gt; Kidney Int. 17: 102-112, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7374014/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7374014&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ki.1980.12&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7374014">Pearson et al. (1980)</a> suggested that altered renovascular responsivity to systemic hypotension in the disorder may lead to ischemia and subsequent sclerosis of glomeruli. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7374014" 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 patients with FD, <a href="#20" class="mim-tip-reference" title="Gadoth, N., Schlaen, N., Maschkowski, D., Bechar, M. &lt;strong&gt;The pupil cycle time in familial dysautonomia: further evidence for denervation hypersensitivity.&lt;/strong&gt; Metab. Pediat. Syst. Ophthal. 7: 131-134, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6656621/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6656621&lt;/a&gt;]" pmid="6656621">Gadoth et al. (1983)</a> found a prolonged pupil cycle time (light response) and interpreted it as indicative of denervation hypersensitivity. Parenterally administered Mecholyl caused overflow tearing and temporary normalization of deep tendon reflexes and response to intradermal histamine, suggesting functional rather than structural denervation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6656621" 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="#4" class="mim-tip-reference" title="Axelrod, F. B., Abularrage, J. J. &lt;strong&gt;Familial dysautonomia: a prospective study of survival.&lt;/strong&gt; J. Pediat. 101: 234-236, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7097419/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7097419&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(82)80130-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7097419">Axelrod and Abularrage (1982)</a> reported on survival in dysautonomia. From 1969 to 1982, 227 patients had been referred to the Dysautonomia Center at New York University. At the time of report, 59 patients were 20 years of age or older and accounted for 33% of the living patients. The oldest was 38 years old. <a href="#9" class="mim-tip-reference" title="Axelrod, F. B. &lt;strong&gt;Familial dysautonomia: a 47-year perspective. How technology confirms clinical acumen.&lt;/strong&gt; J. Pediat. 132: S2-S5, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9546030/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9546030&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(98)70521-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9546030">Axelrod (1998)</a> provided an update of the patients at the Dysautonomia Center. In 1998, 40% of the active population of 307 patients were over the age of 20 years. In addition to worsening peripheral sensory dysfunction, the adults complained of poor balance, unsteady gait, and difficulty concentrating. They were prone to depression, anxieties, and even phobias. Sympathovagal balance became more precarious with worsening of orthostatic hypotension, development of supine hypertension, and even occasional bradyarrhythmias. <a href="#19" class="mim-tip-reference" title="Fishbein, D., Grossman, R. F. &lt;strong&gt;Pulmonary manifestations of familial dysautonomia in an adult.&lt;/strong&gt; Am. J. Med. 80: 709-712, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3963047/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3963047&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(86)90830-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3963047">Fishbein and Grossman (1986)</a> described the pulmonary complications in a 29-year-old man with familial dysautonomia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3963047+7097419+9546030" 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 an extensive review of HSAN3, <a href="#5" class="mim-tip-reference" title="Axelrod, F. B., Hilz, M. J. &lt;strong&gt;Inherited autonomic neuropathies.&lt;/strong&gt; Semin. Neurol. 23: 381-390, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15088259/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15088259&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1055/s-2004-817722&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15088259">Axelrod and Hilz (2003)</a> noted that autonomic disturbances are very prominent, including alacrima, episodic hyperhidrosis, and vasomotor and cardiovascular perturbations. Patients can exhibit both extreme hypertension and profound and rapid postural hypotension without compensatory tachycardia. There is also a relative insensitivity to hypoxemia. Patients often experience episodes termed 'dysautonomic crises,' which are characterized by nausea and vomiting, agitation, tachycardia, and hypertension, and are often triggered by emotional or physical stress. Somatic growth is poor, and by 10 years of age, 85% of patients have scoliosis. Seizures with decerebrate posturing can follow breath-holding episodes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15088259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pathologic Findings</em></strong></p><p>
<a href="#14" class="mim-tip-reference" title="Brown, W. J., Beauchemin, J. A., Linde, L. M. &lt;strong&gt;A neuropathological study of familial dysautonomia (Riley-Day syndrome) in siblings.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 27: 131-139, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14152534/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14152534&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.27.2.131&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14152534">Brown et al. (1964)</a> described autopsy findings in 2 Jewish sibs with HSAN3, which included demyelination in the medulla, pontine reticular formation, and dorsolongitudinal tracts, and degeneration, pigmentation, and loss of cells in autonomic ganglia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14152534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Pearson, J., Dancis, J., Axelrod, F., Grover, N. &lt;strong&gt;The sural nerve in familial dysautonomia.&lt;/strong&gt; J. Neuropath. Exp. Neurol. 34: 413-424, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1176995/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1176995&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00005072-197509000-00004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1176995">Pearson et al. (1975)</a> reported that sural nerve biopsy from patients with HSAN3 showed reduced transverse fascicular area, diminished numbers of myelinated axons, especially those of small diameter, and very few nonmyelinated axons. In addition, catecholamine-containing nerve endings were not identified in accompanying arteries. The authors noted that the changes were compatible with the clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1176995" 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="#45" class="mim-tip-reference" title="Pearson, J., Pytel, B. A., Grover-Johnson, N., Axelrod, F., Dancis, J. &lt;strong&gt;Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in familial dysautonomia.&lt;/strong&gt; J. Neurol. Sci. 35: 77-92, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/624961/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;624961&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(78)90103-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="624961">Pearson et al. (1978)</a> stated that intrauterine development and postnatal maintenance of dorsal root ganglion neurons are abnormal in FD. They found that neurons in dorsal root ganglia were markedly diminished in young patients and continued to deplete with increasing age. Quantitative studies on C8 dorsal root ganglia showed that FD patients had as little as 10% the number of neurons as controls, with the smallest number being in the oldest patient. Lateral spinal root entry zones and loss of dorsal column myelinated axons were also found. The findings correlated with clinical features of diminished sensation and coordination of limb movements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=624961" 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 adult patients with FD, <a href="#46" class="mim-tip-reference" title="Pearson, J., Pytel, B. A. &lt;strong&gt;Quantitative studies of sympathetic ganglia and spinal cord intermedio-lateral gray columns in familial dysautonomia.&lt;/strong&gt; J. Neurol. Sci. 39: 47-59, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/731273/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;731273&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(78)90187-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="731273">Pearson and Pytel (1978)</a> found that the mean volume of superior cervical sympathetic ganglia was reduced to 34% of normal. The mean totals of preganglionic neurons in the first 3 thoracic cord segments were reduced by about 50%. The authors noted that defects in sympathetic neurons account for many of the autonomic manifestations of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=731273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#23" class="mim-tip-reference" title="Goodall, M., Gitlow, S. E., Alton, H. &lt;strong&gt;Decreased noradrenaline (norepinephrine) synthesis in familial dysautonomia.&lt;/strong&gt; J. Clin. Invest. 50: 2734-2740, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5129321/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5129321&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI106774&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5129321">Goodall et al. (1971)</a> demonstrated a decrease in synthesis of noradrenaline in patients with FD. <a href="#58" class="mim-tip-reference" title="Weinshilboum, R. M., Axelrod, J. &lt;strong&gt;Reduced plasma dopamine-beta-hydroxylase activity in familial dysautonomia.&lt;/strong&gt; New Eng. J. Med. 285: 938-942, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5096225/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5096225&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197110212851703&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5096225">Weinshilboum and Axelrod (1971)</a> found decreased dopamine-beta-hydroxylase (DBH; <a href="/entry/223360">223360</a>), the enzyme that converts dopamine to norepinephrine. Some dysautonomic children had no plasma DBH activity and their mothers had decreased activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5129321+5096225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Pearson, J., Brandeis, L., Cuello, A. C. &lt;strong&gt;Depletion of substance P-containing axons in substantia gelatinosa of patients with diminished pain sensitivity.