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Entry
- #600116 - PARKINSON DISEASE 2, AUTOSOMAL RECESSIVE JUVENILE; PARK2
- OMIM
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<span class="h4">#600116</span>
<br />
<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/600116"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS168600"> <strong>Phenotypic Series</strong> </a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#otherFeatures">Other Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#references"><strong>References</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=PARKINSON DISEASE 2, AUTOSOMAL RECESSIVE JUVENILE" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=932&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0060368" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/600116" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://omia.org/OMIA002748/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0060368" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
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</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:600116" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
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</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>ORPHA:</strong> 2828<br />
<strong>DO:</strong> 0060368<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
600116
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
PARKINSON DISEASE 2, AUTOSOMAL RECESSIVE JUVENILE; PARK2
</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">
PARKINSON DISEASE, JUVENILE, AUTOSOMAL RECESSIVE; PDJ<br />
PARKINSONISM, EARLY-ONSET, WITH DIURNAL FLUCTUATION; EPDF
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/1011?start=-3&limit=10&highlight=1011">
6q26
</a>
</span>
</td>
<td>
<span class="mim-font">
Parkinson disease, juvenile, type 2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600116"> 600116 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
PRKN
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602544"> 602544 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
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<a href="/clinicalSynopsis/600116" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<a href="/phenotypicSeries/PS168600" class="btn btn-info" role="button"> Phenotypic Series </a>
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<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>
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<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/600116" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/600116" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> 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, early-onset <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838631&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838631</a>]</span><br /> -
Bradykinesia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399317006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399317006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0233565&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0233565</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002067" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002067</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002067" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002067</a>]</span><br /> -
Rigidity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16046003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16046003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700109&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700109</a>, <a href="https://bioportal.bioontology.org/search?q=C0026837&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026837</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002063" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002063</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002063" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002063</a>]</span><br /> -
Postural instability <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843921&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843921</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002172" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002172</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002172" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002172</a>]</span><br /> -
Tremor <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26079004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26079004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R25.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R25.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0040822&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040822</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001337</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001337</a>]</span><br /> -
Gait disturbances <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22325002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22325002</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0575081&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575081</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span><br /> -
Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
Hyperreflexia may occur <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838632&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838632</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86854008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86854008</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span><br /> -
Diurnal fluctuations of symptoms (in a subset of patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838633&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838633</a>]</span><br /> -
No dementia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838634&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838634</a>]</span><br /> -
Neuronal loss and gliosis in the substantia nigra pars compacta <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838635&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838635</a>]</span><br /> -
Neuronal loss in the locus ceruleus <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838636&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838636</a>]</span><br /> -
No Lewy bodies <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838637&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838637</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset before age 40 years<br /> -
Symptoms improve following sleep<br /> -
Levodopa-responsive<br /> -
High frequency of levodopa-induced dyskinesias<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the parkin RBR E3 ubiquitin protein ligase gene (PARK2, <a href="/entry/602544#0001">602544.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Parkinson disease
- <a href="/phenotypicSeries/PS168600">PS168600</a>
- 34 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/115?start=-3&limit=10&highlight=115"> 1p36.23 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606324"> Parkinson disease 7, autosomal recessive early-onset </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606324"> 606324 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602533"> DJ1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602533"> 602533 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/208?start=-3&limit=10&highlight=208"> 1p36.13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606693"> Kufor-Rakeb syndrome </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606693"> 606693 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610513"> ATP13A2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610513"> 610513 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/244?start=-3&limit=10&highlight=244"> 1p36.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605909"> Parkinson disease 6, early onset </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605909"> 605909 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608309"> PINK1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608309"> 608309 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/601?start=-3&limit=10&highlight=601"> 1p32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606852"> {Parkinson disease 10} </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606852"> 606852 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606852"> PARK10 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606852"> 606852 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/688?start=-3&limit=10&highlight=688"> 1p31.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615528"> Parkinson disease 19a, juvenile-onset </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615528"> 615528 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608375"> DNAJC6 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608375"> 608375 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/688?start=-3&limit=10&highlight=688"> 1p31.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615528"> Parkinson disease 19b, early-onset </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615528"> 615528 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608375"> DNAJC6 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608375"> 608375 </a>
</span>
</td>
</tr>
<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">
<a href="/entry/168600"> {Parkinson disease, late-onset, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Multifactorial">Mu</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> 168600 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606463"> GBA1 </a>
</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/1/1546?start=-3&limit=10&highlight=1546"> 1q32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613164"> {Parkinson disease 16} </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613164"> 613164 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613164"> PARK16 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613164"> 613164 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/314?start=-3&limit=10&highlight=314"> 2p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602404"> {Parkinson disease 3} </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602404"> 602404 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602404"> PARK3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602404"> 602404 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/389?start=-3&limit=10&highlight=389"> 2p13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610297"> {Parkinson disease 13} </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610297"> 610297 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606441"> HTRA2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606441"> 606441 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/1118?start=-3&limit=10&highlight=1118"> 2q37.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607688"> {Parkinson disease 11} </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607688"> 607688 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612003"> GIGYF2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612003"> 612003 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/668?start=-3&limit=10&highlight=668"> 3q22 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616361"> Parkinson disease 21 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616361"> 616361 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616361"> PARK21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616361"> 616361 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/917?start=-3&limit=10&highlight=917"> 3q27.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614251"> {Parkinson disease 18} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614251"> 614251 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600495"> EIF4G1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600495"> 600495 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/174?start=-3&limit=10&highlight=174"> 4p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613643"> {?Parkinson disease 5, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613643"> 613643 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191342"> UCHL1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191342"> 191342 </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">
<a href="/entry/168601"> Parkinson disease 1 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168601"> 168601 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/163890"> SNCA </a>
</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/4/411?start=-3&limit=10&highlight=411"> 4q22.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605543"> Parkinson disease 4 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605543"> 605543 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/163890"> SNCA </a>
</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/4/432?start=-3&limit=10&highlight=432"> 4q23 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> {Parkinson disease, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Multifactorial">Mu</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> 168600 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/103730"> ADH1C </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/103730"> 103730 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/929?start=-3&limit=10&highlight=929"> 6q24.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620923"> {Parkinson disease 26, autosomal dominant, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620923"> 620923 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612906"> RAB32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612906"> 612906 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/1011?start=-3&limit=10&highlight=1011"> 6q26 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600116"> Parkinson disease, juvenile, type 2 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600116"> 600116 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602544"> PRKN </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602544"> 602544 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/1041?start=-3&limit=10&highlight=1041"> 6q27 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> {Parkinson disease, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Multifactorial">Mu</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> 168600 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600075"> TBP </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600075"> 600075 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/284?start=-3&limit=10&highlight=284"> 7p11.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616710"> Parkinson disease 22, autosomal dominant </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616710"> 616710 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616244"> CHCHD2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616244"> 616244 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/565?start=-3&limit=10&highlight=565"> 9q34.11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620482"> Parkinson disease 25, autosomal recessive early-onset, with impaired intellectual development </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620482"> 620482 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600756"> PTPA </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600756"> 600756 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/283?start=-3&limit=10&highlight=283"> 10q22.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619491"> {Parkinson disease 24, autosomal dominant, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619491"> 619491 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176801"> PSAP </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176801"> 176801 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/290?start=-3&limit=10&highlight=290"> 12q12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607060"> {Parkinson disease 8} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607060"> 607060 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609007"> LRRK2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609007"> 609007 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/813?start=-3&limit=10&highlight=813"> 12q24.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> {Parkinson disease, late-onset, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Multifactorial">Mu</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> 168600 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601517"> ATXN2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601517"> 601517 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/13/213?start=-3&limit=10&highlight=213"> 13q21.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> {Parkinson disease, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Multifactorial">Mu</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> 168600 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603680"> ATXN8OS </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603680"> 603680 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/466?start=-3&limit=10&highlight=466"> 14q32.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> {Parkinson disease, late-onset, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Multifactorial">Mu</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> 168600 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607047"> ATXN3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607047"> 607047 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/264?start=-3&limit=10&highlight=264"> 15q22.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616840"> Parkinson disease 23, autosomal recessive, early onset </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616840"> 616840 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608879"> VPS13C </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608879"> 608879 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/404?start=-3&limit=10&highlight=404"> 16q11.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614203"> {Parkinson disease 17} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614203"> 614203 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601501"> VPS35 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601501"> 601501 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/663?start=-3&limit=10&highlight=663"> 17q21.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> {Parkinson disease, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Multifactorial">Mu</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168600"> 168600 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/157140"> MAPT </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/157140"> 157140 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/21/62?start=-3&limit=10&highlight=62"> 21q22.11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615530"> Parkinson disease 20, early-onset </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615530"> 615530 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604297"> SYNJ1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604297"> 604297 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/204?start=-3&limit=10&highlight=204"> 22q12.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/260300"> Parkinson disease 15, autosomal recessive </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/260300"> 260300 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605648"> FBXO7 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605648"> 605648 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/268?start=-3&limit=10&highlight=268"> 22q13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612953"> Parkinson disease 14, autosomal recessive </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612953"> 612953 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603604"> PLA2G6 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603604"> 603604 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/X/445?start=-3&limit=10&highlight=445"> Xq21-q25 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300557"> {Parkinson disease 12} </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300557"> 300557 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300557"> PARK12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300557"> 300557 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
