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Entry
- #257220 - NIEMANN-PICK DISEASE, TYPE C1; NPC1
- OMIM
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<span class="h4">#257220</span>
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/257220"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#diagnosis">Diagnosis</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#heterogeneity">Heterogeneity</a>
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<a href="#pathogenesis">Pathogenesis</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="#nomenclature">Nomenclature</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=NIEMANN-PICK DISEASE, TYPE" 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 class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0070113" 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/257220" 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/OMIA000725/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0070113" 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">
<div style="display: table-row">
<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:257220" 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>
</span>
</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> 66751000<br />
<strong>ICD10CM:</strong> E75.242<br />
<strong>ORPHA:</strong> 646<br />
<strong>DO:</strong> 0070113<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>
257220
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
NIEMANN-PICK DISEASE, TYPE C1; NPC1
</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">
NIEMANN-PICK DISEASE, TYPE C; NPC<br />
NIEMANN-PICK DISEASE WITH CHOLESTEROL ESTERIFICATION BLOCK<br />
NIEMANN-PICK DISEASE, SUBACUTE JUVENILE FORM<br />
NIEMANN-PICK DISEASE, CHRONIC NEURONOPATHIC FORM<br />
NIEMANN-PICK DISEASE WITHOUT SPHINGOMYELINASE DEFICIENCY<br />
NEUROVISCERAL STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
NIEMANN-PICK DISEASE, TYPE D, INCLUDED
</span>
</div>
<div>
<span class="h4 mim-font">
NIEMANN-PICK DISEASE, NOVA SCOTIAN TYPE, INCLUDED
</span>
</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/18/95?start=-3&limit=10&highlight=95">
18q11.2
</a>
</span>
</td>
<td>
<span class="mim-font">
Niemann-Pick disease, type D
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/257220"> 257220 </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">
NPC1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607623"> 607623 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/18/95?start=-3&limit=10&highlight=95">
18q11.2
</a>
</span>
</td>
<td>
<span class="mim-font">
Niemann-Pick disease, type C1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/257220"> 257220 </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">
NPC1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607623"> 607623 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/257220" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&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/257220" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/257220" 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> 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">
- Vertical supranuclear gaze palsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843369&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843369</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000511" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000511</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000511" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000511</a>]</span><br />
</span>
</div>
</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> Liver </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hepatomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80515008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80515008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019209&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019209</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span><br /> -
Neonatal jaundice <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/387712008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">387712008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/P59.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">P59.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0022353&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022353</a>, <a href="https://bioportal.bioontology.org/search?q=C1859236&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859236</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006579" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006579</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006579" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006579</a>]</span><br /> -
Fatal liver failure in infancy (occasional) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850364&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850364</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006583" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006583</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spleen </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Splenomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16294009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16294009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038002&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038002</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Dysphagia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/288939007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">288939007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40739000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40739000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/787.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011168</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</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> Central 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 /> -
Developmental delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
Dysarthria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8011004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8011004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.13</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/784.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span><br /> -
Loss of speech <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0542223&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0542223</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002371" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002371</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002371" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002371</a>]</span><br /> -
Mental deterioration <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001268</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001268</a>]</span><br /> -
Dementia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52448006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52448006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12348006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12348006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F03.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03.90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F03" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/290.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/294.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">294.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011265&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011265</a>, <a href="https://bioportal.bioontology.org/search?q=C0497327&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0497327</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span><br /> -
Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Cerebellar ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br /> -
Cataplexy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/46263000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">46263000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0007384&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007384</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002524" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002524</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002524" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002524</a>]</span><br /> -
Neuronal loss, particularly of cerebellar Purkinje cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2749478&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2749478</a>]</span><br /> -
Neurofibrillary tangles <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85775002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85775002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085400&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085400</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002185" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002185</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002185" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002185</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">
- Poor school performance <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843367&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843367</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
Behavioral problems <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/277843001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">277843001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5886745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5886745</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000708" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000708</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000708" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000708</a>]</span><br /> -
Psychosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/191525009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">191525009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/69322001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">69322001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F29" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F29</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/298.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">298.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290-299.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290-299.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349204&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349204</a>, <a href="https://bioportal.bioontology.org/search?q=C0033975&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033975</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000709" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000709</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000709" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000709</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Foam cells on bone marrow biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843375&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843375</a>]</span><br /> -
'Sea-blue' histiocytes <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39474009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39474009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0333836&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0333836</a>]</span><br />
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<strong> PRENATAL MANIFESTATIONS </strong>
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- Fetal ascites <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/363125002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">363125002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1285291&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1285291</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001791" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001791</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001791" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001791</a>]</span><br />
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<strong> LABORATORY ABNORMALITIES </strong>
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- Normal or mildly reduced sphingomyelinase activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843370&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843370</a>]</span><br /> -
Low cholesterol esterification rates <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843371&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843371</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003349" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003349</a>]</span><br /> -
Abnormal cholesterol homeostasis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4025656&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4025656</a>, <a href="https://bioportal.bioontology.org/search?q=C1843372&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843372</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003107</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003107</a>]</span><br /> -
Foam cells in visceral organs and CNS <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843373&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843373</a>]</span><br /> -
Foam cells contain polymorphic cytoplasmic inclusions consisting of lamellar osmiophilic membranes on electron microscopy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843374&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843374</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Genetic heterogeneity (see NPC2, <a href="/entry/607625">607625</a>) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242960&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242960</a>]</span><br /> -
Disease usually becomes apparent in early childhood<br /> -
Death usually in teenage years<br /> -
Variable phenotype <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837514&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837514</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span><br /> -
Four major groups: early infantile, late infantile, juvenile, adult<br /> -
Earlier onset associated with faster progression and shorter life span<br /> -
Incidence of 1 in 150,000 live births in the general population<br /> -
Incidence of 1% in Yarmouth County, Nova Scotia<br /> -
Estimated carrier frequency of 10-25% in Yarmouth County, Nova Scotia<br /> -
Nova Scotian variant (type D) is considered a genetic isolate of NPC1 and is associated with a mutation in the NPC1 gene (<a href="/entry/607623#0004">607623.0004</a>)<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the NPC intracellular cholesterol transporter 1 gene (NPC1, <a href="/entry/607623#0001">607623.0001</a>)<br />
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<p>A number sign (#) is used with this entry because Niemann-Pick disease type C1 and Niemann-Pick disease type D, also known as the Nova Scotian type, are caused by homozygous or compound heterozygous mutation in the NPC1 gene (<a href="/entry/607623">607623</a>) on chromosome 18q11.</p>
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<strong>Description</strong>
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<p>Niemann-Pick type C (NPC) disease is an autosomal recessive lipid storage disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene (<a href="/entry/601015">601015</a>), referred to as type C2 (<a href="/entry/607625">607625</a>). The clinical manifestations of types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes (summary by <a href="#74" class="mim-tip-reference" title="Vance, J. E. &lt;strong&gt;Lipid imbalance in the neurological disorder, Niemann-Pick C disease.&lt;/strong&gt; FEBS Lett. 580: 5518-5524, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16797010/&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;16797010&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.febslet.2006.06.008&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="16797010">Vance, 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16797010" 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>Historically, <a href="#19" class="mim-tip-reference" title="Crocker, A. C. &lt;strong&gt;The cerebral defect in Tay-Sachs disease and Niemann-Pick disease.&lt;/strong&gt; J. Neurochem. 7: 69-80, 1961.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13696518/&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;13696518&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1471-4159.1961.tb13499.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="13696518">Crocker (1961)</a> delineated 4 types of Niemann-Pick disease: the classic infantile form (type A; <a href="/entry/257200">257200</a>), the visceral form (type B; <a href="/entry/607616">607616</a>), the subacute or juvenile form (type C), and the Nova Scotian variant (type D). Types C1 and D are indistinguishable except for the occurrence of type D in patients of Nova Scotian Acadian ancestry. Since then, types E and F have also been described (see <a href="/entry/607616">607616</a>), and phenotypic variation within each group has also been described. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13696518" 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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<strong>Clinical Features</strong>
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<p>Niemann-Pick disease type C has a highly variable clinical phenotype. Patients with the 'classic' childhood onset type C usually appear normal for 1 or 2 years with symptoms appearing between 2 and 4 years. They gradually develop neurologic abnormalities which are initially manifested by ataxia, grand mal seizures, and loss of previously learned speech. Spasticity is striking and seizures, particularly myoclonic jerks, are common. Other features include dystonia, vertical supranuclear gaze palsy, dementia, and psychiatric manifestations. In general, hepatosplenomegaly is less striking than in types A and B, although it can be lethal in some. Cholestatic jaundice occurs in some patients. Foamy Niemann-Pick cells and 'sea-blue' histiocytes with distinctive histochemical and ultrastructural appearances are found in the bone marrow. In the childhood-onset form, death usually occurs at age 5 to 15 (<a href="#10" class="mim-tip-reference" title="Brady, R. O. &lt;strong&gt;Sphingomyelin lipidoses: Niemann-Pick disease. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M. S. (eds.): The Metabolic Basis of Inherited Disease. (5th ed.)&lt;/strong&gt; New York: McGraw-Hill (pub.) 1983. P. 731."None>Brady, 1983</a>, <a href="#53" class="mim-tip-reference" title="Patterson, M. C., Vanier, M. T., Suzuki, K., Morris, J. A., Carstea, E., Neufeld, E. B., Blanchette-Mackie, J. E., Pentchev, P. G. &lt;strong&gt;Niemann-Pick disease type C: a lipid trafficking disorder. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (7th ed.)&lt;/strong&gt; New York: McGraw-Hill (pub.) 2001. Pp. 3611-3633."None>Patterson et al., 2001</a>). Adult-onset forms, with insidious onset and slower progression, have also been reported (see, e.g., <a href="#65" class="mim-tip-reference" title="Shulman, L. M., David, N. J., Weiner, W. J. &lt;strong&gt;Psychosis as the initial manifestation of adult-onset Niemann-Pick disease type C.&lt;/strong&gt; Neurology 45: 1739-1743, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7675237/&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;7675237&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.45.9.1739&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="7675237">Shulman et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7675237" 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="#20" class="mim-tip-reference" title="De Leon, G. A., Kaback, M. M., Elfenbein, I. B., Percy, A. K., Brady, R. O. &lt;strong&gt;Juvenile dystonia lipidosis.&lt;/strong&gt; Johns Hopkins Med. J. 125: 62-77, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5347781/&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;5347781&lt;/a&gt;]" pmid="5347781">De Leon et al. (1969)</a> described 2 females and a male in a black kindred with a juvenile form of cerebral lipidosis. Clinical features were onset between age 4 and 9 years, dementia progressing to complete amentia and an akinetic mute state, grand mal and minor motor seizures, progressive dystonia of posture with tendency to flexion of the arms, hyperextension of the spine and extension of the legs, clumsiness and mild atypical ataxia, some intention tremor and athetosis, grasp reflexes and severe reflex trismus in the final stages, tendency to hyperreflexia but preservation of fair strength and normal plantar reflexes until late. Notably absent were retinal degeneration, myoclonus, prominent pyramidal or bulbar involvement, and hepatosplenomegaly. In 1 case, foam histiocytes were demonstrated in the bone marrow. Cerebral sphingolipids in biopsy-obtained material were normal. Electron microscopic findings by <a href="#21" class="mim-tip-reference" title="Elfenbein, I. B. &lt;strong&gt;Dystonic juvenile idiocy without amaurosis: a new syndrome.&lt;/strong&gt; Johns Hopkins Med. J. 123: 205-221, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4879661/&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;4879661&lt;/a&gt;]" pmid="4879661">Elfenbein (1968)</a> supported the distinctness of this entity, which they called 'dystonic juvenile idiocy without amaurosis'. The cases reported by <a href="#38" class="mim-tip-reference" title="Kidd, M. &lt;strong&gt;An electronmicroscopic study of a case of atypical cerebral lipidosis.&lt;/strong&gt; Acta Neuropath. 9: 70-78, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4963519/&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;4963519&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00688159&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="4963519">Kidd (1967)</a> as 'atypical cerebral lipidosis', and <a href="#37" class="mim-tip-reference" title="Karpati, G., Carpenter, S., Wolfe, L. S., Andermann, F. &lt;strong&gt;Juvenile dystonic lipidosis: an unusual form of neurovisceral storage disease.&lt;/strong&gt; Neurology 27: 32-42, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/189251/&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;189251&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.27.1.32&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="189251">Karpati et al. (1977)</a> as 'juvenile dystonic lipidosis', are thought to be identical. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=189251+5347781+4963519+4879661" 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="#50" class="mim-tip-reference" title="Neville, B. G. R., Lake, B. D., Stephens, R., Sanders, M. D. &lt;strong&gt;A neurovisceral storage disease with vertical supranuclear ophthalmoplegia, and its relationship to Niemann-Pick disease--a report of nine patients.&lt;/strong&gt; Brain 96: 97-120, 1973.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4695727/&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;4695727&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/96.1.97&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="4695727">Neville et al. (1973)</a> found 3 pairs of affected sibs and an equal sex incidence. Two brothers were reported by <a href="#31" class="mim-tip-reference" title="Grover, W. D., Naiman, J. L. &lt;strong&gt;Progressive paresis of vertical gaze in lipid storage disease.&lt;/strong&gt; Neurology 21: 896-899, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5106253/&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;5106253&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.21.9.896&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="5106253">Grover and Naiman (1971)</a>. Neurologic manifestations included vertical gaze paresis and progressive dysarthria. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4695727+5106253" 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 variant of Niemann-Pick disease, most likely type C, was observed in 9 children in 5 families by <a href="#81" class="mim-tip-reference" title="Wenger, D. A., Barth, G., Githens, J. H. &lt;strong&gt;Nine cases of sphingomyelin lipidosis, a new variant in Spanish-American children.&lt;/strong&gt; Am. J. Dis. Child. 131: 955-961, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/900082/&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;900082&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archpedi.1977.02120220021002&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="900082">Wenger et al. (1977)</a>. Neonatal jaundice, easy bruisability, vertical supranuclear ophthalmoplegia, intellectual and neurologic deterioration, hepatosplenomegaly, and sea-blue or foamy histiocytes were features. All 5 families were from the old Spanish-American population of southern Colorado or New Mexico. Low (average about 30% of normal) activity of sphingomyelinase was found in the fibroblasts of 7 of 8 cases evaluated. A similar case was reported in a Spanish woman from northern New Mexico by <a href="#40" class="mim-tip-reference" title="Kornfeld, M., Appenzeller, O., Saiki, J., Troup, G. M. &lt;strong&gt;Sea blue histiocytes and sural nerve in neurovisceral storage disorder with vertical ophthalmoplegia.&lt;/strong&gt; J. Neurol. Sci. 25: 291-302, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1159447/&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;1159447&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(75)90152-5&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="1159447">Kornfeld et al. (1975)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=900082+1159447" 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>The patient reported by <a href="#46" class="mim-tip-reference" title="Longstreth, W. T., Jr., Daven, J. R., Farrell, D. F., Bolen, J. W., Bird, T. D. &lt;strong&gt;Adult dystonic lipidosis: clinical, histologic and biochemical findings of a neurovisceral storage disease.&lt;/strong&gt; Neurology 32: 1295-1299, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6890167/&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;6890167&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.32.11.1295&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="6890167">Longstreth et al. (1982)</a> as 'adult dystonic lipidosis' may have had this disorder: a 43-year-old man who presented with splenomegaly and a 20-year history of a neurologic disorder that included vertical supranuclear ophthalmoplegia, mild dementia, and a movement disorder. Adult dystonic lipidosis was diagnosed from the clinical picture and demonstration of foamy and sea-blue histiocytes in bone marrow. Niemann-Pick disease was excluded by normal sphingomyelinase activity in cultured skin fibroblasts. The patient, who also had mitral valve prolapse, was able to work as a janitor until age 37 years. Lysosomal storage of neutral fat and phospholipids was suggested by electron microscopy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6890167" 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 ocular histopathologic studies of a girl who died at age 11 years, <a href="#52" class="mim-tip-reference" title="Palmer, M., Green, W. R., Maumenee, I. H., Valle, D. L., Singer, H. S., Morton, S. J., Moser, H. W. &lt;strong&gt;Niemann-Pick disease--type C: ocular histopathologic and electron microscopic studies.&lt;/strong&gt; Arch. Ophthal. 103: 817-822, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4004622/&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;4004622&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archopht.1985.01050060077030&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="4004622">Palmer et al. (1985)</a> noted lipid deposits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4004622" 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="#84" class="mim-tip-reference" title="Witzleben, C. L., Palmieri, M. J., Watkins, J. B., Hogan, P. &lt;strong&gt;Sphingomyelin lipidosis variant with cirrhosis in the pediatric age group.