&lt;/strong&gt; Nature 295: 61-63, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6173753/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6173753&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/295061a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6173753">Pearson et al. (1982)</a> reported anatomically discrete depletion of substance P (<a href="/entry/162320">162320</a>) immunoreactivity in the substantia gelatinosa of spinal cord and medulla of patients with familial dysautonomia. Substance P, an undecapeptide, is involved in transmission of nociceptive information at synapses of primary sensory neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6173753" 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 patients with FD, <a href="#52" class="mim-tip-reference" title="Siggers, D. C., Rogers, J. G., Boyer, S. H., Margolet, L., Dorkin, H. L., Banerjee, S. P., Shooter, E. M. &lt;strong&gt;Increased nerve-growth-factor beta-chain cross-reacting material in familial dysautonomia.&lt;/strong&gt; New Eng. J. Med. 295: 629-634, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/987530/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;987530&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197609162951201&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="987530">Siggers et al. (1976)</a> found a 3-fold increase in serum antigen levels of the nerve growth factor beta unit (NGFB; <a href="/entry/162030">162030</a>) with normal function measurements, suggesting a qualitative abnormality of beta-NGF in the disorder. By bioimmunoassay of cultured fibroblasts from patients with FD, <a href="#51" class="mim-tip-reference" title="Schwartz, J. P., Breakefield, X. O. &lt;strong&gt;Altered nerve growth factor in fibroblasts from patients with familial dysautonomia.&lt;/strong&gt; Proc. Nat. Acad. Sci. 77: 1154-1158, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6244581/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6244581&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.77.2.1154&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6244581">Schwartz and Breakefield (1980)</a> found similar levels of beta-NGF compared to controls, but found that NGF showed about 10% activity compared to controls. The beta-adrenergic agonist isoproterenol produced no change in immunoreactive beta-NGF in dysautonomia, whereas it caused a marked increase in control cells. The authors postulated a defect in the processing of an NGFB precursor or in the structure of biologically active NGFB. In rats and guinea pigs, <a href="#28" class="mim-tip-reference" title="Johnson, E. M., Jr., Gorin, P. D., Brandeis, L. D., Pearson, J. &lt;strong&gt;Dorsal root ganglion neurons are destroyed by exposure in utero to maternal antibody to nerve growth factor.&lt;/strong&gt; Science 210: 916-918, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7192014/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7192014&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.7192014&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7192014">Johnson et al. (1980)</a> showed that dorsal root ganglion neurons are destroyed by in utero exposure to maternal antibody to NGF. Using RFLP analysis of human NGFB and the NGF receptor (<a href="/entry/162010">162010</a>) to examine multiple FD families, <a href="#12" class="mim-tip-reference" title="Breakefield, X. O., Orloff, G., Castiglione, C., Coussens, L., Axelrod, F. B., Ullrich, A. &lt;strong&gt;Structural gene for beta-nerve growth factor not defective in familial dysautonomia.&lt;/strong&gt; Proc. Nat. Acad. Sci. 81: 4213-4216, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6330750/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6330750&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.81.13.4213&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6330750">Breakefield et al. (1984)</a>, <a href="#40" class="mim-tip-reference" title="Ozelius, L., Bothwell, M., Chao, M., Ross, A., Kramer, P., Kidd, K., Gusella, J., Axelrod, F., Breakefield, X. O. &lt;strong&gt;Gene for nerve growth factor receptor excluded in familial dysautonomia. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 39: A215, 1986."None>Ozelius et al. (1986)</a>, and <a href="#13" class="mim-tip-reference" title="Breakefield, X. O., Ozelius, L., Bothwell, M. A., Chao, M. V., Axelrod, F., Kramer, P. L., Kidd, K. K., Lanahan, A. A., Johnson, D. E., Ross, A. H., Gusella, J. F. &lt;strong&gt;DNA polymorphisms for the nerve growth factor receptor gene exclude its role in familial dysautonomia.&lt;/strong&gt; Molec. Biol. Med. 3: 483-494, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2886891/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2886891&lt;/a&gt;]" pmid="2886891">Breakefield et al. (1986)</a> excluded both genes as the site of the FD disease mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6330750+987530+2886891+7192014+6244581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="pathogenesis" class="mim-anchor"></a>
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<strong>Pathogenesis</strong>
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<p><a href="#30" class="mim-tip-reference" title="Lee, G., Papapetrou, E. P., Kim, H., Chambers, S. M., Tomishima, M. J., Fasano, C. A., Ganat, Y. M., Menon, J., Shimizu, F., Viale, A., Tabar, V., Sadelain, M., Studer, L. &lt;strong&gt;Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs.&lt;/strong&gt; Nature 461: 402-406, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19693009/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19693009&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19693009[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature08320&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19693009">Lee et al. (2009)</a> reported the derivation of patient-specific FD induced pluripotent stem cells (iPSCs) and the directed differentiation into cells of all 3 germ layers including peripheral neurons. Gene expression analysis in purified FD iPSC-derived lineages demonstrated tissue-specific missplicing of IKBKAP (<a href="/entry/603722">603722</a>) in vitro. Patient-specific neural crest precursors expressed particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis was further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behavior. Furthermore, <a href="#30" class="mim-tip-reference" title="Lee, G., Papapetrou, E. P., Kim, H., Chambers, S. M., Tomishima, M. J., Fasano, C. A., Ganat, Y. M., Menon, J., Shimizu, F., Viale, A., Tabar, V., Sadelain, M., Studer, L. &lt;strong&gt;Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs.&lt;/strong&gt; Nature 461: 402-406, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19693009/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19693009&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19693009[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature08320&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19693009">Lee et al. (2009)</a> used FD iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. <a href="#30" class="mim-tip-reference" title="Lee, G., Papapetrou, E. P., Kim, H., Chambers, S. M., Tomishima, M. J., Fasano, C. A., Ganat, Y. M., Menon, J., Shimizu, F., Viale, A., Tabar, V., Sadelain, M., Studer, L. &lt;strong&gt;Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs.&lt;/strong&gt; Nature 461: 402-406, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19693009/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19693009&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19693009[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature08320&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19693009">Lee et al. (2009)</a> concluded that their study illustrated the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19693009" 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="#7" class="mim-tip-reference" title="Axelrod, F. B., Pearson, J., Tepperberg, J., Ackerman, B. D. &lt;strong&gt;Congenital sensory neuropathy with skeletal dysplasia.&lt;/strong&gt; J. Pediat. 102: 727-730, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6573468/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6573468&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(83)80246-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6573468">Axelrod et al. (1983)</a> stated that the clinical diagnosis of familial dysautonomia is based on the presence of 5 signs: lack of axon flare after intradermal injection of histamine, absence of fungiform papillae on the tongue, miosis of the pupil after conjunctival instillation of methacholine chloride (2.5%), absent deep tendon reflexes, and diminished tear flow. However, they noted that consistent neuropathologic findings in sural nerve biopsies may be the best diagnostic criterion to differentiate familial dysautonomia from other forms of congenital sensory neuropathy. <a href="#7" class="mim-tip-reference" title="Axelrod, F. B., Pearson, J., Tepperberg, J., Ackerman, B. D. &lt;strong&gt;Congenital sensory neuropathy with skeletal dysplasia.&lt;/strong&gt; J. Pediat. 102: 727-730, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6573468/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6573468&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(83)80246-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6573468">Axelrod et al. (1983)</a> reported the case of a gypsy child with congenital sensory neuropathy who had all 5 signs in addition to skeletal abnormalities, dysmorphic features, and hypohidrosis, but whose sural nerve biopsy was inconsistent with dysautonomia. The authors noted that many non-Jewish cases of 'familial dysautonomia' may be another form of congenital sensory neuropathy (e.g., <a href="/entry/201300">201300</a>, <a href="/entry/256800">256800</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6573468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Axelrod, F. B., Porges, R. F., Sein, M. E. &lt;strong&gt;Neonatal recognition of familial dysautonomia.&lt;/strong&gt; J. Pediat. 110: 946-948, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3585611/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3585611&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(87)80420-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3585611">Axelrod et al. (1987)</a> suggested that the possibility of familial dysautonomia should be suspected in a child of Eastern European Jewish extraction with breech delivery, meconium staining, poor suck, hypotonia, or hypothermia. The diagnosis could be confirmed by inspection of the tongue for fungiform papillae, determination of deep tendon reflexes, and performance of intradermal histamine and intraocular pilocarpine tests. If results in either of the latter 2 tests are normal or equivocal, they should be repeated after 6 weeks of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3585611" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