<div class="text-right small">
<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="text" class="mim-anchor"></a>
<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon &lt;span class='glyphicon glyphicon-plus-sign'&gt;&lt;/span&gt at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
<strong>TEXT</strong>
</span>
</span>
</h4>
<div id="mimTextFold" class="collapse in ">
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because of evidence that autosomal recessive juvenile Parkinson disease-2 (PARK2, or PDJ) is caused by homozygous or compound heterozygous mutation in the parkin gene (PARK2; <a href="/entry/602544">602544</a>) on chromosome 6q26.</p><p>For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see PD (<a href="/entry/168600">168600</a>).</p>
</span>
<div>
<br />
</div>
</div>
<div>
<a id="clinicalFeatures" class="mim-anchor"></a>
<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Clinical Features</strong>
</span>
</h4>
</div>
<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
<span class="mim-text-font">
<p>An autosomal recessive form of familial juvenile parkinsonism, defined as onset before age 40 years, was described in a Japanese family by <a href="#35" class="mim-tip-reference" title="Takahashi, H., Ohama, E., Suzuki, S., Horikawa, Y., Ishikawa, A., Morita, T., Tsuji, S., Ikuta, F. &lt;strong&gt;Familial juvenile parkinsonism: clinical and pathologic study in a family.&lt;/strong&gt; Neurology 44: 437-441, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8145912/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8145912&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.44.3_part_1.437&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8145912">Takahashi et al. (1994)</a>. Juvenile-onset Parkinson disease is symptomatically different in several aspects from classic late-onset Parkinson disease (PD; <a href="/entry/168600">168600</a>), although classic symptoms of PD, such as bradykinesia, rigidity, and tremor, are present. <a href="#35" class="mim-tip-reference" title="Takahashi, H., Ohama, E., Suzuki, S., Horikawa, Y., Ishikawa, A., Morita, T., Tsuji, S., Ikuta, F. &lt;strong&gt;Familial juvenile parkinsonism: clinical and pathologic study in a family.&lt;/strong&gt; Neurology 44: 437-441, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8145912/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8145912&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.44.3_part_1.437&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8145912">Takahashi et al. (1994)</a> commented that the familial occurrence in Japanese PDJ patients with cases was approximately 40 to 50% and that the inheritance pattern appeared to be mostly autosomal recessive. They reported a family in which 4 of 5 sibs were affected and the parents were first cousins. A full pathologic examination of 1 of the sibs, a 67-year-old woman, was presented. The substantia nigra (SN) showed obvious neuronal loss and gliosis in the medial and ventrolateral regions. In the remainder of that region and in the locus ceruleus, the population of neurons was reduced and there was low melanin content in most of the neurons but no detectable gliosis or extraneuronal free melanin pigment suggestive of a neurodegenerative process. There were no Lewy bodies. The entire pathologic picture was different from that of Lewy body Parkinson disease (<a href="/entry/168601">168601</a>). This patient had been well until about the age of 10 years when gait disturbance appeared. By age 14, she was unable to walk long distances. By her forties, she was unable to walk without assistance. There was no evidence of dementia. She had been slow-moving and had shown frozen gait and tremor, more evident on motion, in the head and upper and lower limbs. She showed improvement of the movement disorder after waking up in the morning. When she was young, the improvement lasted until evening, but as she aged it became progressively shorter, eventually lasting only about 10 minutes. In the other sibs, gait disturbance began at the age of 8 or 9 years. One sister had died at age 42 years and a brother at the age of 27 years, both in a bedridden state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8145912" 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="#11" class="mim-tip-reference" title="Ishikawa, A., Tsuji, S. &lt;strong&gt;Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism.&lt;/strong&gt; Neurology 47: 160-166, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8710071/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8710071&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.47.1.160&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8710071">Ishikawa and Tsuji (1996)</a> described the clinical features of 17 patients from 12 Japanese families with familial juvenile parkinsonism. In 11 of these families affected members were products of consanguineous matings. All 12 families resided within the same geographic area, raising the possibility of founder effect. The mean age of onset was 27 years, with a range from 9 to 43. The most prominent symptoms were retropulsion, dystonia of the feet, and hyperreflexia with classic parkinsonism. Symptoms of tremor, rigidity, and bradykinesia were mild. Patients responded to levodopa but dopa-induced dyskinesias and wearing-off phenomena occurred frequently. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8710071" 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="Bonifati, V., Vanacore, N., Meco, G. &lt;strong&gt;Anticipation of onset age in familial Parkinson&#x27;s disease.&lt;/strong&gt; Neurology 44: 1978-1979, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7936260/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7936260&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.44.10.1978&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7936260">Bonifati et al. (1994)</a> reported a man who presented with Parkinson disease at age 28. He was born of a consanguineous mating between a man who developed Parkinson disease at age 74 and his first cousin, who apparently was not affected with parkinsonian symptoms; however, the maternal grandfather developed Parkinson disease at age 65. <a href="#3" class="mim-tip-reference" title="Bonifati, V., Vanacore, N., Meco, G. &lt;strong&gt;Anticipation of onset age in familial Parkinson&#x27;s disease.&lt;/strong&gt; Neurology 44: 1978-1979, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7936260/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7936260&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.44.10.1978&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7936260">Bonifati et al. (1994)</a> speculated that the proband may have been homozygous for a defective Parkinson disease gene, which in heterozygous form gave rise to late-onset Parkinson disease in the affected father and maternal grandfather. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7936260" 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="Mitsui, T., Kawai, H., Sakoda, S., Miyata, M., Saito, S. &lt;strong&gt;Hereditary parkinsonism with multiple system degeneration: beneficial effect of anticholinergics, but not of levodopa.&lt;/strong&gt; J. Neurol. Sci. 125: 153-157, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7807160/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7807160&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(94)90028-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7807160">Mitsui et al. (1994)</a> described a sister and a brother, the only offspring of a first-cousin mating, with atypical juvenile parkinsonism. They presented at age 38 and 40, respectively, with bradykinesia, cogwheel rigidity, and mild pyramidal and cerebellar signs. They were unresponsive to levodopa but responded very well to trihexyphenidyl, an anticholinergic drug. <a href="#23" class="mim-tip-reference" title="Mitsui, T., Kawai, H., Sakoda, S., Miyata, M., Saito, S. &lt;strong&gt;Hereditary parkinsonism with multiple system degeneration: beneficial effect of anticholinergics, but not of levodopa.&lt;/strong&gt; J. Neurol. Sci. 125: 153-157, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7807160/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7807160&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(94)90028-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7807160">Mitsui et al. (1994)</a> proposed that this was a new hereditary variant of early-onset Parkinson disease, distinct from the levodopa-sensitive form of juvenile Parkinson disease. They commented that responsiveness to anticholinergics but not levodopa may also be seen in Joseph disease (SCA3; <a href="/entry/109150">109150</a>). MRI studies demonstrated atrophy of the cerebellar hemisphere and vermis, as well as high intensity areas in both pyramidal tracts. This juxtaposition of extrapyramidal and cerebellar signs usually results in classification of a disease as a multisystem atrophy or an olivopontocerebellar degeneration and is characteristic of many adult-onset spinocerebellar atrophies, most of which are transmitted as autosomal dominant traits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7807160" 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="#39" class="mim-tip-reference" title="Yamamura, Y., Sobue, I., Ando, K., Iida, M., Yanagi, T., Kono, C. &lt;strong&gt;Paralysis agitans of early onset with marked diurnal fluctuation of symptoms.&lt;/strong&gt; Neurology 23: 239-244, 1973.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4735177/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4735177&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.23.3.239&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4735177">Yamamura et al. (1973)</a> reported familial cases of juvenile parkinsonism with marked diurnal fluctuation in symptoms. The disorder was found to show nigral cell loss and occurred in a setting of inbreeding; it undoubtedly represented a subtype of autosomal recessive juvenile parkinsonism (<a href="#26" class="mim-tip-reference" title="Nygaard, T. G. &lt;strong&gt;Personal Communication.&lt;/strong&gt; New York, N. Y. 12/21/1993."None>Nygaard, 1993</a>). <a href="#22" class="mim-tip-reference" title="Matsumine, H., Yamamura, Y., Kobayashi, T., Nakamura, S., Kuzuhara, S., Mizuno, Y. &lt;strong&gt;Early onset parkinsonism with diurnal fluctuation maps to a locus for juvenile parkinsonism.&lt;/strong&gt; Neurology 50: 1340-1345, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9595984/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9595984&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.50.5.1340&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9595984">Matsumine et al. (1998)</a> noted that early-onset parkinsonism with diurnal fluctuation (EPDF) is also a dopa-responsive form of parkinsonism and is associated with selective degeneration in the zona compacta of the substantia nigra without Lewy body formation. A distinguishing feature of this phenotype is a benefit from sleep with lessening of parkinsonian symptoms after awakening. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9595984+4735177" 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="Portman, A. T., Giladi, N., Leenders, K. L., Maguire, P., Veenma-van der Duin, L., Swart, J., Pruim, J., Simon, E. S., Hassin-Baer, S., Korczyn, A. D. &lt;strong&gt;The nigrostriatal dopaminergic system in familial early onset parkinsonism with parkin mutations.&lt;/strong&gt; Neurology 56: 1759-1762, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11425950/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11425950&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.56.12.1759&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11425950">Portman et al. (2001)</a> performed PET scans on 2 brothers with early-onset parkinsonism caused by mutations in the parkin gene and found marked reduction of fluorodopa (FDOPA) uptake in the caudate and putamen. <a href="#30" class="mim-tip-reference" title="Portman, A. T., Giladi, N., Leenders, K. L., Maguire, P., Veenma-van der Duin, L., Swart, J., Pruim, J., Simon, E. S., Hassin-Baer, S., Korczyn, A. D. &lt;strong&gt;The nigrostriatal dopaminergic system in familial early onset parkinsonism with parkin mutations.&lt;/strong&gt; Neurology 56: 1759-1762, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11425950/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11425950&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.56.12.1759&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11425950">Portman et al. (2001)</a> noted that this was a different nigrostriatal dopaminergic pattern than that found in sporadic PD, thus suggesting a different pathophysiology for the early-onset disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11425950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Ohsawa, Y., Kurokawa, K., Sonoo, M., Yamada, H., Hemmi, S., Iwatsuki, K., Hagiwara, H., Murakami, T., Shirabe, T., Shimizu, T., Sunada, Y. &lt;strong&gt;Reduced amplitude of the sural nerve sensory action potential in PARK2 patients.&lt;/strong&gt; Neurology 65: 459-462, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16087916/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16087916&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000171859.85078.3d&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16087916">Ohsawa et al. (2005)</a> found that 8 of 9 patients with PARK2 mutations had significantly reduced sural sensory nerve action potential (SNAP) amplitude compared to 8 patients with idiopathic Parkinson disease. However, 6 PARK2 carriers had absence of decreased vibration sense in the foot, and only 2 had subjective sensory symptoms. Two patients with a presumptive diagnosis of idiopathic PD who showed a reduced SNAP amplitude were subsequently diagnosed with PARK2 as a result of DNA analysis. <a href="#27" class="mim-tip-reference" title="Ohsawa, Y., Kurokawa, K., Sonoo, M., Yamada, H., Hemmi, S., Iwatsuki, K., Hagiwara, H., Murakami, T., Shirabe, T., Shimizu, T., Sunada, Y. &lt;strong&gt;Reduced amplitude of the sural nerve sensory action potential in PARK2 patients.&lt;/strong&gt; Neurology 65: 459-462, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16087916/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16087916&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000171859.85078.3d&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16087916">Ohsawa et al. (2005)</a> suggested that reduced SNAP amplitude in patients with PD under 60 years of age may be a diagnostic indicator of PARK2 mutations, and concluded that sensory axonal neuropathy may be a common feature of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16087916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pathologic Findings</em></strong></p><p>
