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Entry
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- #127750 - DEMENTIA, LEWY BODY; DLB
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- OMIM
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<span class="h4">#127750</span>
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<strong>Table of Contents</strong>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#diagnosis">Diagnosis</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="#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://www.diseaseinfosearch.org/x/4215" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/dementia-with-lewy-bodies" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:12217" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/127750" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/OMIA002378/" 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>
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<div><a href="https://wormbase.org/resources/disease/DOID:12217" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:127750" 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>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 312991009, 80098002<br />
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<strong>ICD10CM:</strong> G31.83<br />
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<strong>ICD9CM:</strong> 331.82<br />
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<strong>DO:</strong> 12217<br />
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">ICD+</a>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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127750
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
|
|
|
|
DEMENTIA, LEWY BODY; DLB
|
|
|
|
</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">
|
|
LEWY BODY DEMENTIA<br />
|
|
DIFFUSE LEWY BODY DISEASE
|
|
</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">
|
|
DIFFUSE LEWY BODY DISEASE WITH GAZE PALSY, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
LEWY BODY VARIANT OF ALZHEIMER DISEASE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
|
|
|
|
|
|
<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/1/1217?start=-3&limit=10&highlight=1217">
|
|
1q22
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Lewy body dementia, susceptibility to}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/127750"> 127750 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
GBA1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606463"> 606463 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/4/411?start=-3&limit=10&highlight=411">
|
|
4q22.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Dementia, Lewy body
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/127750"> 127750 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
SNCA
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/163890"> 163890 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/5/793?start=-3&limit=10&highlight=793">
|
|
5q35.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Dementia, Lewy body
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/127750"> 127750 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
SNCB
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/602569"> 602569 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/127750" 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>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<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/127750" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/127750" 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 dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
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|
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|
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|
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|
|
|
|
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|
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|
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|
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|
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|
|
|
|
<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">
|
|
|
|
- Parkinsonism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32798002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32798002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G20.C" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G20.C</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242422&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242422</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001300" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001300</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001300" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001300</a>]</span><br /> -
|
|
Visual hallucinations <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64269007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64269007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R44.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R44.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0233763&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0233763</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002367" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002367</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002367" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002367</a>]</span><br /> -
|
|
Delusions <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/2073000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">2073000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011253&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011253</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000746" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000746</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000746" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000746</a>]</span><br /> -
|
|
Progressive 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>]</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/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=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 /> -
|
|
Fluctuations in consciousness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851959&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851959</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007159" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007159</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007159" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007159</a>]</span><br /> -
|
|
Sensitivity to neuroleptic medication <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851960&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851960</a>]</span><br /> -
|
|
Diffuse Lewy bodies throughout the brain (cortical and subcortical regions) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851961&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851961</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
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- Caused by mutation in the alpha-synuclein gene (SNCA, <a href="/entry/163890#0004">163890.0004</a>)<br /> -
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<p>A number sign (#) is used with this entry because dementia with Lewy bodies (DLB) can be caused by mutation in the alpha-synuclein (SNCA; <a href="/entry/163890">163890</a>) or beta-synuclein (SNCB; <a href="/entry/602569">602569</a>) genes.</p><p>Mutation in the SNCA gene can also cause familial Parkinson disease-1 (PARK1; <a href="/entry/168601">168601</a>) and Parkinson disease-4 (PARK4; <a href="/entry/605543">605543</a>).</p><p>The epsilon-4 allele of the APOE gene (<a href="/entry/107741">107741</a>) and the B allele of the CYP2D6 gene (<a href="/entry/124030">124030</a>), a cytochrome P-450 monooxygenase, have also been implicated in DLB.</p><p>A mutation in the prion protein gene (PRNP; see <a href="/entry/176640#0017">176640.0017</a>) has been identified in 1 patient with DLB. Some patients with a diagnosis consistent with Lewy body disease or dementia have mutations in the LRRK2 gene (<a href="/entry/609007">609007</a>), which is associated with Parkinson disease-8 (PARK8; <a href="/entry/607060">607060</a>) (<a href="#7" class="mim-tip-reference" title="Giasson, B. I., Covy, J. P., Bonini, N. M., Hurtig, H. I., Farrer, M. J., Trojanowski, J. Q., Van Deerlin, V. M. <strong>Biochemical and pathological characterization of Lrrk2.</strong> Ann. Neurol. 59: 315-322, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16437584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16437584</a>] [<a href="https://doi.org/10.1002/ana.20791" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16437584">Giasson et al., 2006</a>; <a href="#27" class="mim-tip-reference" title="Ross, O. A., Toft, M., Whittle, A. J., Johnson, J. L., Papapetropoulos, S., Mash, D. C., Litvan, I., Gordon, M. F., Wszolek, Z. K., Farrer, M. J., Dickson, D. W. <strong>Lrrk2 and Lewy body disease.</strong> Ann. Neurol. 59: 388-393, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16437559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16437559</a>] [<a href="https://doi.org/10.1002/ana.20731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16437559">Ross et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16437559+16437584" 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>One family with a mutation in the PSEN2 gene (<a href="/entry/600759#0009">600759.0009</a>), usually associated with Alzheimer disease-4 (AD4; <a href="/entry/606889">606889</a>), had clinical and neuropathologic findings consistent with DLB (<a href="#26" class="mim-tip-reference" title="Piscopo, P., Marcon, G., Piras, M. R., Crestini, A., Campeggi, L. M., Deiana, E., Cherchi, R., Tanda, F., Deplano, A., Vanacore, N., Tagliavini, F., Pocchiari, M., Giaccone, G., Confaloni, A. <strong>A novel PSEN2 mutation associated with a peculiar phenotype.</strong> Neurology 70: 1549-1554, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18427071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18427071</a>] [<a href="https://doi.org/10.1212/01.wnl.0000310643.53587.