<a href="#18" class="mim-tip-reference" title="Eng, C. M., Slaugenhaupt, S. A., Blumenfeld, A., Axelrod, F. B., Gusella, J. F., Desnick, R. J. &lt;strong&gt;Prenatal diagnosis of familial dysautonomia by analysis of linked CA-repeat polymorphisms on chromosome 9q31-q33.&lt;/strong&gt; Am. J. Med. Genet. 59: 349-355, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8599360/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8599360&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320590314&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8599360">Eng et al. (1995)</a> used CA-repeat polymorphisms located in the 9q31-q33 region for prenatal diagnosis of familial dysautonomia. All 7 families studied were informative for the markers, and fetal diagnoses were made in 8 pregnancies. Six fetal diagnoses were predicted with more than 98% accuracy, whereas 2 with recombinations were predicted with at least 88% and 92% accuracy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8599360" 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 linkage and linkage disequilibrium analyses with highly polymorphic dinucleotide repeat markers known to flank the familial dysautonomia locus, <a href="#38" class="mim-tip-reference" title="Oddoux, C., Reich, E., Axelrod, F., Blumenfeld, A., Maayan, C., Slaugenhaupt, S., Gusella, J., Ostrer, H. &lt;strong&gt;Prenatal diagnostic testing for familial dysautonomia using linked genetic markers.&lt;/strong&gt; Prenatal Diag. 15: 817-826, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8559751/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8559751&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/pd.1970150905&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8559751">Oddoux et al. (1995)</a> performed prenatal diagnosis in 8 pregnancies in 7 informative families. All of the fetuses were predicted to be heterozygous unaffected; 7 had come to term and were normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8559751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="clinicalManagement" class="mim-anchor"></a>
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<strong>Clinical Management</strong>
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<p>The most prevalent causative mutation in FD is an IKBKAP splice site mutation that results in deletion of exon 20, producing a truncated protein (<a href="/entry/603722#0001">603722.0001</a>). The polyphenol (-)-epigallocatechin gallate (EGCG) downregulates expression of HNRNPA2B1 (<a href="/entry/600124">600124</a>), a transactivating factor that encourages the use of intron-distal 5-prime splice sites. <a href="#3" class="mim-tip-reference" title="Anderson, S. L., Qiu, J., Rubin, B. Y. &lt;strong&gt;EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 310: 627-633, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14521957/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14521957&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.bbrc.2003.09.019&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14521957">Anderson et al. (2003)</a> found that EGCG treatment of cultured FD-derived fibroblasts increased the use of the intron-proximal splice site, resulting in the generation of more exon 20-containing IKBKAP transcript. EGCG did not alter IKBKAP splicing in normal cells. <a href="#3" class="mim-tip-reference" title="Anderson, S. L., Qiu, J., Rubin, B. Y. &lt;strong&gt;EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 310: 627-633, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14521957/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14521957&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.bbrc.2003.09.019&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14521957">Anderson et al. (2003)</a> observed synergistic production of correctly spliced transcript and full-length IKBKAP protein in FD fibroblasts treated with the combination of EGCG and tocotrienol, a vitamin E isoform that can upregulate transcription of the IKBKAP gene. They suggested that EGCG may be a therapeutic modality for individuals with FD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14521957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#54" class="mim-tip-reference" title="Slaugenhaupt, S. A., Mull, J., Leyne, M., Cuajungco, M. P., Gill, S. P., Hims, M. M., Quintero, F., Axelrod, F. B., Gusella, J. F. &lt;strong&gt;Rescue of a human mRNA splicing defect by the plant cytokinin kinetin.&lt;/strong&gt; Hum. Molec. Genet. 13: 429-436, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14709595/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14709595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddh046&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14709595">Slaugenhaupt et al. (2004)</a> showed that treating FD lymphoblast cells with the plant cytokinin kinetin altered splicing of IKBKAP. Kinetin significantly increased inclusion of exon 20 from the endogenous gene, as well as from an IKBKAP minigene, but did not enhance inclusion of alternatively spliced exon 31 in MYO5A (<a href="/entry/160777">160777</a>). Benzyladenine, the most closely related cytokinin, showed a similar but less dramatic effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14709595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="mapping" class="mim-anchor"></a>
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Mapping</strong>
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<p>By family linkage studies, <a href="#10" class="mim-tip-reference" title="Blumenfeld, A., Slaugenhaupt, S. A., Axelrod, F. B., Lucente, D. E., Maayan, C., Liebert, C. B., Ozelius, L. J., Trofatter, J. A., Haines, J. L., Breakefield, X. O., Gusella, J. F. &lt;strong&gt;Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis.&lt;/strong&gt; Nature Genet. 4: 160-164, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8102296/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8102296&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0693-160&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8102296">Blumenfeld et al. (1993)</a> assigned the familial dysautonomia locus to chromosome 9q31-q33, with a maximum lod score of 21.1 at marker D9S58. Marker D9S58 also showed strong linkage disequilibrium with FD, with one allele present on 73% of affected chromosomes compared to 5.4% of controls. D9S53 and D9S105 represented the closest flanking markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8102296" 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 11 new polymorphic markers, <a href="#11" class="mim-tip-reference" title="Blumenfeld, A., Slaugenhaupt, S. A., Liebert, C. B., Temper, V., Maayan, C., Gill, S., Lucente, D. E., Idelson, M., MacCormack, K., Monahan, M. A., Mull, J., Leyne, M., Mendillo, M., Schiripo, T., Mishori, E., Breakefield, X., Axelrod, F. B., Gusella, J. F. &lt;strong&gt;Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.&lt;/strong&gt; Am. J. Hum. Genet. 64: 1110-1118, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10090896/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10090896&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302339&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10090896">Blumenfeld et al. (1999)</a> narrowed the FD locus to less than 0.5 cM, between 2 specific markers. Two markers within this interval showed no recombination with the disorder. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, may have represented independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated FD carrier frequency of 1 in 32, and none of the 4 haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. The haplotype information made it possible to provide accurate genetic testing both for families with FD and for carriers on the basis of close flanking markers and the capacity to identify more than 98% of FD chromosomes by their haplotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10090896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p><a href="#53" class="mim-tip-reference" title="Slaugenhaupt, S. A., Blumenfeld, A., Gill, S. P., Leyne, M., Mull, J., Cuajungco, M. P., Liebert, C. B., Chadwick, B., Idelson, M., Reznik, L., Robbins, C. M., Makalowska, I., Brownstein, M. J., Krappmann, D., Scheidereit, C., Maayan, C., Axelrod, F. B., Gusella, J. F. &lt;strong&gt;Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia.&lt;/strong&gt; Am. J. Hum. Genet. 68: 598-605, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11179008/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11179008&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11179008[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/318810&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11179008">Slaugenhaupt et al. (2001)</a> and <a href="#2" class="mim-tip-reference" title="Anderson, S. L., Coli, R., Daly, I. W., Kichula, E. A., Rork, M. J., Volpi, S. A., Ekstein, J., Rubin, B. Y. &lt;strong&gt;Familial dysautonomia is caused by mutations of the IKAP gene.&lt;/strong&gt; Am. J. Hum. Genet. 