<a href="#24" class="mim-tip-reference" title="Mori, H., Kondo, T., Yokochi, M., Matsumine, H., Nakagawa-Hattori, Y., Miyake, T., Suda, K., Mizuno, Y. &lt;strong&gt;Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q.&lt;/strong&gt; Neurology 51: 890-892, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9748052/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9748052&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.51.3.890&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9748052">Mori et al. (1998)</a> reported neuropathologic findings in a patient with PARK2 confirmed by genetic analysis. The patient had disease onset at age 24 years and died from unrelated complications at age 62. Grossly, the substantia nigra showed marked depigmentation. Melanin-containing neurons in the pars compacta were moderately decreased, and neuronal loss and gliosis were especially marked in the ventrolateral and medial regions. Most of the remaining nigral neurons contained melanin pigments. The pars reticulata was spared. Lewy bodies were not identified. Neurofibrillary tangles and argyrophilic astrocytes were identified in the SN, the locus ceruleus, posterior hypothalamus, the hippocampus, and various cortical areas. However, the pattern was not consistent with Alzheimer disease. Tyrosine hydroxylase (<a href="/entry/191290">191290</a>) activity was markedly reduced in the caudate and putamen, and modestly reduced in the SN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9748052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Hayashi, S., Wakabayashi, K., Ishikawa, A., Nagai, H.,, Saito, M., Maruyama, M., Takahashi, T., Ozawa, T., Tsuji, S., Takahashi, H. &lt;strong&gt;An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene.&lt;/strong&gt; Mov. Disord. 15: 884-888, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11009195/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11009195&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1531-8257(200009)15:5&lt;884::aid-mds1019&gt;3.0.co;2-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11009195">Hayashi et al. (2000)</a> reported neuropathologic findings in a Japanese patient with a mutation in the PARK2 gene (<a href="/entry/602544#0002">602544.0002</a>) who had previously been reported by <a href="#10" class="mim-tip-reference" title="Ishikawa, A., Miyatake, T. &lt;strong&gt;A family with hereditary juvenile dystonia-parkinsonism.&lt;/strong&gt; Mov. Disord. 10: 482-488, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7565830/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7565830&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/mds.870100413&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7565830">Ishikawa and Miyatake (1995)</a>. Loss of pigmented neurons and gliosis were most pronounced in the medial and ventrolateral regions of the substantia nigra pars compacta and in the locus ceruleus. Remaining neurons had low amounts of melanin. There was mild neuronal loss and gliosis in the substantia nigra pars reticulata. No Lewy bodies were identified. Some neurofibrillary tangles and senile plaques were observed in the cerebral cortex, although there was no clinical evidence of dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11009195+7565830" 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="#37" class="mim-tip-reference" title="van de Warrenburg, B. P. C., Lammens, M., Lucking, C. B., Denefle, P., Wesseling, P., Booij, J., Praamstra, P., Quinn, N., Brice, A., Horstink, M. W. I. M. &lt;strong&gt;Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations.&lt;/strong&gt; Neurology 56: 555-557, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11222808/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11222808&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.56.4.555&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11222808">Van de Warrenburg et al. (2001)</a> reported a Dutch family with PARK2 confirmed by genetic analysis. Neuropathologic examination of the proband showed depigmentation of the substantia nigra, with severe loss of pigmented neurons in the pars compacta, deposition of extraneuronal melanin, and mild gliosis. No Lewy bodies or neurofibrillary tangles were seen. However, there was a diffuse spread of tau (MAPT; <a href="/entry/157140">157140</a>)-positive thorn-shaped astrocytes in the caudate, putamen, and subthalamic nucleus, and a few tau-positive astrocytes in the SN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11222808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Farrer, M., Chan, P., Chen, R., Tan, L., Lincoln, S., Hernandez, D., Forno, L., Gwinn-Hardy, K., Petrucelli, L., Hussey, J., Singleton, A., Tanner, C., Hardy, J., Langston, J. W. &lt;strong&gt;Lewy bodies and parkinsonism in families with parkin mutations.&lt;/strong&gt; Ann. Neurol. 50: 293-300, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11558785/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11558785&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.1132&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11558785">Farrer et al. (2001)</a> reported a patient who was compound heterozygous for 2 mutations in the PARK2 gene. At autopsy, Lewy body pathology typical of idiopathic Parkinson disease was found, which was noted to be unusual for this form of parkinsonism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11558785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Sasaki, S., Shirata, A., Yamane, K., Iwata, M. &lt;strong&gt;Parkin-positive autosomal recessive juvenile parkinsonism with alpha-synuclein-positive inclusions.&lt;/strong&gt; Neurology 63: 678-682, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15326242/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15326242&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000134657.25904.0b&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15326242">Sasaki et al. (2004)</a> reported neuropathologic examination of a patient with Parkinson disease due to homozygous exon 3 deletion in the PARK2 gene (<a href="/entry/602544#0005">602544.0005</a>). The patient had disease onset at age 33 years and died of respiratory failure at age 70. The substantia nigra showed marked depigmentation, and melanin-containing neurons of the pars compacta were moderately to severely depleted, particularly in the ventrolateral group and medial part. Some dopaminergic neurons remained, but most were atrophic, and free melanin was observed. The pars reticulata of the SN was spared. In the locus ceruleus, neurons were mildly decreased, and free melanin was seen. Lewy bodies were not observed in the SN or locus ceruleus. There were alpha-synuclein-positive and ubiquitin-positive, round or donut-shaped inclusions in the neuropils of the pedunculopontine nucleus, but no such inclusions were seen in the SN, locus ceruleus, or subthalamic nucleus. The inclusions were somewhat basophilic, distinguishing them from Lewy bodies, which show an eosinophilic tint. No immunoreactivity to phosphorylated tau was seen in any region of the brain. <a href="#33" class="mim-tip-reference" title="Sasaki, S., Shirata, A., Yamane, K., Iwata, M. &lt;strong&gt;Parkin-positive autosomal recessive juvenile parkinsonism with alpha-synuclein-positive inclusions.&lt;/strong&gt; Neurology 63: 678-682, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15326242/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15326242&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000134657.25904.0b&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15326242">Sasaki et al. (2004)</a> suggested that a functioning parkin protein may be required for Lewy body formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15326242" 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>Olfactory impairment is one of the earliest manifestations of Parkinson disease and reflects Lewy body infiltration in the olfactory bulb and tract before the disease affects the substantia nigra. <a href="#2" class="mim-tip-reference" title="Alcalay, R. N., Siderowf, A., Ottman, R., Caccappolo, E., Mejia-Santana, H., Tang, M.-X., Rosado, L., Louis, E., Ruiz, D., Waters, C., Fahn, S., Cote, L., and 22 others. &lt;strong&gt;Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study.&lt;/strong&gt; Neurology 76: 319-326, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21205674/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21205674&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e31820882aa&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21205674">Alcalay et al. (2011)</a> tested olfactory function in 44 probands with early-onset PD, including 9 with 2 parkin mutations, 10 with 1 parkin mutation, and 25 with PD without parkin mutations, as well as 80 of their family members without PD, including 18 with 1 parkin mutation, 2 with 2 parkin mutations, and 60 without parkin mutations. Among those with PD, patients with 2 parkin mutations had significantly better olfaction than patients with 1 parkin mutation or PD patients with no parkin mutation. Among those without PD, olfaction was similar in carriers of 1 parkin mutation and those without mutations, but better than PD patients with 1 parkin mutation. <a href="#2" class="mim-tip-reference" title="Alcalay, R. N., Siderowf, A., Ottman, R., Caccappolo, E., Mejia-Santana, H., Tang, M.-X., Rosado, L., Louis, E., Ruiz, D., Waters, C., Fahn, S., Cote, L., and 22 others. &lt;strong&gt;Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study.&lt;/strong&gt; Neurology 76: 319-326, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21205674/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21205674&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e31820882aa&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21205674">Alcalay et al. (2011)</a> suggested that PD patients with parkin mutations have better olfaction compared to other PD patients, and also suggested that heterozygosity for 1 parkin mutation does not confer an increased risk of neuropathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21205674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<strong>Inheritance</strong>
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<p>Recessive homozygous mutations in the parkin gene result in early-onset Parkinson disease. Heterozygous mutations in the parkin gene have been identified in some patients with later onset disease, raising the possibility that heterozygous mutations may confer increased susceptibility to the disease. <a href="#38" class="mim-tip-reference" title="Wang, Y., Clark, L. N., Louis, E. D., Mejia-Santana, H., Harris, J., Cote, L. J., Waters, C., Andrews, H., Ford, B., Frucht, S., Fahn, S., Ottman, R., Rabinowitz, D., Marder, K. &lt;strong&gt;Risk of Parkinson disease in carriers of parkin mutations: estimation using the kin-cohort method.&lt;/strong&gt; Arch. Neurol. 65: 467-474, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18413468/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18413468&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.65.4.467&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18413468">Wang et al. (2008)</a> identified mutations in the parkin gene in 25 (10.1%) of 247 probands with disease onset before age 50. Eighteen patients had heterozygous mutations. Using a kin-cohort study design, which does not require information about mutation status, they estimated the cumulative incidence of PD to age 65 in relatives of mutation carriers to be 7.0%, compared to 1.7% in noncarrier relatives and 1.1% in relatives of controls. <a href="#38" class="mim-tip-reference" title="Wang, Y., Clark, L. N., Louis, E. D., Mejia-Santana, H., Harris, J., Cote, L. J., Waters, C., Andrews, H., Ford, B., Frucht, S., Fahn, S., Ottman, R., Rabinowitz, D., Marder, K. &lt;strong&gt;Risk of Parkinson disease in carriers of parkin mutations: estimation using the kin-cohort method.&lt;/strong&gt; Arch. Neurol. 65: 467-474, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18413468/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18413468&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.65.4.467&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18413468">Wang et al. (2008)</a> noted the limitations to their study, including the inability to assess risk of PD among heterozygotes separately and the low age of some relatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18413468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="mapping" class="mim-anchor"></a>
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<strong>Mapping</strong>
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<p>By linkage analysis using a diallelic polymorphism of the manganese superoxide dismutase gene (SOD2; <a href="/entry/147460">147460</a>), <a href="#21" class="mim-tip-reference" title="Matsumine, H., Saito, M., Shimoda-Matsubayashi, S., Tanaka, H., Ishikawa, A., Nakagawa-Hattori, Y., Yokochi, M., Kobayashi, T., Igarashi, S., Takano, H., Sanpei, K., Koike, R., Mori, H., Kondo, T., Mizutani, Y., Schaffer, A. A., Yamamura, Y., Nakamura, S., Kuzuhura, S., Tsuji, S., Mizuno, Y. &lt;strong&gt;Localization of a gene for an autosomal recessive form of juvenile parkinsonism to chromosome 6q25.2-27.&lt;/strong&gt; Am. J. Hum. Genet. 60: 588-596, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9042918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9042918&lt;/a&gt;]" pmid="9042918">Matsumine et al. (1997)</a> found perfect segregation of the disease with the SOD2 locus. By extending the linkage analysis to 13 families with autosomal recessive juvenile parkinsonism, they discovered strong evidence for the localization of the gene at 6q25.2-q27, including the SOD2 locus, with the maximum cumulative pairwise lod scores of 7.26 and 7.71 at D6S305 (theta = 0.03) and D6S253 (theta = 0.02), respectively. Nucleotide sequence analysis of the coding regions of the SOD2 gene did not show causative mutations, suggesting that another, as yet unidentified gene in this region is responsible for autosomal recessive juvenile parkinsonism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9042918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a group of 15 families from 4 distinct ethnic backgrounds, <a href="#12" class="mim-tip-reference" title="Jones, A. C., Yamamura, Y., Almasy, L., Bohlega, S., Elibol, B., Hubble, J., Kuzuhara, S., Uchida, M., Yanagi, T., Weeks, D. E., Nygaard, T. G. &lt;strong&gt;Autosomal recessive juvenile parkinsonism maps to 6q25.2-q27 in four ethnic groups: detailed genetic mapping of the linked region.&lt;/strong&gt; Am. J. Hum. Genet. 63: 80-87, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9634534/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9634534&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/301937&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9634534">Jones et al. (1998)</a> found that the locus for autosomal recessive juvenile parkinsonism in all mapped to 6q25.2-q27. A full genomic screen excluded other candidate regions. They constructed a detailed genetic map of the linked region and mapped the position of the SOD2 gene. Recombination events restricted the chromosome 6 Parkinson disease locus to a 6.9-cM region and excluded SOD2. <a href="#36" class="mim-tip-reference" title="Tassin, J., Durr, A., de Broucker, T., Abbas, N., Bonifati, V., De Michele, G., Bonnet, A.-M., Broussolle, E., Pollak, P., Vidailhet, M., De Mari, M., Marconi, R., Medjbeur, S., Filla, A., Meco, G., Agid, Y., Brice, A., French Parkinson&#x27;s Disease Genetics Study Group, European Consortium on Genetic Susceptibility in Parkinson&#x27;s Disease. &lt;strong&gt;Chromosome 6-linked autosomal recessive early-onset parkinsonism: linkage in European and Algerian families, extension of the clinical spectrum, and evidence of a small homozygous deletion in one family.&lt;/strong&gt; Am. J. Hum. Genet. 63: 88-94, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9634531/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9634531&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/301934&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9634531">Tassin et al. (1998)</a> likewise found linkage of the gene for PDJ to 6q25.2-q27 in 1 Algerian and 10 European multiplex families. They found the clinical spectrum of the disease in these families, with age at onset up to 58 years and the presence of painful dystonia in some patients, to be broader than that reported previously. In all patients examined, 2 of the 3 cardinal signs of PD (akinesia, rigidity, and tremor) were found. Marked improvement with levodopa treatment occurred in all except 2 untreated secondary cases found in family studies. Age at onset was less than 40 years for at least 1 affected sib. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9634534+9634531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Saito, M., Matsumine, H., Tanaka, H., Ishikawa, A., Shimoda-Matsubayashi, S., Schaffer, A. A., Mizuno, Y., Tsuji, S. &lt;strong&gt;Refinement of the gene locus for autosomal recessive juvenile parkinsonism (AR-JP) on chromosome 6q25.2-27 and identification of markers exhibiting linkage disequilibrium.&lt;/strong&gt; J. Hum. Genet. 43: 22-31, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9609994/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9609994&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s100380050032&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9609994">Saito et al. (1998)</a> narrowed the assignment of the PARK2 locus to a 4-cM region encompassing D6S1579 and D6S1599. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9609994" 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="Matsumine, H., Yamamura, Y., Kobayashi, T., Nakamura, S., Kuzuhara, S., Mizuno, Y. &lt;strong&gt;Early onset parkinsonism with diurnal fluctuation maps to a locus for juvenile parkinsonism.&lt;/strong&gt; Neurology 50: 1340-1345, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9595984/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9595984&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.50.5.1340&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9595984">Matsumine et al. (1998)</a> demonstrated that the disorder reported by <a href="#39" class="mim-tip-reference" title="Yamamura, Y., Sobue, I., Ando, K., Iida, M., Yanagi, T., Kono, C. &lt;strong&gt;Paralysis agitans of early onset with marked diurnal fluctuation of symptoms.&lt;/strong&gt; Neurology 23: 239-244, 1973.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4735177/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4735177&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.23.3.239&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4735177">Yamamura et al. (1973)</a> (EPDF) showed linkage to the same region on chromosome 6 as did autosomal recessive juvenile Parkinson disease. In studies of 17 families with EPDF, they found a peak lod score of 14.2 at 1.0 cM telomeric to D6S305 and placed the disease locus in the 17-cM interval between D6S437 and D6S253, which is exactly the same position to which PDJ had been mapped. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9595984+4735177" 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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<div>
<a id="molecularGenetics" class="mim-anchor"></a>
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Molecular Genetics</strong>