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18427071">Piscopo et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18427071" 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>Dementia with Lewy bodies (DLB) is a neurodegenerative disorder clinically characterized by dementia and parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Pathologically, Lewy bodies are present in a pattern more widespread than usually observed in Parkinson disease (see PD; <a href="/entry/168600">168600</a>). Alzheimer disease (AD; <a href="/entry/104300">104300</a>)-associated pathology and spongiform changes may also be seen (<a href="#19" class="mim-tip-reference" title="McKeith, I. G., Galasko, D., Kosaka, K., Perry, E. K., Dickson, D. W., Hansen, L. A., Salmon, D. P., Lowe, J., Mirra, S. S., Byrne, E. J., Lennox, G., Quinn, N. P., Edwardson, J. A., Ince, P. G., Bergeron, C., Burns, A., Miller, B. L., Lovestone, S., Collerton, D., Jansen, E. N., Ballard, C., de Vos, R. A., Wilcock, G. K., Jellinger, K. A., Perry, R. H. <strong>Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.</strong> Neurology 47: 1113-1124, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8909416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8909416</a>] [<a href="https://doi.org/10.1212/wnl.47.5.1113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8909416">McKeith et al., 1996</a>; <a href="#20" class="mim-tip-reference" title="Mizutani, T. <strong>Diagnostic criteria of diffuse Lewy body disease.</strong> Nippon Rinsho 58: 2044-2048, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11068444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11068444</a>]" pmid="11068444">Mizutani, 2000</a>; <a href="#18" class="mim-tip-reference" title="McKeith, I. G., Dickson, D. W., Lowe, J., Emre, M., O'Brien, J. T., Feldman, H., Cummings, J., Duda, J. E., Lippa, C., Perry, E. K., Aarsland, D., Arai, H., and 33 others. <strong>Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium.</strong> Neurology 65: 1863-1872, 2005. Note: Erratum: Neurology 65: 1992 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16237129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16237129</a>] [<a href="https://doi.org/10.1212/01.wnl.0000187889.17253.b1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16237129">McKeith et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16237129+11068444+8909416" 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="#13" class="mim-tip-reference" title="Ishikawa, A., Takahashi, H., Tanaka, H., Hayashi, T., Tsuji, S. <strong>Clinical features of familial diffuse Lewy body disease.</strong> Europ. Neurol. 38 (suppl. 1): 34-38, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9276199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9276199</a>] [<a href="https://doi.org/10.1159/000113459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9276199">Ishikawa et al. (1997)</a> reported 2 unrelated families with familial autosomal dominant diffuse Lewy body disease. In family A, 4 patients over 3 generations presented with parkinsonism, vertical ocular limitation, progressive dementia, and delusions or visual hallucinations. Two of the patients developed neuroleptic malignant syndrome (NMS). Family S had 3 affected members over 3 generations. One was examined in detail and presented with parkinsonism and progressive dementia and later developed NMS. In a member of family S reported by <a href="#13" class="mim-tip-reference" title="Ishikawa, A., Takahashi, H., Tanaka, H., Hayashi, T., Tsuji, S. <strong>Clinical features of familial diffuse Lewy body disease.</strong> Europ. Neurol. 38 (suppl. 1): 34-38, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9276199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9276199</a>] [<a href="https://doi.org/10.1159/000113459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9276199">Ishikawa et al. (1997)</a>, <a href="#12" class="mim-tip-reference" title="Ishikawa, A., Piao, Y.-S., Miyashita, A., Kuwano, R., Onodera, O., Ohtake, H., Suzuki, M., Nishizawa, M., Takahashi, H. <strong>A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease.</strong> Ann. Neurol. 57: 429-434, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732120</a>] [<a href="https://doi.org/10.1002/ana.20393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732120">Ishikawa et al. (2005)</a> identified a mutation in the PSEN1 gene (<a href="/entry/104311#0032">104311.0032</a>). No mutations were identified in the SNCA gene. The phenotype was an overlap between DLB and Alzheimer disease with spastic paraparesis (<a href="/entry/607822">607822</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15732120+9276199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Denson, M. A., Wszolek, Z. K., Pfeiffer, R. F., Wszolek, E. K., Paschall, T. M., McComb, R. D. <strong>Familial parkinsonism, dementia, and Lewy body disease: study of family G.</strong> Ann. Neurol. 42: 638-643, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9382476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9382476</a>] [<a href="https://doi.org/10.1002/ana.410420415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9382476">Denson et al. (1997)</a> reported 10 individuals with Lewy body disease in 3 successive generations of 2 closely intermarried families. The phenotype was variable: 4 patients displayed parkinsonian features only, 3 had dementia only, and 3 had combined parkinsonism and dementia. Mean age of onset was 62 years. Linkage studies were inconclusive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9382476" 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="#30" class="mim-tip-reference" title="Wakabayashi, K., Hayashi, S., Ishikawa, A., Hayashi, T., Okuizumi, K., Tanaka, H., Tsuji, S., Takahashi, H. <strong>Autosomal dominant diffuse Lewy body disease.</strong> Acta Neuropath. 96: 207-210, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9705138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9705138</a>] [<a href="https://doi.org/10.1007/s004010050883" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9705138">Wakabayashi et al. (1998)</a> described a Japanese family with parkinsonism and later-onset dementia. The proband developed parkinsonism at the age of 61 years, followed by dementia starting when she was 67. Her uncle, who was also her husband, died at the age of 78 years after 7- and 5-year histories of parkinsonism and dementia, respectively. Her 2 sons developed similar parkinsonism at the ages of 39 and 28 years and also suffered later-onset dementia. The apolipoprotein E genotype of the proband, her uncle, and 1 of their sons was E3/4 and that of the other son was E4/4. The authors concluded that this represented autosomal dominant diffuse Lewy body disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9705138" 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="Ohara, K., Takauchi, S., Kokai, M., Morimura, Y., Nakajima, T., Morita, Y. <strong>Familial dementia with Lewy bodies (DLB).</strong> Clin. Neuropath. 18: 232-239, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10505432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10505432</a>]" pmid="10505432">Ohara et al. (1999)</a> presented a familial case of dementia with Lewy bodies in 3 sibs, born of first-cousin parents, who demonstrated progressive dementia with a progressive language disorder characterized by dysarthria, paraphasia, and difficulty in finding words. The 2 brothers presented with parkinsonism and fluctuating cognition. The sister and one of the brothers also had visual hallucinations. No mutations in the alpha-synuclein gene (SNCA; <a href="/entry/163890">163890</a>), the parkin gene (PARK2; <a href="/entry/602544">602544</a>), or the ubiquitin carboxyl-terminal esterase L1 gene (UCHL1; <a href="/entry/191342">191342</a>) were found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10505432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Graeber, M. B., Muller, U. <strong>Dementia with Lewy bodies: disease concept and genetics.</strong> Neurogenetics 4: 157-162, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12898286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12898286</a>] [<a href="https://doi.org/10.1007/s10048-003-0155-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12898286">Graeber and Muller (2003)</a> provided a review of DLB, which they stated is the second most common degenerative dementia after Alzheimer disease. Clinically, DLB differs from Alzheimer disease in that disease symptoms are prone to fluctuate and patients often suffer from visual hallucinations, though short-term memory is relatively preserved. As many as 70% of patients have parkinsonism and up to 50% are sensitive to the extrapyramidal side effects of neuroleptic drugs. <a href="#9" class="mim-tip-reference" title="Graeber, M. B., Muller, U. <strong>Dementia with Lewy bodies: disease concept and genetics.</strong> Neurogenetics 4: 157-162, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12898286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12898286</a>] [<a href="https://doi.org/10.1007/s10048-003-0155-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12898286">Graeber and Muller (2003)</a> suggested that DLB is a complex disorder with both genetic and environmental factors involved in the pathogenesis, as is the case for many common disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12898286" 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="#24" class="mim-tip-reference" title="Ohtake, H., Limprasert, P., Fan, Y., Onodera, O., Kakita, A., Takahashi, H., Bonner, L. T., Tsuang, D. W., Murray, I. V. J., Lee, V. M.-Y., Trojanowski, J. Q., Ishikawa, A., Idezuka, J., Murata, M., Toda, T., Bird, T. D., Leverenz, J. B., Tsuji, S., La Spada, A. R. <strong>Beta-synuclein gene alterations in dementia with Lewy bodies.</strong> Neurology 63: 805-811, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15365127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15365127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15365127[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/01.wnl.0000139870.14385.3c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15365127">Ohtake et al. (2004)</a> reported a patient with DLB and a mutation in the SNCB gene (<a href="/entry/602569#0002">602569.0002</a>). He presented at age 64 years with a 3-year history of mild dementia and deterioration in his handwriting. He had frontal lobe involvement manifesting as executive and language dysfunction. He later developed depression, motor apraxia, parkinsonism, and audio and visual hallucinations. Neuropathologic examination showed extensive Lewy bodies in the hippocampus, amygdala, and substantia nigra. Several family members were affected or possibly affected in an autosomal dominant pattern of inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15365127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pathologic Findings</em></strong></p><p>