68: 753-758, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11179021/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11179021&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11179021[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/318808&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11179021">Anderson et al. (2001)</a> demonstrated that the major haplotype of familial dysautonomia is associated with a mutation in the IKBKAP gene (<a href="/entry/603722#0001">603722.0001</a>). A minor haplotype was found to be associated with a different mutation (R696P; <a href="/entry/603722#0002">603722.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11179008+11179021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In the United States, HSAN3 is a disorder almost completely limited to persons of Ashkenazi Jewish extraction (<a href="#15" class="mim-tip-reference" title="Brunt, P. W., McKusick, V. A. &lt;strong&gt;Familial dysautonomia: a report of genetic and clinical studies, with a review of the literature.&lt;/strong&gt; Medicine 49: 343-374, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4322121/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4322121&lt;/a&gt;]" pmid="4322121">Brunt and McKusick, 1970</a>). In Israel, as in the United States, most cases were Ashkenazim from Poland, according to <a href="#22" class="mim-tip-reference" title="Goldstein-Nieviazhski, C., Wallis, K. &lt;strong&gt;Riley-Day syndrome (familial dysautonomia): survey of 27 cases.&lt;/strong&gt; Ann. Paediat. 206: 188-194, 1966.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5953423/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5953423&lt;/a&gt;]" pmid="5953423">Goldstein-Nieviazhski and Wallis (1966)</a>. <a href="#32" class="mim-tip-reference" title="Maayan, C., Kaplan, E., Shachar, S., Peleg, O., Godfrey, S. &lt;strong&gt;Incidence of familial dysautonomia in Israel 1977-1981.&lt;/strong&gt; Clin. Genet. 32: 106-108, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3652488/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3652488&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1987.tb03334.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3652488">Maayan et al. (1987)</a> calculated an incidence of 1 in 3,703 for familial dysautonomia among Ashkenazi Jews in Israel. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3652488+5953423+4322121" 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>Rare non-Jewish cases of presumed familial dysautonomia have been reported (e.g., <a href="#16" class="mim-tip-reference" title="Burke, V. &lt;strong&gt;Familial dysautonomia.&lt;/strong&gt; Aust. Paediat. J. 2: 58-63, 1966."None>Burke, 1966</a>), but the diagnosis is usually in question. For example, the patient of <a href="#16" class="mim-tip-reference" title="Burke, V. &lt;strong&gt;Familial dysautonomia.&lt;/strong&gt; Aust. Paediat. J. 2: 58-63, 1966."None>Burke (1966)</a> was later seen by <a href="#50" class="mim-tip-reference" title="Rogers, J. G. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Melbourne, Australia 8/26/1993."None>Rogers (1993)</a> who concluded that although the patient had a hereditary sensory neuropathy, the disorder was not familial dysautonomia. However, <a href="#31" class="mim-tip-reference" title="Leyne, M., Mull, J., Gill, S. P., Cuajungco, M. P., Oddoux, C., Blumenfeld, A., Maayan, C., Guesella, J. F., Axelrod, F. B., Slaugenhaupt, S. A. &lt;strong&gt;Identification of the first non-Jewish mutation in familial dysautonomia.&lt;/strong&gt; Am. J. Med. Genet. 118A: 305-308, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12687659/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12687659&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20052&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12687659">Leyne et al. (2003)</a> identified a patient, previously described by <a href="#11" class="mim-tip-reference" title="Blumenfeld, A., Slaugenhaupt, S. A., Liebert, C. B., Temper, V., Maayan, C., Gill, S., Lucente, D. E., Idelson, M., MacCormack, K., Monahan, M. A., Mull, J., Leyne, M., Mendillo, M., Schiripo, T., Mishori, E., Breakefield, X., Axelrod, F. B., Gusella, J. F. &lt;strong&gt;Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.&lt;/strong&gt; Am. J. Hum. Genet. 64: 1110-1118, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10090896/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10090896&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302339&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10090896">Blumenfeld et al. (1999)</a>, who fulfilled all diagnostic criteria other than pure Ashkenazi Jewish ancestry (the patient's mother was of Irish-German/Sicilian heritage) and identified a novel mutation in the IKBKAP gene (<a href="/entry/603722#0003">603722.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12687659+10090896" 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="#26" class="mim-tip-reference" title="Hims, M. M., Shetty, R. S., Pickel, J., Mull, J., Leyne, M., Liu, L., Gusella, J. F., Slaugenhaupt, S. A. &lt;strong&gt;A humanized IKBKAP transgenic mouse models a tissue-specific human splicing defect.&lt;/strong&gt; Genomics 90: 389-396, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17644305/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17644305&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ygeno.2007.05.012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17644305">Hims et al. (2007)</a> created transgenic mice expressing human IKBKAP with the FD-associated IVS20DS+6T-C splice mutation (<a href="/entry/603722#0001">603722.0001</a>). The mutant IKBKAP transgene was misspliced in transgenic mice in a tissue-specific manner that replicated the pattern seen in FD patient tissues. In both FD and transgenic mouse tissues, missplicing predominated in neuronal tissues compared with nonneuronal tissues, and the most accurate splicing was seen in heart and kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17644305" 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="#36" class="mim-tip-reference" title="Morini, E., Dietrich, P., Salani, M., Downs, H. M., Wojtkiewicz, G. R., Alli, S., Brenner, A., Nilbratt, M., LeClair, J. W., Oaklander, A. L., Slaugenhaupt, S. A., Dragatsis, I. &lt;strong&gt;Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia.&lt;/strong&gt; Hum. Molec. Genet. 25: 1116-1128, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26769677/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26769677&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddv634&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26769677">Morini et al. (2016)</a> generated a transgenic mouse model of FD with the exon 20 splice site mutation (TgFD9;Ikbkap(delta20/flox)). Mutant mice recapitulated many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26769677" 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 transgenic male mice carrying the human exon 20 splice site mutation, <a href="#37" class="mim-tip-reference" title="Morini, E., Gao, D., Montgomery, C. M., Salani, M., Mazzasette, C., Krussig, T. A., Swain, B., Dietrich, P., Narasimhan, J., Gabbeta, V., Dakka, A., Hedrick, J., Zhao, X., Weetall, M., Naryshkin, N. A., Wojtkiewicz, G. G., Ko, C.-P., Talkowski, M. E., Dragatsis, I., Slaugenhaupt, S. A. &lt;strong&gt;ELP1 splicing correction reverses proprioceptive sensory loss in familial dysautonomia.&lt;/strong&gt; Am. J. Hum. Genet. 104: 638-650, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30905397/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30905397&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2019.02.009&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30905397">Morini et al. (2019)</a> found that treatment beginning right after birth with oral kinetin, a small molecule splicing modulator, resulted in improved sensorimotor coordination, prevention of spinal deformities, and significantly increased survival of proprioceptive neurons in the peripheral nervous system. These clinical benefits were associated with the increased expression of normal IKBKAP transcripts, as well as increased protein expression. Treatment of human fibroblasts carrying the splice site mutation resulted in increased IKBKAP gene expression without significant changes in overall genomic splicing, suggesting that kinetin shows selective splicing modulation activity. The study provided a proof of concept that targeting the underlying genetic mechanism in FD can result in clinical benefits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30905397" 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="#9" class="mim-tip-reference" title="Axelrod, F. B. &lt;strong&gt;Familial dysautonomia: a 47-year perspective. How technology confirms clinical acumen.&lt;/strong&gt; J. Pediat. 132: S2-S5, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9546030/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9546030&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(98)70521-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9546030">Axelrod (1998)</a> provided a historical perspective on familial dysautonomia, highlighting the early contributions of Dancis. Recognition of this disorder, first described by <a href="#48" class="mim-tip-reference" title="Riley, C. M., Day, R. L., Greeley, D. M., Langford, W. S. &lt;strong&gt;Central autonomic dysfunction with defective lacrimation: report of five cases.&lt;/strong&gt; Pediatrics 3: 468-478, 1949.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18118947/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18118947&lt;/a&gt;]" pmid="18118947">Riley et al. (1949)</a>, spans almost 50 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18118947+9546030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Aguayo1971" class="mim-tip-reference" title="Aguayo, A. J., Nair, C. P. V., Bray, G. M. &lt;strong&gt;Peripheral nerve abnormalities in the Riley-Day syndrome. Findings in a sural nerve biopsy.&lt;/strong&gt; Arch. Neurol. 24: 106-116, 1971.">Aguayo et al. (1971)</a>; <a href="#De1978" class="mim-tip-reference" title="De Jong, J. G. Y., Delleman, J. W. &lt;strong&gt;Report on three cases of familial dysautonomia (Riley-Day) in the Netherlands.&lt;/strong&gt; Doc. Ophthal. Proc. Ser. 17: 409-415, 1978.">De Jong and Delleman (1978)</a>; <a href="#Gitlow1970" class="mim-tip-reference" title="Gitlow, S. E., Bertani, L. M., Wilk, E., Li, B. L., Dziedzic, S. &lt;strong&gt;Excretion of catecholamine metabolites by children with familial dysautonomia.&lt;/strong&gt; Pediatrics 46: 513-522, 1970.">Gitlow et al.