&lt;/strong&gt; Arch. Path. Lab. Med. 110: 508-512, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3085631/&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;3085631&lt;/a&gt;]" pmid="3085631">Witzleben et al. (1986)</a> emphasized that childhood cirrhosis is a feature of NPC. They reported 2 unrelated cases. Skin fibroblasts in one showed sphingomyelinase activity that was 42% of control values. The hepatic storage underlying the cirrhosis was typically inconspicuous; however, sea-blue histiocytes in the marrow could be considered a valuable diagnostic clue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3085631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a collaborative study in Lyon, France, Denver, Colorado, and Bethesda, Maryland, <a href="#78" class="mim-tip-reference" title="Vanier, M. T., Wenger, D. A., Comly, M. E., Rousson, R., Brady, R. O., Pentchev, P. G. &lt;strong&gt;Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification: a collaborative study on 70 patients.&lt;/strong&gt; Clin. Genet. 33: 331-348, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3378364/&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;3378364&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1988.tb03460.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="3378364">Vanier et al. (1988)</a> studied 70 patients with type C Niemann-Pick disease clinically and biochemically. Age of onset ranged from the neonatal period to 55 years. More than 90% of the patients had some degree of splenomegaly and/or hepatomegaly, but notably, some had none. Neurologic deterioration was a central characteristic of the disease, but onset and progression varied. In infancy, there was hypotonia, developmental delay, mental deterioration, and spasticity. In childhood, there was cerebellar ataxia, poor school performance, dysarthria, dystonia, vertical supranuclear gaze palsy, and seizures. Two patients had adult-onset disease with neurologic and psychiatric manifestations. Bone marrow biopsies consistently showed foam cells and/or sea-blue histiocytes. Sphingomyelinase activity was normal or somewhat reduced (47% of controls). Very low cholesterol esterification rates were observed in more than 90% of the patients, including all cases with the most severe forms of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3378364" 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>On the basis of the analysis of 22 patients, <a href="#24" class="mim-tip-reference" title="Fink, J. K., Filling-Katz, M. R., Sokol, J., Cogan, D. G., Pikus, A., Sonies, B., Soong, B., Pentchev, P. G., Comly, M. E., Brady, R. O., Barton, N. W. &lt;strong&gt;Clinical spectrum of Niemann-Pick disease type C.&lt;/strong&gt; Neurology 39: 1040-1049, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2761697/&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;2761697&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.39.8.1040&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="2761697">Fink et al. (1989)</a> delineated 3 phenotypes of NPC: (1) an early-onset, rapidly progressive form associated with severe hepatic dysfunction and psychomotor delay during infancy and later with supranuclear vertical gaze paresis, ataxia, marked spasticity, and dementia; (2) a delayed-onset, slowly progressive form heralded by the appearance, usually in early childhood, of mild intellectual impairment, supranuclear vertical gaze paresis, and ataxia, and later associated with dementia and, variably, seizures and extrapyramidal deficits; and (3) a late-onset, slowly progressive form distinguished from the second pattern by later age of onset (adolescence or adulthood) and a much slower rate of progression. Phenotypes 1 and 2 have been observed in the same sibship. <a href="#51" class="mim-tip-reference" title="Omura, K., Suzuki, Y., Norose, N., Sato, M., Maruyama, K., Koeda, T. &lt;strong&gt;Type C Niemann-Pick disease: clinical and biochemical studies on 6 cases.&lt;/strong&gt; Brain Dev. 11: 57-61, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2522288/&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;2522288&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0387-7604(89)80010-5&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="2522288">Omura et al. (1989)</a> reported 6 cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2761697+2522288" 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="#73" class="mim-tip-reference" title="Turpin, J. C., Masson, M., Baumann, N. &lt;strong&gt;Clinical aspects of Niemann-Pick type C disease in the adult.&lt;/strong&gt; Dev. Neurosci. 13: 304-306, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1817035/&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;1817035&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000112177&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="1817035">Turpin et al. (1991)</a> discussed the form of type C Niemann-Pick disease that starts in adolescence or adulthood and shows a slower evolution than does the infantile form. Psychomotor retardation is a consistent feature. Cerebellar ataxia and extrapyramidal manifestations are often found rather than pyramidal manifestations. Supranuclear ophthalmoplegia with paralysis of down-gaze is nearly constant. Cataplexy and other types of seizures may be found during the evolution of the disease. In some cases a psychosis may be the only manifestation for several years; the treatment by psychotropic drugs raises the question of a superimposition of a drug-induced lipidosis. Although hepatosplenomegaly is a consistent finding in children in the infantile form of the disease, hepatomegaly is often absent in the adult forms and splenomegaly, although generally present, is not pronounced. Foam cells or sea-blue histiocytes are found on bone marrow biopsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1817035" 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="#32" class="mim-tip-reference" title="Imrie, J., Vijayaraghaven, S., Whitehouse, C., Harris, S., Heptinstall, L., Church, H., Cooper, A., Besley, G. T. N., Wraith, J. E. &lt;strong&gt;Niemann-Pick disease type C in adults.&lt;/strong&gt; J. Inherit. Metab. Dis. 25: 491-500, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12555942/&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;12555942&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1021259403196&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="12555942">Imrie et al. (2002)</a> reported 17 patients with Niemann-Pick type disease type C who presented in late childhood or adulthood. They suggested that adult patients are often referred to clinicians with psychosis or other major psychiatric problems. The dystonia with preserved intellectual functioning can be mistaken for other basal ganglia disorders such as Wilson disease (<a href="/entry/277900">277900</a>). The presence of vertical gaze palsy is an important clinical clue and, in the presence of a modest increase in plasma chitotriosidase activity, can be helpful in the differential diagnosis. <a href="#32" class="mim-tip-reference" title="Imrie, J., Vijayaraghaven, S., Whitehouse, C., Harris, S., Heptinstall, L., Church, H., Cooper, A., Besley, G. T. N., Wraith, J. E. &lt;strong&gt;Niemann-Pick disease type C in adults.&lt;/strong&gt; J. Inherit. Metab. Dis. 25: 491-500, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12555942/&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;12555942&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1021259403196&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="12555942">Imrie et al. (2002)</a> concluded that the diagnosis should be confirmed in suspected cases by filipin staining of cultured fibroblasts, as well as cholesterol esterification studies and DNA mutation analysis. They stated that in most adult-onset patients the presenting neurologic abnormality will be a combination of ataxia and dysarthria. As the disease progresses, dystonia and seizures may occur. The characteristic ocular abnormality (supranuclear gaze palsy) usually appears early in the course of the disease but can be very subtle initially and only detected by detailed ophthalmologic assessment. In 3 patients, symptoms of the disease appeared with or were exacerbated by pregnancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12555942" 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="#35" class="mim-tip-reference" title="Josephs, K. A., Matsumoto, J. Y., Lindor, N. M. &lt;strong&gt;Heterozygous Niemann-Pick disease type C presenting with tremor.&lt;/strong&gt; Neurology 63: 2189-2190, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15596783/&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;15596783&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000145710.25588.2f&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="15596783">Josephs et al. (2004)</a> reported a 75-year-old woman who was a heterozygous carrier of an NPC1 mutation (<a href="/entry/607623#0013">607623.0013</a>). She presented with a 10-year history of tremor, initially a side-to-side head tremor, which later progressed to her upper extremities. The tremor was worse at rest and worsened with mental activity, and she was initially diagnosed with Parkinson disease (<a href="/entry/168600">168600</a>). The patient had 3 brothers who were affected by a severe childhood-onset neurologic disorder characterized by spastic dysarthria, tremor, paresis of vertical eye movements, disturbance of gait, and splenomegaly (<a href="#82" class="mim-tip-reference" title="Willvonseder, R., Goldstein, N. P., McCall, J. T., Yoss, R. E., Tauxe, W. N. &lt;strong&gt;A hereditary disorder with dementia, spastic dysarthria, vertical eye movement paresis, gait disturbance, splenomegaly, and abnormal copper metabolism.&lt;/strong&gt; Neurology 23: 1039-1049, 1973.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4795418/&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;4795418&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.23.10.1039&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="4795418">Willvonseder et al., 1973</a>). <a href="#35" class="mim-tip-reference" title="Josephs, K. A., Matsumoto, J. Y., Lindor, N. M. &lt;strong&gt;Heterozygous Niemann-Pick disease type C presenting with tremor.&lt;/strong&gt; Neurology 63: 2189-2190, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15596783/&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;15596783&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000145710.25588.2f&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="15596783">Josephs et al. (2004)</a> concluded that their patient was a manifesting carrier of Niemann-Pick disease type C and that her brothers likely carried 2 mutations in the NPC1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15596783+4795418" 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="#26" class="mim-tip-reference" title="Garver, W. S., Francis, G. A., Jelinek, D., Shepherd, G., Flynn, J., Castro, G., Vockley, C. W., Coppock, D. L., Pettit, K. M., Heidenreich, R. A., Meaney, F. J. &lt;strong&gt;The National Niemann-Pick C1 Disease Database: report of clinical features and health problems.&lt;/strong&gt; Am. J. Med. Genet. 143A: 1204-1211, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17497724/&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;17497724&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31735&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="17497724">Garver et al. (2007)</a> analyzed data from 87 questionnaires received from Niemann-Pick type C1 families living in the United States and reported that the average age of diagnosis was 10.4 years, with one-half of patients being diagnosed before the age of 6.9 years, and the average age of death was 16.2 years, with one-half of all patients dying before the age of 12.5 years. The most common clinical symptom reported at birth was neonatal jaundice (52%), followed by enlargement of the spleen (36%) and liver (31%); ascites (19%) and neonatal hypotonia (6%) were much less frequent. Common developmental difficulties included clumsiness (87%), learning difficulties (87%), ataxia (83%), dysphagia (80%), and vertical gaze palsy (81%). The questionnaires formed the basis for the National NPC1 Disease Database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17497724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of ocular movements of 3 adult patients with biochemically confirmed NPC disease, <a href="#1" class="mim-tip-reference" title="Abel, L. A., Walterfang, M., Fietz, M., Bowman, E. A., Velakoulis, D. &lt;strong&gt;Saccades in adult Niemann-Pick disease type C reflect frontal, brainstem, and biochemical deficits.&lt;/strong&gt; Neurology 72: 1083-1086, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19307542/&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;19307542&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000345040.01917.9d&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="19307542">Abel et al. (2009)</a> found that reflexive saccade latency ranged from shorter to longer than normal, reflexive saccade gain was reduced, asymptotic peak velocity was reduced, fewer self-paced saccades were generated, and increased errors on antisaccades were made by patients compared to controls. Patients with more severe biochemical, cognitive, and symptom deficits performed most poorly on brainstem and frontal ocular motor measures. Paradoxically, less severe illness was associated with an abnormally reduced saccadic latency. The findings suggested that reduced saccadic latency may result from inadequate fixation input from abnormally functioning frontal eye fields. All patients had presented with a psychotic illness. <a href="#1" class="mim-tip-reference" title="Abel, L. A., Walterfang, M., Fietz, M., Bowman, E. A., Velakoulis, D. &lt;strong&gt;Saccades in adult Niemann-Pick disease type C reflect frontal, brainstem, and biochemical deficits.&lt;/strong&gt; Neurology 72: 1083-1086, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19307542/&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;19307542&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000345040.01917.9d&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="19307542">Abel et al. (2009)</a> concluded that ocular motor measures may provide an index of disease severity in Niemann-Pick disease type C, and may be a useful adjunct for monitoring disease progression and medication response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19307542" 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="#79" class="mim-tip-reference" title="Walterfang, M., Fahey, M., Desmond, P., Wood, A., Seal, M. L., Steward, C., Adamson, C., Kokkinos, C., Fietz, M., Velakoulis, D. &lt;strong&gt;White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study.&lt;/strong&gt; Neurology 75: 49-56, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20484681/&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;20484681&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181e6210e&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="20484681">Walterfang et al. (2010)</a> reported the neuroradiologic findings of 6 patients with adult-onset NPC who presented with psychosis, ophthalmoplegia, or a dysexecutive syndrome. Compared to controls, patients had bilateral focal gray matter reductions in the hippocampus, thalamus, superior cerebellum, and insula, in addition to smaller regions of the inferoposterior cortex. These changes corresponded to the clinical findings in adults, although the frontal cortex did not show changes on imaging. Fractional anisotropy showed widespread reductions in major white matter tracts affecting most brain regions, which appeared to be due to both impaired myelination and altered axonal structure. Overall, the findings were consistent with a selective vulnerability of certain neuronal populations; the more widespread white matter changes were consistent with the hypothesis that disrupted myelination and axonal structure may predate changes to the neuronal cell body. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20484681" 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>Fetal Niemann-Pick Disease Type C</em></strong></p><p>
<a href="#69" class="mim-tip-reference" title="Spiegel, R., Raas-Rothschild, A., Reish, O., Regev, M., Meiner, V., Bargal, R., Sury, V., Meir, K., Nadjari, M., Hermann, G., Iancu, T. C., Shalev, S. A., Zeigler, M. &lt;strong&gt;The clinical spectrum of fetal Niemann-Pick type C.&lt;/strong&gt; Am. J. Med. Genet. 149A: 446-450, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19206179/&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;19206179&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32642&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="19206179">Spiegel et al. (2009)</a> reported 7 patients from 5 unrelated families with fetal onset of NPC. Three of the families were consanguineous: 2 of Arab Muslim descent and 1 of Ashkenazi Jewish descent. Two fetuses were diagnosed prenatally based on the combination of splenomegaly and ascites early in the third trimester, followed by analysis of cultured amniocytes. Three patients were diagnosed postnatally, and the last 2 were diagnosed based on an affected sib. The prognosis was very poor in all patients: 1 died in utero, 1 pregnancy was terminated, and 4 died within the first 7 months of life from neonatal cholestatic disease. The seventh patient had developmental regression at age 10 months, followed by rapid neurologic deterioration with spastic quadriplegia, profound mental retardation, seizures, and generalized white matter dysmyelination. The fetal presentations included in utero splenomegaly (6 of 7), in utero hepatomegaly (5 of 7), in utero ascites (4 of 7), intrauterine growth retardation (2 of 7), and oligohydramnios (2 of 7). Placentomegaly and intervillous thrombosis was present in 2 of 3 pregnancies examined. Congenital thrombocytopenia (4 of 4), congenital anemia (2 of 4), and petechial rash (2 of 5) were diagnosed immediately after birth in some. Genetic analysis confirmed the diagnosis in all cases. <a href="#69" class="mim-tip-reference" title="Spiegel, R., Raas-Rothschild, A., Reish, O., Regev, M., Meiner, V., Bargal, R., Sury, V., Meir, K., Nadjari, M., Hermann, G., Iancu, T. C., Shalev, S. A., Zeigler, M. &lt;strong&gt;The clinical spectrum of fetal Niemann-Pick type C.&lt;/strong&gt; Am. J. Med. Genet. 149A: 446-450, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19206179/&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;19206179&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32642&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="19206179">Spiegel et al. (2009)</a> suggested that fetal onset may represent a unique subset of neonatal NPC with a grave prognosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206179" 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>Niemann-Pick Disease, Type D (Nova Scotian)</em></strong></p><p>
Although Niemann-Pick disease type C and type D are clinically similar, <a href="#28" class="mim-tip-reference" title="Greer, W. L., Riddell, D. C., Byers, D. M., Welch, J. P., Girouard, G. S., Sparrow, S. M., Gillan, T. L., Neumann, P. E. &lt;strong&gt;Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C.&lt;/strong&gt; Am. J. Hum. Genet. 61: 139-142, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9245994/&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;9245994&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/513899&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="9245994">Greer et al. (1997)</a> suggested that NPD has a more homogeneous expression than NPC and that patients with NPD resemble less severely affected NPC patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9245994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Studying a 13-year-old Nova Scotian case, <a href="#60" class="mim-tip-reference" title="Rao, B. G., Spence, M. W. &lt;strong&gt;Niemann-Pick disease type D: lipid analyses and studies on sphingomyelinases.&lt;/strong&gt; Ann. Neurol. 1: 385-392, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31133/&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;31133&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410010410&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="31133">Rao and Spence (1977)</a> found elevated sphingomyelin, especially in the spleen, and even greater elevation of free cholesterol. They could not demonstrate deficiency of total sphingomyelinase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Jan, M. M. S., Camfield, P. R. &lt;strong&gt;Nova Scotia Niemann-Pick disease (type D): clinical study of 20 cases.&lt;/strong&gt; J. Child Neurol. 13: 75-78, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9512307/&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;9512307&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1177/088307389801300206&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="9512307">Jan and Camfield (1998)</a> performed a retrospective clinical study of 20 cases of Nova Scotian NPD. The female-to-male ratio was 2 to 1. Five of the children had severe neonatal jaundice. Early milestones were normal in the majority. Neurologic symptoms developed between 5 and 10 years of age, with a mean age at diagnosis of 7.2 years. Seizures developed in all children between 4.5 and 16 years of age and were followed by significant physical and mental deterioration. Age at death was between 11 and 22.5 years, with the majority dying of pneumonia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9512307" 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>Niemann-Pick disease type C is an autosomal recessive disorder (<a href="#76" class="mim-tip-reference" title="Vanier, M. T., Millat, G. &lt;strong&gt;Niemann-Pick disease type C.&lt;/strong&gt; Clin. Genet. 64: 269-281, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12974729/&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;12974729&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1034/j.1399-0004.2003.00147.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="12974729">Vanier and Millat, 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12974729" 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>Inheritance of Type D</em></strong></p><p>
<a href="#83" class="mim-tip-reference" title="Winsor, E. J. T., Welch, J. P. &lt;strong&gt;Genetic and demographic aspects of Nova Scotia Niemann-Pick disease (type D).&lt;/strong&gt; Am. J. Hum. Genet. 30: 530-538, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/736041/&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;736041&lt;/a&gt;]" pmid="736041">Winsor and Welch (1978)</a> gave a full genetic discussion of the Nova Scotian or type D Niemann-Pick disease. They identified 19 cases distributed in 15 sibships, in French Acadians of Yarmouth County, N.S. All 30 parents traced back to Joseph Muise, married to Marie Amirault, who lived in the late 1600s and early 1700s. Two other common ancestral couples were identified, but the Muise-Amirault couple had by far the largest number of 'valid coincidences.' (Since all forebears of a common ancestor appear on both sides of the pedigree, not every match will indicate a 'real' common ancestor, which occurs when the common ancestor's child on the father's side is different on the mother's side. <a href="#48" class="mim-tip-reference" title="Mange, A. P. &lt;strong&gt;Fortran programs for computing Wright&#x27;s coefficient of inbreeding in human and nonhuman pedigrees. (Letter)&lt;/strong&gt; Am. J. Hum. Genet. 16: 484, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17948490/&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;17948490&lt;/a&gt;]" pmid="17948490">Mange (1964)</a> termed the latter situation a 'valid coincidence.') Carrier frequency was presumably high, because none of the affected sibships had closely related parents and because a considerable proportion of children chosen at random could be traced to the Muise couple. <a href="#25" class="mim-tip-reference" title="Fredrickson, D. S., Sloan, H. R. &lt;strong&gt;Sphingomyelin lipidosis: Niemann-Pick disease. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.): The Metabolic Basis of Inherited Disease. (3rd ed.)&lt;/strong&gt; New York: McGraw-Hill (pub.) 1972. Pp. 783-807."None>Fredrickson and Sloan (1972)</a> described 3 sibs with a disorder clinically identical to the Nova Scotian disorder. The father could be traced to the Muise couple; the mother was Italian. <a href="#83" class="mim-tip-reference" title="Winsor, E. J. T., Welch, J. P. &lt;strong&gt;Genetic and demographic aspects of Nova Scotia Niemann-Pick disease (type D).&lt;/strong&gt; Am. J. Hum. Genet. 30: 530-538, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/736041/&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;736041&lt;/a&gt;]" pmid="736041">Winsor and Welch (1978)</a> suggested these children might have a genetic compound disorder, the Acadian mutation being unique. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=736041+17948490" 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="#3" class="mim-tip-reference" title="Argoff, C. E., Kaneski, C. R., Blanchette-Mackie, E. J., Comly, M., Dwyer, N. K., Brown, A., Brady, R. O., Pentchev, P. G. &lt;strong&gt;Type C Niemann-Pick disease: documentation of abnormal LDL processing in lymphocytes.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 171: 38-45, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2393397/&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;2393397&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0006-291x(90)91353-t&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="2393397">Argoff et al. (1990)</a> suggested that assay for the deficiency, which shows impaired ability of cultured fibroblasts to esterify exogenously supplied cholesterol, is useful for confirming the diagnosis in patients with atypical presentation. <a href="#8" class="mim-tip-reference" title="Boustany, R.-M. N., Kaye, E., Alroy, J. &lt;strong&gt;Ultrastructural findings in skin from patients with Niemann-Pick disease, type C.&lt;/strong&gt; Pediat. Neurol. 6: 177-183, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2360958/&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;2360958&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0887-8994(90)90059-a&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="2360958">Boustany et al. (1990)</a> a suggested that characteristic ultrastructural changes may be useful to the diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2393397+2360958" 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="#77" class="mim-tip-reference" title="Vanier, M. T., Rodriguez-Lafrasse, C., Rousson, R., Duthel, S., Harzer, K., Pentchev, P. G., Revol, A., Louisot, P. &lt;strong&gt;Type C Niemann-Pick disease: biochemical aspects and phenotypic heterogeneity.&lt;/strong&gt; Dev. Neurosci. 13: 307-314, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1817036/&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;1817036&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000112178&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="1817036">Vanier et al. (1991)</a> reported on a personal experience with 134 cases, which indicated that the diagnosis is best reached by the combined demonstration of a deficient induction of esterification of cholesterol and of an intravesicular cholesterol storage by cytochemistry after filipin staining. They gave brief reports of 6 adult-onset cases. Although there was a wide phenotypic spectrum, complementation studies yielded no evidence of separate complementation groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1817036" 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="#17" class="mim-tip-reference" title="Ceuterick, C., Martin, J. J. &lt;strong&gt;Nerve biopsy findings in Niemann-Pick type II (NPC). (Letter)&lt;/strong&gt; Acta Neuropath. 88: 602-603, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7879612/&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;7879612&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00296502&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="7879612">Ceuterick and Martin (1994)</a> demonstrated osmiophilic pleomorphic lamellar inclusions in dermal fibroblasts and perivascular histiocytes in skin biopsies in 8 Niemann-Pick type C patients but not in 473 controls. They emphasized that a skin biopsy may be useful diagnostically. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7879612" 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="#33" class="mim-tip-reference" title="Imrie, J., Wraith, J. E. &lt;strong&gt;Niemann-Pick disease type C.&lt;/strong&gt; Arch. Dis. Child. 