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<a href="#14" class="mim-tip-reference" title="Khachaturian, Z. S. <strong>Diagnosis of Alzheimer's disease.</strong> Arch. Neurol. 42: 1097-1105, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2864910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2864910</a>] [<a href="https://doi.org/10.1001/archneur.1985.04060100083029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2864910">Khachaturian (1985)</a> performed an autopsy series of elderly individuals with dementia and found that the second most common pathology after the senile plaques and neurofibrillary tangles of Alzheimer disease was that of Lewy bodies found in subcortical and cortical regions. Patients with such 'Lewy body dementia' also have a sufficient number of hippocampal and neocortical senile plaques to meet the diagnostic criteria for Alzheimer disease. <a href="#10" class="mim-tip-reference" title="Hansen, L., Salmon, D., Galasko, D., Masliah, E., Katzman, R., DeTeresa, R., Thal, L., Pay, M. M., Hofstetter, R., Klauber, M., Rice, V., Butters, N., Alford, M. <strong>The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity.</strong> Neurology 40: 1-8, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2153271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2153271</a>] [<a href="https://doi.org/10.1212/wnl.40.1.1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2153271">Hansen et al. (1990)</a> referred to such patients as having the 'Lewy body variant of Alzheimer disease.' The term 'diffuse Lewy body disease' is reserved for patients with brainstem and cortical Lewy bodies but an insufficient number of senile plaques to fulfill the diagnostic criteria for Alzheimer disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2153271+2864910" 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="#30" class="mim-tip-reference" title="Wakabayashi, K., Hayashi, S., Ishikawa, A., Hayashi, T., Okuizumi, K., Tanaka, H., Tsuji, S., Takahashi, H. <strong>Autosomal dominant diffuse Lewy body disease.</strong> Acta Neuropath. 96: 207-210, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9705138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9705138</a>] [<a href="https://doi.org/10.1007/s004010050883" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9705138">Wakabayashi et al. (1998)</a> reported that pathologic examination of their 2 patients showed marked neuronal loss with Lewy bodies in the brainstem, pigmented nuclei, and numerous cortical Lewy bodies and ubiquitin-positive hippocampal neurites. Brain examination of 1 patient studied by <a href="#13" class="mim-tip-reference" title="Ishikawa, A., Takahashi, H., Tanaka, H., Hayashi, T., Tsuji, S. <strong>Clinical features of familial diffuse Lewy body disease.</strong> Europ. Neurol. 38 (suppl. 1): 34-38, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9276199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9276199</a>] [<a href="https://doi.org/10.1159/000113459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9276199">Ishikawa et al. (1997)</a> showed neuronal loss with gliosis and many Lewy bodies in the cerebral cortex and brainstem. One affected individual from the kindred reported by <a href="#4" class="mim-tip-reference" title="Denson, M. A., Wszolek, Z. K., Pfeiffer, R. F., Wszolek, E. K., Paschall, T. M., McComb, R. D. <strong>Familial parkinsonism, dementia, and Lewy body disease: study of family G.</strong> Ann. Neurol. 42: 638-643, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9382476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9382476</a>] [<a href="https://doi.org/10.1002/ana.410420415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9382476">Denson et al. (1997)</a> showed neuronal loss and gliosis as well as many Lewy bodies throughout the cerebral cortex and brainstem. Neurofibrillary tangles and neuritic plaques were present, but rare. Neuropathology of the proband reported by <a href="#23" class="mim-tip-reference" title="Ohara, K., Takauchi, S., Kokai, M., Morimura, Y., Nakajima, T., Morita, Y. <strong>Familial dementia with Lewy bodies (DLB).</strong> Clin. Neuropath. 18: 232-239, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10505432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10505432</a>]" pmid="10505432">Ohara et al. (1999)</a> demonstrated numerous Lewy bodies in the cerebral cortex and brain stem, with no neurofibrillary tangles or neuritic plaques. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9705138+9382476+10505432+9276199" 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="Obi, T., Nishioka, K., Ross, O. A., Terada, T., Yamazaki, K., Sugiura, A., Takanashi, M., Mizoguchi, K., Mori, H., Mizuno, Y., Hattori, N. <strong>Clinicopathologic study of a SNCA gene duplication patient with parkinson disease and dementia.</strong> Neurology 70: 238-241, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18195271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18195271</a>] [<a href="https://doi.org/10.1212/01.wnl.0000299387.59159.db" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18195271">Obi et al. (2008)</a> reported the neuropathologic findings of a Japanese patient with PD and later-onset dementia who was heterozygous for a duplication of the SNCA gene (<a href="/entry/163890#0005">163890.0005</a>) (<a href="#21" class="mim-tip-reference" title="Nishioka, K., Hayashi, S., Farrer, M. J., Singleton, A. B., Yoshino, H., Imai, H., Kitami, T., Sato, K., Kuroda, R., Tomiyama, H., Mizoguchi, K., Murata, M., Toda, T., Imoto, I., Inazawa, J., Mizuno, Y., Hattori, N. <strong>Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease.</strong> Ann. Neurol. 59: 298-309, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16358335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16358335</a>] [<a href="https://doi.org/10.1002/ana.20753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16358335">Nishioka et al., 2006</a>). The patient presented with classic levodopa-responsive parkinsonism at age 47. Loss of memory, visual hallucinations, and progressive cognitive decline began at age 60. Brain MRI showed medial temporal lobe atrophy on both sides, and single photon emission computed tomography (SPECT) showed hypoperfusion of the frontotemporal and occipital lobes. He later became bedridden and died of pneumonia at age 67. Postmortem examination showed mild frontal lobe atrophy and severe depigmentation of the substantia nigra and locus ceruleus. Severe neuronal loss was noted in the substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus nerve, the amygdala, and the CA2/3 of the hippocampus. SNCA-immunostaining revealed multiple Lewy bodies in the cerebral cortex, hippocampus, and brainstem. The Lewy body-related pathology was graded as diffuse neocortical type based on the pathologic classification of dementia with Lewy bodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16358335+18195271" 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>Diffuse Lewy Body Disease with Gaze Palsy</em></strong></p><p>
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<a href="#16" class="mim-tip-reference" title="Lewis, A. J., Gawel, M. J. <strong>Diffuse Lewy body disease with dementia and oculomotor dysfunction.</strong> Mov. Disord. 5: 143-147, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2157979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2157979</a>] [<a href="https://doi.org/10.1002/mds.870050209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2157979">Lewis and Gawel (1990)</a> and <a href="#5" class="mim-tip-reference" title="Fearnley, J. M., Revesz, T., Brooks, D. J., Frackowiak, R. S. J., Lees, A. J. <strong>Diffuse Lewy body disease presenting with a supranuclear gaze palsy.</strong> J. Neurol. Neurosurg. Psychiat. 54: 159-161, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1850451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1850451</a>] [<a href="https://doi.org/10.1136/jnnp.54.2.159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1850451">Fearnley et al. (1991)</a> each presented a case report in which a patient (71 and 76 years old) with dementia and parkinsonism also presented with horizontal and vertical supranuclear gaze palsy, prompting an initial diagnosis of progressive supranuclear palsy (PSP; <a href="/entry/601104">601104</a>). Pathologic diagnosis in both cases revealed diffuse Lewy body disease with Lewy bodies in areas believed to be associated with gaze control. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1850451+2157979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="de Bruin, V. M. S., Lees, A. J., Daniel, S. E. <strong>Diffuse Lewy body disease presenting with supranuclear gaze palsy, parkinsonism, and dementia: a case report.</strong> Mov. Disord. 7: 355-358, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1484531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1484531</a>] [<a href="https://doi.org/10.1002/mds.870070410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1484531">De Bruin et al. (1992)</a> reported a 67-year-old man with a family history of parkinsonism who presented with supranuclear gaze palsy and later developed parkinsonism and mental impairment. A diagnosis of PSP was made initially, but postmortem pathologic examination revealed diffuse Lewy body disease with multiple Lewy bodies in the neocortex and brainstem, as well as lesser numbers of neuritic plaques and neurofibrillary tangles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1484531" 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="Brett, F. M., Henson, C., Staunton, H. <strong>Familial diffuse Lewy body disease, eye movement abnormalities, and distribution of pathology.</strong> Arch. Neurol. 59: 464-467, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11890854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11890854</a>] [<a href="https://doi.org/10.1001/archneur.59.3.464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11890854">Brett et al. (2002)</a> reported 2 sibs with onset in their 60s of a disorder characterized by parkinsonism, dementia, and visual hallucinations, which progressed to incapacity. One patient exhibited vertical supranuclear gaze palsy, and the other patient could not be tested. Pathologic examination of both cases showed diffuse Lewy body disease, with changes in the posterior commissure, the rostral interstitial nucleus of the medial longitudinal fasciculus, and the interstitial nucleus of Cajal, areas that subserve vertical gaze. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11890854" 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 International Consortium on Dementia with Lewy bodies in 1995 established guidelines for the clinical and pathologic diagnosis of DLB. Mental impairment leading to dementia is the central core feature, with fluctuation in cognitive function, visual hallucinations, and motor features of parkinsonism being other key symptoms. Brainstem or cortical Lewy bodies are the only essential pathologic features, although other pathologic changes may be present as well (<a href="#19" class="mim-tip-reference" title="McKeith, I. G., Galasko, D., Kosaka, K., Perry, E. K., Dickson, D. W., Hansen, L. A., Salmon, D. P., Lowe, J., Mirra, S. S., Byrne, E. J., Lennox, G., Quinn, N. P., Edwardson, J. A., Ince, P. G., Bergeron, C., Burns, A., Miller, B. L., Lovestone, S., Collerton, D., Jansen, E. N., Ballard, C., de Vos, R. A., Wilcock, G. K., Jellinger, K. A., Perry, R. H. <strong>Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.</strong> Neurology 47: 1113-1124, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8909416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8909416</a>] [<a href="https://doi.org/10.1212/wnl.47.5.1113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8909416">McKeith et al., 1996</a>). The guidelines were updated in 2005 (<a href="#18" class="mim-tip-reference" title="McKeith, I. G., Dickson, D. W., Lowe, J., Emre, M., O'Brien, J. T., Feldman, H., Cummings, J., Duda, J. E., Lippa, C., Perry, E. K., Aarsland, D., Arai, H., and 33 others. <strong>Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium.</strong> Neurology 65: 1863-1872, 2005. Note: Erratum: Neurology 65: 1992 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16237129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16237129</a>] [<a href="https://doi.org/10.1212/01.wnl.0000187889.17253.b1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16237129">McKeith et al., 2005</a>) to include sleep disturbances, neuroleptic sensitivity, reduced striatal dopamine transporter activity on functional neuroimaging, and pathologic grading. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16237129+8909416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In Lewy body diseases, including Parkinson disease with or without dementia, dementia with Lewy bodies, and Alzheimer disease with Lewy body copathology, alpha-synuclein aggregates in neurons as Lewy bodies and Lewy neurites. By contrast, in multiple system atrophy (<a href="/entry/146500">146500</a>) alpha-synuclein accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs). <a href="#25" class="mim-tip-reference" title="Peng, C., Gathagan, R. J., Covell, D. J., Medellin, C., Stieber, A., Robinson, J. L., Zhang, B., Pitkin, R. M., Olufemi, M. F., Luk, K. C., Trojanowski, J. Q., Lee, V. M.-Y. <strong>Cellular milieu imparts distinct pathological alpha-synuclein strains in alpha-synucleinopathies.</strong> Nature 557: 558-563, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29743672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29743672</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29743672[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0104-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29743672">Peng et al. (2018)</a> reported that pathologic alpha-synuclein in GCIs and Lewy bodies is conformationally and biologically distinct. GCI-alpha-synuclein forms structures that are more compact and is about 1,000-fold more potent than Lewy body alpha-synuclein in seeding alpha-synuclein aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-alpha-synuclein and Lewy body alpha-synuclein show no cell-type preference in seeding alpha-synuclein pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. <a href="#25" class="mim-tip-reference" title="Peng, C., Gathagan, R. J., Covell, D. J., Medellin, C., Stieber, A., Robinson, J. L., Zhang, B., Pitkin, R. M., Olufemi, M. F., Luk, K. C., Trojanowski, J. Q., Lee, V. M.-Y. <strong>Cellular milieu imparts distinct pathological alpha-synuclein strains in alpha-synucleinopathies.</strong> Nature 557: 558-563, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29743672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29743672</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29743672[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0104-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29743672">Peng et al. (2018)</a> found that oligodendrocytes, but not neurons, transform misfolded alpha-synuclein into a GCI-like strain, highlighting the fact that distinct alpha-synuclein strains are generated by different intracellular milieus. Moreover, GCI-alpha-synuclein maintains its high seeding activity when propagated in neurons. Thus, alpha-synuclein strains are determined by both misfolded seeds and intracellular environments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29743672" 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="#31" class="mim-tip-reference" title="Zarranz, J. J., Alegre, J., Gomez-Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., Vidal, L., Hoenicka, J., Rodriguez, O., Atares, B., Llorens, V., Gomez Tortosa, E., del Ser, T., Munoz, D. G., de Yebenes, J. G. <strong>The new mutation, E46K, of alpha-synuclein causes parkinson and Lewy body dementia.</strong> Ann. Neurol. 55: 164-173, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14755719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14755719</a>] [<a href="https://doi.org/10.1002/ana.10795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14755719">Zarranz et al. (2004)</a> reported a Spanish family with autosomal dominant parkinsonism and dementia with Lewy bodies, diagnosed using strict criteria. Neuropathologic examination showed diffuse distribution of Lewy bodies in cortical and subcortical areas. Molecular analysis identified a mutation in the SNCA gene (<a href="/entry/163890#0004">163890.0004</a>) that cosegregated with the disease phenotype. <a href="#31" class="mim-tip-reference" title="Zarranz, J. J., Alegre, J., Gomez-Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., Vidal, L., Hoenicka, J., Rodriguez, O., Atares, B., Llorens, V., Gomez Tortosa, E., del Ser, T., Munoz, D. G., de Yebenes, J. G. <strong>The new mutation, E46K, of alpha-synuclein causes parkinson and Lewy body dementia.</strong> Ann. Neurol. 55: 164-173, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14755719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14755719</a>] [<a href="https://doi.org/10.1002/ana.10795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14755719">Zarranz et al. (2004)</a> noted that because there is clinical and pathologic overlap between PD and DLB, the distinction and/or relationship between the 2 disorders is difficult to discern. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14755719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 1 of the Japanese families reported by <a href="#13" class="mim-tip-reference" title="Ishikawa, A., Takahashi, H., Tanaka, H., Hayashi, T., Tsuji, S. <strong>Clinical features of familial diffuse Lewy body disease.</strong> Europ. Neurol. 38 (suppl. 1): 34-38, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9276199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9276199</a>] [<a href="https://doi.org/10.1159/000113459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9276199">Ishikawa et al. (1997)</a> with early-onset parkinsonism and dementia, <a href="#11" class="mim-tip-reference" title="Ikeuchi, T., Kakita, A., Shiga, A., Kasuga, K., Kaneko, H., Tan, C.-F., Idezuka, J., Wakabayashi, K., Onodera, O., Iwatsubo, T., Nishizawa, M., Takahashi, H., Ishikawa, A. <strong>Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia.</strong> Arch. Neurol. 65: 514-519, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18413475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18413475</a>] [<a href="https://doi.org/10.1001/archneur.65.4.514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18413475">Ikeuchi et al. (2008)</a> identified a duplication of the SNCA gene (<a href="/entry/163890#0005">163890.0005</a>). Three patients were heterozygous for the duplication, and 1 was homozygous for the duplication, having 4 copies of the SNCA gene. The entire duplication segment spanned 5 Mb and included at least 10 neighboring genes. The homozygous patient showed earlier onset and earlier death, with more severe cognitive impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18413475+9276199" 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="#29" class="mim-tip-reference" title="Uchiyama, T., Ikeuchi, T., Ouchi, Y., Sakamoto, M., Kasuga, K., Shiga, A., Suzuki, M., Ito, M., Atsumi, T., Shimizu, T., Ohashi, T. <strong>Prominent psychiatric symptoms and glucose hypometabolism in a family with a SNCA duplication.</strong> Neurology 71: 1289-1290, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18852445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18852445</a>] [<a href="https://doi.org/10.1212/01.wnl.0000327607.28928.e6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18852445">Uchiyama et al. (2008)</a> reported a Japanese mother and son with duplication of the SNCA gene associated with variable features of parkinsonism and dementia. The son had prominent parkinsonism in his late forties, followed by fluctuating cognitive decline, visual hallucinations, and deficits in verbal fluency a few years later. The mother presented later at age 72 with memory disturbances and fluctuating cognitive deficits. She then developed mild parkinsonism and visual hallucinations. PET studies showed that both patients had diffuse hypometabolism in the brain that extended to the occipital visual cortex in the mother. <a href="#29" class="mim-tip-reference" title="Uchiyama, T., Ikeuchi, T., Ouchi, Y., Sakamoto, M., Kasuga, K., Shiga, A., Suzuki, M., Ito, M., Atsumi, T., Shimizu, T., Ohashi, T. <strong>Prominent psychiatric symptoms and glucose hypometabolism in a family with a SNCA duplication.</strong> Neurology 71: 1289-1290, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18852445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18852445</a>] [<a href="https://doi.org/10.1212/01.wnl.0000327607.28928.e6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18852445">Uchiyama et al. (2008)</a> noted that the diagnoses in the son and mother were compatible with PD dementia and Lewy body dementia, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18852445" 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>SNCB Gene</em></strong></p><p>