(1970)</a>; <a href="#Greene1980" class="mim-tip-reference" title="Greene, L. A., Shooter, E. M. &lt;strong&gt;The nerve growth factor: biochemistry, synthesis, and mechanism of action.&lt;/strong&gt; Ann. Rev. Neurosci. 3: 353-402, 1980.">Greene and Shooter (1980)</a>; <a href="#Grunebaum1975" class="mim-tip-reference" title="Grunebaum, M. &lt;strong&gt;The &#x27;chest-abdomen sign&#x27; in familial dysautonomia.&lt;/strong&gt; Brit. J. Radiol. 48: 23-27, 1975.">Grunebaum (1975)</a>; <a href="#Hutchison1962" class="mim-tip-reference" title="Hutchison, J. H., Hamilton, W. &lt;strong&gt;Familial dysautonomia in two siblings.&lt;/strong&gt; Lancet 279: 1216-1218, 1962. Note: Originally Volume 1.">Hutchison and
Hamilton (1962)</a>; <a href="#Kaplan1985" class="mim-tip-reference" title="Kaplan, M., Schiffman, R., Shapira, Y. &lt;strong&gt;Diagnosis of familial dysautonomia in the neonatal period.&lt;/strong&gt; Acta Paediat. Scand. 74: 131-132, 1985.">Kaplan et al. (1985)</a>; <a href="#McKendrick1958" class="mim-tip-reference" title="McKendrick, T. &lt;strong&gt;Familial dysautonomia.&lt;/strong&gt; Arch. Dis. Child. 33: 465-468, 1958.">McKendrick (1958)</a>; <a href="#McKusick1967" class="mim-tip-reference" title="McKusick, V. A., Norum, R. A., Farkas, H. J., Brunt, P. W., Mahloudji, M. &lt;strong&gt;The Riley-Day syndrome--observations on genetics and survivorship.&lt;/strong&gt; Israel J. Med. Sci. 3: 372-379, 1967.">McKusick et
al. (1967)</a>; <a href="#Mitnick1982" class="mim-tip-reference" title="Mitnick, J. S., Axelrod, F. B., Genieser, N. B., Becker, M. &lt;strong&gt;Aseptic necrosis in familial dysautonomia.&lt;/strong&gt; Radiology 142: 89-91, 1982.">Mitnick et al. (1982)</a>; <a href="#Orbeck1977" class="mim-tip-reference" title="Orbeck, H., Oftedal, G. &lt;strong&gt;Familial dysautonomia in a non-Jewish child.&lt;/strong&gt; Acta Paediat. Scand. 66: 777-781, 1977.">Orbeck and Oftedal (1977)</a>; <a href="#Pearson1970" class="mim-tip-reference" title="Pearson, J. F., Finegold, M. J., Budzilovich, G. &lt;strong&gt;The tongue and taste in familial dysautonomia.&lt;/strong&gt; Pediatrics 45: 739-745, 1970.">Pearson
et al. (1970)</a>; <a href="#Porges1978" class="mim-tip-reference" title="Porges, R. F., Axelrod, F. B., Richards, M. &lt;strong&gt;Pregnancy in familial dysautonomia.&lt;/strong&gt; Am. J. Obstet. Gynec. 132: 485-488, 1978.">Porges et al. (1978)</a>; <a href="#Riley1952" class="mim-tip-reference" title="Riley, C. M. &lt;strong&gt;Familial autonomic dysfunction.&lt;/strong&gt; J. Am. Med. Assoc. 149: 1532-1535, 1952.">Riley (1952)</a>; <a href="#Smith1963" class="mim-tip-reference" title="Smith, A. A., Dancis, J. &lt;strong&gt;Response to intradermal histamine in familial dysautonomia: a diagnostic test.&lt;/strong&gt; J. Pediat. 63: 889-894, 1963.">Smith and Dancis
(1963)</a>; <a href="#Yatsu1964" class="mim-tip-reference" title="Yatsu, F., Zussman, W. &lt;strong&gt;Familial dysautonomia (Riley-Day syndrome). Case report with post-mortem findings of a patient at age 31.&lt;/strong&gt; Arch. Neurol. 10: 459-463, 1964.">Yatsu and Zussman (1964)</a>; <a href="#Ziegler1976" class="mim-tip-reference" title="Ziegler, M. G., Lake, C. R., Kopin, I. J. &lt;strong&gt;Deficient sympathetic nervous response in familial dysautonomia.&lt;/strong&gt; New Eng. J. Med. 294: 630-633, 1976.">Ziegler et al. (1976)</a>
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<a id="1" class="mim-anchor"></a>
<a id="Aguayo1971" class="mim-anchor"></a>
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Aguayo, A. J., Nair, C. P. V., Bray, G. M.
<strong>Peripheral nerve abnormalities in the Riley-Day syndrome. Findings in a sural nerve biopsy.</strong>
Arch. Neurol. 24: 106-116, 1971.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4322165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4322165</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4322165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archneur.1971.00480320034003" target="_blank">Full Text</a>]
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<a id="Anderson2001" class="mim-anchor"></a>
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Anderson, S. L., Coli, R., Daly, I. W., Kichula, E. A., Rork, M. J., Volpi, S. A., Ekstein, J., Rubin, B. Y.
<strong>Familial dysautonomia is caused by mutations of the IKAP gene.</strong>
Am. J. Hum. Genet. 68: 753-758, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179021</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179021[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=11179021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/318808" target="_blank">Full Text</a>]
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<a id="Anderson2003" class="mim-anchor"></a>
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Anderson, S. L., Qiu, J., Rubin, B. Y.
<strong>EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia.</strong>
Biochem. Biophys. Res. Commun. 310: 627-633, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14521957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14521957</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14521957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.bbrc.2003.09.019" target="_blank">Full Text</a>]
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<a id="Axelrod1982" class="mim-anchor"></a>
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<p class="mim-text-font">
Axelrod, F. B., Abularrage, J. J.
<strong>Familial dysautonomia: a prospective study of survival.</strong>
J. Pediat. 101: 234-236, 1982.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7097419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7097419</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7097419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(82)80130-3" target="_blank">Full Text</a>]
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<a id="Axelrod2003" class="mim-anchor"></a>
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Axelrod, F. B., Hilz, M. J.
<strong>Inherited autonomic neuropathies.</strong>
Semin. Neurol. 23: 381-390, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15088259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15088259</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15088259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1055/s-2004-817722" target="_blank">Full Text</a>]
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<a id="Axelrod1981" class="mim-anchor"></a>
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Axelrod, F. B., Iyer, K., Fish, I., Pearson, J., Sein, M. E., Spielholz, N.
<strong>Progressive sensory loss in familial dysautonomia.</strong>
Pediatrics 67: 517-522, 1981.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7254974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7254974</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7254974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Axelrod1983" class="mim-anchor"></a>
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Axelrod, F. B., Pearson, J., Tepperberg, J., Ackerman, B. D.
<strong>Congenital sensory neuropathy with skeletal dysplasia.</strong>
J. Pediat. 102: 727-730, 1983.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6573468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6573468</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6573468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(83)80246-7" target="_blank">Full Text</a>]
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<a id="Axelrod1987" class="mim-anchor"></a>
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Axelrod, F. B., Porges, R. F., Sein, M. E.
<strong>Neonatal recognition of familial dysautonomia.</strong>
J. Pediat. 110: 946-948, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3585611/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3585611</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3585611" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(87)80420-1" target="_blank">Full Text</a>]
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<a id="Axelrod1998" class="mim-anchor"></a>
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Axelrod, F. B.
<strong>Familial dysautonomia: a 47-year perspective. How technology confirms clinical acumen.</strong>
J. Pediat. 132: S2-S5, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9546030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9546030</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9546030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(98)70521-9" target="_blank">Full Text</a>]
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<a id="Blumenfeld1993" class="mim-anchor"></a>
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Blumenfeld, A., Slaugenhaupt, S. A., Axelrod, F. B., Lucente, D. E., Maayan, C., Liebert, C. B., Ozelius, L. J., Trofatter, J. A., Haines, J. L., Breakefield, X. O., Gusella, J. F.
<strong>Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis.</strong>
Nature Genet. 4: 160-164, 1993.
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[<a href="https://doi.org/10.1038/ng0693-160" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302339" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.81.13.4213" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jnnp.27.2.131" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320590314" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9343(86)90830-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI106774" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1146/annurev.ne.03.030180.002033" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(62)92257-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1148/radiology.142.1.7053554" target="_blank">Full Text</a>]
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Morini, E., Dietrich, P., Salani, M., Downs, H. M., Wojtkiewicz, G. R., Alli, S., Brenner, A., Nilbratt, M., LeClair, J. W., Oaklander, A. L., Slaugenhaupt, S. A., Dragatsis, I.