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<p>In several patients with PDJ, <a href="#16" class="mim-tip-reference" title="Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., Shimizu, N. &lt;strong&gt;Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.&lt;/strong&gt; Nature 392: 605-608, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9560156/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9560156&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/33416&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9560156">Kitada et al. (1998)</a> identified deletions in the PARK2 gene (see, e.g., <a href="/entry/602544#0001">602544.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9560156" 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="Hoenicka, J., Vidal, L., Morales, B., Ampuero, I., Jimenez-Jimenez, F. J., Berciano, J., del Ser, T., Jimenez, A., Ruiz, P. G., de Yebenes, J. G. &lt;strong&gt;Molecular findings in familial Parkinson disease in Spain.&lt;/strong&gt; Arch. Neurol. 59: 966-970, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12056932/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12056932&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.59.6.966&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12056932">Hoenicka et al. (2002)</a> found 5 different mutations in the PARK2 gene in 5 of 13 Spanish families with recessive inheritance. Two of the mutations were novel (<a href="/entry/602544#0013">602544.0013</a> and <a href="/entry/602544#0012">602544.0012</a>). <a href="#9" class="mim-tip-reference" title="Hoenicka, J., Vidal, L., Morales, B., Ampuero, I., Jimenez-Jimenez, F. J., Berciano, J., del Ser, T., Jimenez, A., Ruiz, P. G., de Yebenes, J. G. &lt;strong&gt;Molecular findings in familial Parkinson disease in Spain.&lt;/strong&gt; Arch. Neurol. 59: 966-970, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12056932/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12056932&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.59.6.966&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12056932">Hoenicka et al. (2002)</a> found 2 simple heterozygous PARK2 mutation carriers who developed clinical symptoms, either in late adulthood or after brief exposure to parkinsonizing agents. The authors suggested that heterozygosity may be a risk factor for PD. In 14 other Spanish kindreds with familial PD, 8 autosomal recessive, 4 autosomal dominant and 2 of uncertain inheritance, <a href="#9" class="mim-tip-reference" title="Hoenicka, J., Vidal, L., Morales, B., Ampuero, I., Jimenez-Jimenez, F. J., Berciano, J., del Ser, T., Jimenez, A., Ruiz, P. G., de Yebenes, J. G. &lt;strong&gt;Molecular findings in familial Parkinson disease in Spain.&lt;/strong&gt; Arch. Neurol. 59: 966-970, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12056932/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12056932&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.59.6.966&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12056932">Hoenicka et al. (2002)</a> found no mutations in the alpha-synuclein (SNCA; <a href="/entry/163890">163890</a>) or UCHL1 (<a href="/entry/191342">191342</a>) genes related to PARK1 (<a href="/entry/168601">168601</a>) and PARK5 (<a href="/entry/191342">191342</a>), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12056932" 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="#19" class="mim-tip-reference" title="Lucking, C. B., Bonifati, V., Periquet, M., Vanacore, N., Brice, A., Meco, G. &lt;strong&gt;Pseudo-dominant inheritance and exon 2 triplication in a family with parkin gene mutations.&lt;/strong&gt; Neurology 57: 924-927, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11552035/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11552035&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.57.5.924&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11552035">Lucking et al. (2001)</a> described an Italian family in which parkinsonism was associated with mutations in the PARK2 gene in a pseudodominant pattern of inheritance. The father (with disease onset at age 57 years) was homozygous for a triplication of exon 2, a previously undescribed mutation. The unaffected mother was heterozygous for deletions of exons 3 and 4, and the son (with disease onset at age 31 years) was a compound heterozygote carrying both mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11552035" 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 10 affected members of a consanguineous Brazilian family with early-onset parkinsonism, <a href="#4" class="mim-tip-reference" title="Chien, H. F., Rohe, C. F., Costa, M. D. L., Breedveld, G. J., Oostra, B. A., Barbosa, E. R., Bonifati, V. &lt;strong&gt;Early-onset Parkinson&#x27;s disease caused by a novel mutation in a genetic isolate from north-eastern Brazil.&lt;/strong&gt; Neurogenetics 7: 13-19, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16328510/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16328510&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-005-0017-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16328510">Chien et al. (2006)</a> identified a homozygous splice site mutation in the PARK2 gene (<a href="/entry/602544#0020">602544.0020</a>). The family was from an isolated region in northeastern Brazil, and their ancestors had originated from Portugal. One individual who was heterozygous for the mutation developed neuroleptic-induced parkinsonism, suggesting that haploinsufficiency was a predisposing factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16328510" 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="#13" class="mim-tip-reference" title="Kay, D. M., Moran, D., Moses, L., Poorkaj, P., Zabetian, C. P., Nutt, J., Factor, S. A., Yu, C.-E., Montimurro, J. S., Keefe, R. G., Schellenberg, G. D., Payami, H. &lt;strong&gt;Heterozygous parkin point mutations are as common in control subjects as in Parkinson&#x27;s patients.&lt;/strong&gt; Ann. Neurol. 61: 47-54, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17187375/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17187375&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21039&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17187375">Kay et al. (2007)</a> found that heterozygous parkin mutations were as common in 301 controls as in 302 PD patients, and they replicated the finding in an independent set of 1,260 PD patients and 1,657 controls. Thirty-four variants, including 21 novel variants, were identified. <a href="#13" class="mim-tip-reference" title="Kay, D. M., Moran, D., Moses, L., Poorkaj, P., Zabetian, C. P., Nutt, J., Factor, S. A., Yu, C.-E., Montimurro, J. S., Keefe, R. G., Schellenberg, G. D., Payami, H. &lt;strong&gt;Heterozygous parkin point mutations are as common in control subjects as in Parkinson&#x27;s patients.&lt;/strong&gt; Ann. Neurol. 61: 47-54, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17187375/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17187375&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21039&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17187375">Kay et al. (2007)</a> concluded that heterozygous mutations in the parkin gene are not likely to contribute to the development of Parkinson disease. Quantitative gene dosage was not examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17187375" 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="Alcalay, R. N., Caccappolo, E., Mejia-Santana, H., Tang, M. X., Rosado, L., Ross, B. M., Verbitsky, M., Kisselev, S., Louis, E. D., Comella, C., Colcher, A., Jennings, D., and 21 others. &lt;strong&gt;Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study.&lt;/strong&gt; Arch. Neurol. 67: 1116-1122, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20837857/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20837857&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2010.194&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20837857">Alcalay et al. (2010)</a> identified mutations in the PARK2 gene in 64 (6.7%) of 953 patients with early-onset PD before age 51, including 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. Thirty-three patients had a heterozygous PARK2 mutation, and 27 had homozygous or compound heterozygous mutations. Four of 64 patients had a PARK2 mutation and another mutation in the LRRK2 (<a href="/entry/609007">609007</a>) or GBA (<a href="/entry/606463">606463</a>) genes. Hispanic individuals were more likely to be PARK2 mutation carriers than non-Hispanic individuals (15.6% vs 5.9%; p = 0.003). <a href="#20" class="mim-tip-reference" title="Marder, K. S., Tang, M. X., Mejia-Santana, H., Rosado, L., Louis, E. D., Comella, C. L., Colcher, A., Siderowf, A. D., Jennings, D., Nance, M. A., Bressman, S., Scott, W. K., and 22 others. &lt;strong&gt;Predictors of parkin mutations in early-onset Parkinson disease: the consortium on risk for early-onset Parkinson disease study.&lt;/strong&gt; Arch. Neurol. 67: 731-738, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20558392/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20558392&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2010.95&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20558392">Marder et al. (2010)</a> examined the same dataset reported by <a href="#1" class="mim-tip-reference" title="Alcalay, R. N., Caccappolo, E., Mejia-Santana, H., Tang, M. X., Rosado, L., Ross, B. M., Verbitsky, M., Kisselev, S., Louis, E. D., Comella, C., Colcher, A., Jennings, D., and 21 others. &lt;strong&gt;Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study.&lt;/strong&gt; Arch. Neurol. 67: 1116-1122, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20837857/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20837857&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2010.194&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20837857">Alcalay et al. (2010)</a>, with specific focus on PARK2 mutation carriers. Of the 64 patients with parkin mutations, 37 were heterozygous (including 4 with mutations in other genes), 6 homozygous, and 21 compound heterozygous. Compound heterozygous and homozygous carriers had a significantly younger age at onset compared to heterozygous carriers. Significant associations were found between parkin mutation carrier status and Hispanic origin (odds ratio (OR) of 2.7), younger age at onset (less than 40 years) (OR of 5.0), and family history of PD in a first-degree relative (OR of 2.8). Deletions in exons 3 and 4 and 255delA (<a href="/entry/602544#0014">602544.0014</a>) were common among Hispanics, specifically Puerto Ricans. In addition, those with heterozygous parkin mutations had younger age at onset compared to PD patients without parkin mutations, suggesting that heterozygosity is a susceptibility factor for disease development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20558392+20837857" 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="#14" class="mim-tip-reference" title="Kay, D. M., Stevens, C. F., Hamza, T. H., Montimurro, J. S., Zabetian, C. P., Factor, S. A., Samii, A., Griffith, A., Roberts, J. W., Molho, E. S., Higgins, D. S., Gancher, S., Moses, L., Zareparsi, S., Poorkaj, P., Bird, T., Nutt, J., Schellenberg, G. D., Payami, H. &lt;strong&gt;A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2.&lt;/strong&gt; Neurology 75: 1189-1194, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20876472/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20876472&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181f4d832&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20876472">Kay et al. (2010)</a> identified heterozygous copy number variations (CNV) in the parkin gene in 0.95% of 1,686 controls and 0.86% of 2,091 PD patients, suggesting that heterozygous PARK2 CNV mutations are not associated with PD risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20876472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To examine the effects of heterozygous mutations in the PRKN gene on the risk of Parkinson disease, <a href="#40" class="mim-tip-reference" title="Zhu, W., Huang, X., Yoon, E., Bandres-Ciga, S., Blauwendraat, C., Billingsley, K. J., Cade, J. H., Wu, B. P., Williams, V. H., Schindler, A. B., Brooks, J., Gibbs, J. R., Hernandez, D. G., Ehrlich, D., Singleton, A. B., Narendra, D. P. &lt;strong&gt;Heterozygous PRKN mutations are common but do not increase the risk of Parkinson&#x27;s disease.&lt;/strong&gt; Brain 145: 2077-2091, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/35640906/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;35640906&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=35640906[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awab456&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="35640906">Zhu et al. (2022)</a> examined 2 large cohorts: an NIH Parkinson disease control cohort with whole-exome screening data, and the UK Biobank cohort with whole-exome sequencing and genotyping array data. Using the NIH cohort, the authors validated genotyping array screening for the detection of patients with biallelic PRKN mutations. Functional assays performed on patients from the NIH cohort were able to rule out second cryptic variants in patients with one heterozygous pathogenic mutation. Using the UK Biobank data, they found that 1.8% of participants had 1 pathogenic PRKN variant and 1/7800 participants had biallelic variants. Those with 1 PRKN pathologic variant were equally as likely as noncarriers to have Parkinson disease or a parent with Parkinson disease, providing evidence that heterozygosity for pathogenic PRKN mutations does not increase the risk of Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35640906" 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>Associations Pending Confirmation</em></strong></p><p>
For discussion of a possible association between autosomal recessive juvenile-onset Parkinson disease and variation in the PODXL gene, see <a href="/entry/602632#0002">602632.0002</a>.</p>
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<p><a href="#6" class="mim-tip-reference" title="Foroud, T., Uniacke, S. K., Liu, L., Pankratz, N., Rudolph, A., Halter, C., Shults, C., Marder, K., Conneally, P. M., Nichols, W. C., Parkinson Study Group. &lt;strong&gt;Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease.&lt;/strong&gt; Neurology 60: 796-801, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12629236/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12629236&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000049470.00180.07&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12629236">Foroud et al. (2003)</a> identified 25 different parkin mutations in 103 affected individuals from 47 families with PD, including 41 individuals with mutations in both alleles and 62 individuals with a single mutation in only 1 allele. Individuals with 2 parkin mutations had an earlier age at disease onset and longer disease duration than those with 1 mutation. Thirty-five subjects (35%) with a parkin mutation had an age at onset of 60 years or above, with 30 of these 35 having only 1 mutant allele. The authors concluded that mutations in the parkin gene occur among individuals with PD with an older age at onset (greater than 60 years) who have a positive family history of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12629236" 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 16 of 307 (5%) families with PD, <a href="#28" class="mim-tip-reference" title="Oliveira, S. A., Scott, W. K., Martin, E. R., Nance, M. A., Watts, R. L., Hubble, J. P., Koller, W. C., Pahwa, R., Stern, M. B., Hiner, B. C., Ondo, W. G., Allen, F. H., Jr., and 12 others. &lt;strong&gt;Parkin mutations and susceptibility alleles in late-onset Parkinson&#x27;s disease.&lt;/strong&gt; Ann. Neurol. 53: 624-629, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12730996/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12730996&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10524&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12730996">Oliveira et al. (2003)</a> identified mutations in the parkin gene, which included 18% of all early-onset and 2% of all late-onset families. Three families were homozygous, 3 families were compound heterozygous, and in 10 families, all the patients had heterozygous mutations. The results showed that mutations in exon 7 were observed primarily in heterozygous PD patients with a later age at onset. <a href="#28" class="mim-tip-reference" title="Oliveira, S. A., Scott, W. K., Martin, E. R., Nance, M. A., Watts, R. L., Hubble, J. P., Koller, W. C., Pahwa, R., Stern, M. B., Hiner, B. C., Ondo, W. G., Allen, F. H., Jr., and 12 others. &lt;strong&gt;Parkin mutations and susceptibility alleles in late-onset Parkinson&#x27;s disease.&lt;/strong&gt; Ann. Neurol. 53: 624-629, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12730996/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12730996&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10524&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12730996">Oliveira et al. (2003)</a> concluded that mutations in the parkin gene contribute to the common form of PD, and that heterozygous mutations act as susceptibility alleles for the late-onset form of PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730996" 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="#18" class="mim-tip-reference" title="Lohmann, E., Periquet, M., Bonifati, V., Wood, N. W., De Michele, G., Bonnet, A.-M., Fraix, V., Broussolle, E., Horstink, M. W. I. M., Vidailhet, M., Verpillat, P., Gasser, T., French Parkinson&#x27;s Disease Genetics Study Group, European Consortium on Genetic Susceptibility in Parkinson&#x27;s Disease, and 11 others. &lt;strong&gt;How much phenotypic variation can be attributed to parkin genotype?&lt;/strong&gt; Ann. Neurol. 