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In 2 unrelated patients with dementia with Lewy bodies, 1 of whom had a family history of the disorder, <a href="#24" class="mim-tip-reference" title="Ohtake, H., Limprasert, P., Fan, Y., Onodera, O., Kakita, A., Takahashi, H., Bonner, L. T., Tsuang, D. W., Murray, I. V. J., Lee, V. M.-Y., Trojanowski, J. Q., Ishikawa, A., Idezuka, J., Murata, M., Toda, T., Bird, T. D., Leverenz, J. B., Tsuji, S., La Spada, A. R. <strong>Beta-synuclein gene alterations in dementia with Lewy bodies.</strong> Neurology 63: 805-811, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15365127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15365127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15365127[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/01.wnl.0000139870.14385.3c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15365127">Ohtake et al. (2004)</a> identified 2 different heterozygous mutations in the SNCB gene (<a href="/entry/602569#0001">602569.0001</a>; <a href="/entry/602569#0002">602569.0002</a>). <a href="#24" class="mim-tip-reference" title="Ohtake, H., Limprasert, P., Fan, Y., Onodera, O., Kakita, A., Takahashi, H., Bonner, L. T., Tsuang, D. W., Murray, I. V. J., Lee, V. M.-Y., Trojanowski, J. Q., Ishikawa, A., Idezuka, J., Murata, M., Toda, T., Bird, T. D., Leverenz, J. B., Tsuji, S., La Spada, A. R. <strong>Beta-synuclein gene alterations in dementia with Lewy bodies.</strong> Neurology 63: 805-811, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15365127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15365127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15365127[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/01.wnl.0000139870.14385.3c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15365127">Ohtake et al. (2004)</a> postulated that an alteration in SNCB may impair its normal inhibitory action on the formation of toxic alpha-synuclein fibrils, thereby indirectly contributing to disease pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15365127" 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>PRNP Gene</em></strong></p><p>
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In a 55-year-old man with slowly progressive dementia, dysarthria, gait disturbance, and rigidity, but no myoclonus or EEG abnormalities, <a href="#15" class="mim-tip-reference" title="Koide, T., Ohtake, H., Nakajima, T., Furukawa, H., Sakai, K., Kamei, H., Makifuchi, T., Fukuhara, N. <strong>A patient with dementia with Lewy bodies and codon 232 mutation of PRNP.</strong> Neurology 59: 1619-1621, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12451207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12451207</a>] [<a href="https://doi.org/10.1212/01.wnl.0000033796.33205.b4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12451207">Koide et al. (2002)</a> identified a heterozygous met232-to-arg mutation in the PRNP gene (M232R; <a href="/entry/176640#0017">176640.0017</a>). The patient was given a preliminary diagnosis of Creutzfeldt-Jakob disease (CJD; <a href="/entry/123400">123400</a>). However, postmortem brain examination showed many Lewy bodies in the substantia nigra and cerebral cortices as well as lack of prion protein immunoreactivity, and final diagnosis was dementia with Lewy bodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12451207" 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>Gene Associations</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Galasko, D., Saitoh, T., Xia, Y., Thal, L. J., Katzman, R., Hill, L. R., Hansen, L. <strong>The apolipoprotein E allele epsilon-4 is overrepresented in patients with the Lewy body variant of Alzheimer's disease.</strong> Neurology 44: 1950-1951, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7936253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7936253</a>] [<a href="https://doi.org/10.1212/wnl.44.10.1950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7936253">Galasko et al. (1994)</a> analyzed the frequency of the apolipoprotein epsilon-4 allele (APOE4) in 74 subjects with Alzheimer disease, 40 patients with the Lewy body variant of Alzheimer disease, and 8 with diffuse Lewy body disease. The APOE4 allele frequency was 39.6% in pure Alzheimer disease, 29% in the Lewy body variant of Alzheimer disease, and only 6.25% in the 8 patients with diffuse Lewy body disease. <a href="#6" class="mim-tip-reference" title="Galasko, D., Saitoh, T., Xia, Y., Thal, L. J., Katzman, R., Hill, L. R., Hansen, L. <strong>The apolipoprotein E allele epsilon-4 is overrepresented in patients with the Lewy body variant of Alzheimer's disease.</strong> Neurology 44: 1950-1951, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7936253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7936253</a>] [<a href="https://doi.org/10.1212/wnl.44.10.1950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7936253">Galasko et al. (1994)</a> argued that this further supported their conclusion that dementia in the Lewy body variant is caused by the Alzheimer disease lesions, whereas the cause of the dementia in diffuse Lewy body disease is distinct. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7936253" 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="Saitoh, T., Xia, Y., Chen, X., Masliah, E., Galasko, D., Shults, C., Thal, L. J., Hansen, L. A., Katzman, R. <strong>The CYP2D6B mutant allele is overrepresented in the Lewy body variant of Alzheimer's disease.</strong> Ann. Neurol. 37: 110-112, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7818242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7818242</a>] [<a href="https://doi.org/10.1002/ana.410370120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7818242">Saitoh et al. (1995)</a> analyzed the allele frequency of debrisoquine 4-hydroxylase (CYP2D6; <a href="/entry/124030#0001">124030.0001</a>) in an autopsy series consisting of all Caucasian samples. Forty-four of these had Lewy body dementia, which they defined as meeting neuropathologic criteria for Alzheimer disease, having at least 1 Lewy body, and having a primary clinical manifestation of dementia rather than Parkinson disease. In addition, there were 83 controls who had pure Alzheimer disease and 37 controls who had dementia without Alzheimer disease. The CYP2D6B allele frequency in Lewy body dementia was 0.307, considerably higher than the 0.163 allele frequency in pure Alzheimer disease and the 0.122 frequency in non-Alzheimer disease dementia. <a href="#28" class="mim-tip-reference" title="Saitoh, T., Xia, Y., Chen, X., Masliah, E., Galasko, D., Shults, C., Thal, L. J., Hansen, L. A., Katzman, R. <strong>The CYP2D6B mutant allele is overrepresented in the Lewy body variant of Alzheimer's disease.</strong> Ann. Neurol. 37: 110-112, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7818242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7818242</a>] [<a href="https://doi.org/10.1002/ana.410370120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7818242">Saitoh et al. (1995)</a> suggested that the CYP2D6B allele is a risk factor for Lewy body disease, and that this may have therapeutic implications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7818242" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Beyer, K., Domingo-Sabat, M., Humbert, J., Carrato, C., Ferrer, I., Ariza, A. <strong>Differential expression of alpha-synuclein, parkin, and synphilin-1 isoforms in Lewy body disease.</strong> Neurogenetics 9: 163-172, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18335262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18335262</a>] [<a href="https://doi.org/10.1007/s10048-008-0124-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18335262">Beyer et al. (2008)</a> found different disease-specific expression of isoforms of the SNCA, PARK2, and synphilin-1 (SNCAIP; <a href="/entry/603779">603779</a>) genes in frontal lobe cortices from patients with 4 diseases: pure Lewy body dementia, so-called 'common' Lewy body disease, in which amyloid plaques can also be seen, Parkinson disease, and Alzheimer disease. The data indicated that each disease can be characterized by its own molecular mechanisms and that different molecular mechanisms can lead to the development of similar neuropathologic changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18335262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Goker-Alpan, O., Giasson, B. I., Eblan, M. J., Nguyen, J., Hurtig, H. I., Lee, V. M.-Y., Trojanowski, J. Q., Sidransky, E. <strong>Glucocerebrosidase mutations are an important risk factor for Lewy body disorders.</strong> Neurology 67: 908-910, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16790605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16790605</a>] [<a href="https://doi.org/10.1212/01.wnl.0000230215.41296.18" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16790605">Goker-Alpan et al. (2006)</a> identified heterozygous mutations in the glucocerebrosidase gene (GBA; <a href="/entry/606463">606463</a>) in 8 (23%) of 35 patients with dementia with Lewy bodies. The authors postulated that a mutant GBA enzyme may take on a different and unexpected role that may contribute to the development of synucleinopathies. In 2 (3.5%) of 57 European patients with Lewy body dementia, <a href="#17" class="mim-tip-reference" title="Mata, I. F., Samii, A., Schneer, S. H., Roberts, J. W., Griffith, A., Leis, B. C., Schellenberg, G. D., Sidransky, E., Bird, T. D., Leverenz, J. B., Tsuang, D., Zabetian, C. P. <strong>Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders.</strong> Arch. Neurol. 65: 379-382, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18332251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18332251</a>] [<a href="https://doi.org/10.1001/archneurol.2007.68" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18332251">Mata et al. (2008)</a> identified heterozygous mutations in the GBA gene: 1 patient had the L444P mutation (<a href="/entry/606463#0001">606463.0001</a>), and the other had the N370S mutation (<a href="/entry/606463#0003">606463.0003</a>). The authors estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18332251+16790605" 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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Beyer, K., Domingo-Sabat, M., Humbert, J., Carrato, C., Ferrer, I., Ariza, A.