<strong>Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia.</strong>
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[<a href="https://doi.org/10.1093/hmg/ddv634" target="_blank">Full Text</a>]
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Morini, E., Gao, D., Montgomery, C. M., Salani, M., Mazzasette, C., Krussig, T. A., Swain, B., Dietrich, P., Narasimhan, J., Gabbeta, V., Dakka, A., Hedrick, J., Zhao, X., Weetall, M., Naryshkin, N. A., Wojtkiewicz, G. G., Ko, C.-P., Talkowski, M. E., Dragatsis, I., Slaugenhaupt, S. A.
<strong>ELP1 splicing correction reverses proprioceptive sensory loss in familial dysautonomia.</strong>
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[<a href="https://doi.org/10.1016/j.ajhg.2019.02.009" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/pd.1970150905" target="_blank">Full Text</a>]
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<strong>Familial dysautonomia in a non-Jewish child.</strong>
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[<a href="https://doi.org/10.1111/j.1651-2227.1977.tb07988.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/295061a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00005072-197509000-00004" target="_blank">Full Text</a>]
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<strong>Renal disease in familial dysautonomia.</strong>
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[<a href="https://doi.org/10.1038/ki.1980.12" target="_blank">Full Text</a>]
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<strong>Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in familial dysautonomia.</strong>
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[<a href="https://doi.org/10.1016/0022-510x(78)90103-x" target="_blank">Full Text</a>]
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Pearson, J., Pytel, B. A.
<strong>Quantitative studies of sympathetic ganglia and spinal cord intermedio-lateral gray columns in familial dysautonomia.</strong>
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[<a href="https://doi.org/10.1016/0022-510x(78)90187-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9378(78)90740-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/jama.1952.02930340016006" target="_blank">Full Text</a>]
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Schwartz, J. P., Breakefield, X. O.
<strong>Altered nerve growth factor in fibroblasts from patients with familial dysautonomia.</strong>
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[<a href="https://doi.org/10.1073/pnas.77.2.1154" target="_blank">Full Text</a>]
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<strong>Increased nerve-growth-factor beta-chain cross-reacting material in familial dysautonomia.</strong>
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[<a href="https://doi.org/10.1056/NEJM197609162951201" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/318810" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh046" target="_blank">Full Text</a>]
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<strong>Response to intradermal histamine in familial dysautonomia: a diagnostic test.</strong>
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[<a href="https://doi.org/10.1016/s0022-3476(63)80219-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.147.3661.1040" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197110212851703" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1964.00460170029004" target="_blank">Full Text</a>]
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<strong>Deficient sympathetic nervous response in familial dysautonomia.</strong>
New Eng. J. Med. 294: 630-633, 1976.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1246255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1246255</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1246255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM197603182941202" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 02/10/2020
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Ada Hamosh - updated : 10/19/2009<br>George E. Tiller - updated : 12/5/2006<br>Patricia A. Hartz - updated : 4/20/2005<br>Deborah L. Stone - updated : 12/22/2004<br>Cassandra L. Kniffin - reorganized : 5/21/2004<br>Cassandra L. Kniffin - updated : 5/18/2004<br>Victor A. McKusick - updated : 3/19/2001<br>Victor A. McKusick - updated : 4/9/1999<br>Victor A. McKusick - updated : 5/19/1998
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Victor A. McKusick : 6/3/1986
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alopez : 11/20/2020
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carol : 02/12/2020<br>alopez : 02/11/2020<br>ckniffin : 02/10/2020<br>carol : 05/24/2019<br>carol : 05/23/2019<br>carol : 04/12/2016<br>carol : 4/18/2012<br>alopez : 10/26/2009<br>terry : 10/19/2009<br>terry : 6/3/2009<br>terry : 5/4/2009<br>wwang : 8/27/2008<br>wwang : 12/5/2006<br>mgross : 4/20/2005<br>carol : 12/22/2004<br>carol : 5/21/2004<br>ckniffin : 5/18/2004<br>carol : 4/29/2003<br>cwells : 3/29/2001<br>terry : 3/19/2001<br>carol : 4/12/1999<br>terry : 4/9/1999<br>terry : 10/26/1998<br>dholmes : 7/22/1998<br>carol : 5/28/1998<br>terry : 5/19/1998<br>terry : 5/19/1998<br>terry : 5/19/1998<br>alopez : 7/10/1997<br>mark : 7/16/1996<br>mark : 1/24/1996<br>mark : 1/22/1996<br>mark : 12/20/1995<br>terry : 12/13/1995<br>davew : 6/1/1994<br>warfield : 4/15/1994<br>mimadm : 2/19/1994<br>carol : 9/22/1993<br>carol : 9/21/1993<br>carol : 9/13/1993
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<strong>#</strong> 223900
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NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE III; HSAN3
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<em>Alternative titles; symbols</em>
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HSAN III<br />
DYSAUTONOMIA, FAMILIAL; DYS; FD<br />
RILEY-DAY SYNDROME
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<strong>SNOMEDCT:</strong> 29159009; &nbsp;
<strong>ICD10CM:</strong> G90.1; &nbsp;
<strong>ORPHA:</strong> 1764; &nbsp;
<strong>DO:</strong> 11589; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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9q31.3
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Dysautonomia, familial
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223900
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Autosomal recessive
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3
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ELP1
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603722
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because hereditary sensory and autonomic neuropathy type III (HSAN3), or familial dysautonomia (FD), is caused by homozygous or compound heterozygous mutation in the IKBKAP gene (ELP1; 603722) on chromosome 9q31.</p>
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<strong>Description</strong>
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<p>Hereditary sensory and autonomic neuropathy type III (HSAN3) is an autosomal recessive neurodegenerative disorder with onset soon after birth. Affected individuals show progressive symptoms resulting from depletion of sensory proprioceptive and autonomic neurons. Features include gastrointestinal dysfunction, gastroesophageal reflux, vomiting crises, recurrent pneumonia, seizures, gait abnormalities with loss of ambulation, kyphoscoliosis, postural hypotension, hypertension crises, absence of fungiform papillae on the tongue, decreased deep tendon reflexes, defective lacrimation, and impaired pain and temperature perception. The disorder is inevitably fatal, with only 50% of patients reaching 40 years of age. HSAN3 has a high carrier frequency in the Ashkenazi Jewish population (summary by Morini et al., 2016). </p><p>For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).</p>
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<strong>Clinical Features</strong>
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<p>Riley et al. (1949) first described this disorder in 5 Jewish patients with autonomic dysfunction and defective lacrimation. Other features included episodic hypertension, hyperhidrosis, cyclic vomiting, and skin blotching. Smith and Dancis (1963) noted the lack of an axon flare after intradermal histamine, and Smith et al. (1965) noted the absence of fungiform papillae on the tongue. These authors also described Ashkenazi Jewish heritage and decreased deep tendon reflexes. </p><p>In an extensive review of 210 children with familial dysautonomia from 172 families, Brunt and McKusick (1970) concluded that FD is an autosomal recessive disorder occurring almost exclusively in persons of Ashkenazi Jewish descent. Common features included alacrima, absence of lingual fungiform papillae with impaired taste, vasomotor instability, hypoactive or absent deep tendon reflexes, and relative indifference to pain and temperature. Patients showed incoordination, and neuropathic joints and scoliosis were often seen. Although emotional instability occurred, intellect was unimpaired. Patients also showed increased sensitivity to adrenergic and cholinergic agents, suggesting functional autonomic denervation. Axelrod et al. (1981) demonstrated clinical variability in sensory impairment among 75 patients with FD. Older patients tended to have increased dysfunction in pain sensation, joint position and Romberg sign, and vibratory sense. Testing after a 5-year interval showed significant worsening with increased age. </p><p>Pearson et al. (1980) demonstrated glomerulosclerosis in 10 or 13 autopsied and biopsied