84: 427-429, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11316691/&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;11316691&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.84.5.427&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="11316691">Imrie and Wraith (2001)</a> described 4 patients with Niemann-Pick disease type C in whom the presentation was isolated splenic enlargement; this remained the only abnormality for a number of years. They stated that the diagnosis can be suggested by either finding abnormal storage material in a tissue biopsy specimen or by showing a modest elevation in plasma chitotriosidase activity. In patients with suggestive abnormalities, filipin staining of a skin fibroblast sample should confirm the abnormality in cholesterol trafficking. They suggested that formal esterification studies and mutation analysis should be performed, especially if prenatal testing is to be done in subsequent pregnancies. If the diagnosis is not considered and established, the family is at risk of having further affected children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11316691" 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>The biochemical diagnosis of NPC relies on the use of patient skin fibroblasts in an assay to demonstrate delayed low-density lipoprotein (LDL)-derived cholesterol esterification and a cytologic technique (filipin staining) to demonstrate the intracellular accumulation of cholesterol. A few patients, referred to as 'NPC variants,' present with clinical symptoms of NPC but show near-normal results of these biochemical tests. <a href="#71" class="mim-tip-reference" title="Sun, X., Marks, D. L., Park, W. D., Wheatley, C. L., Puri, V., O&#x27;Brien, J. F., Kraft, D. L., Lundquist, P. A., Patterson, M. C., Pagano, R. E., Snow, K. &lt;strong&gt;Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1.&lt;/strong&gt; Am. J. Hum. Genet. 68: 1361-1372, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11349231/&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;11349231&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11349231[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/10.1086/320599&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="11349231">Sun et al. (2001)</a> demonstrated that NPC-variant fibroblast samples can be detected as sphingolipid storage disease cells by using a fluorescent sphingolipid analog that accumulates in endosomes/lysosomes in variant cells preincubated with LDL cholesterol but targeted to the Golgi complex in normal cells under these conditions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11349231" 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="#67" class="mim-tip-reference" title="Sidhu, R., Kell, P., Dietzen, D. J., Farhat, N. Y., Do, A. N. D., Porter, F. D., Brry-Kravis, E., Vite, C. H., Reunert, J., Marquardt, T., Giugliani, R., Lourenco, C. M., Bodamer, O., Wang, R. Y., Plummer, E., Schaffer, J. E., Ory, D., Jiang, X. &lt;strong&gt;Application of N-palmitoyl-O-phosphocholineserine for diagnosis and assessment of response to treatment in Niemann-Pick type C disease.&lt;/strong&gt; Molec. Genet. Metab. 129: 292-302, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32033912/&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;32033912&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=32033912[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/10.1016/j.ymgme.2020.01.007&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="32033912">Sidhu et al. (2020)</a> developed and validated a mass spectrometry method to measure N-palmitoyl-O-phosphocholineserine (PPCS), a lipid found to be elevated in NPC1, in biomaterials including plasma, serum, and cerebrospinal fluid (CSF). At a cutoff of 248 ng/mL in plasma, PPCS has 100% specificity and 96.6% specificity in differentiating NPC1 patients from controls and NPC1 carriers, respectively. <a href="#67" class="mim-tip-reference" title="Sidhu, R., Kell, P., Dietzen, D. J., Farhat, N. Y., Do, A. N. D., Porter, F. D., Brry-Kravis, E., Vite, C. H., Reunert, J., Marquardt, T., Giugliani, R., Lourenco, C. M., Bodamer, O., Wang, R. Y., Plummer, E., Schaffer, J. E., Ory, D., Jiang, X. &lt;strong&gt;Application of N-palmitoyl-O-phosphocholineserine for diagnosis and assessment of response to treatment in Niemann-Pick type C disease.&lt;/strong&gt; Molec. Genet. Metab. 129: 292-302, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32033912/&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;32033912&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=32033912[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/10.1016/j.ymgme.2020.01.007&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="32033912">Sidhu et al. (2020)</a> also found that elevation of PPCS in CSF from patients with NPC1 correlates with NPC neurologic disease severity scores. In a clinical trial with intravenous 2-hydroxypropyl-beta-cyclodextrin, plasma PPCS was significantly reduced, thus demonstrating that this biomarker can be used to evaluate the peripheral treatment efficacy of intravenous 2-hydroxypropyl-beta-cyclodextrin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32033912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Boenzi, S., Catesini, G., Sacchetti, E., Tagliaferri, F., Dionisi-Vici, C., Deodato, F. &lt;strong&gt;Comprehensive-targeted lipidomic analysis in Niemann-Pick C disease.&lt;/strong&gt; Molec. Genet. Metab. 134: 337-343, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34810067/&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;34810067&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2021.11.005&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="34810067">Boenzi et al. (2021)</a> performed lipidomics analysis in plasma of 15 patients with Niemann-Pick disease type C and 15 controls. Classic NPC biomarkers including 2 oxysterols (7-ketocholesterol and Triol) and 2 lyso-sphingolipids (Lyso-SM and Lyso-SM-509) were elevated in patients compared to controls. <a href="#7" class="mim-tip-reference" title="Boenzi, S., Catesini, G., Sacchetti, E., Tagliaferri, F., Dionisi-Vici, C., Deodato, F. &lt;strong&gt;Comprehensive-targeted lipidomic analysis in Niemann-Pick C disease.&lt;/strong&gt; Molec. Genet. Metab. 134: 337-343, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34810067/&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;34810067&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2021.11.005&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="34810067">Boenzi et al. (2021)</a> found a significant positive correlation between these 4 biomarkers and 7 main lipid species that were elevated in the NPC1 patients and a significant negative correlation between these 4 biomarkers and 6 main lipid species that were decreased in the NPC1 patients. <a href="#7" class="mim-tip-reference" title="Boenzi, S., Catesini, G., Sacchetti, E., Tagliaferri, F., Dionisi-Vici, C., Deodato, F. &lt;strong&gt;Comprehensive-targeted lipidomic analysis in Niemann-Pick C disease.&lt;/strong&gt; Molec. Genet. Metab. 134: 337-343, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34810067/&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;34810067&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2021.11.005&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="34810067">Boenzi et al. (2021)</a> noted that the altered plasma lipid profiles in the NPC1 patients involved lipids involved in processes such as inflammation and cell oxidative stress regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34810067" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The locus corresponding to the mouse NPC phenotype (<a href="#54" class="mim-tip-reference" title="Pentchev, P. G., Boothe, A. D., Kruth, H. S., Weintroub, H., Stivers, J., Brady, R. O. &lt;strong&gt;A genetic storage disorder in BALB/C mice with a metabolic block in esterification of exogenous cholesterol.&lt;/strong&gt; J. Biol. Chem. 259: 5784-5791, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6325448/&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;6325448&lt;/a&gt;]" pmid="6325448">Pentchev et al., 1984</a>), symbolized spm, was shown by <a href="#63" class="mim-tip-reference" title="Sakai, Y., Miyawaki, S., Shimizu, A., Ohno, K., Watanabe, T. &lt;strong&gt;A molecular genetic linkage map of mouse chromosome 18, including spm, Grl-1, Fim-2/c-fms, and Mbp.&lt;/strong&gt; Biochem. Genet. 29: 103-113, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1679325/&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;1679325&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00578243&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="1679325">Sakai et al. (1991)</a> to be on mouse chromosome 18. Since mouse chromosome 18 has extensive syntenic homology with human chromosomes 5 and 18, <a href="#16" class="mim-tip-reference" title="Carstea, E. D., Polymeropoulos, M. H., Parker, C. C., Detera-Wadleigh, S. D., O&#x27;Neill, R. R., Patterson, M. C., Goldin, E., Xiao, H., Straub, R. E., Vanier, M. T., Brady, R. O., Pentchev, P. G. &lt;strong&gt;Linkage of Niemann-Pick disease type C to human chromosome 18.&lt;/strong&gt; Proc. Nat. Acad. Sci. 90: 2002-2004, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8446622/&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;8446622&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.90.5.2002&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="8446622">Carstea et al. (1993)</a> undertook linkage analysis with markers specific to these chromosomes. No linkage was found with chromosome 5, but strong evidence of linkage was found with chromosome 18. Within affected offspring, the chromosome 18 parental contribution was identical, as demonstrated by allele-specific microsatellite markers. Significant linkage of NPC to an 18p genomic marker, D18S40, was indicated by a 2-point lod score of 3.84. Three recombinants detected among the 28 informative individuals represented a recombination fraction of 0.07. Analysis of meiotic chromosomal breakpoint patterns among the affected individuals indicated that the NPC gene is located in the pericentromeric region of chromosome 18, probably on the short arm. In their Figure 2, <a href="#16" class="mim-tip-reference" title="Carstea, E. D., Polymeropoulos, M. H., Parker, C. C., Detera-Wadleigh, S. D., O&#x27;Neill, R. R., Patterson, M. C., Goldin, E., Xiao, H., Straub, R. E., Vanier, M. T., Brady, R. O., Pentchev, P. G. &lt;strong&gt;Linkage of Niemann-Pick disease type C to human chromosome 18.&lt;/strong&gt; Proc. Nat. Acad. Sci. 90: 2002-2004, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8446622/&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;8446622&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.90.5.2002&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="8446622">Carstea et al. (1993)</a> demonstrated how chromosome 18 was divided into 6 regions, designated A through F, and how meiotic recombination resulted in divergent segregation of one or more markers and the NPC phenotype. Only 1 of the 6 intervals, a pericentromeric one, showed no evidence of meiotic recombination. By linkage studies, <a href="#15" class="mim-tip-reference" title="Carstea, E. D., Parker, C. C., Fandino, L. B., Vanier, M. T., Overhauser, J., Weissenbach, J., Pentchev, P. G., Brady, R. O., Polymeropoulos, M. H. &lt;strong&gt;Localizing the human Niemann-Pick C gene to 18q11-12. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 55 (suppl.): A182, 1994."None>Carstea et al. (1994)</a> located the NPC gene to a region defined by DNA markers in the 18q11-q12 region. In 1 family linkage to this region was excluded, suggesting the existence of a separate gene that codes for an additional component required for intracellular movement of cholesterol (see below). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8446622+6325448+1679325" 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="#28" class="mim-tip-reference" title="Greer, W. L., Riddell, D. C., Byers, D. M., Welch, J. P., Girouard, G. S., Sparrow, S. M., Gillan, T. L., Neumann, P. E. &lt;strong&gt;Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C.&lt;/strong&gt; Am. J. Hum. Genet. 61: 139-142, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9245994/&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;9245994&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/513899&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="9245994">Greer et al. (1997)</a> presented linkage evidence supporting allelism of NPC and NPD. They found that NPD in Nova Scotia is tightly linked (recombination fraction = 0.00; maximum lod score = 4.50) to a microsatellite marker, D18S480, from the centromeric region of 18q. This is the same site as that to which the NPC1 gene (<a href="/entry/607623">607623</a>) was mapped by <a href="#15" class="mim-tip-reference" title="Carstea, E. D., Parker, C. C., Fandino, L. B., Vanier, M. T., Overhauser, J., Weissenbach, J., Pentchev, P. G., Brady, R. O., Polymeropoulos, M. H. &lt;strong&gt;Localizing the human Niemann-Pick C gene to 18q11-12. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 55 (suppl.): A182, 1994."None>Carstea et al. (1994)</a>. In a study of a single large kindred with NPD, <a href="#30" class="mim-tip-reference" title="Greer, W. L., Riddell, D. C., Murty, S., Gillan, T. L., Girouard, G. S., Sparrow, S. M., Tatlidil, C., Dobson, M. J., Neumann, P. E. &lt;strong&gt;Linkage disequilibrium mapping of the Nova Scotia variant of Niemann-Pick disease.&lt;/strong&gt; Clin. Genet. 55: 248-255, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10361985/&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;10361985&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1034/j.1399-0004.1999.550406.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="10361985">Greer et al. (1999)</a> used linkage disequilibrium mapping and 5 newly developed polymorphic microsatellite markers to narrow the NPC1 critical region to a 5-cM interval. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9245994+10361985" 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="heterogeneity" class="mim-anchor"></a>
<h4 href="#mimHeterogeneityFold" id="mimHeterogeneityToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Heterogeneity</strong>
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<p><strong><em>Genetic Heterogeneity</em></strong></p><p>
To investigate the possibility that mutation at more than one locus can cause the disorder, <a href="#70" class="mim-tip-reference" title="Steinberg, S. J., Ward, C. P., Fensom, A. H. &lt;strong&gt;Complementation studies in Niemann-Pick disease type C indicate the existence of a second group.&lt;/strong&gt; J. Med. Genet. 31: 317-320, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8071958/&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;8071958&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.31.4.317&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="8071958">Steinberg et al. (1994)</a> undertook somatic cell hybridization experiments using skin fibroblast strains from 12 patients representing a wide clinical spectrum. Using filipin staining of free cholesterol as a marker for complementation, they found evidence for the existence of 1 major group, called group alpha, and a minor group, called group beta, represented by 1 mutant strain. Other experiments in which sphingomyelinase activity was measured as a marker for complementation using 5 mutant strains showed activity consistently less than 40% of control levels, confirming the existence of the second group, later termed NPC2. Further support for the genetic heterogeneity was provided by <a href="#75" class="mim-tip-reference" title="Vanier, M. T., Duthel, S., Rodriguez-Lafrasse, C., Pentchev, P., Carstea, E. D. &lt;strong&gt;Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis.&lt;/strong&gt; Am. J. Hum. Genet. 58: 118-125, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8554047/&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;8554047&lt;/a&gt;]" pmid="8554047">Vanier et al. (1996)</a> from complementation studies by somatic cell hybridization and linkage analysis. Crosses between various cell lines revealed a major complementation group (type C1) comprising 27 unrelated patients and a second minor group (type C2) comprising 5 patients. Linkage analysis in a multiplex family belonging to the minor complementation group showed that the mutated gene did not map to 18q11-q12 where the major gene is located. Patients in the first group spanned the whole spectrum of clinical and cellular phenotypes. No consistent clinical or biochemical phenotype was associated with the second complementation group; however, 3 of the 5 patients in group 2 presented with severe pulmonary involvement leading to death with the first year of life (see NPC2; <a href="/entry/607625">607625</a>). The causative NPC2 gene was later identified (see <a href="/entry/601015">601015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8554047+8071958" 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="#76" class="mim-tip-reference" title="Vanier, M. T., Millat, G. &lt;strong&gt;Niemann-Pick disease type C.&lt;/strong&gt; Clin. Genet. 64: 269-281, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12974729/&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;12974729&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1034/j.1399-0004.2003.00147.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="12974729">Vanier and Millat (2003)</a> stated that approximately 95% of patients with Niemann-Pick disease type C have mutations in the NPC1 gene, which encodes a large membrane glycoprotein primarily located to late endosomes, and the remainder have mutations in the NPC2 gene, which encodes a small soluble lysosomal protein with cholesterol-binding properties. The identical biochemical patterns observed in NPC1 and NPC2 mutants suggested that the 2 proteins function in a coordinate fashion. The NPC1 and NPC2 proteins are involved in the cellular postlysosomal/late endosomal transport of cholesterol, glycolipids, and other cargo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12974729" 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>
<h4 href="#mimPathogenesisFold" id="mimPathogenesisToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Pathogenesis</strong>
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<p><a href="#9" class="mim-tip-reference" title="Brady, R. O. &lt;strong&gt;Sphingomyelin lipidosis: Niemann-Pick disease. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.): Metabolic Basis of Inherited Disease. (4th ed.)&lt;/strong&gt; New York: McGraw-Hill (pub.) 1978. Pp. 718-730."None>Brady (1978)</a> pointed out that sphingomyelinase is deficient in type C as well as in types A and B. Although he stated that total sphingomyelinase activity may be 'attenuated' in some patients with types D and E, he raised doubts about the classification of type D as a sphingomyelin storage disease.</p><p>On the basis of somatic cell hybridization studies, <a href="#5" class="mim-tip-reference" title="Besley, G. T. N., Hoogeboom, A. J. M., Hoogeveen, A., Kleijer, W. J., Galjaard, H. &lt;strong&gt;Somatic cell hybridisation studies showing different gene mutations in Niemann-Pick variants.&lt;/strong&gt; Hum. Genet. 54: 409-412, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6249719/&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;6249719&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00291589&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="6249719">Besley et al. (1980)</a> suggested that types A and B may be genetically distinct from type C. Fusion of type C cells with either type A or type B cells resulted in restoration of sphingomyelinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6249719" 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="#27" class="mim-tip-reference" title="Gilbert, E. F., Callahan, J., Viseskul, C., Opitz, J. M. &lt;strong&gt;Niemann-Pick disease type C: pathological, histochemical, ultrastructural and biochemical studies.&lt;/strong&gt; Europ. J. Pediat. 136: 263-274, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7262098/&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;7262098&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00442993&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="7262098">Gilbert et al. (1981)</a> reported extensively on the cases of 2 sisters who died at ages 8 and 7 years of the progressive CNS degenerative process of Niemann-Pick disease type C. Biochemical analyses showed elevated levels of sphingomyelin in liver and spleen with normal total sphingomyelinase activity. However, by isoelectric focusing, sphingomyelinase activity in the range of pI 4.6-5.2 was markedly reduced, whereas normal amounts of more acidic components were found. A similar explanation for 'Niemann-Pick disease without sphingomyelinase deficiency' may obtain in other cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7262098" 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="#56" class="mim-tip-reference" title="Pentchev, P. G., Comly, M. E., Kruth, H. S., Vanier, M. T., Wenger, D. A., Patel, S., Brady, R. O. &lt;strong&gt;A defect in cholesterol esterification in Niemann-Pick disease (type C) patients.&lt;/strong&gt; Proc. Nat. Acad. Sci. 82: 8247-8251, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3865225/&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;3865225&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.82.23.8247&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="3865225">Pentchev et al. (1985)</a> were prompted to study cholesterol esterification in Niemann-Pick disease because of the similar phenotypic findings in a murine mutation affecting cholesterol esterification (<a href="#54" class="mim-tip-reference" title="Pentchev, P. G., Boothe, A. D., Kruth, H. S., Weintroub, H., Stivers, J., Brady, R. O. &lt;strong&gt;A genetic storage disorder in BALB/C mice with a metabolic block in esterification of exogenous cholesterol.&lt;/strong&gt; J. Biol. Chem. 259: 5784-5791, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6325448/&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;6325448&lt;/a&gt;]" pmid="6325448">Pentchev et al., 1984</a>). They found esterification to be normal in 6 type A and 8 type B Niemann-Pick cell lines. In striking contrast, all 24 type C Niemann-Pick cell lines showed a major block in cholesterol esterification, whereas internalization and lysosomal processing of lipoprotein cholesterol was apparently normal. Acyl-CoA:cholesterol acyltransferase activity was also normal in type C cell extracts. Fluorescent microscopy showed that type C cells grown in fetal calf serum stored much unesterified cholesterol. The partial expression of the esterification defect (50% of normal) in heterozygous mice indicated that it is the primary fault. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6325448+3865225" 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="Kruth, H. S., Comly, M. E., Butler, J. D., Vanier, M. T., Fink, J. K., Wenger, D. A., Patel, S., Pentchev, P. G. &lt;strong&gt;Type C Niemann-Pick disease: abnormal metabolism of low density lipoprotein in homozygous and heterozygous fibroblasts.&lt;/strong&gt; J. Biol. Chem. 261: 16769-16774, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3782141/&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;3782141&lt;/a&gt;]" pmid="3782141">Kruth et al. (1986)</a> and <a href="#58" class="mim-tip-reference" title="Pentchev, P. G., Kruth, H. S., Comly, M. E., Butler, J. D., Vanier, M. T., Wenger, D. A., Patel, S. &lt;strong&gt;Type C Niemann-Pick disease: a parallel loss of regulatory responses in both the uptake and esterification of low-density lipoprotein-derived cholesterol in cultured fibroblasts.&lt;/strong&gt; J. Biol. Chem. 261: 16775-16780, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3782142/&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;3782142&lt;/a&gt;]" pmid="3782142">Pentchev et al. (1986)</a> discussed the abnormality of cholesterol metabolism in this disorder. In both heterozygous and homozygous type C Niemann-Pick fibroblasts, excessive uptake of LDL cholesterol and deficient esterification of the internalized cholesterol were observed. As reported by <a href="#57" class="mim-tip-reference" title="Pentchev, P. G., Comly, M. E., Vanier, M. T., Kruth, H. S., Patel, S., Brady, R. O. &lt;strong&gt;Type C Niemann-Pick disease: a defect in intracellular esterification. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 37: A15, 1985."None>Pentchev et al. (1985)</a>, <a href="#43" class="mim-tip-reference" title="Liscum, L., Faust, J. R. &lt;strong&gt;Low density lipoprotein (LDL)-mediated suppression of cholesterol synthesis and LDL uptake is defective in Niemann-Pick type C fibroblasts.&lt;/strong&gt; J. Biol. Chem. 262: 17002-17008, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3680287/&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;3680287&lt;/a&gt;]" pmid="3680287">Liscum and Faust (1987)</a> found that LDL does not stimulate cholesterol esterification in this disorder; however, they also showed that LDL does not down-regulate cholesterol synthesis or LDL receptor activity normally. They suggested that the intracellular processing of LDL-derived cholesterol may be defective in NPC fibroblasts. This suggestion was corroborated by the findings of <a href="#68" class="mim-tip-reference" title="Sokol, J., Blanchette-Mackie, E. J., Kruth, H. S., Dwyer, N. K., Amende, L. M., Butler, J. D., Robinson, E., Patel, S., Brady, R. O., Comly, M. E., Vanier, M. T., Pentchev, P. G. &lt;strong&gt;Type C Niemann-Pick disease: lysosomal accumulation and defective intracellular mobilization of low density lipoprotein cholesterol.&lt;/strong&gt; J. Biol. Chem. 263: 3411-3417, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3277970/&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;3277970&lt;/a&gt;]" pmid="3277970">Sokol et al. (1988)</a>, who examined the intracellular accumulation of unesterified cholesterol in normal and Niemann-Pick C fibroblasts. They found that the plasma membrane cholesterol of normal cells was more readily replenished by internalized LDL cholesterol than that of mutant fibroblasts. Their studies suggested that deficient translocation of exogenously derived cholesterol from lysosomes to other intracellular membrane sites may have an important pathophysiologic role in type C Niemann-Pick disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3782142+3277970+3782141+3680287" 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="#78" class="mim-tip-reference" title="Vanier, M. T., Wenger, D. A., Comly, M. E., Rousson, R., Brady, R. O., Pentchev, P. G. &lt;strong&gt;Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification: a collaborative study on 70 patients.&lt;/strong&gt; Clin. Genet. 33: 331-348, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3378364/&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;3378364&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1988.tb03460.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="3378364">Vanier et al. (1988)</a> demonstrated that cultured homozygous NPC cells challenged with pure human low-density lipoproteins showed a pronounced deficiency in cholesterol esterification and that heterozygotes showed intermediate rates of esterification. All other pathologic conditions studied, including types A and B Niemann-Pick disease, gave normal results. There appeared to be a correlation between the clinical phenotype and severity of the biochemical lesion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3378364" 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="#6" class="mim-tip-reference" title="Blanchette-Mackie, E. J., Dwyer, N. K., Amende, L. M., Kruth, H. S., Butler, J. D., Sokol, J., Comly, M. E., Vanier, M. T., August, J. T., Brady, R. O., Pentchev, P. G. &lt;strong&gt;Type-C Niemann-Pick disease: low density lipoprotein uptake is associated with premature cholesterol accumulation in the Golgi complex and excessive cholesterol storage in lysosomes.&lt;/strong&gt; Proc. Nat. Acad. Sci. 85: 8022-8026, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3186703/&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;3186703&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.85.21.8022&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="3186703">Blanchette-Mackie et al. (1988)</a> showed that incubation of fibroblasts from patients with type C Niemann-Pick disease with low density lipoprotein resulted in excessive intracellular accumulation of unesterified cholesterol not only in lysosomes but also at an early stage in the Golgi complex. They suggested that the Golgi complex may play a role in the intracellular translocation of exogenously derived cholesterol and that disruptions of the cholesterol transport pathway at the Golgi may, in part, be responsible for the deficiency in cholesterol utilization in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3186703" 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="#72" class="mim-tip-reference" title="Thomas, G. H., Tuck-Muller, C. M., Miller, C. S., Reynolds, L. W. &lt;strong&gt;Correction of sphingomyelinase deficiency in Niemann-Pick type C fibroblasts by removal of lipoprotein fraction from culture media.