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<strong>Differential expression of alpha-synuclein, parkin, and synphilin-1 isoforms in Lewy body disease.</strong>
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Neurogenetics 9: 163-172, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18335262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18335262</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18335262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Brett, F. M., Henson, C., Staunton, H.
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<strong>Familial diffuse Lewy body disease, eye movement abnormalities, and distribution of pathology.</strong>
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Arch. Neurol. 59: 464-467, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11890854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11890854</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11890854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archneur.59.3.464" target="_blank">Full Text</a>]
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de Bruin, V. M. S., Lees, A. J., Daniel, S. E.
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<strong>Diffuse Lewy body disease presenting with supranuclear gaze palsy, parkinsonism, and dementia: a case report.</strong>
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Mov. Disord. 7: 355-358, 1992.
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[<a href="https://doi.org/10.1002/mds.870070410" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.44.10.1950" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20791" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000230215.41296.18" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-003-0155-y" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.65.4.514" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1985.04060100083029" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000033796.33205.b4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20753" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000299387.59159.db" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000139870.14385.3c" target="_blank">Full Text</a>]
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<a id="Peng2018" class="mim-anchor"></a>
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Peng, C., Gathagan, R. J., Covell, D. J., Medellin, C., Stieber, A., Robinson, J. L., Zhang, B., Pitkin, R. M., Olufemi, M. F., Luk, K. C., Trojanowski, J. Q., Lee, V. M.-Y.
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[<a href="https://doi.org/10.1038/s41586-018-0104-4" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18427071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18427071</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18427071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000310643.53587.87" target="_blank">Full Text</a>]
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<a id="Ross2006" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1002/ana.20731" target="_blank">Full Text</a>]
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<a id="Saitoh1995" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7818242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7818242</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7818242" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.410370120" target="_blank">Full Text</a>]
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<a id="Uchiyama2008" class="mim-anchor"></a>
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Uchiyama, T., Ikeuchi, T., Ouchi, Y., Sakamoto, M., Kasuga, K., Shiga, A., Suzuki, M., Ito, M., Atsumi, T., Shimizu, T., Ohashi, T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18852445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18852445</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18852445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000327607.28928.e6" target="_blank">Full Text</a>]
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<a id="Wakabayashi1998" class="mim-anchor"></a>
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Wakabayashi, K., Hayashi, S., Ishikawa, A., Hayashi, T., Okuizumi, K., Tanaka, H., Tsuji, S., Takahashi, H.
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<strong>Autosomal dominant diffuse Lewy body disease.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9705138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9705138</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9705138" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004010050883" target="_blank">Full Text</a>]
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<a id="Zarranz2004" class="mim-anchor"></a>
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Zarranz, J. J., Alegre, J., Gomez-Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., Vidal, L., Hoenicka, J., Rodriguez, O., Atares, B., Llorens, V., Gomez Tortosa, E., del Ser, T., Munoz, D. G., de Yebenes, J. G.
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<strong>The new mutation, E46K, of alpha-synuclein causes parkinson and Lewy body dementia.</strong>
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Ann. Neurol. 55: 164-173, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14755719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14755719</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14755719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.10795" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 06/27/2018
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Cassandra L. Kniffin - updated : 3/27/2009<br>Cassandra L. Kniffin - updated : 2/3/2009<br>Cassandra L. Kniffin - updated : 1/9/2009<br>Cassandra L. Kniffin - updated : 11/3/2008<br>Cassandra L. Kniffin - updated : 10/1/2008<br>Cassandra L. Kniffin - updated : 8/3/2007<br>Cassandra L. Kniffin - updated : 4/20/2006<br>Cassandra L. Kniffin - updated : 7/25/2005<br>Cassandra L. Kniffin - updated : 6/13/2005<br>Cassandra L. Kniffin - updated : 6/4/2004<br>Victor A. McKusick - updated : 10/13/2003<br>Cassandra L. Kniffin - updated : 1/22/2003<br>Cassandra L. Kniffin - reorganized : 10/14/2002<br>Cassandra L. Kniffin - updated : 10/10/2002<br>Orest Hurko - updated : 9/27/1995
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Victor A. McKusick : 6/4/1986
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alopez : 03/02/2022<br>alopez : 06/27/2018<br>alopez : 08/04/2016<br>terry : 12/21/2012<br>terry : 4/26/2011<br>ckniffin : 3/24/2011<br>wwang : 4/7/2009<br>ckniffin : 3/27/2009<br>wwang : 2/9/2009<br>ckniffin : 2/3/2009<br>wwang : 1/15/2009<br>ckniffin : 1/9/2009<br>wwang : 11/10/2008<br>ckniffin : 11/3/2008<br>wwang : 10/1/2008<br>ckniffin : 10/1/2008<br>wwang : 8/17/2007<br>ckniffin : 8/3/2007<br>wwang : 4/25/2006<br>ckniffin : 4/20/2006<br>ckniffin : 7/25/2005<br>wwang : 6/16/2005<br>ckniffin : 6/13/2005<br>terry : 2/22/2005<br>tkritzer : 6/11/2004<br>ckniffin : 6/4/2004<br>tkritzer : 10/14/2003<br>tkritzer : 10/13/2003<br>carol : 2/4/2003<br>tkritzer : 1/28/2003<br>ckniffin : 1/22/2003<br>ckniffin : 1/16/2003<br>carol : 1/14/2003<br>ckniffin : 10/14/2002<br>carol : 10/14/2002<br>ckniffin : 10/14/2002<br>ckniffin : 10/10/2002<br>alopez : 10/23/2000<br>terry : 6/3/1998<br>joanna : 4/21/1998<br>carol : 1/13/1995<br>mimadm : 6/25/1994<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/26/1989
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<span class="mim-font">
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<strong>#</strong> 127750
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DEMENTIA, LEWY BODY; DLB
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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LEWY BODY DEMENTIA<br />
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DIFFUSE LEWY BODY DISEASE
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Other entities represented in this entry:
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DIFFUSE LEWY BODY DISEASE WITH GAZE PALSY, INCLUDED
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LEWY BODY VARIANT OF ALZHEIMER DISEASE, INCLUDED
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<strong>SNOMEDCT:</strong> 312991009, 80098002;
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<strong>ICD10CM:</strong> G31.83;
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<strong>ICD9CM:</strong> 331.82;
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<strong>DO:</strong> 12217;
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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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1q22
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<span class="mim-font">
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{Lewy body dementia, susceptibility to}
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127750
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Autosomal dominant
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3
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GBA1
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606463
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4q22.1
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Dementia, Lewy body
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127750
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Autosomal dominant
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3
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SNCA
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163890
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5q35.2
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Dementia, Lewy body
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127750
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Autosomal dominant
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3
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SNCB
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602569