patients with familial dysautonomia. Sympathetic nerve terminals could not be identified in renal vessels from the patients, whereas they were demonstrated in controls. In a review of 79 patients, elevated serum creatinine (32% of patients) and blood urea nitrogen (76% of patients) were found, and an association was found between hypotension and renal dysfunction. Pearson et al. (1980) suggested that altered renovascular responsivity to systemic hypotension in the disorder may lead to ischemia and subsequent sclerosis of glomeruli. </p><p>In patients with FD, Gadoth et al. (1983) found a prolonged pupil cycle time (light response) and interpreted it as indicative of denervation hypersensitivity. Parenterally administered Mecholyl caused overflow tearing and temporary normalization of deep tendon reflexes and response to intradermal histamine, suggesting functional rather than structural denervation. </p><p>Axelrod and Abularrage (1982) reported on survival in dysautonomia. From 1969 to 1982, 227 patients had been referred to the Dysautonomia Center at New York University. At the time of report, 59 patients were 20 years of age or older and accounted for 33% of the living patients. The oldest was 38 years old. Axelrod (1998) provided an update of the patients at the Dysautonomia Center. In 1998, 40% of the active population of 307 patients were over the age of 20 years. In addition to worsening peripheral sensory dysfunction, the adults complained of poor balance, unsteady gait, and difficulty concentrating. They were prone to depression, anxieties, and even phobias. Sympathovagal balance became more precarious with worsening of orthostatic hypotension, development of supine hypertension, and even occasional bradyarrhythmias. Fishbein and Grossman (1986) described the pulmonary complications in a 29-year-old man with familial dysautonomia. </p><p>In an extensive review of HSAN3, Axelrod and Hilz (2003) noted that autonomic disturbances are very prominent, including alacrima, episodic hyperhidrosis, and vasomotor and cardiovascular perturbations. Patients can exhibit both extreme hypertension and profound and rapid postural hypotension without compensatory tachycardia. There is also a relative insensitivity to hypoxemia. Patients often experience episodes termed 'dysautonomic crises,' which are characterized by nausea and vomiting, agitation, tachycardia, and hypertension, and are often triggered by emotional or physical stress. Somatic growth is poor, and by 10 years of age, 85% of patients have scoliosis. Seizures with decerebrate posturing can follow breath-holding episodes. </p><p><strong><em>Pathologic Findings</em></strong></p><p>
Brown et al. (1964) described autopsy findings in 2 Jewish sibs with HSAN3, which included demyelination in the medulla, pontine reticular formation, and dorsolongitudinal tracts, and degeneration, pigmentation, and loss of cells in autonomic ganglia. </p><p>Pearson et al. (1975) reported that sural nerve biopsy from patients with HSAN3 showed reduced transverse fascicular area, diminished numbers of myelinated axons, especially those of small diameter, and very few nonmyelinated axons. In addition, catecholamine-containing nerve endings were not identified in accompanying arteries. The authors noted that the changes were compatible with the clinical phenotype. </p><p>Pearson et al. (1978) stated that intrauterine development and postnatal maintenance of dorsal root ganglion neurons are abnormal in FD. They found that neurons in dorsal root ganglia were markedly diminished in young patients and continued to deplete with increasing age. Quantitative studies on C8 dorsal root ganglia showed that FD patients had as little as 10% the number of neurons as controls, with the smallest number being in the oldest patient. Lateral spinal root entry zones and loss of dorsal column myelinated axons were also found. The findings correlated with clinical features of diminished sensation and coordination of limb movements. </p><p>In adult patients with FD, Pearson and Pytel (1978) found that the mean volume of superior cervical sympathetic ganglia was reduced to 34% of normal. The mean totals of preganglionic neurons in the first 3 thoracic cord segments were reduced by about 50%. The authors noted that defects in sympathetic neurons account for many of the autonomic manifestations of the disorder. </p>
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<strong>Biochemical Features</strong>
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<p>Goodall et al. (1971) demonstrated a decrease in synthesis of noradrenaline in patients with FD. Weinshilboum and Axelrod (1971) found decreased dopamine-beta-hydroxylase (DBH; 223360), the enzyme that converts dopamine to norepinephrine. Some dysautonomic children had no plasma DBH activity and their mothers had decreased activity. </p><p>Pearson et al. (1982) reported anatomically discrete depletion of substance P (162320) immunoreactivity in the substantia gelatinosa of spinal cord and medulla of patients with familial dysautonomia. Substance P, an undecapeptide, is involved in transmission of nociceptive information at synapses of primary sensory neurons. </p><p>In patients with FD, Siggers et al. (1976) found a 3-fold increase in serum antigen levels of the nerve growth factor beta unit (NGFB; 162030) with normal function measurements, suggesting a qualitative abnormality of beta-NGF in the disorder. By bioimmunoassay of cultured fibroblasts from patients with FD, Schwartz and Breakefield (1980) found similar levels of beta-NGF compared to controls, but found that NGF showed about 10% activity compared to controls. The beta-adrenergic agonist isoproterenol produced no change in immunoreactive beta-NGF in dysautonomia, whereas it caused a marked increase in control cells. The authors postulated a defect in the processing of an NGFB precursor or in the structure of biologically active NGFB. In rats and guinea pigs, Johnson et al. (1980) showed that dorsal root ganglion neurons are destroyed by in utero exposure to maternal antibody to NGF. Using RFLP analysis of human NGFB and the NGF receptor (162010) to examine multiple FD families, Breakefield et al. (1984), Ozelius et al. (1986), and Breakefield et al. (1986) excluded both genes as the site of the FD disease mutation. </p>
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<strong>Pathogenesis</strong>
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<p>Lee et al. (2009) reported the derivation of patient-specific FD induced pluripotent stem cells (iPSCs) and the directed differentiation into cells of all 3 germ layers including peripheral neurons. Gene expression analysis in purified FD iPSC-derived lineages demonstrated tissue-specific missplicing of IKBKAP (603722) in vitro. Patient-specific neural crest precursors expressed particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis was further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behavior. Furthermore, Lee et al. (2009) used FD iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Lee et al. (2009) concluded that their study illustrated the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment. </p>
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<strong>Diagnosis</strong>
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<p>Axelrod et al. (1983) stated that the clinical diagnosis of familial dysautonomia is based on the presence of 5 signs: lack of axon flare after intradermal injection of histamine, absence of fungiform papillae on the tongue, miosis of the pupil after conjunctival instillation of methacholine chloride (2.5%), absent deep tendon reflexes, and diminished tear flow. However, they noted that consistent neuropathologic findings in sural nerve biopsies may be the best diagnostic criterion to differentiate familial dysautonomia from other forms of congenital sensory neuropathy. Axelrod et al. (1983) reported the case of a gypsy child with congenital sensory neuropathy who had all 5 signs in addition to skeletal abnormalities, dysmorphic features, and hypohidrosis, but whose sural nerve biopsy was inconsistent with dysautonomia. The authors noted that many non-Jewish cases of 'familial dysautonomia' may be another form of congenital sensory neuropathy (e.g., 201300, 256800). </p><p>Axelrod et al. (1987) suggested that the possibility of familial dysautonomia should be suspected in a child of Eastern European Jewish extraction with breech delivery, meconium staining, poor suck, hypotonia, or hypothermia. The diagnosis could be confirmed by inspection of the tongue for fungiform papillae, determination of deep tendon reflexes, and performance of intradermal histamine and intraocular pilocarpine tests. If results in either of the latter 2 tests are normal or equivocal, they should be repeated after 6 weeks of age. </p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
Eng et al. (1995) used CA-repeat polymorphisms located in the 9q31-q33 region for prenatal diagnosis of familial dysautonomia. All 7 families studied were informative for the markers, and fetal diagnoses were made in 8 pregnancies. Six fetal diagnoses were predicted with more than 98% accuracy, whereas 2 with recombinations were predicted with at least 88% and 92% accuracy. </p><p>Using linkage and linkage disequilibrium analyses with highly polymorphic dinucleotide repeat markers known to flank the familial dysautonomia locus, Oddoux et al. (1995) performed prenatal diagnosis in 8 pregnancies in 7 informative families. All of the fetuses were predicted to be heterozygous unaffected; 7 had come to term and were normal. </p>