&lt;/strong&gt; J. Inherit. Metab. Dis. 12: 139-151, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2547109/&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;2547109&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01800716&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="2547109">Thomas et al. (1989)</a> found that the sphingomyelinase deficiency (37.9% of normal on the average) could be corrected in fibroblasts from Niemann-Pick type C patients by removal of the lipoprotein fraction from the culture medium. This is consistent with the view that the primary defect is one affecting the cellular transport and/or processing of free cholesterol and that it is the intracellular storage of cholesterol that causes a marked attenuation of lysosomal sphingomyelinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2547109" 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>Although some biochemical differences may exist between type C and type D Niemann-Pick disease, both show evidence of defective regulation of intracellular cholesterol esterification and storage. Complementation of cholesterol esterification was not observed either when NPC and NPD fibroblasts were fused with polyethylene glycol (<a href="#66" class="mim-tip-reference" title="Sidhu, H. S., Rastogi, S. A. R., Byers, D. M., Guernsey, D. L., Cook, H. W., Palmer, F. B. St. C., Spence, M. W. &lt;strong&gt;Regulation of low density lipoprotein receptor and 3-hydroxy-3-methyl-glutaryl-CoA reductase activities are differentially affected in Niemann-Pick type C and type D fibroblasts.&lt;/strong&gt; Biochem. Cell Biol. 71: 467-474, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8192899/&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;8192899&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1139/o93-069&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="8192899">Sidhu et al., 1993</a>) or when activity was measured directly in mixed-cell homogenates (<a href="#13" class="mim-tip-reference" title="Byers, D. M., Rastogi, S. R., Cook, H. W., Palmer, F. B. St. C., Spence, M. W. &lt;strong&gt;Defective activity of acyl-CoA: cholesterol O-acyltransferase in Niemann-Pick type C and type D fibroblasts.&lt;/strong&gt; Biochem. J. 262: 713-719, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2590161/&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;2590161&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1042/bj2620713&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="2590161">Byers et al., 1989</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2590161+8192899" 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="#61" class="mim-tip-reference" title="Roff, C. F., Goldin, E., Comly, M. E., Cooney, A., Brown, A., Vanier, M. T., Miller, S. P. F., Brady, R. O., Pentchev, P. G. &lt;strong&gt;Type C Niemann-Pick disease: use of hydrophobic amines to study defective cholesterol transport.&lt;/strong&gt; Dev. Neurosci. 13: 315-319, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1817037/&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;1817037&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000112179&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="1817037">Roff et al. (1991)</a> pointed out that a number of hydrophobic amines such as imipramine inhibit low-density lipoprotein-induced esterification of cholesterol and cause unesterified cholesterol to accumulate in perinuclear vesicles. When stained with filipin, the appearance is indistinguishable from that seen in NPC fibroblasts. Thus, these agents produce a cholesterol lipidosis similar to that of NPC, which is due to defective post-lysosomal cholesterol transport. <a href="#61" class="mim-tip-reference" title="Roff, C. F., Goldin, E., Comly, M. E., Cooney, A., Brown, A., Vanier, M. T., Miller, S. P. F., Brady, R. O., Pentchev, P. G. &lt;strong&gt;Type C Niemann-Pick disease: use of hydrophobic amines to study defective cholesterol transport.&lt;/strong&gt; Dev. Neurosci. 13: 315-319, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1817037/&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;1817037&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000112179&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="1817037">Roff et al. (1991)</a> raised the possibility that an endogenous hydrophobic amine such as sphinganine may inhibit cholesterol transport in NPC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1817037" 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>Nerve cells demonstrate not only storage of cholesterol but also neurofibrillary tangles containing paired helical filaments, similar to the neurofibrillary tangles present in Alzheimer disease (see <a href="/entry/104300">104300</a>), Kufs disease (see <a href="/entry/204300">204300</a>), Down syndrome (<a href="/entry/190685">190685</a>), tuberous sclerosis (see <a href="/entry/191100">191100</a>), progressive supranuclear palsy (<a href="/entry/601104">601104</a>), and neurodegeneration with brain iron accumulation-1 (NBIA1; <a href="/entry/234200">234200</a>), among others. The presence of neurofibrillary tangles in Niemann-Pick type C distinguishes it from other types of Niemann-Pick disease. <a href="#4" class="mim-tip-reference" title="Auer, I. A., Schmidt, M. L., Lee, V. M.-Y., Curry, B., Suzuki, K., Shin, R.-W., Pentchev, P. G., Carstea, E. D., Trojanowski, J. Q. &lt;strong&gt;Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer&#x27;s disease.&lt;/strong&gt; Acta Neuropath. 90: 547-551, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8615074/&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;8615074&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00318566&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="8615074">Auer et al. (1995)</a> demonstrated tau protein (<a href="/entry/157140">157140</a>) in Western blots from brain tissue in 5 cases of Niemann-Pick type C. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8615074" 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 3 patients in their thirties with genetically confirmed Niemann-Pick disease type C who were homozygous for the APOE4 (<a href="/entry/107741">107741</a>) allele, <a href="#62" class="mim-tip-reference" title="Saito, Y., Suzuki, K., Nanba, E., Yamamoto, T., Ohno, K., Murayama, S. &lt;strong&gt;Niemann-Pick type C disease: accelerated neurofibrillary tangle formation and amyloid beta deposition associated with apolipoprotein E epsilon-4 homozygosity.&lt;/strong&gt; Ann. Neurol. 52: 351-355, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12205649/&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;12205649&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10266&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="12205649">Saito et al. (2002)</a> found abundant neurofibrillary tangles, widespread increased beta-amyloid diffuse plaques, and severe tau pathology. The authors suggested that NPC1 gene mutations combined with homozygosity of APOE4 alleles leads to pathology similar to that found in Alzheimer disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12205649" 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="#74" class="mim-tip-reference" title="Vance, J. E. &lt;strong&gt;Lipid imbalance in the neurological disorder, Niemann-Pick C disease.&lt;/strong&gt; FEBS Lett. 580: 5518-5524, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16797010/&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;16797010&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.febslet.2006.06.008&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="16797010">Vance (2006)</a> provided a detailed review of the cellular mechanisms of lipid imbalance in NPC. Accumulation of cholesterol and gangliosides disrupts intracellular trafficking and affects normal cholesterol use within the cell. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16797010" 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="Lloyd-Evans, E., Morgan, A. J., He, X., Smith, D. A., Elliot-Smith, E., Sillence, D. J., Churchill, G. C., Schuchman, E. H., Galione, A., Platt, F. M. &lt;strong&gt;Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium.&lt;/strong&gt; Nature Med. 14: 1247-1255, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18953351/&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;18953351&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm.1876&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="18953351">Lloyd-Evans et al. (2008)</a> found that lysosomal sphingosine storage and reduced lysosomal calcium levels were early events in development of the NPC phenotype in normal human cells exposed to the NPC-inducing drug U18666A. In this model, accumulation of cholesterol, sphingomyelin, and glycerosphingolipid was a secondary event. Pharmacologic elevation of cytosolic calcium or reduction of sphingosine content reversed the NPC phenotype in several cellular models of NPC, and sphingosine alone induced the abnormal calcium phenotype in a concentration-dependent manner. Treatment of Npc1 -/- mice with curcumin, a weak SERCA (see <a href="/entry/108730">108730</a>) antagonist that elevates cytosolic calcium levels, increased life expectancy by 35% and slowed the rate of disease progression by 3 weeks. <a href="#45" class="mim-tip-reference" title="Lloyd-Evans, E., Morgan, A. J., He, X., Smith, D. A., Elliot-Smith, E., Sillence, D. J., Churchill, G. C., Schuchman, E. H., Galione, A., Platt, F. M. &lt;strong&gt;Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium.&lt;/strong&gt; Nature Med. 14: 1247-1255, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18953351/&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;18953351&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm.1876&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="18953351">Lloyd-Evans et al. (2008)</a> concluded that NPC1 is involved in sphingosine efflux from lysosomes, and that lysosomal sphingosine accumulation in NPC alters intracellular calcium concentration and causes abnormal endocytic trafficking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18953351" 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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<p>In several patients with Niemann-Pick disease type C, <a href="#14" class="mim-tip-reference" title="Carstea, E. D., Morris, J. A., Coleman, K. G., Loftus, S. K., Zhang, D., Cummings, C., Gu, J., Rosenfeld, M. A., Pavan, W. J., Krizman, D. B., Nagle, J., Polymeropoulos, M. H., and 26 others. &lt;strong&gt;Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.&lt;/strong&gt; Science 277: 228-231, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9211849/&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;9211849&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.277.5323.228&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="9211849">Carstea et al. (1997)</a> identified mutations in the NPC1 gene (<a href="/entry/607623#0001">607623.0001</a>-<a href="/entry/607623#0003">607623.0003</a>). In a study of cDNA and genomic DNA isolated from the fibroblasts of 11 patients with NPC1, 10 Japanese (7 late infantile, 2 juvenile, and 1 adult form of the disease) and 1 Caucasian, <a href="#86" class="mim-tip-reference" title="Yamamoto, T., Nanba, E., Ninomiya, H., Higaki, K., Taniguchi, M., Zhang, H., Akaboshi, S., Watanabe, Y., Takeshima, T., Inui, K., Okada, S., Tanaka, A., Sakuragawa, N., Millat, G., Vanier, M. T., Morris, J. A., Pentchev, P. G., Ohno, K. &lt;strong&gt;NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C.&lt;/strong&gt; Hum. Genet. 105: 10-16, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10480349/&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;10480349&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004399900059&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="10480349">Yamamoto et al. (1999)</a> found 14 novel mutations in the NPC1 gene, including small deletions and point mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9211849+10480349" 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="#87" class="mim-tip-reference" title="Yamamoto, T., Ninomiya, H., Matsumoto, M., Ohta, Y., Nanba, E., Tsutsumi, Y., Yamakawa, K., Millat, G., Vanier, M. T., Pentchev, P. G., Ohno, K. &lt;strong&gt;Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts.&lt;/strong&gt; J. Med. Genet. 37: 707-711, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11182931/&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;11182931&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.37.9.707&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="11182931">Yamamoto et al. (2000)</a> studied 15 Japanese and 2 white patients with NPC. They found that in those patients with the late infantile form of the disease, there was a clear reduction of the NPC1 protein level regardless of the type of mutation, and 5 fibroblast lines expressed undetectable levels of NPC1 protein. Patients with a late clinical onset were distinct in that all of their skin fibroblasts expressed considerable levels of mutant NPC1 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11182931" 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 the Nova Scotian variant of Niemann-Pick disease, <a href="#29" class="mim-tip-reference" title="Greer, W. L., Riddell, D. C., Gillan, T. L., Girouard, G. S., Sparrow, S. M., Byers, D. M., Dobson, M. J., Neumann, P. E. &lt;strong&gt;The Nova Scotia (type D) form of Niemann-Pick disease is caused by a 3097G-T transversion in NPC1.&lt;/strong&gt; Am. J. Hum. Genet. 63: 52-54, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9634529/&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;9634529&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/301931&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="9634529">Greer et al. (1998)</a> demonstrated a 3097G-T transversion in the NPC1 gene, resulting in a gly992-to-trp amino acid substitution (<a href="/entry/607623#0004">607623.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9634529" 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="Kaminski, W. E., Klunemann, H. H., Ibach, B., Aslanidis, C., Klein, H. E., Schmitz, G. &lt;strong&gt;Identification of novel mutations in the NPC1 gene in German patients with Niemann-Pick C disease.&lt;/strong&gt; J. Inherit. Metab. Dis. 25: 385-389, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12408188/&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;12408188&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1020151801060&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="12408188">Kaminski et al. (2002)</a> analyzed the NPC1 gene in 5 German patients with NPC1-related families. They identified a total of 5 novel mutations in the coding region of NPC1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12408188" 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="populationGenetics" class="mim-anchor"></a>
<h4 href="#mimPopulationGeneticsFold" id="mimPopulationGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Population Genetics</strong>
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<p><a href="#28" class="mim-tip-reference" title="Greer, W. L., Riddell, D. C., Byers, D. M., Welch, J. P., Girouard, G. S., Sparrow, S. M., Gillan, T. L., Neumann, P. E. &lt;strong&gt;Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C.&lt;/strong&gt; Am. J. Hum. Genet. 61: 139-142, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9245994/&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;9245994&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/513899&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="9245994">Greer et al. (1997)</a> noted that Yarmouth County in Nova Scotia appears to have the world's highest incidence of Niemann-Pick type II disease (encompassing types C and D). The frequency of affected children in 1 region of the county was said to be about 1% and the frequency of heterozygous carriers was estimated to be 10 to 26% (<a href="#83" class="mim-tip-reference" title="Winsor, E. J. T., Welch, J. P. &lt;strong&gt;Genetic and demographic aspects of Nova Scotia Niemann-Pick disease (type D).&lt;/strong&gt; Am. J. Hum. Genet. 30: 530-538, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/736041/&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;736041&lt;/a&gt;]" pmid="736041">Winsor and Welch, 1978</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9245994+736041" 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>To determine the incidence rate of NPC1 and NPC2 (<a href="/entry/607625">607625</a>), <a href="#80" class="mim-tip-reference" title="Wassif, C. A., Cross, J. L., Iben, J., Sanchez-Pulido, L., Cougnoux, A., Platt, F. M., Ory, D. S., Ponting, C., Bailey-Wilson, J. E., Biesecker, L. G., Porter, F. D. &lt;strong&gt;High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets.&lt;/strong&gt; Genet. Med. 18: 41-48, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25764212/&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;25764212&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25764212[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/gim.2015.25&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="25764212">Wassif et al. (2016)</a> analyzed 4 large independent massively parallel exome sequencing projects containing a total 17,754 chromosomes in which no patient had been screened for the diagnosis of Niemann-Pick disease, and analyzed every variant for pathogenicity. The data suggested an incidence rate for NPC1 of 1 in 92,104 and for NPC2 of 1 in 2,858,998. Evaluation of common NPC1 variants, however, suggested that there may be a late-onset NPC1 phenotype with a markedly higher incidence, on the order of 1 in 19,000 to 1 in 36,000. <a href="#80" class="mim-tip-reference" title="Wassif, C. A., Cross, J. L., Iben, J., Sanchez-Pulido, L., Cougnoux, A., Platt, F. M., Ory, D. S., Ponting, C., Bailey-Wilson, J. E., Biesecker, L. G., Porter, F. D. &lt;strong&gt;High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets.&lt;/strong&gt; Genet. Med. 18: 41-48, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25764212/&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;25764212&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25764212[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/gim.2015.25&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="25764212">Wassif et al. (2016)</a> determined a combined incidence of classical NPC of 1 in 89,229, or 1.12 affected patients per 100,000 conceptions, but predicted incomplete ascertainment of a late-onset phenotype of NPC1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25764212" 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 diagnosis coding information from an administrative database that collates billing-related data from pharmacies and medical facilities, <a href="#12" class="mim-tip-reference" title="Burton, B. K., Ellis, A. G., Orr, B., Chatlani, S., Yoon, K., Shoaff, J. R., Gallo, D. &lt;strong&gt;Estimating the prevalence of Niemann-Pick disease type C (NPC) in the United States.&lt;/strong&gt; Molec. Genet. Metab. 134: 182-187, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34304992/&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;34304992&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2021.06.011&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="34304992">Burton et al. (2021)</a> estimated a prevalence of NPC in the United States of 0.99 per million. However, when the NPC prevalence in the United States was calculated based on the number of new cases published in the literature per year, the prevalence was estimated at 2.9 cases per million. <a href="#12" class="mim-tip-reference" title="Burton, B. K., Ellis, A. G., Orr, B., Chatlani, S., Yoon, K., Shoaff, J. R., Gallo, D. &lt;strong&gt;Estimating the prevalence of Niemann-Pick disease type C (NPC) in the United States.&lt;/strong&gt; Molec. Genet. Metab. 134: 182-187, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34304992/&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;34304992&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2021.06.011&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="34304992">Burton et al. (2021)</a> concluded that NPC is underdiagnosed in the United States. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34304992" 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="nomenclature" class="mim-anchor"></a>
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<strong>Nomenclature</strong>
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<p>Niemann Pick disease has been classified by some into type I and type II: type I encompasses 2 subtypes, A and B (<a href="/entry/607616">607616</a>), which show deficiency of sphingomyelinase, and type II encompasses 2 subtypes, type C (NPC1; <a href="/entry/257220">257220</a>, NPC2; <a href="/entry/607625">607625</a>) and type D (<a href="#28" class="mim-tip-reference" title="Greer, W. L., Riddell, D. C., Byers, D. M., Welch, J. P., Girouard, G. S., Sparrow, S. M., Gillan, T. L., Neumann, P. E. &lt;strong&gt;Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C.&lt;/strong&gt; Am. J. Hum. Genet. 61: 139-142, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9245994/&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;9245994&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/513899&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="9245994">Greer et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9245994" 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="history" class="mim-anchor"></a>
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<strong>History</strong>
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<p><a href="#18" class="mim-tip-reference" title="Christomanou, H. &lt;strong&gt;Niemann-Pick disease, type C: evidence for the deficiency of an activating factor stimulating sphingomyelin and glucocerebroside degradation.&lt;/strong&gt; Hoppe Seylers Z. Physiol. Chem. 361: 1489-1502, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6256275/&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;6256275&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1515/bchm2.1980.361.2.1489&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="6256275">Christomanou (1980)</a> reported that some patients with the juvenile form of Niemann-Pick disease may be missing a required activator protein. With the fifth edition of The Metabolic Basis of Inherited Disease, types A, B, and C were said to 'appear to be allelic disorders in which 1 of at least 3 different mutations affects the activity of sphingomyelinase' (<a href="#10" class="mim-tip-reference" title="Brady, R. O. &lt;strong&gt;Sphingomyelin lipidoses: Niemann-Pick disease. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M. S. (eds.): The Metabolic Basis of Inherited Disease. (5th ed.)&lt;/strong&gt; New York: McGraw-Hill (pub.) 1983. P. 731."None>Brady, 1983</a>). Subsequently, type C proved to be due to mutation in a different gene on a different chromosome from that mutant in types A and B. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6256275" 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="animalModel" class="mim-anchor"></a>
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<p>Two independently derived mutant mouse colonies played a pivotal role in delineating the biochemical basis of NPC. One was a BALB/c mouse presenting clinical and biochemical features of NPC (<a href="#54" class="mim-tip-reference" title="Pentchev, P. G., Boothe, A. D., Kruth, H. S., Weintroub, H., Stivers, J., Brady, R. O. &lt;strong&gt;A genetic storage disorder in BALB/C mice with a metabolic block in esterification of exogenous cholesterol.&lt;/strong&gt; J. Biol. Chem. 259: 5784-5791, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6325448/&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;6325448&lt;/a&gt;]" pmid="6325448">Pentchev et al., 1984</a>); the other was the C57BL/Ks mouse characterized as a sphingomyelinosis because of attenuated sphingomyelinase activity and excess sphingomyelin accumulation (<a href="#49" class="mim-tip-reference" title="Miyawaki, S., Yoshida, H., Mitsuoka, S., Enomoto, H., Ikehara, S. &lt;strong&gt;A mouse model for Niemann-Pick disease: influence of genetic background on disease expression in spm/spm mice.&lt;/strong&gt; J. Hered. 77: 379-384, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3559164/&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;3559164&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/oxfordjournals.jhered.a110265&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="3559164">Miyawaki et al., 1986</a>; <a href="#39" class="mim-tip-reference" title="Kitagawa, T. &lt;strong&gt;An animal model of human acid sphingomyelinase deficiency (Niemann-Pick disease) and the study of its enzyme replacement.&lt;/strong&gt; Jpn. J. Hum. Genet. 32: 55-69, 1987."None>Kitagawa, 1987</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6325448+3559164" 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="#55" class="mim-tip-reference" title="Pentchev, P. G., Comly, M. E., Kruth, H. S., Patel, S., Proestel, M., Weintroub, H. &lt;strong&gt;The cholesterol storage disorder of the mutant BALB/c mouse: a primary genetic lesion closely linked to defective esterification of exogenously derived cholesterol and its relationship to human type C Niemann-Pick disease.&lt;/strong&gt; J. Biol. Chem. 261: 2772-2777, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3949747/&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;3949747&lt;/a&gt;]" pmid="3949747">Pentchev et al. (1986)</a> reviewed the findings in the murine disorder and in type C Niemann-Pick disease. The esterification defect concerns exogenously derived cholesterol; synthesis of cholesteryl ester from labeled mevalonic acid and squalene was normal in affected fibroblasts as was endogenous cholesteryl ester synthesis from endogenous cholesterol induced by 25-hydroxycholesterol. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3949747" 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="#47" class="mim-tip-reference" title="Lowenthal, A. C., Cummings, J. F., Wenger, D. A., Thrall, M. A., Wood, P. A., de Lahunta, A. &lt;strong&gt;Feline sphingolipidosis resembling Niemann-Pick disease type C.&lt;/strong&gt; Acta Neuropath. 81: 189-197, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2127982/&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;2127982&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00334507&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="2127982">Lowenthal et al. (1990)</a> described Niemann-Pick disease type C in a domestic short-hair kitten. The dam and littermates were donated to Colorado State University, and a breeding colony was established. <a href="#11" class="mim-tip-reference" title="Brown, D. E., Thrall, M. A., Walkley, S. U., Wenger, D. A., Mitchell, T. W., Smith, M. O., Royals, K. L., March, P. A., Allison, R. W. &lt;strong&gt;Feline Niemann-Pick disease type C.&lt;/strong&gt; Am. J. Path. 144: 1412-1415, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8203477/&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;8203477&lt;/a&gt;]" pmid="8203477">Brown et al. (1994)</a> reported on the clinical, biochemical, and morphologic findings in 26 affected cats. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2127982+8203477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Akaboshi, S., Yano, T., Miyawaki, S., Ohno, K., Takeshita, K. &lt;strong&gt;A C57BL/KsJ mouse model of Niemann-Pick disease (spm) belongs to the same complementation group as the major childhood type of Niemann-Pick disease type C.&lt;/strong&gt; Hum. Genet. 