54: 176-185, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12891670/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12891670&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10613&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12891670">Lohmann et al. (2003)</a> compared 146 PD patients with parkin mutations to 250 PD patients without parkin mutations; they found that patients with the parkin mutations had a significantly earlier and more symmetric onset, a slower progression of disease, and a tendency toward greater response to L-DOPA despite lower doses. However, both groups had a similar wide range for age at onset (7 to 70 years and 12 to 76 years, respectively). In families with autosomal recessive parkinsonism, more than 80% of patients with an age at onset of 20 years or younger had parkin mutations, compared to 28% of those between the ages of 46 and 55 years. Carriers of at least 1 parkin missense mutation had a more severe phenotype than those with 2 truncating mutations, suggesting that missense mutations result in more than a loss of function. Patients with a single heterozygous parkin mutation had significantly later and more asymmetric onset and more frequent L-DOPA-induced difficulties than those with 2 parkin mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12891670" 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="Poorkaj, P., Nutt, J. G., James, D., Gancher, S., Bird, T. D., Steinbart, E., Schellenberg, G. D., Payami, H. &lt;strong&gt;Parkin mutation analysis in clinic patients with early-onset Parkinson&#x27;s disease.&lt;/strong&gt; Am. J. Med. Genet. 129A: 44-50, 2004. Note: Erratum: Am. J. Med. Genet. 139A: 56 only, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15266615/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15266615&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30157&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15266615">Poorkaj et al. (2004)</a> undertook a study to determine whether patients with early-onset PD should be screened for parkin mutations as part of their clinical workup. Patients with a diagnosis of PD and onset at or before 40 years of age were selected for genotyping by sequence and dosage analysis for all 12 exons. Mutations were found in 7 of 39 patients. Two of these were compound heterozygous; 5 were heterozygous. Early-onset PD accounted for 10% of PD patients, and 18% of the early-onset patients had parkin mutations. Assuming a strictly recessive inheritance, only 5% of early-onset cases had a pathogenic parkin genotype. The remaining 13% were heterozygous, and whether heterozygous parkin mutations were the cause of early-onset PD in these patients was unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15266615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using PET scan, <a href="#15" class="mim-tip-reference" title="Khan, N. L., Scherfler, C., Graham, E., Bhatia, K. P., Quinn, N., Lees, A. J., Brooks, D. J., Wood, N. W., Piccini, P. &lt;strong&gt;Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation.&lt;/strong&gt; Neurology 64: 134-136, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15642918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15642918&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.WNL.0000148725.48740.6D&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15642918">Khan et al. (2005)</a> found that 13 asymptomatic heterozygous carriers of a PARK2 mutation had significantly decreased fluorodopa uptake in the caudate, putamen, and ventral and dorsal midbrain compared to controls. Four of the heterozygous carriers had subtle extrapyramidal signs. <a href="#15" class="mim-tip-reference" title="Khan, N. L., Scherfler, C., Graham, E., Bhatia, K. P., Quinn, N., Lees, A. J., Brooks, D. J., Wood, N. W., Piccini, P. &lt;strong&gt;Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation.&lt;/strong&gt; Neurology 64: 134-136, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15642918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15642918&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.WNL.0000148725.48740.6D&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15642918">Khan et al. (2005)</a> concluded that parkin heterozygosity is a risk factor for nigrostriatal dysfunction and suggested that parkin heterozygosity may contribute to late-onset PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15642918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Klein, C., Pramstaller, P. P., Kis, B., Page, C. C., Kann, M., Leung, J., Woodward, H., Castellan, C. C., Scherer, M., Vieregge, P., Breakefield, X. O., Kramer, P. L., Ozelius, L. J. &lt;strong&gt;Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype.&lt;/strong&gt; Ann. Neurol. 48: 65-71, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10894217/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10894217&lt;/a&gt;]" pmid="10894217">Klein et al. (2000)</a> reported a large kindred from a remote village in the Western Alps of South Tyrol in northern Italy affected with adult-onset Parkinson disease inherited in an autosomal dominant pattern. The clinical features were indistinguishable from idiopathic Parkinson disease, and none of the patients demonstrated typical features of PARK2, such as diurnal fluctuation, sleep benefit, foot dystonia, hyperreflexia, or early susceptibility to levodopa-induced dyskinesias. Haplotype analysis implicated the parkin locus on chromosome 6q. Molecular analysis showed that 4 affected male sibs were compound heterozygous for 2 deletions in the PARK2 gene: a large deletion, which was later determined by <a href="#8" class="mim-tip-reference" title="Hedrich, K., Kann, M., Lanthaler, A. J., Dalski, A., Eskelson, C., Landt, O., Schwinger, E., Vieregge, P., Lang, A. E., Breakefield, X. O., Ozelius, L. J., Pramstaller, P. P., Klein, C. &lt;strong&gt;The importance of gene dosage studies: mutational analysis of the parkin gene in early-onset parkinsonism.&lt;/strong&gt; Hum. Molec. Genet. 10: 1649-1656, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11487568/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11487568&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.16.1649&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11487568">Hedrich et al. (2001)</a> to be a deletion of only exon 7 (<a href="/entry/602544#0010">602544.0010</a>), and a 1-bp deletion in exon 9 (<a href="/entry/602544#0019">602544.0019</a>). Two affected females were heterozygous for the 1-bp deletion. <a href="#17" class="mim-tip-reference" title="Klein, C., Pramstaller, P. P., Kis, B., Page, C. C., Kann, M., Leung, J., Woodward, H., Castellan, C. C., Scherer, M., Vieregge, P., Breakefield, X. O., Kramer, P. L., Ozelius, L. J. &lt;strong&gt;Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype.&lt;/strong&gt; Ann. Neurol. 48: 65-71, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10894217/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10894217&lt;/a&gt;]" pmid="10894217">Klein et al. (2000)</a> concluded that the phenotypic spectrum associated with mutations in the PARK2 gene are broad and that PARK2 may play a role in the etiology of late-onset typical PD. <a href="#31" class="mim-tip-reference" title="Pramstaller, P. P., Schlossmacher, M. G., Jacques, T. S., Scaravilli, F., Eskelson, C., Pepivani, I., Hedrich, K., Adel, S., Gonzales-McNeal, M., Hilker, R., Kramer, P. L., Klein, C. &lt;strong&gt;Lewy body Parkinson&#x27;s disease in a large pedigree with 77 parkin mutation carriers.&lt;/strong&gt; Ann. Neurol. 58: 411-422, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16130111/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16130111&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20587&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16130111">Pramstaller et al. (2005)</a> provided detailed clinical and molecular follow-up of the family reported by <a href="#17" class="mim-tip-reference" title="Klein, C., Pramstaller, P. P., Kis, B., Page, C. C., Kann, M., Leung, J., Woodward, H., Castellan, C. C., Scherer, M., Vieregge, P., Breakefield, X. O., Kramer, P. L., Ozelius, L. J. &lt;strong&gt;Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype.&lt;/strong&gt; Ann. Neurol. 48: 65-71, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10894217/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10894217&lt;/a&gt;]" pmid="10894217">Klein et al. (2000)</a>. Ancestors could be traced back to the year 1657; relevant clinical data were obtained from 196 individuals spanning 7 generations. The mean age at onset was 52.8 years, but ranged from 20 to 76 years. Five of 25 definitely affected individuals were found to be compound heterozygous for the 2 previously identified PARK2 deletions; 8 patients had only 1 of these deletions; the mutational status of 5 deceased patients was unknown; and 7 patients had no PARK2 mutations. Patients who were compound heterozygous had earlier onset than those with heterozygous mutations. <a href="#31" class="mim-tip-reference" title="Pramstaller, P. P., Schlossmacher, M. G., Jacques, T. S., Scaravilli, F., Eskelson, C., Pepivani, I., Hedrich, K., Adel, S., Gonzales-McNeal, M., Hilker, R., Kramer, P. L., Klein, C. &lt;strong&gt;Lewy body Parkinson&#x27;s disease in a large pedigree with 77 parkin mutation carriers.&lt;/strong&gt; Ann. Neurol. 58: 411-422, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16130111/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16130111&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20587&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16130111">Pramstaller et al. (2005)</a> concluded that heterozygous mutations in the PARK2 gene contribute to idiopathic PD. Postmortem analysis of 1 of the patients reported by <a href="#31" class="mim-tip-reference" title="Pramstaller, P. P., Schlossmacher, M. G., Jacques, T. S., Scaravilli, F., Eskelson, C., Pepivani, I., Hedrich, K., Adel, S., Gonzales-McNeal, M., Hilker, R., Kramer, P. L., Klein, C. &lt;strong&gt;Lewy body Parkinson&#x27;s disease in a large pedigree with 77 parkin mutation carriers.&lt;/strong&gt; Ann. Neurol. 58: 411-422, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16130111/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16130111&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20587&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16130111">Pramstaller et al. (2005)</a> with both PARK2 mutations showed SNCA-positive Lewy bodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10894217+16130111+11487568" 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="#40" class="mim-tip-reference" title="Zhu, W., Huang, X., Yoon, E., Bandres-Ciga, S., Blauwendraat, C., Billingsley, K. J., Cade, J. H., Wu, B. P., Williams, V. H., Schindler, A. B., Brooks, J., Gibbs, J. R., Hernandez, D. G., Ehrlich, D., Singleton, A. B., Narendra, D. P. &lt;strong&gt;Heterozygous PRKN mutations are common but do not increase the risk of Parkinson&#x27;s disease.&lt;/strong&gt; Brain 145: 2077-2091, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/35640906/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;35640906&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=35640906[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awab456&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="35640906">Zhu et al. (2022)</a> compared phenotypes among patients with idiopathic Parkinson disease, patients with heterozygous PRKN variants, and patients with biallelic PRKN variants consistent with PARK2. Age of onset was significantly younger and standardized testing of olfaction was better among patients with biallelic mutations than for patients with idiopathic Parkinson disease and heterozygous PRKN groups. Age of onset of PRKN biallelic patients was 38 years of age or younger. In contrast, standard cognitive assessment and an assessment of disease severity were not significantly different among the groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35640906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="pathogenesis" class="mim-anchor"></a>
<h4 href="#mimPathogenesisFold" id="mimPathogenesisToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimPathogenesisToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
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<strong>Pathogenesis</strong>
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<p><a href="#16" class="mim-tip-reference" title="Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., Shimizu, N. &lt;strong&gt;Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.&lt;/strong&gt; Nature 392: 605-608, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9560156/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9560156&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/33416&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9560156">Kitada et al. (1998)</a> suggested that parkin may function similarly to ubiquitin family members, and its defect in PDJ may interfere with the ubiquitin-mediated proteolytic pathway leading to the death of nigral neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9560156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Shimura, H., Schlossmacher, M. G., Hattori, N., Frosch, M. P., Trockenbacher, A., Schneider, R., Mizuno, Y., Kosik, K. S., Selkoe, D. J. &lt;strong&gt;Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson&#x27;s disease.&lt;/strong&gt; Science 293: 263-269, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11431533/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11431533&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1060627&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11431533">Shimura et al. (2001)</a> hypothesized that alpha-synuclein and parkin interact functionally, namely, that parkin ubiquitinates alpha-synuclein normally and that this process is altered in autosomal recessive Parkinson disease. <a href="#34" class="mim-tip-reference" title="Shimura, H., Schlossmacher, M. G., Hattori, N., Frosch, M. P., Trockenbacher, A., Schneider, R., Mizuno, Y., Kosik, K. S., Selkoe, D. J. &lt;strong&gt;Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson&#x27;s disease.&lt;/strong&gt; Science 293: 263-269, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11431533/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11431533&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1060627&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11431533">Shimura et al. (2001)</a> identified a protein complex in normal human brain that includes parkin as the E3 ubiquitin ligase, UBCH7 (<a href="/entry/603721">603721</a>) as its associated E2 ubiquitin-conjugating enzyme, and a novel 22-kD glycosylated form of alpha-synuclein (alpha-Sp22) as its substrate. In contrast to normal parkin, mutant parkin associated with autosomal recessive Parkinson disease failed to bind alpha-Sp22. In an in vitro ubiquitination assay, alpha-Sp22 was modified by normal, but not mutant, parkin into polyubiquitinated, high molecular weight species. Accordingly, alpha-Sp22 accumulated in a nonubiquitinated form in parkin-deficient Parkinson disease brains. <a href="#34" class="mim-tip-reference" title="Shimura, H., Schlossmacher, M. G., Hattori, N., Frosch, M. P., Trockenbacher, A., Schneider, R., Mizuno, Y., Kosik, K. S., Selkoe, D. J. &lt;strong&gt;Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson&#x27;s disease.&lt;/strong&gt; Science 293: 263-269, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11431533/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11431533&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1060627&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11431533">Shimura et al. (2001)</a> concluded that alpha-Sp22 is a substrate for parkin's ubiquitin ligase activity in normal human brain and that loss of parkin function causes pathologic accumulation of alpha-Sp22. These findings demonstrated a critical biochemical reaction between the 2 Parkinson disease-linked gene products and suggested that this reaction underlies the accumulation of ubiquitinated alpha-synuclein in conventional Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431533" 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="#25" class="mim-tip-reference" title="Mortiboys, H., Thomas, K. J., Koopman, W. J. H., Klaffke, S., Abou-Sleiman, P., Olpin, S., Wood, N. W., Willems, P. H. G. M., Smeitink, J. A. M., Cookson, M. R., Bandmann, O. &lt;strong&gt;Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts.&lt;/strong&gt; Ann. Neurol. 64: 555-565, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19067348/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19067348&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19067348[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21492&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19067348">Mortiboys et al. (2008)</a> found that fibroblasts derived from PD patients with biallelic mutations in the PARK2 gene had significantly decreased mitochondrial complex I activity and ATP production compared to controls. Patient fibroblasts also showed altered morphology, including a greater degree of mitochondrial branching, as well as increased susceptibility to mitochondrial toxins. Complete knockdown of parkin using siRNA in control fibroblasts confirmed that the effects were due to parkin deficiency. In contrast, 50% knockdown of parkin, mimicking haploinsufficiency in humans, did not result in impaired mitochondrial function or morphology. Treatment with experimental neuroprotective glutathione replacement compounds resulted in restoration of the mitochondrial membrane potential. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19067348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Alcalay2010" class="mim-anchor"></a>
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<p class="mim-text-font">
Alcalay, R. N., Caccappolo, E., Mejia-Santana, H., Tang, M. X., Rosado, L., Ross, B. M., Verbitsky, M., Kisselev, S., Louis, E. D., Comella, C., Colcher, A., Jennings, D., and 21 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20837857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20837857</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20837857" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archneurol.2010.194" target="_blank">Full Text</a>]
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<a id="Alcalay2011" class="mim-anchor"></a>
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Alcalay, R. N., Siderowf, A., Ottman, R., Caccappolo, E., Mejia-Santana, H., Tang, M.-X., Rosado, L., Louis, E., Ruiz, D., Waters, C., Fahn, S., Cote, L., and 22 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21205674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21205674</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21205674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/WNL.0b013e31820882aa" target="_blank">Full Text</a>]
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<a id="Bonifati1994" class="mim-anchor"></a>
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Bonifati, V., Vanacore, N., Meco, G.