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because dementia with Lewy bodies (DLB) can be caused by mutation in the alpha-synuclein (SNCA; 163890) or beta-synuclein (SNCB; 602569) genes.</p><p>Mutation in the SNCA gene can also cause familial Parkinson disease-1 (PARK1; 168601) and Parkinson disease-4 (PARK4; 605543).</p><p>The epsilon-4 allele of the APOE gene (107741) and the B allele of the CYP2D6 gene (124030), a cytochrome P-450 monooxygenase, have also been implicated in DLB.</p><p>A mutation in the prion protein gene (PRNP; see 176640.0017) has been identified in 1 patient with DLB. Some patients with a diagnosis consistent with Lewy body disease or dementia have mutations in the LRRK2 gene (609007), which is associated with Parkinson disease-8 (PARK8; 607060) (Giasson et al., 2006; Ross et al., 2006). </p><p>One family with a mutation in the PSEN2 gene (600759.0009), usually associated with Alzheimer disease-4 (AD4; 606889), had clinical and neuropathologic findings consistent with DLB (Piscopo et al., 2008). </p>
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<strong>Description</strong>
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<p>Dementia with Lewy bodies (DLB) is a neurodegenerative disorder clinically characterized by dementia and parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Pathologically, Lewy bodies are present in a pattern more widespread than usually observed in Parkinson disease (see PD; 168600). Alzheimer disease (AD; 104300)-associated pathology and spongiform changes may also be seen (McKeith et al., 1996; Mizutani, 2000; McKeith et al., 2005). </p>
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<strong>Clinical Features</strong>
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<p>Ishikawa et al. (1997) reported 2 unrelated families with familial autosomal dominant diffuse Lewy body disease. In family A, 4 patients over 3 generations presented with parkinsonism, vertical ocular limitation, progressive dementia, and delusions or visual hallucinations. Two of the patients developed neuroleptic malignant syndrome (NMS). Family S had 3 affected members over 3 generations. One was examined in detail and presented with parkinsonism and progressive dementia and later developed NMS. In a member of family S reported by Ishikawa et al. (1997), Ishikawa et al. (2005) identified a mutation in the PSEN1 gene (104311.0032). No mutations were identified in the SNCA gene. The phenotype was an overlap between DLB and Alzheimer disease with spastic paraparesis (607822). </p><p>Denson et al. (1997) reported 10 individuals with Lewy body disease in 3 successive generations of 2 closely intermarried families. The phenotype was variable: 4 patients displayed parkinsonian features only, 3 had dementia only, and 3 had combined parkinsonism and dementia. Mean age of onset was 62 years. Linkage studies were inconclusive. </p><p>Wakabayashi et al. (1998) described a Japanese family with parkinsonism and later-onset dementia. The proband developed parkinsonism at the age of 61 years, followed by dementia starting when she was 67. Her uncle, who was also her husband, died at the age of 78 years after 7- and 5-year histories of parkinsonism and dementia, respectively. Her 2 sons developed similar parkinsonism at the ages of 39 and 28 years and also suffered later-onset dementia. The apolipoprotein E genotype of the proband, her uncle, and 1 of their sons was E3/4 and that of the other son was E4/4. The authors concluded that this represented autosomal dominant diffuse Lewy body disease. </p><p>Ohara et al. (1999) presented a familial case of dementia with Lewy bodies in 3 sibs, born of first-cousin parents, who demonstrated progressive dementia with a progressive language disorder characterized by dysarthria, paraphasia, and difficulty in finding words. The 2 brothers presented with parkinsonism and fluctuating cognition. The sister and one of the brothers also had visual hallucinations. No mutations in the alpha-synuclein gene (SNCA; 163890), the parkin gene (PARK2; 602544), or the ubiquitin carboxyl-terminal esterase L1 gene (UCHL1; 191342) were found. </p><p>Graeber and Muller (2003) provided a review of DLB, which they stated is the second most common degenerative dementia after Alzheimer disease. Clinically, DLB differs from Alzheimer disease in that disease symptoms are prone to fluctuate and patients often suffer from visual hallucinations, though short-term memory is relatively preserved. As many as 70% of patients have parkinsonism and up to 50% are sensitive to the extrapyramidal side effects of neuroleptic drugs. Graeber and Muller (2003) suggested that DLB is a complex disorder with both genetic and environmental factors involved in the pathogenesis, as is the case for many common disorders. </p><p>Ohtake et al. (2004) reported a patient with DLB and a mutation in the SNCB gene (602569.0002). He presented at age 64 years with a 3-year history of mild dementia and deterioration in his handwriting. He had frontal lobe involvement manifesting as executive and language dysfunction. He later developed depression, motor apraxia, parkinsonism, and audio and visual hallucinations. Neuropathologic examination showed extensive Lewy bodies in the hippocampus, amygdala, and substantia nigra. Several family members were affected or possibly affected in an autosomal dominant pattern of inheritance. </p><p><strong><em>Pathologic Findings</em></strong></p><p>
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Khachaturian (1985) performed an autopsy series of elderly individuals with dementia and found that the second most common pathology after the senile plaques and neurofibrillary tangles of Alzheimer disease was that of Lewy bodies found in subcortical and cortical regions. Patients with such 'Lewy body dementia' also have a sufficient number of hippocampal and neocortical senile plaques to meet the diagnostic criteria for Alzheimer disease. Hansen et al. (1990) referred to such patients as having the 'Lewy body variant of Alzheimer disease.' The term 'diffuse Lewy body disease' is reserved for patients with brainstem and cortical Lewy bodies but an insufficient number of senile plaques to fulfill the diagnostic criteria for Alzheimer disease. </p><p>Wakabayashi et al. (1998) reported that pathologic examination of their 2 patients showed marked neuronal loss with Lewy bodies in the brainstem, pigmented nuclei, and numerous cortical Lewy bodies and ubiquitin-positive hippocampal neurites. Brain examination of 1 patient studied by Ishikawa et al. (1997) showed neuronal loss with gliosis and many Lewy bodies in the cerebral cortex and brainstem. One affected individual from the kindred reported by Denson et al. (1997) showed neuronal loss and gliosis as well as many Lewy bodies throughout the cerebral cortex and brainstem. Neurofibrillary tangles and neuritic plaques were present, but rare. Neuropathology of the proband reported by Ohara et al. (1999) demonstrated numerous Lewy bodies in the cerebral cortex and brain stem, with no neurofibrillary tangles or neuritic plaques. </p><p>Obi et al. (2008) reported the neuropathologic findings of a Japanese patient with PD and later-onset dementia who was heterozygous for a duplication of the SNCA gene (163890.0005) (Nishioka et al., 2006). The patient presented with classic levodopa-responsive parkinsonism at age 47. Loss of memory, visual hallucinations, and progressive cognitive decline began at age 60. Brain MRI showed medial temporal lobe atrophy on both sides, and single photon emission computed tomography (SPECT) showed hypoperfusion of the frontotemporal and occipital lobes. He later became bedridden and died of pneumonia at age 67. Postmortem examination showed mild frontal lobe atrophy and severe depigmentation of the substantia nigra and locus ceruleus. Severe neuronal loss was noted in the substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus nerve, the amygdala, and the CA2/3 of the hippocampus. SNCA-immunostaining revealed multiple Lewy bodies in the cerebral cortex, hippocampus, and brainstem. The Lewy body-related pathology was graded as diffuse neocortical type based on the pathologic classification of dementia with Lewy bodies. </p><p><strong><em>Diffuse Lewy Body Disease with Gaze Palsy</em></strong></p><p>
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Lewis and Gawel (1990) and Fearnley et al. (1991) each presented a case report in which a patient (71 and 76 years old) with dementia and parkinsonism also presented with horizontal and vertical supranuclear gaze palsy, prompting an initial diagnosis of progressive supranuclear palsy (PSP; 601104). Pathologic diagnosis in both cases revealed diffuse Lewy body disease with Lewy bodies in areas believed to be associated with gaze control. </p><p>De Bruin et al. (1992) reported a 67-year-old man with a family history of parkinsonism who presented with supranuclear gaze palsy and later developed parkinsonism and mental impairment. A diagnosis of PSP was made initially, but postmortem pathologic examination revealed diffuse Lewy body disease with multiple Lewy bodies in the neocortex and brainstem, as well as lesser numbers of neuritic plaques and neurofibrillary tangles. </p><p>Brett et al. (2002) reported 2 sibs with onset in their 60s of a disorder characterized by parkinsonism, dementia, and visual hallucinations, which progressed to incapacity. One patient exhibited vertical supranuclear gaze palsy, and the other patient could not be tested. Pathologic examination of both cases showed diffuse Lewy body disease, with changes in the posterior commissure, the rostral interstitial nucleus of the medial longitudinal fasciculus, and the interstitial nucleus of Cajal, areas that subserve vertical gaze. </p>
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<strong>Diagnosis</strong>
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<p>The International Consortium on Dementia with Lewy bodies in 1995 established guidelines for the clinical and pathologic diagnosis of DLB. Mental impairment leading to dementia is the central core feature, with fluctuation in cognitive function, visual hallucinations, and motor features of parkinsonism being other key symptoms. Brainstem or cortical Lewy bodies are the only essential pathologic features, although other pathologic changes may be present as well (McKeith et al., 1996). The guidelines were updated in 2005 (McKeith et al., 2005) to include sleep disturbances, neuroleptic sensitivity, reduced striatal dopamine transporter activity on functional neuroimaging, and pathologic grading. </p>