99: 350-353, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9050921/&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;9050921&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004390050370&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="9050921">Akaboshi et al. (1997)</a> reported that a cell line derived from the C57BL/KsJ mouse model of NPC shows biochemical abnormalities similar to those in fibroblasts derived from human patients. Somatic cell hybridization analysis of these cells and 5 fibroblast strains derived from NPC patients (4 childhood cases and 1 adult case) was carried out. The criterion for complementation was the restoration of the normal intracellular fluorescent pattern in multinucleated cells stained with filipin to demonstrate cholesterol accumulation. These cells could be assigned to 2 complementation groups. The mutant mouse cells did not complement cell strains derived from childhood-type NPC, while they complemented a cell strain derived from an adult patient. The results indicated that the mouse is an authentic model of a major complementation group of NPC, and that NPC consists of genetically heterogeneous groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9050921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Studying the mutant BALB/c mouse model of NPC, <a href="#64" class="mim-tip-reference" title="Schedin, S., Sindelar, P. J., Pentchev, P., Brunk, U., Dallner, G. &lt;strong&gt;Peroxisomal impairment in Niemann-Pick type C disease.&lt;/strong&gt; J. Biol. Chem. 272: 6245-6251, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9045641/&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;9045641&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.272.10.6245&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="9045641">Schedin et al. (1997)</a> investigated enzymatic markers for lysosomes, mitochondria, microsomes, and peroxisomes in liver and brain. In addition to the lysosomal changes, they found a sizable decrease of peroxisomal beta-oxidation of fatty acids and catalase activity in these 2 organs. Isolated peroxisomes displayed a significant decrease in these enzyme activities. Furthermore, the only phospholipid change in brain was a decreased content of the plasmalogen form of phosphatidylethanolamine, and the dimethylacetal pattern was also modified. The electron microscopic appearance of peroxisomes did not show any large changes. The defect of peroxisomal enzymes was already present 18 days before the onset of the disease. In contrast, the lysosomal marker enzyme increased in activity only 6 days after the appearance of the symptoms. The events of the pathologic process had previously been considered to be elicited by lysosomal deficiency, but this study showed disturbances similar to those in a number of peroxisomal diseases. The peroxisomal impairment appeared to be an early event in the process and could be a factor in the development of Niemann-Pick type C disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9045641" 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="#85" class="mim-tip-reference" title="Xie, C., Turley, S. D., Dietschy, J. M. &lt;strong&gt;Cholesterol accumulation in tissues of the Niemann-Pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coated-pit pathway in each organ.&lt;/strong&gt; Proc. Nat. Acad. Sci. 96: 11992-11997, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10518564/&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;10518564&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10518564[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/10.1073/pnas.96.21.11992&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="10518564">Xie et al. (1999)</a> used the NPC mouse to determine whether the accumulation of unesterified cholesterol in this disorder represents sterol carried in low density lipoprotein (LDL) and chylomicrons (CMs) taken up into the tissues through the coated-pit pathway. A series of observations strongly supported the conclusion that, in Niemann-Pick disease type C, it is the cholesterol carried in LDL and CMs that is sequestered in the tissues, and not sterol that is newly synthesized and carried in high density lipoprotein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10518564" 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="#23" class="mim-tip-reference" title="Erickson, R. P., Garver, W. S., Camargo, F., Hossain, G. S., Heidenreich, R. A. &lt;strong&gt;Pharmacological and genetic modifications of somatic cholesterol do not substantially alter the course of CNS disease in Niemann-Pick C mice.&lt;/strong&gt; J. Inherit. Metab. Dis. 23: 54-62, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10682308/&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;10682308&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1005650930330&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="10682308">Erickson et al. (2000)</a> used a mouse model with a disrupted Npc1 gene to study 2 cholesterol-lowering drugs (nifedipine and probucol) and the effects of introducing a null mutation in the low density lipoprotein receptor (LDLR; <a href="/entry/606945">606945</a>). Although these treatments significantly ameliorated liver cholesterol storage, there was little effect on the onset of neurologic symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10682308" 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="Liu, Y., Wu, Y.-P., Wada, R., Neufeld, E. B., Mullin, K. A., Howard, A. C., Pentchev, P. G., Vanier, M. T., Suzuki, K., Proia, R. L. &lt;strong&gt;Alleviation of neuronal ganglioside storage does not improve the clinical course of the Niemann-Pick C disease mouse.&lt;/strong&gt; Hum. Molec. Genet. 9: 1087-1092, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10767333/&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;10767333&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/9.7.1087&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="10767333">Liu et al. (2000)</a> determined the relative contribution of ganglioside accumulation in the neuropathogenesis of NPC by breeding NPC model mice with mice carrying a targeted mutation in GalNAc-T (<a href="/entry/601873">601873</a>), the gene encoding the beta-1-4GalNAc transferase responsible for the synthesis of GM2 and complex gangliosides. Unlike the NPC model mice, the double mutant mice did not exhibit central nervous system (CNS) accumulation of gangliosides GM2 or of glycolipids GA1 and GA2. Histologic analysis revealed that the characteristic neuronal storage pathology of NPC disease was substantially reduced in the double mutant mice. By contrast, visceral pathology was similar in the NPC and double mutant mice. Most notably, the clinical phenotype of the double mutant mice, in the absence of CNS ganglioside accumulation and associated neuronal pathology, did not improve. The authors concluded that complex ganglioside storage, while responsible for much of the neuronal pathology, did not significantly influence the clinical phenotype of the NPC model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10767333" 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="Langmade, S. J., Gale, S. E., Frolov, A., Mohri, I., Suzuki, K., Mellon, S. H., Walkley, S. U., Covey, D. F., Schaffer, J. E., Ory, D. S. &lt;strong&gt;Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 103: 13807-13812, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16940355/&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;16940355&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16940355[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/10.1073/pnas.0606218103&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="16940355">Langmade et al. (2006)</a> noted that the failure to properly traffic lipoprotein cholesterol in NPC1 results in impaired oxysterol and steroid synthesis. <a href="#42" class="mim-tip-reference" title="Langmade, S. J., Gale, S. E., Frolov, A., Mohri, I., Suzuki, K., Mellon, S. H., Walkley, S. U., Covey, D. F., Schaffer, J. E., Ory, D. S. &lt;strong&gt;Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 103: 13807-13812, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16940355/&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;16940355&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16940355[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/10.1073/pnas.0606218103&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="16940355">Langmade et al. (2006)</a> found that treatment of Npc1 -/- mice with the neurosteroid allopregnanolone and a synthetic oxysterol ligand delayed the onset of neurologic symptoms and prolonged life span, suggesting that the treatment bypassed the cholesterol trafficking defect. The therapy preserved Purkinje cells, suppressed cerebellar expression of microglial-associated genes, and reduced infiltration of microglia in cerebellar tissue. Transfection assays correlated the efficacy of treatment with activation of murine PXR (NR1I2; <a href="/entry/603065">603065</a>) in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16940355" 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="#22" class="mim-tip-reference" title="Elrick, M. J., Pacheco, C. D., Yu, T., Dadgar, N., Shakkottai, V. G., Ware, C., Paulson, H. L., Lieberman, A. P. &lt;strong&gt;Conditional Niemann-Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration.&lt;/strong&gt; Hum. Molec. Genet. 19: 837-847, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20007718/&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;20007718&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20007718[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/10.1093/hmg/ddp552&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="20007718">Elrick et al. (2010)</a> generated Npc1 conditional null mutant mice. Deletion of Npc1 in mature cerebellar Purkinje cells led to an age-dependent impairment in motor tasks, including rotarod and balance beam performance. These mice did not show the early death or weight loss characteristic of global Npc1-null mice, suggesting that Purkinje cell degeneration may not underlie these phenotypes. Histologic examination revealed the progressive loss of Purkinje cells in an anterior-to-posterior gradient. This cell-autonomous neurodegeneration occurred in a spatiotemporal pattern similar to that of global knockout mice. A subpopulation of Purkinje cells in the posterior cerebellum exhibited marked resistance to cell death despite Npc1 deletion. Purkinje cells in both vulnerable and resistant subpopulations displayed no electrophysiologic abnormalities prior to degeneration. The authors concluded that Npc1 deficiency leads to cell-autonomous, selective neurodegeneration and suggested that the ataxic symptoms of NPC disease may arise from Purkinje cell death rather than cellular dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20007718" 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="#Philippart1969" class="mim-tip-reference" title="Philippart, M., Martin, L., Martin, J. J., Menkes, J. H. &lt;strong&gt;Niemann-Pick disease: morphologic and biochemical studies in the visceral form with late central nervous system involvement (Crocker&#x27;s group C).&lt;/strong&gt; Arch. Neurol. 20: 227-238, 1969.">Philippart et al. (1969)</a>; <a href="#Yatziv1983" class="mim-tip-reference" title="Yatziv, S., Leibovitz-Ben Gershon, Z., Ornoy, A., Bach, G. &lt;strong&gt;Clinical heterogeneity in a sibship with Niemann-Pick disease type C.&lt;/strong&gt; Clin. Genet. 23: 125-131, 1983.">Yatziv et al. (1983)</a>
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<strong>REFERENCES</strong>
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<a id="Abel2009" class="mim-anchor"></a>
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<p class="mim-text-font">
Abel, L. A., Walterfang, M., Fietz, M., Bowman, E. A., Velakoulis, D.
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<a id="Akaboshi1997" class="mim-anchor"></a>
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<p class="mim-text-font">
Akaboshi, S., Yano, T., Miyawaki, S., Ohno, K., Takeshita, K.
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<a id="Argoff1990" class="mim-anchor"></a>
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<p class="mim-text-font">
Argoff, C. E., Kaneski, C. R., Blanchette-Mackie, E. J., Comly, M., Dwyer, N. K., Brown, A., Brady, R. O., Pentchev, P. G.
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Auer, I. A., Schmidt, M. L., Lee, V. M.-Y., Curry, B., Suzuki, K., Shin, R.-W., Pentchev, P. G., Carstea, E. D., Trojanowski, J. Q.
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[<a href="https://doi.org/10.1007/BF00318566" target="_blank">Full Text</a>]
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<a id="Besley1980" class="mim-anchor"></a>
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Besley, G. T. N., Hoogeboom, A. J. M., Hoogeveen, A., Kleijer, W. J., Galjaard, H.
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Hum. Genet. 54: 409-412, 1980.
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[<a href="https://doi.org/10.1007/BF00291589" target="_blank">Full Text</a>]
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<a id="Blanchette-Mackie1988" class="mim-anchor"></a>
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<p class="mim-text-font">
Blanchette-Mackie, E. J., Dwyer, N. K., Amende, L. M., Kruth, H. S., Butler, J. D., Sokol, J., Comly, M. E., Vanier, M. T., August, J. T., Brady, R. O., Pentchev, P. G.
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[<a href="https://doi.org/10.1073/pnas.85.21.8022" target="_blank">Full Text</a>]
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Boenzi, S., Catesini, G., Sacchetti, E., Tagliaferri, F., Dionisi-Vici, C., Deodato, F.
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[<a href="https://doi.org/10.1016/j.ymgme.2021.11.005" target="_blank">Full Text</a>]
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Boustany, R.-M. N., Kaye, E., Alroy, J.
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[<a href="https://doi.org/10.1016/0887-8994(90)90059-a" target="_blank">Full Text</a>]
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Brady, R. O.
<strong>Sphingomyelin lipidosis: Niemann-Pick disease. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.): Metabolic Basis of Inherited Disease. (4th ed.)</strong>
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Brady, R. O.
<strong>Sphingomyelin lipidoses: Niemann-Pick disease. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M. S. (eds.): The Metabolic Basis of Inherited Disease. (5th ed.)</strong>
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Brown, D. E., Thrall, M. A., Walkley, S. U., Wenger, D. A., Mitchell, T. W., Smith, M. O., Royals, K. L., March, P. A., Allison, R. W.
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<p class="mim-text-font">
Burton, B. K., Ellis, A. G., Orr, B., Chatlani, S., Yoon, K., Shoaff, J. R., Gallo, D.
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[<a href="https://doi.org/10.1016/j.ymgme.2021.06.011" target="_blank">Full Text</a>]
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<a id="Byers1989" class="mim-anchor"></a>
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Byers, D. M., Rastogi, S. R., Cook, H. W., Palmer, F. B. St. C., Spence, M. W.
<strong>Defective activity of acyl-CoA: cholesterol O-acyltransferase in Niemann-Pick type C and type D fibroblasts.</strong>
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[<a href="https://doi.org/10.1042/bj2620713" target="_blank">Full Text</a>]
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Carstea, E. D., Morris, J. A., Coleman, K. G., Loftus, S. K., Zhang, D., Cummings, C., Gu, J., Rosenfeld, M. A., Pavan, W. J., Krizman, D. B., Nagle, J., Polymeropoulos, M. H., and 26 others.
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[<a href="https://doi.org/10.1126/science.277.5323.228" target="_blank">Full Text</a>]
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Carstea, E. D., Parker, C. C., Fandino, L. B., Vanier, M. T., Overhauser, J., Weissenbach, J., Pentchev, P. G., Brady, R. O., Polymeropoulos, M. H.
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Carstea, E. D., Polymeropoulos, M. H., Parker, C. C., Detera-Wadleigh, S. D., O'Neill, R. R., Patterson, M. C., Goldin, E., Xiao, H., Straub, R. E., Vanier, M. T., Brady, R. O., Pentchev, P. G.
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[<a href="https://doi.org/10.1073/pnas.90.5.2002" target="_blank">Full Text</a>]
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Ceuterick, C., Martin, J. J.
<strong>Nerve biopsy findings in Niemann-Pick type II (NPC). (Letter)</strong>
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[<a href="https://doi.org/10.1007/BF00296502" target="_blank">Full Text</a>]
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Christomanou, H.
<strong>Niemann-Pick disease, type C: evidence for the deficiency of an activating factor stimulating sphingomyelin and glucocerebroside degradation.</strong>
Hoppe Seylers Z. Physiol. Chem. 361: 1489-1502, 1980.
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[<a href="https://doi.org/10.1515/bchm2.1980.361.2.1489" target="_blank">Full Text</a>]
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Crocker, A. C.
<strong>The cerebral defect in Tay-Sachs disease and Niemann-Pick disease.</strong>
J. Neurochem. 7: 69-80, 1961.
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[<a href="https://doi.org/10.1111/j.1471-4159.1961.tb13499.x" target="_blank">Full Text</a>]
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<a id="De Leon1969" class="mim-anchor"></a>
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De Leon, G. A., Kaback, M. M., Elfenbein, I. B., Percy, A. K., Brady, R. O.
<strong>Juvenile dystonia lipidosis.</strong>
Johns Hopkins Med. J. 125: 62-77, 1969.
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<a id="Elfenbein1968" class="mim-anchor"></a>
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Elfenbein, I. B.
<strong>Dystonic juvenile idiocy without amaurosis: a new syndrome.</strong>
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Elrick, M. J., Pacheco, C. D., Yu, T., Dadgar, N., Shakkottai, V. G., Ware, C., Paulson, H. L., Lieberman, A. P.
<strong>Conditional Niemann-Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration.</strong>
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[<a href="https://doi.org/10.1093/hmg/ddp552" target="_blank">Full Text</a>]
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<a id="Erickson2000" class="mim-anchor"></a>
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Erickson, R. P., Garver, W. S., Camargo, F., Hossain, G. S., Heidenreich, R. A.
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[<a href="https://doi.org/10.1023/a:1005650930330" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.39.8.1040" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00442993" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/513899" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/301931" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1034/j.1399-0004.1999.550406.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.21.9.896" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/a:1021259403196" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/adc.84.5.427" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1177/088307389801300206" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/a:1020151801060" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.27.1.32" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00688159" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0022-510x(75)90152-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0606218103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.7.1087" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.32.11.1295" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00334507" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/oxfordjournals.jhered.a110265" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/96.1.97" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0387-7604(89)80010-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archopht.1985.01050060077030" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.82.23.8247" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1969.00480090015001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.410010410" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000112179" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00578243" target="_blank">Full Text</a>]
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<a id="Sun2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Sun, X., Marks, D. L., Park, W. D., Wheatley, C. L., Puri, V., O'Brien, J. F., Kraft, D. L., Lundquist, P. A., Patterson, M. C., Pagano, R. E., Snow, K.
<strong>Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1.</strong>
Am. J. Hum. Genet. 68: 1361-1372, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11349231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11349231</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11349231[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=11349231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/320599" target="_blank">Full Text</a>]
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<a id="72" class="mim-anchor"></a>
<a id="Thomas1989" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Thomas, G. H., Tuck-Muller, C. M., Miller, C. S., Reynolds, L. W.
<strong>Correction of sphingomyelinase deficiency in Niemann-Pick type C fibroblasts by removal of lipoprotein fraction from culture media.</strong>
J. Inherit. Metab. Dis. 12: 139-151, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2547109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2547109</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2547109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF01800716" target="_blank">Full Text</a>]
</p>
</div>
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<a id="73" class="mim-anchor"></a>
<a id="Turpin1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Turpin, J. C., Masson, M., Baumann, N.
<strong>Clinical aspects of Niemann-Pick type C disease in the adult.</strong>
Dev. Neurosci. 13: 304-306, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1817035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1817035</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1817035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1159/000112177" target="_blank">Full Text</a>]
</p>
</div>
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<a id="74" class="mim-anchor"></a>
<a id="Vance2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vance, J. E.
<strong>Lipid imbalance in the neurological disorder, Niemann-Pick C disease.</strong>
FEBS Lett. 580: 5518-5524, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16797010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16797010</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16797010" 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.febslet.2006.06.008" target="_blank">Full Text</a>]
</p>
</div>
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<a id="75" class="mim-anchor"></a>
<a id="Vanier1996" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vanier, M. T., Duthel, S., Rodriguez-Lafrasse, C., Pentchev, P., Carstea, E. D.
<strong>Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis.</strong>
Am. J. Hum. Genet. 58: 118-125, 1996.
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</p>
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<a id="76" class="mim-anchor"></a>
<a id="Vanier2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vanier, M. T., Millat, G.
<strong>Niemann-Pick disease type C.</strong>
Clin. Genet. 64: 269-281, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12974729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12974729</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12974729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1034/j.1399-0004.2003.00147.x" target="_blank">Full Text</a>]
</p>
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<a id="77" class="mim-anchor"></a>
<a id="Vanier1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vanier, M. T., Rodriguez-Lafrasse, C., Rousson, R., Duthel, S., Harzer, K., Pentchev, P. G., Revol, A., Louisot, P.
<strong>Type C Niemann-Pick disease: biochemical aspects and phenotypic heterogeneity.</strong>
Dev. Neurosci. 13: 307-314, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1817036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1817036</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1817036" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1159/000112178" target="_blank">Full Text</a>]
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<a id="78" class="mim-anchor"></a>
<a id="Vanier1988" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vanier, M. T., Wenger, D. A., Comly, M. E., Rousson, R., Brady, R. O., Pentchev, P. G.
<strong>Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification: a collaborative study on 70 patients.</strong>
Clin. Genet. 33: 331-348, 1988.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3378364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3378364</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3378364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.1988.tb03460.x" target="_blank">Full Text</a>]
</p>
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<a id="Walterfang2010" class="mim-anchor"></a>
<div class="">
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Walterfang, M., Fahey, M., Desmond, P., Wood, A., Seal, M. L., Steward, C., Adamson, C., Kokkinos, C., Fietz, M., Velakoulis, D.
<strong>White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study.</strong>
Neurology 75: 49-56, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20484681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20484681</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20484681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/WNL.0b013e3181e6210e" target="_blank">Full Text</a>]
</p>
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<a id="Wassif2016" class="mim-anchor"></a>
<div class="">
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Wassif, C. A., Cross, J. L., Iben, J., Sanchez-Pulido, L., Cougnoux, A., Platt, F. M., Ory, D. S., Ponting, C., Bailey-Wilson, J. E., Biesecker, L. G., Porter, F. D.
<strong>High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets.</strong>
Genet. Med. 18: 41-48, 2016.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25764212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25764212</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25764212[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=25764212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/gim.2015.25" target="_blank">Full Text</a>]
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<a id="81" class="mim-anchor"></a>
<a id="Wenger1977" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wenger, D. A., Barth, G., Githens, J. H.
<strong>Nine cases of sphingomyelin lipidosis, a new variant in Spanish-American children.</strong>
Am. J. Dis. Child. 131: 955-961, 1977.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/900082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">900082</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=900082" 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/archpedi.1977.02120220021002" target="_blank">Full Text</a>]
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<a id="Willvonseder1973" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Willvonseder, R., Goldstein, N. P., McCall, J. T., Yoss, R. E., Tauxe, W. N.
<strong>A hereditary disorder with dementia, spastic dysarthria, vertical eye movement paresis, gait disturbance, splenomegaly, and abnormal copper metabolism.</strong>
Neurology 23: 1039-1049, 1973.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4795418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4795418</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4795418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.23.10.1039" target="_blank">Full Text</a>]
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<a id="83" class="mim-anchor"></a>
<a id="Winsor1978" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Winsor, E. J. T., Welch, J. P.
<strong>Genetic and demographic aspects of Nova Scotia Niemann-Pick disease (type D).</strong>
Am. J. Hum. Genet. 30: 530-538, 1978.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/736041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">736041</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=736041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="84" class="mim-anchor"></a>
<a id="Witzleben1986" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Witzleben, C. L., Palmieri, M. J., Watkins, J. B., Hogan, P.