<strong>Anticipation of onset age in familial Parkinson's disease.</strong>
Neurology 44: 1978-1979, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7936260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7936260</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7936260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.44.10.1978" target="_blank">Full Text</a>]
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<a id="Chien2006" class="mim-anchor"></a>
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Chien, H. F., Rohe, C. F., Costa, M. D. L., Breedveld, G. J., Oostra, B. A., Barbosa, E. R., Bonifati, V.
<strong>Early-onset Parkinson's disease caused by a novel mutation in a genetic isolate from north-eastern Brazil.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16328510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16328510</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16328510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s10048-005-0017-x" target="_blank">Full Text</a>]
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<a id="Farrer2001" class="mim-anchor"></a>
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Farrer, M., Chan, P., Chen, R., Tan, L., Lincoln, S., Hernandez, D., Forno, L., Gwinn-Hardy, K., Petrucelli, L., Hussey, J., Singleton, A., Tanner, C., Hardy, J., Langston, J. W.
<strong>Lewy bodies and parkinsonism in families with parkin mutations.</strong>
Ann. Neurol. 50: 293-300, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11558785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11558785</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11558785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.1132" target="_blank">Full Text</a>]
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<a id="Foroud2003" class="mim-anchor"></a>
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Foroud, T., Uniacke, S. K., Liu, L., Pankratz, N., Rudolph, A., Halter, C., Shults, C., Marder, K., Conneally, P. M., Nichols, W. C., Parkinson Study Group.
<strong>Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease.</strong>
Neurology 60: 796-801, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12629236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12629236</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12629236" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/01.wnl.0000049470.00180.07" target="_blank">Full Text</a>]
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<a id="Hayashi2000" class="mim-anchor"></a>
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Hayashi, S., Wakabayashi, K., Ishikawa, A., Nagai, H.,, Saito, M., Maruyama, M., Takahashi, T., Ozawa, T., Tsuji, S., Takahashi, H.
<strong>An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene.</strong>
Mov. Disord. 15: 884-888, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11009195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11009195</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11009195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/1531-8257(200009)15:5&lt;884::aid-mds1019&gt;3.0.co;2-8" target="_blank">Full Text</a>]
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<a id="Hedrich2001" class="mim-anchor"></a>
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Hedrich, K., Kann, M., Lanthaler, A. J., Dalski, A., Eskelson, C., Landt, O., Schwinger, E., Vieregge, P., Lang, A. E., Breakefield, X. O., Ozelius, L. J., Pramstaller, P. P., Klein, C.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11487568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11487568</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11487568" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/10.16.1649" target="_blank">Full Text</a>]
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<a id="Hoenicka2002" class="mim-anchor"></a>
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Hoenicka, J., Vidal, L., Morales, B., Ampuero, I., Jimenez-Jimenez, F. J., Berciano, J., del Ser, T., Jimenez, A., Ruiz, P. G., de Yebenes, J. G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12056932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12056932</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12056932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archneur.59.6.966" target="_blank">Full Text</a>]
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<a id="Ishikawa1995" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ishikawa, A., Miyatake, T.
<strong>A family with hereditary juvenile dystonia-parkinsonism.</strong>
Mov. Disord. 10: 482-488, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7565830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7565830</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7565830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/mds.870100413" target="_blank">Full Text</a>]
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<a id="Ishikawa1996" class="mim-anchor"></a>
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<p class="mim-text-font">
Ishikawa, A., Tsuji, S.
<strong>Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism.</strong>
Neurology 47: 160-166, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8710071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8710071</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8710071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.47.1.160" target="_blank">Full Text</a>]
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<a id="Jones1998" class="mim-anchor"></a>
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Jones, A. C., Yamamura, Y., Almasy, L., Bohlega, S., Elibol, B., Hubble, J., Kuzuhara, S., Uchida, M., Yanagi, T., Weeks, D. E., Nygaard, T. G.
<strong>Autosomal recessive juvenile parkinsonism maps to 6q25.2-q27 in four ethnic groups: detailed genetic mapping of the linked region.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634534</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9634534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/301937" target="_blank">Full Text</a>]
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<a id="Kay2007" class="mim-anchor"></a>
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Kay, D. M., Moran, D., Moses, L., Poorkaj, P., Zabetian, C. P., Nutt, J., Factor, S. A., Yu, C.-E., Montimurro, J. S., Keefe, R. G., Schellenberg, G. D., Payami, H.
<strong>Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17187375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17187375</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17187375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.21039" target="_blank">Full Text</a>]
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<a id="Kay2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kay, D. M., Stevens, C. F., Hamza, T. H., Montimurro, J. S., Zabetian, C. P., Factor, S. A., Samii, A., Griffith, A., Roberts, J. W., Molho, E. S., Higgins, D. S., Gancher, S., Moses, L., Zareparsi, S., Poorkaj, P., Bird, T., Nutt, J., Schellenberg, G. D., Payami, H.
<strong>A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2.</strong>
Neurology 75: 1189-1194, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20876472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20876472</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20876472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/WNL.0b013e3181f4d832" target="_blank">Full Text</a>]
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<a id="Khan2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Khan, N. L., Scherfler, C., Graham, E., Bhatia, K. P., Quinn, N., Lees, A. J., Brooks, D. J., Wood, N. W., Piccini, P.
<strong>Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation.</strong>
Neurology 64: 134-136, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15642918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15642918</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15642918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/01.WNL.0000148725.48740.6D" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/33416" target="_blank">Full Text</a>]
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Klein, C., Pramstaller, P. P., Kis, B., Page, C. C., Kann, M., Leung, J., Woodward, H., Castellan, C. C., Scherer, M., Vieregge, P., Breakefield, X. O., Kramer, P. L., Ozelius, L. J.
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[<a href="https://doi.org/10.1002/ana.10613" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.57.5.924" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2010.95" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.50.5.1340" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0022-510x(94)90028-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.51.3.890" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.21492" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000171859.85078.3d" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30157" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.56.12.1759" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.44.3_part_1.437" target="_blank">Full Text</a>]
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Neurology 56: 555-557, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11222808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11222808</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11222808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.56.4.555" target="_blank">Full Text</a>]
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<a id="Wang2008" class="mim-anchor"></a>
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Wang, Y., Clark, L. N., Louis, E. D., Mejia-Santana, H., Harris, J., Cote, L. J., Waters, C., Andrews, H., Ford, B., Frucht, S., Fahn, S., Ottman, R., Rabinowitz, D., Marder, K.
<strong>Risk of Parkinson disease in carriers of parkin mutations: estimation using the kin-cohort method.</strong>
Arch. Neurol. 65: 467-474, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18413468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18413468</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18413468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archneur.65.4.467" target="_blank">Full Text</a>]
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<a id="Yamamura1973" class="mim-anchor"></a>
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<p class="mim-text-font">
Yamamura, Y., Sobue, I., Ando, K., Iida, M., Yanagi, T., Kono, C.
<strong>Paralysis agitans of early onset with marked diurnal fluctuation of symptoms.</strong>
Neurology 23: 239-244, 1973.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4735177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4735177</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4735177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.23.3.239" target="_blank">Full Text</a>]
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<a id="Zhu2022" class="mim-anchor"></a>
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Zhu, W., Huang, X., Yoon, E., Bandres-Ciga, S., Blauwendraat, C., Billingsley, K. J., Cade, J. H., Wu, B. P., Williams, V. H., Schindler, A. B., Brooks, J., Gibbs, J. R., Hernandez, D. G., Ehrlich, D., Singleton, A. B., Narendra, D. P.