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<strong>Clinical Management</strong>
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<p>The most prevalent causative mutation in FD is an IKBKAP splice site mutation that results in deletion of exon 20, producing a truncated protein (603722.0001). The polyphenol (-)-epigallocatechin gallate (EGCG) downregulates expression of HNRNPA2B1 (600124), a transactivating factor that encourages the use of intron-distal 5-prime splice sites. Anderson et al. (2003) found that EGCG treatment of cultured FD-derived fibroblasts increased the use of the intron-proximal splice site, resulting in the generation of more exon 20-containing IKBKAP transcript. EGCG did not alter IKBKAP splicing in normal cells. Anderson et al. (2003) observed synergistic production of correctly spliced transcript and full-length IKBKAP protein in FD fibroblasts treated with the combination of EGCG and tocotrienol, a vitamin E isoform that can upregulate transcription of the IKBKAP gene. They suggested that EGCG may be a therapeutic modality for individuals with FD. </p><p>Slaugenhaupt et al. (2004) showed that treating FD lymphoblast cells with the plant cytokinin kinetin altered splicing of IKBKAP. Kinetin significantly increased inclusion of exon 20 from the endogenous gene, as well as from an IKBKAP minigene, but did not enhance inclusion of alternatively spliced exon 31 in MYO5A (160777). Benzyladenine, the most closely related cytokinin, showed a similar but less dramatic effect. </p>
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<strong>Mapping</strong>
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<p>By family linkage studies, Blumenfeld et al. (1993) assigned the familial dysautonomia locus to chromosome 9q31-q33, with a maximum lod score of 21.1 at marker D9S58. Marker D9S58 also showed strong linkage disequilibrium with FD, with one allele present on 73% of affected chromosomes compared to 5.4% of controls. D9S53 and D9S105 represented the closest flanking markers. </p><p>Using 11 new polymorphic markers, Blumenfeld et al. (1999) narrowed the FD locus to less than 0.5 cM, between 2 specific markers. Two markers within this interval showed no recombination with the disorder. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, may have represented independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated FD carrier frequency of 1 in 32, and none of the 4 haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. The haplotype information made it possible to provide accurate genetic testing both for families with FD and for carriers on the basis of close flanking markers and the capacity to identify more than 98% of FD chromosomes by their haplotype. </p>
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<strong>Molecular Genetics</strong>
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<p>Slaugenhaupt et al. (2001) and Anderson et al. (2001) demonstrated that the major haplotype of familial dysautonomia is associated with a mutation in the IKBKAP gene (603722.0001). A minor haplotype was found to be associated with a different mutation (R696P; 603722.0002). </p>
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<p>In the United States, HSAN3 is a disorder almost completely limited to persons of Ashkenazi Jewish extraction (Brunt and McKusick, 1970). In Israel, as in the United States, most cases were Ashkenazim from Poland, according to Goldstein-Nieviazhski and Wallis (1966). Maayan et al. (1987) calculated an incidence of 1 in 3,703 for familial dysautonomia among Ashkenazi Jews in Israel. </p><p>Rare non-Jewish cases of presumed familial dysautonomia have been reported (e.g., Burke, 1966), but the diagnosis is usually in question. For example, the patient of Burke (1966) was later seen by Rogers (1993) who concluded that although the patient had a hereditary sensory neuropathy, the disorder was not familial dysautonomia. However, Leyne et al. (2003) identified a patient, previously described by Blumenfeld et al. (1999), who fulfilled all diagnostic criteria other than pure Ashkenazi Jewish ancestry (the patient's mother was of Irish-German/Sicilian heritage) and identified a novel mutation in the IKBKAP gene (603722.0003). </p>
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<strong>Animal Model</strong>
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<p>Hims et al. (2007) created transgenic mice expressing human IKBKAP with the FD-associated IVS20DS+6T-C splice mutation (603722.0001). The mutant IKBKAP transgene was misspliced in transgenic mice in a tissue-specific manner that replicated the pattern seen in FD patient tissues. In both FD and transgenic mouse tissues, missplicing predominated in neuronal tissues compared with nonneuronal tissues, and the most accurate splicing was seen in heart and kidney. </p><p>Morini et al. (2016) generated a transgenic mouse model of FD with the exon 20 splice site mutation (TgFD9;Ikbkap(delta20/flox)). Mutant mice recapitulated many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments. </p><p>In transgenic male mice carrying the human exon 20 splice site mutation, Morini et al. (2019) found that treatment beginning right after birth with oral kinetin, a small molecule splicing modulator, resulted in improved sensorimotor coordination, prevention of spinal deformities, and significantly increased survival of proprioceptive neurons in the peripheral nervous system. These clinical benefits were associated with the increased expression of normal IKBKAP transcripts, as well as increased protein expression. Treatment of human fibroblasts carrying the splice site mutation resulted in increased IKBKAP gene expression without significant changes in overall genomic splicing, suggesting that kinetin shows selective splicing modulation activity. The study provided a proof of concept that targeting the underlying genetic mechanism in FD can result in clinical benefits. </p>
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<strong>History</strong>
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<p>Axelrod (1998) provided a historical perspective on familial dysautonomia, highlighting the early contributions of Dancis. Recognition of this disorder, first described by Riley et al. (1949), spans almost 50 years. </p>
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<strong>See Also:</strong>
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Aguayo et al. (1971); De Jong and Delleman (1978); Gitlow et al.
(1970); Greene and Shooter (1980); Grunebaum (1975); Hutchison and
Hamilton (1962); Kaplan et al. (1985); McKendrick (1958); McKusick et
al. (1967); Mitnick et al. (1982); Orbeck and Oftedal (1977); Pearson
et al. (1970); Porges et al. (1978); Riley (1952); Smith and Dancis
(1963); Yatsu and Zussman (1964); Ziegler et al. (1976)
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<strong>REFERENCES</strong>
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<p class="mim-text-font">
Aguayo, A. J., Nair, C. P. V., Bray, G. M.
<strong>Peripheral nerve abnormalities in the Riley-Day syndrome. Findings in a sural nerve biopsy.</strong>
Arch. Neurol. 24: 106-116, 1971.
[PubMed: 4322165]
[Full Text: https://doi.org/10.1001/archneur.1971.00480320034003]
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Anderson, S. L., Coli, R., Daly, I. W., Kichula, E. A., Rork, M. J., Volpi, S. A., Ekstein, J., Rubin, B. Y.
<strong>Familial dysautonomia is caused by mutations of the IKAP gene.</strong>
Am. J. Hum. Genet. 68: 753-758, 2001.
[PubMed: 11179021]
[Full Text: https://doi.org/10.1086/318808]
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<li>
<p class="mim-text-font">
Anderson, S. L., Qiu, J., Rubin, B. Y.
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Axelrod, F. B., Iyer, K., Fish, I., Pearson, J., Sein, M. E., Spielholz, N.
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</ol>
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Contributors:
</span>
</div>
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Cassandra L. Kniffin - updated : 02/10/2020<br>Ada Hamosh - updated : 10/19/2009<br>George E. Tiller - updated : 12/5/2006<br>Patricia A. Hartz - updated : 4/20/2005<br>Deborah L. Stone - updated : 12/22/2004<br>Cassandra L. Kniffin - reorganized : 5/21/2004<br>Cassandra L. Kniffin - updated : 5/18/2004<br>Victor A. McKusick - updated : 3/19/2001<br>Victor A. McKusick - updated : 4/9/1999<br>Victor A. McKusick - updated : 5/19/1998
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Creation Date:
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<span class="mim-text-font">
Victor A. McKusick : 6/3/1986
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alopez : 11/20/2020<br>carol : 02/12/2020<br>alopez : 02/11/2020<br>ckniffin : 02/10/2020<br>carol : 05/24/2019<br>carol : 05/23/2019<br>carol : 04/12/2016<br>carol : 4/18/2012<br>alopez : 10/26/2009<br>terry : 10/19/2009<br>terry : 6/3/2009<br>terry : 5/4/2009<br>wwang : 8/27/2008<br>wwang : 12/5/2006<br>mgross : 4/20/2005<br>carol : 12/22/2004<br>carol : 5/21/2004<br>ckniffin : 5/18/2004<br>carol : 4/29/2003<br>cwells : 3/29/2001<br>terry : 3/19/2001<br>carol : 4/12/1999<br>terry : 4/9/1999<br>terry : 10/26/1998<br>dholmes : 7/22/1998<br>carol : 5/28/1998<br>terry : 5/19/1998<br>terry : 5/19/1998<br>terry : 5/19/1998<br>alopez : 7/10/1997<br>mark : 7/16/1996<br>mark : 1/24/1996<br>mark : 1/22/1996<br>mark : 12/20/1995<br>terry : 12/13/1995<br>davew : 6/1/1994<br>warfield : 4/15/1994<br>mimadm : 2/19/1994<br>carol : 9/22/1993<br>carol : 9/21/1993<br>carol : 9/13/1993
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