<strong>Sphingomyelin lipidosis variant with cirrhosis in the pediatric age group.</strong>
Arch. Path. Lab. Med. 110: 508-512, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3085631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3085631</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3085631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="85" class="mim-anchor"></a>
<a id="Xie1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Xie, C., Turley, S. D., Dietschy, J. M.
<strong>Cholesterol accumulation in tissues of the Niemann-Pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coated-pit pathway in each organ.</strong>
Proc. Nat. Acad. Sci. 96: 11992-11997, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10518564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10518564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10518564[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=10518564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.96.21.11992" target="_blank">Full Text</a>]
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<a id="Yamamoto1999" class="mim-anchor"></a>
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Yamamoto, T., Nanba, E., Ninomiya, H., Higaki, K., Taniguchi, M., Zhang, H., Akaboshi, S., Watanabe, Y., Takeshima, T., Inui, K., Okada, S., Tanaka, A., Sakuragawa, N., Millat, G., Vanier, M. T., Morris, J. A., Pentchev, P. G., Ohno, K.
<strong>NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C.</strong>
Hum. Genet. 105: 10-16, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10480349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10480349</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10480349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s004399900059" target="_blank">Full Text</a>]
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<a id="Yamamoto2000" class="mim-anchor"></a>
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Yamamoto, T., Ninomiya, H., Matsumoto, M., Ohta, Y., Nanba, E., Tsutsumi, Y., Yamakawa, K., Millat, G., Vanier, M. T., Pentchev, P. G., Ohno, K.
<strong>Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts.</strong>
J. Med. Genet. 37: 707-711, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11182931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11182931</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11182931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.37.9.707" target="_blank">Full Text</a>]
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<a id="Yatziv1983" class="mim-anchor"></a>
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Yatziv, S., Leibovitz-Ben Gershon, Z., Ornoy, A., Bach, G.
<strong>Clinical heterogeneity in a sibship with Niemann-Pick disease type C.</strong>
Clin. Genet. 23: 125-131, 1983.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6839525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6839525</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6839525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.1983.tb01860.x" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 06/23/2022
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Hilary J. Vernon - updated : 02/17/2022<br>Hilary J. Vernon - updated : 05/26/2020<br>Ada Hamosh - updated : 2/23/2016<br>George E. Tiller - updated : 11/7/2011<br>Cassandra L. Kniffin - updated : 6/20/2011<br>Cassandra L. Kniffin - updated : 2/16/2010<br>Cassandra L. Kniffin - updated : 7/7/2009<br>Patricia A. Hartz - updated : 12/3/2008<br>Marla J. F. O'Neill - updated : 2/1/2008<br>Cassandra L. Kniffin - updated : 3/13/2007<br>Cassandra L. Kniffin - updated : 10/4/2006<br>Cassandra L. Kniffin - updated : 3/17/2005<br>Victor A. McKusick - updated : 11/4/2003<br>Ada Hamosh - updated : 10/7/2003<br>Ada Hamosh - updated : 9/22/2003<br>Cassandra L. Kniffin - reorganized : 3/13/2003<br>Cassandra L. Kniffin - updated : 12/13/2002<br>Victor A. McKusick - updated : 1/15/2002<br>Ada Hamosh - updated : 1/9/2002<br>Michael J. Wright - updated : 11/6/2001<br>Victor A. McKusick - updated : 8/29/2001<br>Victor A. McKusick - updated : 7/17/2001<br>Victor A. McKusick - updated : 6/20/2001<br>Victor A. McKusick - updated : 6/20/2001<br>Ada Hamosh - updated : 5/16/2001<br>Victor A. McKusick - updated : 5/14/2001<br>Ada Hamosh - updated : 1/4/2001<br>George E. Tiller - updated : 5/12/2000<br>Victor A. McKusick - updated : 2/22/2000<br>Victor A. McKusick - updated : 11/29/1999<br>Victor A. McKusick - updated : 11/9/1999<br>Victor A. McKusick - updated : 9/29/1999<br>Victor A. McKusick - updated : 8/23/1999<br>Victor A. McKusick - updated : 3/18/1999<br>Victor A. McKusick - updated : 3/16/1999<br>Victor A. McKusick - updated : 7/17/1998<br>Victor A. McKusick - updated : 2/25/1998<br>Victor A. McKusick - updated : 9/10/1997<br>Victor A. McKusick - updated : 7/10/1997<br>Victor A. McKusick - updated : 3/4/1997<br>Orest Hurko - edited : 4/13/1996<br>Orest Hurko - updated : 4/4/1996<br>Orest Hurko - updated : 9/21/1995
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Victor A. McKusick : 6/4/1986
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carol : 06/24/2022
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carol : 06/23/2022<br>carol : 02/18/2022<br>carol : 02/17/2022<br>carol : 05/26/2020<br>carol : 09/09/2016<br>carol : 07/08/2016<br>carol : 7/7/2016<br>carol : 5/25/2016<br>alopez : 2/23/2016<br>carol : 2/25/2014<br>alopez : 11/10/2011<br>terry : 11/7/2011<br>wwang : 6/28/2011<br>ckniffin : 6/20/2011<br>alopez : 5/12/2010<br>terry : 5/11/2010<br>carol : 3/8/2010<br>wwang : 2/18/2010<br>ckniffin : 2/16/2010<br>wwang : 8/3/2009<br>ckniffin : 7/7/2009<br>mgross : 12/3/2008<br>wwang : 2/5/2008<br>terry : 2/1/2008<br>wwang : 6/6/2007<br>wwang : 3/16/2007<br>ckniffin : 3/13/2007<br>wwang : 10/20/2006<br>ckniffin : 10/4/2006<br>tkritzer : 3/29/2005<br>ckniffin : 3/17/2005<br>tkritzer : 11/10/2003<br>tkritzer : 11/6/2003<br>terry : 11/4/2003<br>cwells : 10/7/2003<br>cwells : 10/7/2003<br>alopez : 9/22/2003<br>carol : 3/13/2003<br>ckniffin : 3/13/2003<br>ckniffin : 3/12/2003<br>cwells : 12/20/2002<br>ckniffin : 12/13/2002<br>ckniffin : 6/5/2002<br>alopez : 1/17/2002<br>terry : 1/15/2002<br>terry : 1/9/2002<br>alopez : 12/5/2001<br>alopez : 11/6/2001<br>alopez : 11/6/2001<br>mcapotos : 9/18/2001<br>mcapotos : 8/29/2001<br>mcapotos : 8/7/2001<br>mcapotos : 7/26/2001<br>terry : 7/17/2001<br>cwells : 7/3/2001<br>terry : 6/20/2001<br>terry : 6/20/2001<br>terry : 6/20/2001<br>mcapotos : 5/22/2001<br>mcapotos : 5/18/2001<br>terry : 5/16/2001<br>terry : 5/14/2001<br>carol : 1/12/2001<br>terry : 1/12/2001<br>carol : 1/4/2001<br>terry : 1/4/2001<br>alopez : 5/12/2000<br>carol : 2/23/2000<br>terry : 2/22/2000<br>mgross : 11/29/1999<br>alopez : 11/15/1999<br>terry : 11/9/1999<br>mgross : 10/13/1999<br>terry : 9/29/1999<br>carol : 9/14/1999<br>carol : 9/9/1999<br>jlewis : 9/8/1999<br>terry : 8/23/1999<br>carol : 5/17/1999<br>carol : 5/17/1999<br>carol : 3/18/1999<br>terry : 3/18/1999<br>carol : 3/17/1999<br>terry : 3/16/1999<br>dkim : 12/10/1998<br>carol : 7/21/1998<br>terry : 7/17/1998<br>alopez : 3/16/1998<br>terry : 2/25/1998<br>mark : 10/8/1997<br>terry : 9/16/1997<br>terry : 9/10/1997<br>mark : 7/10/1997<br>terry : 7/9/1997<br>mark : 3/4/1997<br>terry : 3/3/1997<br>mark : 7/22/1996<br>mark : 4/13/1996<br>mark : 4/4/1996<br>mark : 4/4/1996<br>terry : 3/22/1996<br>mark : 1/25/1996<br>terry : 1/22/1996<br>terry : 11/17/1994<br>carol : 9/26/1994<br>davew : 7/26/1994<br>jason : 6/27/1994<br>warfield : 4/19/1994
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<strong>#</strong> 257220
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NIEMANN-PICK DISEASE, TYPE C1; NPC1
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<em>Alternative titles; symbols</em>
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NIEMANN-PICK DISEASE, TYPE C; NPC<br />
NIEMANN-PICK DISEASE WITH CHOLESTEROL ESTERIFICATION BLOCK<br />
NIEMANN-PICK DISEASE, SUBACUTE JUVENILE FORM<br />
NIEMANN-PICK DISEASE, CHRONIC NEURONOPATHIC FORM<br />
NIEMANN-PICK DISEASE WITHOUT SPHINGOMYELINASE DEFICIENCY<br />
NEUROVISCERAL STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA
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Other entities represented in this entry:
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NIEMANN-PICK DISEASE, TYPE D, INCLUDED
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NIEMANN-PICK DISEASE, NOVA SCOTIAN TYPE, INCLUDED
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<strong>SNOMEDCT:</strong> 66751000; &nbsp;
<strong>ICD10CM:</strong> E75.242; &nbsp;
<strong>ORPHA:</strong> 646; &nbsp;
<strong>DO:</strong> 0070113; &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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18q11.2
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Niemann-Pick disease, type D
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257220
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Autosomal recessive
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3
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NPC1
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607623
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18q11.2
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Niemann-Pick disease, type C1
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257220
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Autosomal recessive
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3
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NPC1
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607623
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because Niemann-Pick disease type C1 and Niemann-Pick disease type D, also known as the Nova Scotian type, are caused by homozygous or compound heterozygous mutation in the NPC1 gene (607623) on chromosome 18q11.</p>
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<strong>Description</strong>
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<p>Niemann-Pick type C (NPC) disease is an autosomal recessive lipid storage disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene (601015), referred to as type C2 (607625). The clinical manifestations of types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes (summary by Vance, 2006). </p><p>Historically, Crocker (1961) delineated 4 types of Niemann-Pick disease: the classic infantile form (type A; 257200), the visceral form (type B; 607616), the subacute or juvenile form (type C), and the Nova Scotian variant (type D). Types C1 and D are indistinguishable except for the occurrence of type D in patients of Nova Scotian Acadian ancestry. Since then, types E and F have also been described (see 607616), and phenotypic variation within each group has also been described. </p>
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<strong>Clinical Features</strong>
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<p>Niemann-Pick disease type C has a highly variable clinical phenotype. Patients with the 'classic' childhood onset type C usually appear normal for 1 or 2 years with symptoms appearing between 2 and 4 years. They gradually develop neurologic abnormalities which are initially manifested by ataxia, grand mal seizures, and loss of previously learned speech. Spasticity is striking and seizures, particularly myoclonic jerks, are common. Other features include dystonia, vertical supranuclear gaze palsy, dementia, and psychiatric manifestations. In general, hepatosplenomegaly is less striking than in types A and B, although it can be lethal in some. Cholestatic jaundice occurs in some patients. Foamy Niemann-Pick cells and 'sea-blue' histiocytes with distinctive histochemical and ultrastructural appearances are found in the bone marrow. In the childhood-onset form, death usually occurs at age 5 to 15 (Brady, 1983, Patterson et al., 2001). Adult-onset forms, with insidious onset and slower progression, have also been reported (see, e.g., Shulman et al., 1995). </p><p>De Leon et al. (1969) described 2 females and a male in a black kindred with a juvenile form of cerebral lipidosis. Clinical features were onset between age 4 and 9 years, dementia progressing to complete amentia and an akinetic mute state, grand mal and minor motor seizures, progressive dystonia of posture with tendency to flexion of the arms, hyperextension of the spine and extension of the legs, clumsiness and mild atypical ataxia, some intention tremor and athetosis, grasp reflexes and severe reflex trismus in the final stages, tendency to hyperreflexia but preservation of fair strength and normal plantar reflexes until late. Notably absent were retinal degeneration, myoclonus, prominent pyramidal or bulbar involvement, and hepatosplenomegaly. In 1 case, foam histiocytes were demonstrated in the bone marrow. Cerebral sphingolipids in biopsy-obtained material were normal. Electron microscopic findings by Elfenbein (1968) supported the distinctness of this entity, which they called 'dystonic juvenile idiocy without amaurosis'. The cases reported by Kidd (1967) as 'atypical cerebral lipidosis', and Karpati et al. (1977) as 'juvenile dystonic lipidosis', are thought to be identical. </p><p>Neville et al. (1973) found 3 pairs of affected sibs and an equal sex incidence. Two brothers were reported by Grover and Naiman (1971). Neurologic manifestations included vertical gaze paresis and progressive dysarthria. </p><p>A variant of Niemann-Pick disease, most likely type C, was observed in 9 children in 5 families by Wenger et al. (1977). Neonatal jaundice, easy bruisability, vertical supranuclear ophthalmoplegia, intellectual and neurologic deterioration, hepatosplenomegaly, and sea-blue or foamy histiocytes were features. All 5 families were from the old Spanish-American population of southern Colorado or New Mexico. Low (average about 30% of normal) activity of sphingomyelinase was found in the fibroblasts of 7 of 8 cases evaluated. A similar case was reported in a Spanish woman from northern New Mexico by Kornfeld et al. (1975). </p><p>The patient reported by Longstreth et al. (1982) as 'adult dystonic lipidosis' may have had this disorder: a 43-year-old man who presented with splenomegaly and a 20-year history of a neurologic disorder that included vertical supranuclear ophthalmoplegia, mild dementia, and a movement disorder. Adult dystonic lipidosis was diagnosed from the clinical picture and demonstration of foamy and sea-blue histiocytes in bone marrow. Niemann-Pick disease was excluded by normal sphingomyelinase activity in cultured skin fibroblasts. The patient, who also had mitral valve prolapse, was able to work as a janitor until age 37 years. Lysosomal storage of neutral fat and phospholipids was suggested by electron microscopy. </p><p>In ocular histopathologic studies of a girl who died at age 11 years, Palmer et al. (1985) noted lipid deposits. </p><p>Witzleben et al. (1986) emphasized that childhood cirrhosis is a feature of NPC. They reported 2 unrelated cases. Skin fibroblasts in one showed sphingomyelinase activity that was 42% of control values. The hepatic storage underlying the cirrhosis was typically inconspicuous; however, sea-blue histiocytes in the marrow could be considered a valuable diagnostic clue. </p><p>In a collaborative study in Lyon, France, Denver, Colorado, and Bethesda, Maryland, Vanier et al. (1988) studied 70 patients with type C Niemann-Pick disease clinically and biochemically. Age of onset ranged from the neonatal period to 55 years. More than 90% of the patients had some degree of splenomegaly and/or hepatomegaly, but notably, some had none. Neurologic deterioration was a central characteristic of the disease, but onset and progression varied. In infancy, there was hypotonia, developmental delay, mental deterioration, and spasticity. In childhood, there was cerebellar ataxia, poor school performance, dysarthria, dystonia, vertical supranuclear gaze palsy, and seizures. Two patients had adult-onset disease with neurologic and psychiatric manifestations. Bone marrow biopsies consistently showed foam cells and/or sea-blue histiocytes. Sphingomyelinase activity was normal or somewhat reduced (47% of controls). Very low cholesterol esterification rates were observed in more than 90% of the patients, including all cases with the most severe forms of the disease. </p><p>On the basis of the analysis of 22 patients, Fink et al. (1989) delineated 3 phenotypes of NPC: (1) an early-onset, rapidly progressive form associated with severe hepatic dysfunction and psychomotor delay during infancy and later with supranuclear vertical gaze paresis, ataxia, marked spasticity, and dementia; (2) a delayed-onset, slowly progressive form heralded by the appearance, usually in early childhood, of mild intellectual impairment, supranuclear vertical gaze paresis, and ataxia, and later associated with dementia and, variably, seizures and extrapyramidal deficits; and (3) a late-onset, slowly progressive form distinguished from the second pattern by later age of onset (adolescence or adulthood) and a much slower rate of progression. Phenotypes 1 and 2 have been observed in the same sibship. Omura et al. (1989) reported 6 cases. </p><p>Turpin et al. (1991) discussed the form of type C Niemann-Pick disease that starts in adolescence or adulthood and shows a slower evolution than does the infantile form. Psychomotor retardation is a consistent feature. Cerebellar ataxia and extrapyramidal manifestations are often found rather than pyramidal manifestations. Supranuclear ophthalmoplegia with paralysis of down-gaze is nearly constant. Cataplexy and other types of seizures may be found during the evolution of the disease. In some cases a psychosis may be the only manifestation for several years; the treatment by psychotropic drugs raises the question of a superimposition of a drug-induced lipidosis. Although hepatosplenomegaly is a consistent finding in children in the infantile form of the disease, hepatomegaly is often absent in the adult forms and splenomegaly, although generally present, is not pronounced. Foam cells or sea-blue histiocytes are found on bone marrow biopsy. </p><p>Imrie et al. (2002) reported 17 patients with Niemann-Pick type disease type C who presented in late childhood or adulthood. They suggested that adult patients are often referred to clinicians with psychosis or other major psychiatric problems. The dystonia with preserved intellectual functioning can be mistaken for other basal ganglia disorders such as Wilson disease (277900). The presence of vertical gaze palsy is an important clinical clue and, in the presence of a modest increase in plasma chitotriosidase activity, can be helpful in the differential diagnosis. Imrie et al. (2002) concluded that the diagnosis should be confirmed in suspected cases by filipin staining of cultured fibroblasts, as well as cholesterol esterification studies and DNA mutation analysis. They stated that in most adult-onset patients the presenting neurologic abnormality will be a combination of ataxia and dysarthria. As the disease progresses, dystonia and seizures may occur. The characteristic ocular abnormality (supranuclear gaze palsy) usually appears early in the course of the disease but can be very subtle initially and only detected by detailed ophthalmologic assessment. In 3 patients, symptoms of the disease appeared with or were exacerbated by pregnancy. </p><p>Josephs et al. (2004) reported a 75-year-old woman who was a heterozygous carrier of an NPC1 mutation (607623.0013). She presented with a 10-year history of tremor, initially a side-to-side head tremor, which later progressed to her upper extremities. The tremor was worse at rest and worsened with mental activity, and she was initially diagnosed with Parkinson disease (168600). The patient had 3 brothers who were affected by a severe childhood-onset neurologic disorder characterized by spastic dysarthria, tremor, paresis of vertical eye movements, disturbance of gait, and splenomegaly (Willvonseder et al., 1973). Josephs et al. (2004) concluded that their patient was a manifesting carrier of Niemann-Pick disease type C and that her brothers likely carried 2 mutations in the NPC1 gene. </p><p>Garver et al. (2007) analyzed data from 87 questionnaires received from Niemann-Pick type C1 families living in the United States and reported that the average age of diagnosis was 10.4 years, with one-half of patients being diagnosed before the age of 6.9 years, and the average age of death was 16.2 years, with one-half of all patients dying before the age of 12.5 years. The most common clinical symptom reported at birth was neonatal jaundice (52%), followed by enlargement of the spleen (36%) and liver (31%); ascites (19%) and neonatal hypotonia (6%) were much less frequent. Common developmental difficulties included clumsiness (87%), learning difficulties (87%), ataxia (83%), dysphagia (80%), and vertical gaze palsy (81%). The questionnaires formed the basis for the National NPC1 Disease Database. </p><p>In a study of ocular movements of 3 adult patients with biochemically confirmed NPC disease, Abel et al. (2009) found that reflexive saccade latency ranged from shorter to longer than normal, reflexive saccade gain was reduced, asymptotic peak velocity was reduced, fewer self-paced saccades were generated, and increased errors on antisaccades were made by patients compared to controls. Patients with more severe biochemical, cognitive, and symptom deficits performed most poorly on brainstem and frontal ocular motor measures. Paradoxically, less severe illness was associated with an abnormally reduced saccadic latency. The findings suggested that reduced saccadic latency may result from inadequate fixation input from abnormally functioning frontal eye fields. All patients had presented with a psychotic illness. Abel et al. (2009) concluded that ocular motor measures may provide an index of disease severity in Niemann-Pick disease type C, and may be a useful adjunct for monitoring disease progression and medication response. </p><p>Walterfang et al. (2010) reported the neuroradiologic findings of 6 patients with adult-onset NPC who presented with psychosis, ophthalmoplegia, or a dysexecutive syndrome. Compared to controls, patients had bilateral focal gray matter reductions in the hippocampus, thalamus, superior cerebellum, and insula, in addition to smaller regions of the inferoposterior cortex. These changes corresponded to the clinical findings in adults, although the frontal cortex did not show changes on imaging. Fractional anisotropy showed widespread reductions in major white matter tracts affecting most brain regions, which appeared to be due to both impaired myelination and altered axonal structure. Overall, the findings were consistent with a selective vulnerability of certain neuronal populations; the more widespread white matter changes were consistent with the hypothesis that disrupted myelination and axonal structure may predate changes to the neuronal cell body. </p><p><strong><em>Fetal Niemann-Pick Disease Type C</em></strong></p><p>