<strong>Heterozygous PRKN mutations are common but do not increase the risk of Parkinson's disease.</strong>
Brain 145: 2077-2091, 2022.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35640906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35640906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35640906[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35640906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/brain/awab456" target="_blank">Full Text</a>]
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Sonja A. Rasmussen - updated : 01/31/2023
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Cassandra L. Kniffin - updated : 11/14/2011<br>Cassandra L. Kniffin - updated : 6/23/2011<br>Cassandra L. Kniffin - updated : 3/24/2011<br>Cassandra L. Kniffin - updated : 10/14/2009<br>Cassandra L. Kniffin - updated : 1/14/2009<br>Cassandra L. Kniffin - updated : 3/19/2008<br>Cassandra L. Kniffin - updated : 5/17/2006<br>Cassandra L. Kniffin - updated : 4/21/2006<br>Cassandra L. Kniffin - updated : 11/4/2005<br>Cassandra L. Kniffin - updated : 7/5/2005<br>Cassandra L. Kniffin - updated : 4/5/2005<br>Victor A. McKusick - updated : 1/19/2005<br>Cassandra L. Kniffin - updated : 1/5/2004<br>Cassandra L. Kniffin - reorganized : 9/11/2003<br>Cassandra L. Kniffin - updated : 11/8/2002<br>Victor A. McKusick - updated : 9/17/2002<br>Victor A. McKusick - updated : 1/22/1999<br>Orest Hurko - updated : 11/9/1998<br>Victor A. McKusick - updated : 7/17/1998<br>Victor A. McKusick - updated : 4/22/1998<br>Victor A. McKusick - updated : 4/6/1998<br>Victor A. McKusick - updated : 3/12/1997<br>Orest Hurko - updated : 11/24/1996
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Creation Date:
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Victor A. McKusick : 9/15/1994
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carol : 01/31/2023
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alopez : 03/07/2018<br>ckniffin : 02/28/2018<br>joanna : 08/04/2016<br>carol : 06/23/2016<br>carol : 11/16/2011<br>ckniffin : 11/14/2011<br>wwang : 6/29/2011<br>ckniffin : 6/23/2011<br>wwang : 4/12/2011<br>ckniffin : 3/24/2011<br>alopez : 1/4/2010<br>wwang : 11/13/2009<br>ckniffin : 10/14/2009<br>wwang : 1/16/2009<br>ckniffin : 1/14/2009<br>wwang : 3/31/2008<br>ckniffin : 3/19/2008<br>wwang : 5/24/2006<br>ckniffin : 5/17/2006<br>wwang : 4/26/2006<br>ckniffin : 4/21/2006<br>wwang : 11/22/2005<br>wwang : 11/15/2005<br>ckniffin : 11/4/2005<br>wwang : 7/11/2005<br>ckniffin : 7/5/2005<br>carol : 4/21/2005<br>wwang : 4/18/2005<br>ckniffin : 4/5/2005<br>alopez : 1/19/2005<br>tkritzer : 1/22/2004<br>ckniffin : 1/5/2004<br>ckniffin : 1/5/2004<br>carol : 9/11/2003<br>ckniffin : 9/5/2003<br>carol : 11/13/2002<br>ckniffin : 11/8/2002<br>carol : 10/29/2002<br>carol : 9/23/2002<br>tkritzer : 9/17/2002<br>tkritzer : 9/17/2002<br>alopez : 5/2/2002<br>alopez : 9/28/2001<br>alopez : 8/13/2001<br>terry : 8/13/2001<br>joanna : 6/18/2001<br>carol : 2/5/1999<br>terry : 1/22/1999<br>carol : 12/17/1998<br>carol : 12/3/1998<br>terry : 11/9/1998<br>carol : 7/21/1998<br>terry : 7/17/1998<br>carol : 5/2/1998<br>alopez : 4/22/1998<br>carol : 4/18/1998<br>terry : 4/6/1998<br>mark : 3/12/1997<br>mark : 3/12/1997<br>terry : 3/11/1997<br>mark : 11/24/1996<br>terry : 10/22/1996<br>mimadm : 9/23/1995<br>carol : 1/20/1995<br>carol : 1/13/1995<br>carol : 9/15/1994
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<strong>#</strong> 600116
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PARKINSON DISEASE 2, AUTOSOMAL RECESSIVE JUVENILE; PARK2
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<em>Alternative titles; symbols</em>
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PARKINSON DISEASE, JUVENILE, AUTOSOMAL RECESSIVE; PDJ<br />
PARKINSONISM, EARLY-ONSET, WITH DIURNAL FLUCTUATION; EPDF
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<strong>ORPHA:</strong> 2828; &nbsp;
<strong>DO:</strong> 0060368; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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6q26
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Parkinson disease, juvenile, type 2
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600116
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Autosomal recessive
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3
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PRKN
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602544
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that autosomal recessive juvenile Parkinson disease-2 (PARK2, or PDJ) is caused by homozygous or compound heterozygous mutation in the parkin gene (PARK2; 602544) on chromosome 6q26.</p><p>For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see PD (168600).</p>
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<strong>Clinical Features</strong>
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<p>An autosomal recessive form of familial juvenile parkinsonism, defined as onset before age 40 years, was described in a Japanese family by Takahashi et al. (1994). Juvenile-onset Parkinson disease is symptomatically different in several aspects from classic late-onset Parkinson disease (PD; 168600), although classic symptoms of PD, such as bradykinesia, rigidity, and tremor, are present. Takahashi et al. (1994) commented that the familial occurrence in Japanese PDJ patients with cases was approximately 40 to 50% and that the inheritance pattern appeared to be mostly autosomal recessive. They reported a family in which 4 of 5 sibs were affected and the parents were first cousins. A full pathologic examination of 1 of the sibs, a 67-year-old woman, was presented. The substantia nigra (SN) showed obvious neuronal loss and gliosis in the medial and ventrolateral regions. In the remainder of that region and in the locus ceruleus, the population of neurons was reduced and there was low melanin content in most of the neurons but no detectable gliosis or extraneuronal free melanin pigment suggestive of a neurodegenerative process. There were no Lewy bodies. The entire pathologic picture was different from that of Lewy body Parkinson disease (168601). This patient had been well until about the age of 10 years when gait disturbance appeared. By age 14, she was unable to walk long distances. By her forties, she was unable to walk without assistance. There was no evidence of dementia. She had been slow-moving and had shown frozen gait and tremor, more evident on motion, in the head and upper and lower limbs. She showed improvement of the movement disorder after waking up in the morning. When she was young, the improvement lasted until evening, but as she aged it became progressively shorter, eventually lasting only about 10 minutes. In the other sibs, gait disturbance began at the age of 8 or 9 years. One sister had died at age 42 years and a brother at the age of 27 years, both in a bedridden state. </p><p>Ishikawa and Tsuji (1996) described the clinical features of 17 patients from 12 Japanese families with familial juvenile parkinsonism. In 11 of these families affected members were products of consanguineous matings. All 12 families resided within the same geographic area, raising the possibility of founder effect. The mean age of onset was 27 years, with a range from 9 to 43. The most prominent symptoms were retropulsion, dystonia of the feet, and hyperreflexia with classic parkinsonism. Symptoms of tremor, rigidity, and bradykinesia were mild. Patients responded to levodopa but dopa-induced dyskinesias and wearing-off phenomena occurred frequently. </p><p>Bonifati et al. (1994) reported a man who presented with Parkinson disease at age 28. He was born of a consanguineous mating between a man who developed Parkinson disease at age 74 and his first cousin, who apparently was not affected with parkinsonian symptoms; however, the maternal grandfather developed Parkinson disease at age 65. Bonifati et al. (1994) speculated that the proband may have been homozygous for a defective Parkinson disease gene, which in heterozygous form gave rise to late-onset Parkinson disease in the affected father and maternal grandfather. </p><p>Mitsui et al. (1994) described a sister and a brother, the only offspring of a first-cousin mating, with atypical juvenile parkinsonism. They presented at age 38 and 40, respectively, with bradykinesia, cogwheel rigidity, and mild pyramidal and cerebellar signs. They were unresponsive to levodopa but responded very well to trihexyphenidyl, an anticholinergic drug. Mitsui et al. (1994) proposed that this was a new hereditary variant of early-onset Parkinson disease, distinct from the levodopa-sensitive form of juvenile Parkinson disease. They commented that responsiveness to anticholinergics but not levodopa may also be seen in Joseph disease (SCA3; 109150). MRI studies demonstrated atrophy of the cerebellar hemisphere and vermis, as well as high intensity areas in both pyramidal tracts. This juxtaposition of extrapyramidal and cerebellar signs usually results in classification of a disease as a multisystem atrophy or an olivopontocerebellar degeneration and is characteristic of many adult-onset spinocerebellar atrophies, most of which are transmitted as autosomal dominant traits. </p><p>Yamamura et al. (1973) reported familial cases of juvenile parkinsonism with marked diurnal fluctuation in symptoms. The disorder was found to show nigral cell loss and occurred in a setting of inbreeding; it undoubtedly represented a subtype of autosomal recessive juvenile parkinsonism (Nygaard, 1993). Matsumine et al. (1998) noted that early-onset parkinsonism with diurnal fluctuation (EPDF) is also a dopa-responsive form of parkinsonism and is associated with selective degeneration in the zona compacta of the substantia nigra without Lewy body formation. A distinguishing feature of this phenotype is a benefit from sleep with lessening of parkinsonian symptoms after awakening. </p><p>Portman et al. (2001) performed PET scans on 2 brothers with early-onset parkinsonism caused by mutations in the parkin gene and found marked reduction of fluorodopa (FDOPA) uptake in the caudate and putamen. Portman et al. (2001) noted that this was a different nigrostriatal dopaminergic pattern than that found in sporadic PD, thus suggesting a different pathophysiology for the early-onset disease. </p><p>Ohsawa et al. (2005) found that 8 of 9 patients with PARK2 mutations had significantly reduced sural sensory nerve action potential (SNAP) amplitude compared to 8 patients with idiopathic Parkinson disease. However, 6 PARK2 carriers had absence of decreased vibration sense in the foot, and only 2 had subjective sensory symptoms. Two patients with a presumptive diagnosis of idiopathic PD who showed a reduced SNAP amplitude were subsequently diagnosed with PARK2 as a result of DNA analysis. Ohsawa et al. (2005) suggested that reduced SNAP amplitude in patients with PD under 60 years of age may be a diagnostic indicator of PARK2 mutations, and concluded that sensory axonal neuropathy may be a common feature of the disorder. </p><p><strong><em>Pathologic Findings</em></strong></p><p>
Mori et al. (1998) reported neuropathologic findings in a patient with PARK2 confirmed by genetic analysis. The patient had disease onset at age 24 years and died from unrelated complications at age 62. Grossly, the substantia nigra showed marked depigmentation. Melanin-containing neurons in the pars compacta were moderately decreased, and neuronal loss and gliosis were especially marked in the ventrolateral and medial regions. Most of the remaining nigral neurons contained melanin pigments. The pars reticulata was spared. Lewy bodies were not identified. Neurofibrillary tangles and argyrophilic astrocytes were identified in the SN, the locus ceruleus, posterior hypothalamus, the hippocampus, and various cortical areas. However, the pattern was not consistent with Alzheimer disease. Tyrosine hydroxylase (191290) activity was markedly reduced in the caudate and putamen, and modestly reduced in the SN. </p><p>Hayashi et al. (2000) reported neuropathologic findings in a Japanese patient with a mutation in the PARK2 gene (602544.0002) who had previously been reported by Ishikawa and Miyatake (1995). Loss of pigmented neurons and gliosis were most pronounced in the medial and ventrolateral regions of the substantia nigra pars compacta and in the locus ceruleus. Remaining neurons had low amounts of melanin. There was mild neuronal loss and gliosis in the substantia nigra pars reticulata. No Lewy bodies were identified. Some neurofibrillary tangles and senile plaques were observed in the cerebral cortex, although there was no clinical evidence of dementia. </p><p>Van de Warrenburg et al. (2001) reported a Dutch family with PARK2 confirmed by genetic analysis. Neuropathologic examination of the proband showed depigmentation of the substantia nigra, with severe loss of pigmented neurons in the pars compacta, deposition of extraneuronal melanin, and mild gliosis. No Lewy bodies or neurofibrillary tangles were seen. However, there was a diffuse spread of tau (MAPT; 157140)-positive thorn-shaped astrocytes in the caudate, putamen, and subthalamic nucleus, and a few tau-positive astrocytes in the SN. </p><p>Farrer et al. (2001) reported a patient who was compound heterozygous for 2 mutations in the PARK2 gene. At autopsy, Lewy body pathology typical of idiopathic Parkinson disease was found, which was noted to be unusual for this form of parkinsonism. </p><p>Sasaki et al. (2004) reported neuropathologic examination of a patient with Parkinson disease due to homozygous exon 3 deletion in the PARK2 gene (602544.0005). The patient had disease onset at age 33 years and died of respiratory failure at age 70. The substantia nigra showed marked depigmentation, and melanin-containing neurons of the pars compacta were moderately to severely depleted, particularly in the ventrolateral group and medial part. Some dopaminergic neurons remained, but most were atrophic, and free melanin was observed. The pars reticulata of the SN was spared. In the locus ceruleus, neurons were mildly decreased, and free melanin was seen. Lewy bodies were not observed in the SN or locus ceruleus. There were alpha-synuclein-positive and ubiquitin-positive, round or donut-shaped inclusions in the neuropils of the pedunculopontine nucleus, but no such inclusions were seen in the SN, locus ceruleus, or subthalamic nucleus. The inclusions were somewhat basophilic, distinguishing them from Lewy bodies, which show an eosinophilic tint. No immunoreactivity to phosphorylated tau was seen in any region of the brain. Sasaki et al. (2004) suggested that a functioning parkin protein may be required for Lewy body formation. </p>
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<strong>Other Features</strong>