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<strong>Pathogenesis</strong>
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<p>In Lewy body diseases, including Parkinson disease with or without dementia, dementia with Lewy bodies, and Alzheimer disease with Lewy body copathology, alpha-synuclein aggregates in neurons as Lewy bodies and Lewy neurites. By contrast, in multiple system atrophy (146500) alpha-synuclein accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs). Peng et al. (2018) reported that pathologic alpha-synuclein in GCIs and Lewy bodies is conformationally and biologically distinct. GCI-alpha-synuclein forms structures that are more compact and is about 1,000-fold more potent than Lewy body alpha-synuclein in seeding alpha-synuclein aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-alpha-synuclein and Lewy body alpha-synuclein show no cell-type preference in seeding alpha-synuclein pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. Peng et al. (2018) found that oligodendrocytes, but not neurons, transform misfolded alpha-synuclein into a GCI-like strain, highlighting the fact that distinct alpha-synuclein strains are generated by different intracellular milieus. Moreover, GCI-alpha-synuclein maintains its high seeding activity when propagated in neurons. Thus, alpha-synuclein strains are determined by both misfolded seeds and intracellular environments. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>SNCA Gene</em></strong></p><p>
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Zarranz et al. (2004) reported a Spanish family with autosomal dominant parkinsonism and dementia with Lewy bodies, diagnosed using strict criteria. Neuropathologic examination showed diffuse distribution of Lewy bodies in cortical and subcortical areas. Molecular analysis identified a mutation in the SNCA gene (163890.0004) that cosegregated with the disease phenotype. Zarranz et al. (2004) noted that because there is clinical and pathologic overlap between PD and DLB, the distinction and/or relationship between the 2 disorders is difficult to discern. </p><p>In affected members of 1 of the Japanese families reported by Ishikawa et al. (1997) with early-onset parkinsonism and dementia, Ikeuchi et al. (2008) identified a duplication of the SNCA gene (163890.0005). Three patients were heterozygous for the duplication, and 1 was homozygous for the duplication, having 4 copies of the SNCA gene. The entire duplication segment spanned 5 Mb and included at least 10 neighboring genes. The homozygous patient showed earlier onset and earlier death, with more severe cognitive impairment. </p><p>Uchiyama et al. (2008) reported a Japanese mother and son with duplication of the SNCA gene associated with variable features of parkinsonism and dementia. The son had prominent parkinsonism in his late forties, followed by fluctuating cognitive decline, visual hallucinations, and deficits in verbal fluency a few years later. The mother presented later at age 72 with memory disturbances and fluctuating cognitive deficits. She then developed mild parkinsonism and visual hallucinations. PET studies showed that both patients had diffuse hypometabolism in the brain that extended to the occipital visual cortex in the mother. Uchiyama et al. (2008) noted that the diagnoses in the son and mother were compatible with PD dementia and Lewy body dementia, respectively. </p><p><strong><em>SNCB Gene</em></strong></p><p>
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In 2 unrelated patients with dementia with Lewy bodies, 1 of whom had a family history of the disorder, Ohtake et al. (2004) identified 2 different heterozygous mutations in the SNCB gene (602569.0001; 602569.0002). Ohtake et al. (2004) postulated that an alteration in SNCB may impair its normal inhibitory action on the formation of toxic alpha-synuclein fibrils, thereby indirectly contributing to disease pathogenesis. </p><p><strong><em>PRNP Gene</em></strong></p><p>
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In a 55-year-old man with slowly progressive dementia, dysarthria, gait disturbance, and rigidity, but no myoclonus or EEG abnormalities, Koide et al. (2002) identified a heterozygous met232-to-arg mutation in the PRNP gene (M232R; 176640.0017). The patient was given a preliminary diagnosis of Creutzfeldt-Jakob disease (CJD; 123400). However, postmortem brain examination showed many Lewy bodies in the substantia nigra and cerebral cortices as well as lack of prion protein immunoreactivity, and final diagnosis was dementia with Lewy bodies. </p><p><strong><em>Gene Associations</em></strong></p><p>
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Galasko et al. (1994) analyzed the frequency of the apolipoprotein epsilon-4 allele (APOE4) in 74 subjects with Alzheimer disease, 40 patients with the Lewy body variant of Alzheimer disease, and 8 with diffuse Lewy body disease. The APOE4 allele frequency was 39.6% in pure Alzheimer disease, 29% in the Lewy body variant of Alzheimer disease, and only 6.25% in the 8 patients with diffuse Lewy body disease. Galasko et al. (1994) argued that this further supported their conclusion that dementia in the Lewy body variant is caused by the Alzheimer disease lesions, whereas the cause of the dementia in diffuse Lewy body disease is distinct. </p><p>Saitoh et al. (1995) analyzed the allele frequency of debrisoquine 4-hydroxylase (CYP2D6; 124030.0001) in an autopsy series consisting of all Caucasian samples. Forty-four of these had Lewy body dementia, which they defined as meeting neuropathologic criteria for Alzheimer disease, having at least 1 Lewy body, and having a primary clinical manifestation of dementia rather than Parkinson disease. In addition, there were 83 controls who had pure Alzheimer disease and 37 controls who had dementia without Alzheimer disease. The CYP2D6B allele frequency in Lewy body dementia was 0.307, considerably higher than the 0.163 allele frequency in pure Alzheimer disease and the 0.122 frequency in non-Alzheimer disease dementia. Saitoh et al. (1995) suggested that the CYP2D6B allele is a risk factor for Lewy body disease, and that this may have therapeutic implications. </p><p>Beyer et al. (2008) found different disease-specific expression of isoforms of the SNCA, PARK2, and synphilin-1 (SNCAIP; 603779) genes in frontal lobe cortices from patients with 4 diseases: pure Lewy body dementia, so-called 'common' Lewy body disease, in which amyloid plaques can also be seen, Parkinson disease, and Alzheimer disease. The data indicated that each disease can be characterized by its own molecular mechanisms and that different molecular mechanisms can lead to the development of similar neuropathologic changes. </p><p>Goker-Alpan et al. (2006) identified heterozygous mutations in the glucocerebrosidase gene (GBA; 606463) in 8 (23%) of 35 patients with dementia with Lewy bodies. The authors postulated that a mutant GBA enzyme may take on a different and unexpected role that may contribute to the development of synucleinopathies. In 2 (3.5%) of 57 European patients with Lewy body dementia, Mata et al. (2008) identified heterozygous mutations in the GBA gene: 1 patient had the L444P mutation (606463.0001), and the other had the N370S mutation (606463.0003). The authors estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. </p>
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<strong>Prominent psychiatric symptoms and glucose hypometabolism in a family with a SNCA duplication.</strong>
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Neurology 71: 1289-1290, 2008.
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[PubMed: 18852445]
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[Full Text: https://doi.org/10.1212/01.wnl.0000327607.28928.e6]
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Wakabayashi, K., Hayashi, S., Ishikawa, A., Hayashi, T., Okuizumi, K., Tanaka, H., Tsuji, S., Takahashi, H.
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<strong>Autosomal dominant diffuse Lewy body disease.</strong>
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Acta Neuropath. 96: 207-210, 1998.
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[PubMed: 9705138]
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[Full Text: https://doi.org/10.1007/s004010050883]
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Zarranz, J. J., Alegre, J., Gomez-Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., Vidal, L., Hoenicka, J., Rodriguez, O., Atares, B., Llorens, V., Gomez Tortosa, E., del Ser, T., Munoz, D. G., de Yebenes, J. G.
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<strong>The new mutation, E46K, of alpha-synuclein causes parkinson and Lewy body dementia.</strong>
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Ann. Neurol. 55: 164-173, 2004.
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[PubMed: 14755719]
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[Full Text: https://doi.org/10.1002/ana.10795]
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Ada Hamosh - updated : 06/27/2018<br>Cassandra L. Kniffin - updated : 3/27/2009<br>Cassandra L. Kniffin - updated : 2/3/2009<br>Cassandra L. Kniffin - updated : 1/9/2009<br>Cassandra L. Kniffin - updated : 11/3/2008<br>Cassandra L. Kniffin - updated : 10/1/2008<br>Cassandra L. Kniffin - updated : 8/3/2007<br>Cassandra L. Kniffin - updated : 4/20/2006<br>Cassandra L. Kniffin - updated : 7/25/2005<br>Cassandra L. Kniffin - updated : 6/13/2005<br>Cassandra L. Kniffin - updated : 6/4/2004<br>Victor A. McKusick - updated : 10/13/2003<br>Cassandra L. Kniffin - updated : 1/22/2003<br>Cassandra L. Kniffin - reorganized : 10/14/2002<br>Cassandra L. Kniffin - updated : 10/10/2002<br>Orest Hurko - updated : 9/27/1995
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Victor A. McKusick : 6/4/1986
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