Spiegel et al. (2009) reported 7 patients from 5 unrelated families with fetal onset of NPC. Three of the families were consanguineous: 2 of Arab Muslim descent and 1 of Ashkenazi Jewish descent. Two fetuses were diagnosed prenatally based on the combination of splenomegaly and ascites early in the third trimester, followed by analysis of cultured amniocytes. Three patients were diagnosed postnatally, and the last 2 were diagnosed based on an affected sib. The prognosis was very poor in all patients: 1 died in utero, 1 pregnancy was terminated, and 4 died within the first 7 months of life from neonatal cholestatic disease. The seventh patient had developmental regression at age 10 months, followed by rapid neurologic deterioration with spastic quadriplegia, profound mental retardation, seizures, and generalized white matter dysmyelination. The fetal presentations included in utero splenomegaly (6 of 7), in utero hepatomegaly (5 of 7), in utero ascites (4 of 7), intrauterine growth retardation (2 of 7), and oligohydramnios (2 of 7). Placentomegaly and intervillous thrombosis was present in 2 of 3 pregnancies examined. Congenital thrombocytopenia (4 of 4), congenital anemia (2 of 4), and petechial rash (2 of 5) were diagnosed immediately after birth in some. Genetic analysis confirmed the diagnosis in all cases. Spiegel et al. (2009) suggested that fetal onset may represent a unique subset of neonatal NPC with a grave prognosis. </p><p><strong><em>Niemann-Pick Disease, Type D (Nova Scotian)</em></strong></p><p>
Although Niemann-Pick disease type C and type D are clinically similar, Greer et al. (1997) suggested that NPD has a more homogeneous expression than NPC and that patients with NPD resemble less severely affected NPC patients. </p><p>Studying a 13-year-old Nova Scotian case, Rao and Spence (1977) found elevated sphingomyelin, especially in the spleen, and even greater elevation of free cholesterol. They could not demonstrate deficiency of total sphingomyelinase. </p><p>Jan and Camfield (1998) performed a retrospective clinical study of 20 cases of Nova Scotian NPD. The female-to-male ratio was 2 to 1. Five of the children had severe neonatal jaundice. Early milestones were normal in the majority. Neurologic symptoms developed between 5 and 10 years of age, with a mean age at diagnosis of 7.2 years. Seizures developed in all children between 4.5 and 16 years of age and were followed by significant physical and mental deterioration. Age at death was between 11 and 22.5 years, with the majority dying of pneumonia. </p>
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<strong>Inheritance</strong>
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<p>Niemann-Pick disease type C is an autosomal recessive disorder (Vanier and Millat, 2003). </p><p><strong><em>Inheritance of Type D</em></strong></p><p>
Winsor and Welch (1978) gave a full genetic discussion of the Nova Scotian or type D Niemann-Pick disease. They identified 19 cases distributed in 15 sibships, in French Acadians of Yarmouth County, N.S. All 30 parents traced back to Joseph Muise, married to Marie Amirault, who lived in the late 1600s and early 1700s. Two other common ancestral couples were identified, but the Muise-Amirault couple had by far the largest number of 'valid coincidences.' (Since all forebears of a common ancestor appear on both sides of the pedigree, not every match will indicate a 'real' common ancestor, which occurs when the common ancestor's child on the father's side is different on the mother's side. Mange (1964) termed the latter situation a 'valid coincidence.') Carrier frequency was presumably high, because none of the affected sibships had closely related parents and because a considerable proportion of children chosen at random could be traced to the Muise couple. Fredrickson and Sloan (1972) described 3 sibs with a disorder clinically identical to the Nova Scotian disorder. The father could be traced to the Muise couple; the mother was Italian. Winsor and Welch (1978) suggested these children might have a genetic compound disorder, the Acadian mutation being unique. </p>
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<strong>Diagnosis</strong>
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<p>Argoff et al. (1990) suggested that assay for the deficiency, which shows impaired ability of cultured fibroblasts to esterify exogenously supplied cholesterol, is useful for confirming the diagnosis in patients with atypical presentation. Boustany et al. (1990) a suggested that characteristic ultrastructural changes may be useful to the diagnosis. </p><p>Vanier et al. (1991) reported on a personal experience with 134 cases, which indicated that the diagnosis is best reached by the combined demonstration of a deficient induction of esterification of cholesterol and of an intravesicular cholesterol storage by cytochemistry after filipin staining. They gave brief reports of 6 adult-onset cases. Although there was a wide phenotypic spectrum, complementation studies yielded no evidence of separate complementation groups. </p><p>Ceuterick and Martin (1994) demonstrated osmiophilic pleomorphic lamellar inclusions in dermal fibroblasts and perivascular histiocytes in skin biopsies in 8 Niemann-Pick type C patients but not in 473 controls. They emphasized that a skin biopsy may be useful diagnostically. </p><p>Imrie and Wraith (2001) described 4 patients with Niemann-Pick disease type C in whom the presentation was isolated splenic enlargement; this remained the only abnormality for a number of years. They stated that the diagnosis can be suggested by either finding abnormal storage material in a tissue biopsy specimen or by showing a modest elevation in plasma chitotriosidase activity. In patients with suggestive abnormalities, filipin staining of a skin fibroblast sample should confirm the abnormality in cholesterol trafficking. They suggested that formal esterification studies and mutation analysis should be performed, especially if prenatal testing is to be done in subsequent pregnancies. If the diagnosis is not considered and established, the family is at risk of having further affected children. </p><p>The biochemical diagnosis of NPC relies on the use of patient skin fibroblasts in an assay to demonstrate delayed low-density lipoprotein (LDL)-derived cholesterol esterification and a cytologic technique (filipin staining) to demonstrate the intracellular accumulation of cholesterol. A few patients, referred to as 'NPC variants,' present with clinical symptoms of NPC but show near-normal results of these biochemical tests. Sun et al. (2001) demonstrated that NPC-variant fibroblast samples can be detected as sphingolipid storage disease cells by using a fluorescent sphingolipid analog that accumulates in endosomes/lysosomes in variant cells preincubated with LDL cholesterol but targeted to the Golgi complex in normal cells under these conditions. </p><p>Sidhu et al. (2020) developed and validated a mass spectrometry method to measure N-palmitoyl-O-phosphocholineserine (PPCS), a lipid found to be elevated in NPC1, in biomaterials including plasma, serum, and cerebrospinal fluid (CSF). At a cutoff of 248 ng/mL in plasma, PPCS has 100% specificity and 96.6% specificity in differentiating NPC1 patients from controls and NPC1 carriers, respectively. Sidhu et al. (2020) also found that elevation of PPCS in CSF from patients with NPC1 correlates with NPC neurologic disease severity scores. In a clinical trial with intravenous 2-hydroxypropyl-beta-cyclodextrin, plasma PPCS was significantly reduced, thus demonstrating that this biomarker can be used to evaluate the peripheral treatment efficacy of intravenous 2-hydroxypropyl-beta-cyclodextrin. </p><p>Boenzi et al. (2021) performed lipidomics analysis in plasma of 15 patients with Niemann-Pick disease type C and 15 controls. Classic NPC biomarkers including 2 oxysterols (7-ketocholesterol and Triol) and 2 lyso-sphingolipids (Lyso-SM and Lyso-SM-509) were elevated in patients compared to controls. Boenzi et al. (2021) found a significant positive correlation between these 4 biomarkers and 7 main lipid species that were elevated in the NPC1 patients and a significant negative correlation between these 4 biomarkers and 6 main lipid species that were decreased in the NPC1 patients. Boenzi et al. (2021) noted that the altered plasma lipid profiles in the NPC1 patients involved lipids involved in processes such as inflammation and cell oxidative stress regulation. </p>
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<strong>Mapping</strong>
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<span class="mim-text-font">
<p>The locus corresponding to the mouse NPC phenotype (Pentchev et al., 1984), symbolized spm, was shown by Sakai et al. (1991) to be on mouse chromosome 18. Since mouse chromosome 18 has extensive syntenic homology with human chromosomes 5 and 18, Carstea et al. (1993) undertook linkage analysis with markers specific to these chromosomes. No linkage was found with chromosome 5, but strong evidence of linkage was found with chromosome 18. Within affected offspring, the chromosome 18 parental contribution was identical, as demonstrated by allele-specific microsatellite markers. Significant linkage of NPC to an 18p genomic marker, D18S40, was indicated by a 2-point lod score of 3.84. Three recombinants detected among the 28 informative individuals represented a recombination fraction of 0.07. Analysis of meiotic chromosomal breakpoint patterns among the affected individuals indicated that the NPC gene is located in the pericentromeric region of chromosome 18, probably on the short arm. In their Figure 2, Carstea et al. (1993) demonstrated how chromosome 18 was divided into 6 regions, designated A through F, and how meiotic recombination resulted in divergent segregation of one or more markers and the NPC phenotype. Only 1 of the 6 intervals, a pericentromeric one, showed no evidence of meiotic recombination. By linkage studies, Carstea et al. (1994) located the NPC gene to a region defined by DNA markers in the 18q11-q12 region. In 1 family linkage to this region was excluded, suggesting the existence of a separate gene that codes for an additional component required for intracellular movement of cholesterol (see below). </p><p>Greer et al. (1997) presented linkage evidence supporting allelism of NPC and NPD. They found that NPD in Nova Scotia is tightly linked (recombination fraction = 0.00; maximum lod score = 4.50) to a microsatellite marker, D18S480, from the centromeric region of 18q. This is the same site as that to which the NPC1 gene (607623) was mapped by Carstea et al. (1994). In a study of a single large kindred with NPD, Greer et al. (1999) used linkage disequilibrium mapping and 5 newly developed polymorphic microsatellite markers to narrow the NPC1 critical region to a 5-cM interval. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Heterogeneity</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Genetic Heterogeneity</em></strong></p><p>
To investigate the possibility that mutation at more than one locus can cause the disorder, Steinberg et al. (1994) undertook somatic cell hybridization experiments using skin fibroblast strains from 12 patients representing a wide clinical spectrum. Using filipin staining of free cholesterol as a marker for complementation, they found evidence for the existence of 1 major group, called group alpha, and a minor group, called group beta, represented by 1 mutant strain. Other experiments in which sphingomyelinase activity was measured as a marker for complementation using 5 mutant strains showed activity consistently less than 40% of control levels, confirming the existence of the second group, later termed NPC2. Further support for the genetic heterogeneity was provided by Vanier et al. (1996) from complementation studies by somatic cell hybridization and linkage analysis. Crosses between various cell lines revealed a major complementation group (type C1) comprising 27 unrelated patients and a second minor group (type C2) comprising 5 patients. Linkage analysis in a multiplex family belonging to the minor complementation group showed that the mutated gene did not map to 18q11-q12 where the major gene is located. Patients in the first group spanned the whole spectrum of clinical and cellular phenotypes. No consistent clinical or biochemical phenotype was associated with the second complementation group; however, 3 of the 5 patients in group 2 presented with severe pulmonary involvement leading to death with the first year of life (see NPC2; 607625). The causative NPC2 gene was later identified (see 601015). </p><p>Vanier and Millat (2003) stated that approximately 95% of patients with Niemann-Pick disease type C have mutations in the NPC1 gene, which encodes a large membrane glycoprotein primarily located to late endosomes, and the remainder have mutations in the NPC2 gene, which encodes a small soluble lysosomal protein with cholesterol-binding properties. The identical biochemical patterns observed in NPC1 and NPC2 mutants suggested that the 2 proteins function in a coordinate fashion. The NPC1 and NPC2 proteins are involved in the cellular postlysosomal/late endosomal transport of cholesterol, glycolipids, and other cargo. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Brady (1978) pointed out that sphingomyelinase is deficient in type C as well as in types A and B. Although he stated that total sphingomyelinase activity may be 'attenuated' in some patients with types D and E, he raised doubts about the classification of type D as a sphingomyelin storage disease.</p><p>On the basis of somatic cell hybridization studies, Besley et al. (1980) suggested that types A and B may be genetically distinct from type C. Fusion of type C cells with either type A or type B cells resulted in restoration of sphingomyelinase activity. </p><p>Gilbert et al. (1981) reported extensively on the cases of 2 sisters who died at ages 8 and 7 years of the progressive CNS degenerative process of Niemann-Pick disease type C. Biochemical analyses showed elevated levels of sphingomyelin in liver and spleen with normal total sphingomyelinase activity. However, by isoelectric focusing, sphingomyelinase activity in the range of pI 4.6-5.2 was markedly reduced, whereas normal amounts of more acidic components were found. A similar explanation for 'Niemann-Pick disease without sphingomyelinase deficiency' may obtain in other cases. </p><p>Pentchev et al. (1985) were prompted to study cholesterol esterification in Niemann-Pick disease because of the similar phenotypic findings in a murine mutation affecting cholesterol esterification (Pentchev et al., 1984). They found esterification to be normal in 6 type A and 8 type B Niemann-Pick cell lines. In striking contrast, all 24 type C Niemann-Pick cell lines showed a major block in cholesterol esterification, whereas internalization and lysosomal processing of lipoprotein cholesterol was apparently normal. Acyl-CoA:cholesterol acyltransferase activity was also normal in type C cell extracts. Fluorescent microscopy showed that type C cells grown in fetal calf serum stored much unesterified cholesterol. The partial expression of the esterification defect (50% of normal) in heterozygous mice indicated that it is the primary fault. </p><p>Kruth et al. (1986) and Pentchev et al. (1986) discussed the abnormality of cholesterol metabolism in this disorder. In both heterozygous and homozygous type C Niemann-Pick fibroblasts, excessive uptake of LDL cholesterol and deficient esterification of the internalized cholesterol were observed. As reported by Pentchev et al. (1985), Liscum and Faust (1987) found that LDL does not stimulate cholesterol esterification in this disorder; however, they also showed that LDL does not down-regulate cholesterol synthesis or LDL receptor activity normally. They suggested that the intracellular processing of LDL-derived cholesterol may be defective in NPC fibroblasts. This suggestion was corroborated by the findings of Sokol et al. (1988), who examined the intracellular accumulation of unesterified cholesterol in normal and Niemann-Pick C fibroblasts. They found that the plasma membrane cholesterol of normal cells was more readily replenished by internalized LDL cholesterol than that of mutant fibroblasts. Their studies suggested that deficient translocation of exogenously derived cholesterol from lysosomes to other intracellular membrane sites may have an important pathophysiologic role in type C Niemann-Pick disease. </p><p>Vanier et al. (1988) demonstrated that cultured homozygous NPC cells challenged with pure human low-density lipoproteins showed a pronounced deficiency in cholesterol esterification and that heterozygotes showed intermediate rates of esterification. All other pathologic conditions studied, including types A and B Niemann-Pick disease, gave normal results. There appeared to be a correlation between the clinical phenotype and severity of the biochemical lesion. </p><p>Blanchette-Mackie et al. (1988) showed that incubation of fibroblasts from patients with type C Niemann-Pick disease with low density lipoprotein resulted in excessive intracellular accumulation of unesterified cholesterol not only in lysosomes but also at an early stage in the Golgi complex. They suggested that the Golgi complex may play a role in the intracellular translocation of exogenously derived cholesterol and that disruptions of the cholesterol transport pathway at the Golgi may, in part, be responsible for the deficiency in cholesterol utilization in this disorder. </p><p>Thomas et al. (1989) found that the sphingomyelinase deficiency (37.9% of normal on the average) could be corrected in fibroblasts from Niemann-Pick type C patients by removal of the lipoprotein fraction from the culture medium. This is consistent with the view that the primary defect is one affecting the cellular transport and/or processing of free cholesterol and that it is the intracellular storage of cholesterol that causes a marked attenuation of lysosomal sphingomyelinase activity. </p><p>Although some biochemical differences may exist between type C and type D Niemann-Pick disease, both show evidence of defective regulation of intracellular cholesterol esterification and storage. Complementation of cholesterol esterification was not observed either when NPC and NPD fibroblasts were fused with polyethylene glycol (Sidhu et al., 1993) or when activity was measured directly in mixed-cell homogenates (Byers et al., 1989). </p><p>Roff et al. (1991) pointed out that a number of hydrophobic amines such as imipramine inhibit low-density lipoprotein-induced esterification of cholesterol and cause unesterified cholesterol to accumulate in perinuclear vesicles. When stained with filipin, the appearance is indistinguishable from that seen in NPC fibroblasts. Thus, these agents produce a cholesterol lipidosis similar to that of NPC, which is due to defective post-lysosomal cholesterol transport. Roff et al. (1991) raised the possibility that an endogenous hydrophobic amine such as sphinganine may inhibit cholesterol transport in NPC. </p><p>Nerve cells demonstrate not only storage of cholesterol but also neurofibrillary tangles containing paired helical filaments, similar to the neurofibrillary tangles present in Alzheimer disease (see 104300), Kufs disease (see 204300), Down syndrome (190685), tuberous sclerosis (see 191100), progressive supranuclear palsy (601104), and neurodegeneration with brain iron accumulation-1 (NBIA1; 234200), among others. The presence of neurofibrillary tangles in Niemann-Pick type C distinguishes it from other types of Niemann-Pick disease. Auer et al. (1995) demonstrated tau protein (157140) in Western blots from brain tissue in 5 cases of Niemann-Pick type C. </p><p>In 3 patients in their thirties with genetically confirmed Niemann-Pick disease type C who were homozygous for the APOE4 (107741) allele, Saito et al. (2002) found abundant neurofibrillary tangles, widespread increased beta-amyloid diffuse plaques, and severe tau pathology. The authors suggested that NPC1 gene mutations combined with homozygosity of APOE4 alleles leads to pathology similar to that found in Alzheimer disease. </p><p>Vance (2006) provided a detailed review of the cellular mechanisms of lipid imbalance in NPC. Accumulation of cholesterol and gangliosides disrupts intracellular trafficking and affects normal cholesterol use within the cell. </p><p>Lloyd-Evans et al. (2008) found that lysosomal sphingosine storage and reduced lysosomal calcium levels were early events in development of the NPC phenotype in normal human cells exposed to the NPC-inducing drug U18666A. In this model, accumulation of cholesterol, sphingomyelin, and glycerosphingolipid was a secondary event. Pharmacologic elevation of cytosolic calcium or reduction of sphingosine content reversed the NPC phenotype in several cellular models of NPC, and sphingosine alone induced the abnormal calcium phenotype in a concentration-dependent manner. Treatment of Npc1 -/- mice with curcumin, a weak SERCA (see 108730) antagonist that elevates cytosolic calcium levels, increased life expectancy by 35% and slowed the rate of disease progression by 3 weeks. Lloyd-Evans et al. (2008) concluded that NPC1 is involved in sphingosine efflux from lysosomes, and that lysosomal sphingosine accumulation in NPC alters intracellular calcium concentration and causes abnormal endocytic trafficking. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In several patients with Niemann-Pick disease type C, Carstea et al. (1997) identified mutations in the NPC1 gene (607623.0001-607623.0003). In a study of cDNA and genomic DNA isolated from the fibroblasts of 11 patients with NPC1, 10 Japanese (7 late infantile, 2 juvenile, and 1 adult form of the disease) and 1 Caucasian, Yamamoto et al. (1999) found 14 novel mutations in the NPC1 gene, including small deletions and point mutations. </p><p>Yamamoto et al. (2000) studied 15 Japanese and 2 white patients with NPC. They found that in those patients with the late infantile form of the disease, there was a clear reduction of the NPC1 protein level regardless of the type of mutation, and 5 fibroblast lines expressed undetectable levels of NPC1 protein. Patients with a late clinical onset were distinct in that all of their skin fibroblasts expressed considerable levels of mutant NPC1 protein. </p><p>In the Nova Scotian variant of Niemann-Pick disease, Greer et al. (1998) demonstrated a 3097G-T transversion in the NPC1 gene, resulting in a gly992-to-trp amino acid substitution (607623.0004). </p><p>Kaminski et al. (2002) analyzed the NPC1 gene in 5 German patients with NPC1-related families. They identified a total of 5 novel mutations in the coding region of NPC1. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Greer et al. (1997) noted that Yarmouth County in Nova Scotia appears to have the world's highest incidence of Niemann-Pick type II disease (encompassing types C and D). The frequency of affected children in 1 region of the county was said to be about 1% and the frequency of heterozygous carriers was estimated to be 10 to 26% (Winsor and Welch, 1978). </p><p>To determine the incidence rate of NPC1 and NPC2 (607625), Wassif et al. (2016) analyzed 4 large independent massively parallel exome sequencing projects containing a total 17,754 chromosomes in which no patient had been screened for the diagnosis of Niemann-Pick disease, and analyzed every variant for pathogenicity. The data suggested an incidence rate for NPC1 of 1 in 92,104 and for NPC2 of 1 in 2,858,998. Evaluation of common NPC1 variants, however, suggested that there may be a late-onset NPC1 phenotype with a markedly higher incidence, on the order of 1 in 19,000 to 1 in 36,000. Wassif et al. (2016) determined a combined incidence of classical NPC of 1 in 89,229, or 1.12 affected patients per 100,000 conceptions, but predicted incomplete ascertainment of a late-onset phenotype of NPC1. </p><p>Using diagnosis coding information from an administrative database that collates billing-related data from pharmacies and medical facilities, Burton et al. (2021) estimated a prevalence of NPC in the United States of 0.99 per million. However, when the NPC prevalence in the United States was calculated based on the number of new cases published in the literature per year, the prevalence was estimated at 2.9 cases per million. Burton et al. (2021) concluded that NPC is underdiagnosed in the United States. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Nomenclature</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Niemann Pick disease has been classified by some into type I and type II: type I encompasses 2 subtypes, A and B (607616), which show deficiency of sphingomyelinase, and type II encompasses 2 subtypes, type C (NPC1; 257220, NPC2; 607625) and type D (Greer et al., 1997). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Christomanou (1980) reported that some patients with the juvenile form of Niemann-Pick disease may be missing a required activator protein. With the fifth edition of The Metabolic Basis of Inherited Disease, types A, B, and C were said to 'appear to be allelic disorders in which 1 of at least 3 different mutations affects the activity of sphingomyelinase' (Brady, 1983). Subsequently, type C proved to be due to mutation in a different gene on a different chromosome from that mutant in types A and B. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Two independently derived mutant mouse colonies played a pivotal role in delineating the biochemical basis of NPC. One was a BALB/c mouse presenting clinical and biochemical features of NPC (Pentchev et al., 1984); the other was the C57BL/Ks mouse characterized as a sphingomyelinosis because of attenuated sphingomyelinase activity and excess sphingomyelin accumulation (Miyawaki et al., 1986; Kitagawa, 1987). </p><p>Pentchev et al. (1986) reviewed the findings in the murine disorder and in type C Niemann-Pick disease. The esterification defect concerns exogenously derived cholesterol; synthesis of cholesteryl ester from labeled mevalonic acid and squalene was normal in affected fibroblasts as was endogenous cholesteryl ester synthesis from endogenous cholesterol induced by 25-hydroxycholesterol. </p><p>Lowenthal et al. (1990) described Niemann-Pick disease type C in a domestic short-hair kitten. The dam and littermates were donated to Colorado State University, and a breeding colony was established. Brown et al. (1994) reported on the clinical, biochemical, and morphologic findings in 26 affected cats. </p><p>Akaboshi et al. (1997) reported that a cell line derived from the C57BL/KsJ mouse model of NPC shows biochemical abnormalities similar to those in fibroblasts derived from human patients. Somatic cell hybridization analysis of these cells and 5 fibroblast strains derived from NPC patients (4 childhood cases and 1 adult case) was carried out. The criterion for complementation was the restoration of the normal intracellular fluorescent pattern in multinucleated cells stained with filipin to demonstrate cholesterol accumulation. These cells could be assigned to 2 complementation groups. The mutant mouse cells did not complement cell strains derived from childhood-type NPC, while they complemented a cell strain derived from an adult patient. The results indicated that the mouse is an authentic model of a major complementation group of NPC, and that NPC consists of genetically heterogeneous groups. </p><p>Studying the mutant BALB/c mouse model of NPC, Schedin et al. (1997) investigated enzymatic markers for lysosomes, mitochondria, microsomes, and peroxisomes in liver and brain. In addition to the lysosomal changes, they found a sizable decrease of peroxisomal beta-oxidation of fatty acids and catalase activity in these 2 organs. Isolated peroxisomes displayed a significant decrease in these enzyme activities. Furthermore, the only phospholipid change in brain was a decreased content of the plasmalogen form of phosphatidylethanolamine, and the dimethylacetal pattern was also modified. The electron microscopic appearance of peroxisomes did not show any large changes. The defect of peroxisomal enzymes was already present 18 days before the onset of the disease. In contrast, the lysosomal marker enzyme increased in activity only 6 days after the appearance of the symptoms. The events of the pathologic process had previously been considered to be elicited by lysosomal deficiency, but this study showed disturbances similar to those in a number of peroxisomal diseases. The peroxisomal impairment appeared to be an early event in the process and could be a factor in the development of Niemann-Pick type C disease. </p><p>Xie et al. (1999) used the NPC mouse to determine whether the accumulation of unesterified cholesterol in this disorder represents sterol carried in low density lipoprotein (LDL) and chylomicrons (CMs) taken up into the tissues through the coated-pit pathway. A series of observations strongly supported the conclusion that, in Niemann-Pick disease type C, it is the cholesterol carried in LDL and CMs that is sequestered in the tissues, and not sterol that is newly synthesized and carried in high density lipoprotein. </p><p>Erickson et al. (2000) used a mouse model with a disrupted Npc1 gene to study 2 cholesterol-lowering drugs (nifedipine and probucol) and the effects of introducing a null mutation in the low density lipoprotein receptor (LDLR; 606945). Although these treatments significantly ameliorated liver cholesterol storage, there was little effect on the onset of neurologic symptoms. </p><p>Liu et al. (2000) determined the relative contribution of ganglioside accumulation in the neuropathogenesis of NPC by breeding NPC model mice with mice carrying a targeted mutation in GalNAc-T (601873), the gene encoding the beta-1-4GalNAc transferase responsible for the synthesis of GM2 and complex gangliosides. Unlike the NPC model mice, the double mutant mice did not exhibit central nervous system (CNS) accumulation of gangliosides GM2 or of glycolipids GA1 and GA2. Histologic analysis revealed that the characteristic neuronal storage pathology of NPC disease was substantially reduced in the double mutant mice. By contrast, visceral pathology was similar in the NPC and double mutant mice. Most notably, the clinical phenotype of the double mutant mice, in the absence of CNS ganglioside accumulation and associated neuronal pathology, did not improve. The authors concluded that complex ganglioside storage, while responsible for much of the neuronal pathology, did not significantly influence the clinical phenotype of the NPC model. </p><p>Langmade et al. (2006) noted that the failure to properly traffic lipoprotein cholesterol in NPC1 results in impaired oxysterol and steroid synthesis. Langmade et al. (2006) found that treatment of Npc1 -/- mice with the neurosteroid allopregnanolone and a synthetic oxysterol ligand delayed the onset of neurologic symptoms and prolonged life span, suggesting that the treatment bypassed the cholesterol trafficking defect. The therapy preserved Purkinje cells, suppressed cerebellar expression of microglial-associated genes, and reduced infiltration of microglia in cerebellar tissue. Transfection assays correlated the efficacy of treatment with activation of murine PXR (NR1I2; 603065) in vivo. </p><p>Elrick et al. (2010) generated Npc1 conditional null mutant mice. Deletion of Npc1 in mature cerebellar Purkinje cells led to an age-dependent impairment in motor tasks, including rotarod and balance beam performance. These mice did not show the early death or weight loss characteristic of global Npc1-null mice, suggesting that Purkinje cell degeneration may not underlie these phenotypes. Histologic examination revealed the progressive loss of Purkinje cells in an anterior-to-posterior gradient. This cell-autonomous neurodegeneration occurred in a spatiotemporal pattern similar to that of global knockout mice. A subpopulation of Purkinje cells in the posterior cerebellum exhibited marked resistance to cell death despite Npc1 deletion. Purkinje cells in both vulnerable and resistant subpopulations displayed no electrophysiologic abnormalities prior to degeneration. The authors concluded that Npc1 deficiency leads to cell-autonomous, selective neurodegeneration and suggested that the ataxic symptoms of NPC disease may arise from Purkinje cell death rather than cellular dysfunction. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Philippart et al. (1969); Yatziv et al. (1983)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Abel, L. A., Walterfang, M., Fietz, M., Bowman, E. A., Velakoulis, D.
<strong>Saccades in adult Niemann-Pick disease type C reflect frontal, brainstem, and biochemical deficits.</strong>
Neurology 72: 1083-1086, 2009.
[PubMed: 19307542]
[Full Text: https://doi.org/10.1212/01.wnl.0000345040.01917.9d]
</p>
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<p class="mim-text-font">
Akaboshi, S., Yano, T., Miyawaki, S., Ohno, K., Takeshita, K.
<strong>A C57BL/KsJ mouse model of Niemann-Pick disease (spm) belongs to the same complementation group as the major childhood type of Niemann-Pick disease type C.</strong>
Hum. Genet. 99: 350-353, 1997.
[PubMed: 9050921]
[Full Text: https://doi.org/10.1007/s004390050370]
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<p class="mim-text-font">
Argoff, C. E., Kaneski, C. R., Blanchette-Mackie, E. J., Comly, M., Dwyer, N. K., Brown, A., Brady, R. O., Pentchev, P. G.
<strong>Type C Niemann-Pick disease: documentation of abnormal LDL processing in lymphocytes.</strong>
Biochem. Biophys. Res. Commun. 171: 38-45, 1990.
[PubMed: 2393397]
[Full Text: https://doi.org/10.1016/0006-291x(90)91353-t]
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<p class="mim-text-font">
Auer, I. A., Schmidt, M. L., Lee, V. M.-Y., Curry, B., Suzuki, K., Shin, R.-W., Pentchev, P. G., Carstea, E. D., Trojanowski, J. Q.
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Acta Neuropath. 90: 547-551, 1995.
[PubMed: 8615074]
[Full Text: https://doi.org/10.1007/BF00318566]
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<p class="mim-text-font">
Besley, G. T. N., Hoogeboom, A. J. M., Hoogeveen, A., Kleijer, W. J., Galjaard, H.
<strong>Somatic cell hybridisation studies showing different gene mutations in Niemann-Pick variants.</strong>
Hum. Genet. 54: 409-412, 1980.
[PubMed: 6249719]
[Full Text: https://doi.org/10.1007/BF00291589]
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<p class="mim-text-font">
Blanchette-Mackie, E. J., Dwyer, N. K., Amende, L. M., Kruth, H. S., Butler, J. D., Sokol, J., Comly, M. E., Vanier, M. T., August, J. T., Brady, R. O., Pentchev, P. G.
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Proc. Nat. Acad. Sci. 85: 8022-8026, 1988.
[PubMed: 3186703]
[Full Text: https://doi.org/10.1073/pnas.85.21.8022]
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<p class="mim-text-font">
Boenzi, S., Catesini, G., Sacchetti, E., Tagliaferri, F., Dionisi-Vici, C., Deodato, F.
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[PubMed: 34810067]
[Full Text: https://doi.org/10.1016/j.ymgme.2021.11.005]
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<li>
<p class="mim-text-font">
Boustany, R.-M. N., Kaye, E., Alroy, J.
<strong>Ultrastructural findings in skin from patients with Niemann-Pick disease, type C.</strong>
Pediat. Neurol. 6: 177-183, 1990.
[PubMed: 2360958]
[Full Text: https://doi.org/10.1016/0887-8994(90)90059-a]
</p>
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<li>
<p class="mim-text-font">
Brady, R. O.
<strong>Sphingomyelin lipidosis: Niemann-Pick disease. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.): Metabolic Basis of Inherited Disease. (4th ed.)</strong>
New York: McGraw-Hill (pub.) 1978. Pp. 718-730.
</p>
</li>
<li>
<p class="mim-text-font">
Brady, R. O.
<strong>Sphingomyelin lipidoses: Niemann-Pick disease. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M. S. (eds.): The Metabolic Basis of Inherited Disease. (5th ed.)</strong>
New York: McGraw-Hill (pub.) 1983. P. 731.
</p>
</li>
<li>
<p class="mim-text-font">
Brown, D. E., Thrall, M. A., Walkley, S. U., Wenger, D. A., Mitchell, T. W., Smith, M. O., Royals, K. L., March, P. A., Allison, R. W.
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[PubMed: 8203477]
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<p class="mim-text-font">
Burton, B. K., Ellis, A. G., Orr, B., Chatlani, S., Yoon, K., Shoaff, J. R., Gallo, D.
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[Full Text: https://doi.org/10.1016/j.ymgme.2021.06.011]
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<p class="mim-text-font">
Byers, D. M., Rastogi, S. R., Cook, H. W., Palmer, F. B. St. C., Spence, M. W.
<strong>Defective activity of acyl-CoA: cholesterol O-acyltransferase in Niemann-Pick type C and type D fibroblasts.</strong>
Biochem. J. 262: 713-719, 1989.
[PubMed: 2590161]
[Full Text: https://doi.org/10.1042/bj2620713]
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<p class="mim-text-font">
Carstea, E. D., Morris, J. A., Coleman, K. G., Loftus, S. K., Zhang, D., Cummings, C., Gu, J., Rosenfeld, M. A., Pavan, W. J., Krizman, D. B., Nagle, J., Polymeropoulos, M. H., and 26 others.
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[PubMed: 9211849]
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</p>
</li>
<li>
<p class="mim-text-font">
Carstea, E. D., Parker, C. C., Fandino, L. B., Vanier, M. T., Overhauser, J., Weissenbach, J., Pentchev, P. G., Brady, R. O., Polymeropoulos, M. H.
<strong>Localizing the human Niemann-Pick C gene to 18q11-12. (Abstract)</strong>
Am. J. Hum. Genet. 55 (suppl.): A182, 1994.
</p>
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Thomas, G. H., Tuck-Muller, C. M., Miller, C. S., Reynolds, L. W.
<strong>Correction of sphingomyelinase deficiency in Niemann-Pick type C fibroblasts by removal of lipoprotein fraction from culture media.</strong>
J. Inherit. Metab. Dis. 12: 139-151, 1989.
[PubMed: 2547109]
[Full Text: https://doi.org/10.1007/BF01800716]
</p>
</li>
<li>
<p class="mim-text-font">
Turpin, J. C., Masson, M., Baumann, N.
<strong>Clinical aspects of Niemann-Pick type C disease in the adult.</strong>
Dev. Neurosci. 13: 304-306, 1991.
[PubMed: 1817035]
[Full Text: https://doi.org/10.1159/000112177]
</p>
</li>
<li>
<p class="mim-text-font">
Vance, J. E.
<strong>Lipid imbalance in the neurological disorder, Niemann-Pick C disease.</strong>
FEBS Lett. 580: 5518-5524, 2006.
[PubMed: 16797010]
[Full Text: https://doi.org/10.1016/j.febslet.2006.06.008]
</p>
</li>
<li>
<p class="mim-text-font">
Vanier, M. T., Duthel, S., Rodriguez-Lafrasse, C., Pentchev, P., Carstea, E. D.
<strong>Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis.</strong>
Am. J. Hum. Genet. 58: 118-125, 1996.
[PubMed: 8554047]
</p>
</li>
<li>
<p class="mim-text-font">
Vanier, M. T., Millat, G.
<strong>Niemann-Pick disease type C.</strong>
Clin. Genet. 64: 269-281, 2003.
[PubMed: 12974729]
[Full Text: https://doi.org/10.1034/j.1399-0004.2003.00147.x]
</p>
</li>
<li>
<p class="mim-text-font">
Vanier, M. T., Rodriguez-Lafrasse, C., Rousson, R., Duthel, S., Harzer, K., Pentchev, P. G., Revol, A., Louisot, P.
<strong>Type C Niemann-Pick disease: biochemical aspects and phenotypic heterogeneity.</strong>
Dev. Neurosci. 13: 307-314, 1991.
[PubMed: 1817036]
[Full Text: https://doi.org/10.1159/000112178]
</p>
</li>
<li>
<p class="mim-text-font">
Vanier, M. T., Wenger, D. A., Comly, M. E., Rousson, R., Brady, R. O., Pentchev, P. G.
<strong>Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification: a collaborative study on 70 patients.</strong>
Clin. Genet. 33: 331-348, 1988.
[PubMed: 3378364]
[Full Text: https://doi.org/10.1111/j.1399-0004.1988.tb03460.x]
</p>
</li>
<li>
<p class="mim-text-font">
Walterfang, M., Fahey, M., Desmond, P., Wood, A., Seal, M. L., Steward, C., Adamson, C., Kokkinos, C., Fietz, M., Velakoulis, D.
<strong>White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study.</strong>
Neurology 75: 49-56, 2010.
[PubMed: 20484681]
[Full Text: https://doi.org/10.1212/WNL.0b013e3181e6210e]
</p>
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<li>
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Wassif, C. A., Cross, J. L., Iben, J., Sanchez-Pulido, L., Cougnoux, A., Platt, F. M., Ory, D. S., Ponting, C., Bailey-Wilson, J. E., Biesecker, L. G., Porter, F. D.
<strong>High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets.</strong>
Genet. Med. 18: 41-48, 2016.
[PubMed: 25764212]
[Full Text: https://doi.org/10.1038/gim.2015.25]
</p>
</li>
<li>
<p class="mim-text-font">
Wenger, D. A., Barth, G., Githens, J. H.
<strong>Nine cases of sphingomyelin lipidosis, a new variant in Spanish-American children.</strong>
Am. J. Dis. Child. 131: 955-961, 1977.
[PubMed: 900082]
[Full Text: https://doi.org/10.1001/archpedi.1977.02120220021002]
</p>
</li>
<li>
<p class="mim-text-font">
Willvonseder, R., Goldstein, N. P., McCall, J. T., Yoss, R. E., Tauxe, W. N.
<strong>A hereditary disorder with dementia, spastic dysarthria, vertical eye movement paresis, gait disturbance, splenomegaly, and abnormal copper metabolism.</strong>
Neurology 23: 1039-1049, 1973.
[PubMed: 4795418]
[Full Text: https://doi.org/10.1212/wnl.23.10.1039]
</p>
</li>
<li>
<p class="mim-text-font">
Winsor, E. J. T., Welch, J. P.
<strong>Genetic and demographic aspects of Nova Scotia Niemann-Pick disease (type D).</strong>
Am. J. Hum. Genet. 30: 530-538, 1978.
[PubMed: 736041]
</p>
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<li>
<p class="mim-text-font">
Witzleben, C. L., Palmieri, M. J., Watkins, J. B., Hogan, P.
<strong>Sphingomyelin lipidosis variant with cirrhosis in the pediatric age group.</strong>
Arch. Path. Lab. Med. 110: 508-512, 1986.
[PubMed: 3085631]
</p>
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<li>
<p class="mim-text-font">
Xie, C., Turley, S. D., Dietschy, J. M.
<strong>Cholesterol accumulation in tissues of the Niemann-Pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coated-pit pathway in each organ.</strong>
Proc. Nat. Acad. Sci. 96: 11992-11997, 1999.
[PubMed: 10518564]
[Full Text: https://doi.org/10.1073/pnas.96.21.11992]
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</li>
<li>
<p class="mim-text-font">
Yamamoto, T., Nanba, E., Ninomiya, H., Higaki, K., Taniguchi, M., Zhang, H., Akaboshi, S., Watanabe, Y., Takeshima, T., Inui, K., Okada, S., Tanaka, A., Sakuragawa, N., Millat, G., Vanier, M. T., Morris, J. A., Pentchev, P. G., Ohno, K.
<strong>NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C.</strong>
Hum. Genet. 105: 10-16, 1999.
[PubMed: 10480349]
[Full Text: https://doi.org/10.1007/s004399900059]
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<p class="mim-text-font">
Yamamoto, T., Ninomiya, H., Matsumoto, M., Ohta, Y., Nanba, E., Tsutsumi, Y., Yamakawa, K., Millat, G., Vanier, M. T., Pentchev, P. G., Ohno, K.
<strong>Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts.</strong>
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[PubMed: 11182931]
[Full Text: https://doi.org/10.1136/jmg.37.9.707]
</p>
</li>
<li>
<p class="mim-text-font">
Yatziv, S., Leibovitz-Ben Gershon, Z., Ornoy, A., Bach, G.
<strong>Clinical heterogeneity in a sibship with Niemann-Pick disease type C.</strong>
Clin. Genet. 23: 125-131, 1983.
[PubMed: 6839525]
[Full Text: https://doi.org/10.1111/j.1399-0004.1983.tb01860.x]
</p>
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Hilary J. Vernon - updated : 06/23/2022<br>Hilary J. Vernon - updated : 02/17/2022<br>Hilary J. Vernon - updated : 05/26/2020<br>Ada Hamosh - updated : 2/23/2016<br>George E. Tiller - updated : 11/7/2011<br>Cassandra L. Kniffin - updated : 6/20/2011<br>Cassandra L. Kniffin - updated : 2/16/2010<br>Cassandra L. Kniffin - updated : 7/7/2009<br>Patricia A. Hartz - updated : 12/3/2008<br>Marla J. F. O&#x27;Neill - updated : 2/1/2008<br>Cassandra L. Kniffin - updated : 3/13/2007<br>Cassandra L. Kniffin - updated : 10/4/2006<br>Cassandra L. Kniffin - updated : 3/17/2005<br>Victor A. McKusick - updated : 11/4/2003<br>Ada Hamosh - updated : 10/7/2003<br>Ada Hamosh - updated : 9/22/2003<br>Cassandra L. Kniffin - reorganized : 3/13/2003<br>Cassandra L. Kniffin - updated : 12/13/2002<br>Victor A. McKusick - updated : 1/15/2002<br>Ada Hamosh - updated : 1/9/2002<br>Michael J. Wright - updated : 11/6/2001<br>Victor A. McKusick - updated : 8/29/2001<br>Victor A. McKusick - updated : 7/17/2001<br>Victor A. McKusick - updated : 6/20/2001<br>Victor A. McKusick - updated : 6/20/2001<br>Ada Hamosh - updated : 5/16/2001<br>Victor A. McKusick - updated : 5/14/2001<br>Ada Hamosh - updated : 1/4/2001<br>George E. Tiller - updated : 5/12/2000<br>Victor A. McKusick - updated : 2/22/2000<br>Victor A. McKusick - updated : 11/29/1999<br>Victor A. McKusick - updated : 11/9/1999<br>Victor A. McKusick - updated : 9/29/1999<br>Victor A. McKusick - updated : 8/23/1999<br>Victor A. McKusick - updated : 3/18/1999<br>Victor A. McKusick - updated : 3/16/1999<br>Victor A. McKusick - updated : 7/17/1998<br>Victor A. McKusick - updated : 2/25/1998<br>Victor A. McKusick - updated : 9/10/1997<br>Victor A. McKusick - updated : 7/10/1997<br>Victor A. McKusick - updated : 3/4/1997<br>Orest Hurko - edited : 4/13/1996<br>Orest Hurko - updated : 4/4/1996<br>Orest Hurko - updated : 9/21/1995
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Victor A. McKusick : 6/4/1986
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