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<p>Olfactory impairment is one of the earliest manifestations of Parkinson disease and reflects Lewy body infiltration in the olfactory bulb and tract before the disease affects the substantia nigra. Alcalay et al. (2011) tested olfactory function in 44 probands with early-onset PD, including 9 with 2 parkin mutations, 10 with 1 parkin mutation, and 25 with PD without parkin mutations, as well as 80 of their family members without PD, including 18 with 1 parkin mutation, 2 with 2 parkin mutations, and 60 without parkin mutations. Among those with PD, patients with 2 parkin mutations had significantly better olfaction than patients with 1 parkin mutation or PD patients with no parkin mutation. Among those without PD, olfaction was similar in carriers of 1 parkin mutation and those without mutations, but better than PD patients with 1 parkin mutation. Alcalay et al. (2011) suggested that PD patients with parkin mutations have better olfaction compared to other PD patients, and also suggested that heterozygosity for 1 parkin mutation does not confer an increased risk of neuropathology. </p>
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<strong>Inheritance</strong>
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<p>Recessive homozygous mutations in the parkin gene result in early-onset Parkinson disease. Heterozygous mutations in the parkin gene have been identified in some patients with later onset disease, raising the possibility that heterozygous mutations may confer increased susceptibility to the disease. Wang et al. (2008) identified mutations in the parkin gene in 25 (10.1%) of 247 probands with disease onset before age 50. Eighteen patients had heterozygous mutations. Using a kin-cohort study design, which does not require information about mutation status, they estimated the cumulative incidence of PD to age 65 in relatives of mutation carriers to be 7.0%, compared to 1.7% in noncarrier relatives and 1.1% in relatives of controls. Wang et al. (2008) noted the limitations to their study, including the inability to assess risk of PD among heterozygotes separately and the low age of some relatives. </p>
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<strong>Mapping</strong>
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<p>By linkage analysis using a diallelic polymorphism of the manganese superoxide dismutase gene (SOD2; 147460), Matsumine et al. (1997) found perfect segregation of the disease with the SOD2 locus. By extending the linkage analysis to 13 families with autosomal recessive juvenile parkinsonism, they discovered strong evidence for the localization of the gene at 6q25.2-q27, including the SOD2 locus, with the maximum cumulative pairwise lod scores of 7.26 and 7.71 at D6S305 (theta = 0.03) and D6S253 (theta = 0.02), respectively. Nucleotide sequence analysis of the coding regions of the SOD2 gene did not show causative mutations, suggesting that another, as yet unidentified gene in this region is responsible for autosomal recessive juvenile parkinsonism. </p><p>In a group of 15 families from 4 distinct ethnic backgrounds, Jones et al. (1998) found that the locus for autosomal recessive juvenile parkinsonism in all mapped to 6q25.2-q27. A full genomic screen excluded other candidate regions. They constructed a detailed genetic map of the linked region and mapped the position of the SOD2 gene. Recombination events restricted the chromosome 6 Parkinson disease locus to a 6.9-cM region and excluded SOD2. Tassin et al. (1998) likewise found linkage of the gene for PDJ to 6q25.2-q27 in 1 Algerian and 10 European multiplex families. They found the clinical spectrum of the disease in these families, with age at onset up to 58 years and the presence of painful dystonia in some patients, to be broader than that reported previously. In all patients examined, 2 of the 3 cardinal signs of PD (akinesia, rigidity, and tremor) were found. Marked improvement with levodopa treatment occurred in all except 2 untreated secondary cases found in family studies. Age at onset was less than 40 years for at least 1 affected sib. </p><p>Saito et al. (1998) narrowed the assignment of the PARK2 locus to a 4-cM region encompassing D6S1579 and D6S1599. </p><p>Matsumine et al. (1998) demonstrated that the disorder reported by Yamamura et al. (1973) (EPDF) showed linkage to the same region on chromosome 6 as did autosomal recessive juvenile Parkinson disease. In studies of 17 families with EPDF, they found a peak lod score of 14.2 at 1.0 cM telomeric to D6S305 and placed the disease locus in the 17-cM interval between D6S437 and D6S253, which is exactly the same position to which PDJ had been mapped. </p>
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<strong>Molecular Genetics</strong>
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</div>
<span class="mim-text-font">
<p>In several patients with PDJ, Kitada et al. (1998) identified deletions in the PARK2 gene (see, e.g., 602544.0001). </p><p>Hoenicka et al. (2002) found 5 different mutations in the PARK2 gene in 5 of 13 Spanish families with recessive inheritance. Two of the mutations were novel (602544.0013 and 602544.0012). Hoenicka et al. (2002) found 2 simple heterozygous PARK2 mutation carriers who developed clinical symptoms, either in late adulthood or after brief exposure to parkinsonizing agents. The authors suggested that heterozygosity may be a risk factor for PD. In 14 other Spanish kindreds with familial PD, 8 autosomal recessive, 4 autosomal dominant and 2 of uncertain inheritance, Hoenicka et al. (2002) found no mutations in the alpha-synuclein (SNCA; 163890) or UCHL1 (191342) genes related to PARK1 (168601) and PARK5 (191342), respectively. </p><p>Lucking et al. (2001) described an Italian family in which parkinsonism was associated with mutations in the PARK2 gene in a pseudodominant pattern of inheritance. The father (with disease onset at age 57 years) was homozygous for a triplication of exon 2, a previously undescribed mutation. The unaffected mother was heterozygous for deletions of exons 3 and 4, and the son (with disease onset at age 31 years) was a compound heterozygote carrying both mutations. </p><p>In 10 affected members of a consanguineous Brazilian family with early-onset parkinsonism, Chien et al. (2006) identified a homozygous splice site mutation in the PARK2 gene (602544.0020). The family was from an isolated region in northeastern Brazil, and their ancestors had originated from Portugal. One individual who was heterozygous for the mutation developed neuroleptic-induced parkinsonism, suggesting that haploinsufficiency was a predisposing factor. </p><p>Kay et al. (2007) found that heterozygous parkin mutations were as common in 301 controls as in 302 PD patients, and they replicated the finding in an independent set of 1,260 PD patients and 1,657 controls. Thirty-four variants, including 21 novel variants, were identified. Kay et al. (2007) concluded that heterozygous mutations in the parkin gene are not likely to contribute to the development of Parkinson disease. Quantitative gene dosage was not examined. </p><p>Alcalay et al. (2010) identified mutations in the PARK2 gene in 64 (6.7%) of 953 patients with early-onset PD before age 51, including 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. Thirty-three patients had a heterozygous PARK2 mutation, and 27 had homozygous or compound heterozygous mutations. Four of 64 patients had a PARK2 mutation and another mutation in the LRRK2 (609007) or GBA (606463) genes. Hispanic individuals were more likely to be PARK2 mutation carriers than non-Hispanic individuals (15.6% vs 5.9%; p = 0.003). Marder et al. (2010) examined the same dataset reported by Alcalay et al. (2010), with specific focus on PARK2 mutation carriers. Of the 64 patients with parkin mutations, 37 were heterozygous (including 4 with mutations in other genes), 6 homozygous, and 21 compound heterozygous. Compound heterozygous and homozygous carriers had a significantly younger age at onset compared to heterozygous carriers. Significant associations were found between parkin mutation carrier status and Hispanic origin (odds ratio (OR) of 2.7), younger age at onset (less than 40 years) (OR of 5.0), and family history of PD in a first-degree relative (OR of 2.8). Deletions in exons 3 and 4 and 255delA (602544.0014) were common among Hispanics, specifically Puerto Ricans. In addition, those with heterozygous parkin mutations had younger age at onset compared to PD patients without parkin mutations, suggesting that heterozygosity is a susceptibility factor for disease development. </p><p>Kay et al. (2010) identified heterozygous copy number variations (CNV) in the parkin gene in 0.95% of 1,686 controls and 0.86% of 2,091 PD patients, suggesting that heterozygous PARK2 CNV mutations are not associated with PD risk. </p><p>To examine the effects of heterozygous mutations in the PRKN gene on the risk of Parkinson disease, Zhu et al. (2022) examined 2 large cohorts: an NIH Parkinson disease control cohort with whole-exome screening data, and the UK Biobank cohort with whole-exome sequencing and genotyping array data. Using the NIH cohort, the authors validated genotyping array screening for the detection of patients with biallelic PRKN mutations. Functional assays performed on patients from the NIH cohort were able to rule out second cryptic variants in patients with one heterozygous pathogenic mutation. Using the UK Biobank data, they found that 1.8% of participants had 1 pathogenic PRKN variant and 1/7800 participants had biallelic variants. Those with 1 PRKN pathologic variant were equally as likely as noncarriers to have Parkinson disease or a parent with Parkinson disease, providing evidence that heterozygosity for pathogenic PRKN mutations does not increase the risk of Parkinson disease. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
For discussion of a possible association between autosomal recessive juvenile-onset Parkinson disease and variation in the PODXL gene, see 602632.0002.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Foroud et al. (2003) identified 25 different parkin mutations in 103 affected individuals from 47 families with PD, including 41 individuals with mutations in both alleles and 62 individuals with a single mutation in only 1 allele. Individuals with 2 parkin mutations had an earlier age at disease onset and longer disease duration than those with 1 mutation. Thirty-five subjects (35%) with a parkin mutation had an age at onset of 60 years or above, with 30 of these 35 having only 1 mutant allele. The authors concluded that mutations in the parkin gene occur among individuals with PD with an older age at onset (greater than 60 years) who have a positive family history of the disease. </p><p>In 16 of 307 (5%) families with PD, Oliveira et al. (2003) identified mutations in the parkin gene, which included 18% of all early-onset and 2% of all late-onset families. Three families were homozygous, 3 families were compound heterozygous, and in 10 families, all the patients had heterozygous mutations. The results showed that mutations in exon 7 were observed primarily in heterozygous PD patients with a later age at onset. Oliveira et al. (2003) concluded that mutations in the parkin gene contribute to the common form of PD, and that heterozygous mutations act as susceptibility alleles for the late-onset form of PD. </p><p>Lohmann et al. (2003) compared 146 PD patients with parkin mutations to 250 PD patients without parkin mutations; they found that patients with the parkin mutations had a significantly earlier and more symmetric onset, a slower progression of disease, and a tendency toward greater response to L-DOPA despite lower doses. However, both groups had a similar wide range for age at onset (7 to 70 years and 12 to 76 years, respectively). In families with autosomal recessive parkinsonism, more than 80% of patients with an age at onset of 20 years or younger had parkin mutations, compared to 28% of those between the ages of 46 and 55 years. Carriers of at least 1 parkin missense mutation had a more severe phenotype than those with 2 truncating mutations, suggesting that missense mutations result in more than a loss of function. Patients with a single heterozygous parkin mutation had significantly later and more asymmetric onset and more frequent L-DOPA-induced difficulties than those with 2 parkin mutations. </p><p>Poorkaj et al. (2004) undertook a study to determine whether patients with early-onset PD should be screened for parkin mutations as part of their clinical workup. Patients with a diagnosis of PD and onset at or before 40 years of age were selected for genotyping by sequence and dosage analysis for all 12 exons. Mutations were found in 7 of 39 patients. Two of these were compound heterozygous; 5 were heterozygous. Early-onset PD accounted for 10% of PD patients, and 18% of the early-onset patients had parkin mutations. Assuming a strictly recessive inheritance, only 5% of early-onset cases had a pathogenic parkin genotype. The remaining 13% were heterozygous, and whether heterozygous parkin mutations were the cause of early-onset PD in these patients was unclear. </p><p>Using PET scan, Khan et al. (2005) found that 13 asymptomatic heterozygous carriers of a PARK2 mutation had significantly decreased fluorodopa uptake in the caudate, putamen, and ventral and dorsal midbrain compared to controls. Four of the heterozygous carriers had subtle extrapyramidal signs. Khan et al. (2005) concluded that parkin heterozygosity is a risk factor for nigrostriatal dysfunction and suggested that parkin heterozygosity may contribute to late-onset PD. </p><p>Klein et al. (2000) reported a large kindred from a remote village in the Western Alps of South Tyrol in northern Italy affected with adult-onset Parkinson disease inherited in an autosomal dominant pattern. The clinical features were indistinguishable from idiopathic Parkinson disease, and none of the patients demonstrated typical features of PARK2, such as diurnal fluctuation, sleep benefit, foot dystonia, hyperreflexia, or early susceptibility to levodopa-induced dyskinesias. Haplotype analysis implicated the parkin locus on chromosome 6q. Molecular analysis showed that 4 affected male sibs were compound heterozygous for 2 deletions in the PARK2 gene: a large deletion, which was later determined by Hedrich et al. (2001) to be a deletion of only exon 7 (602544.0010), and a 1-bp deletion in exon 9 (602544.0019). Two affected females were heterozygous for the 1-bp deletion. Klein et al. (2000) concluded that the phenotypic spectrum associated with mutations in the PARK2 gene are broad and that PARK2 may play a role in the etiology of late-onset typical PD. Pramstaller et al. (2005) provided detailed clinical and molecular follow-up of the family reported by Klein et al. (2000). Ancestors could be traced back to the year 1657; relevant clinical data were obtained from 196 individuals spanning 7 generations. The mean age at onset was 52.8 years, but ranged from 20 to 76 years. Five of 25 definitely affected individuals were found to be compound heterozygous for the 2 previously identified PARK2 deletions; 8 patients had only 1 of these deletions; the mutational status of 5 deceased patients was unknown; and 7 patients had no PARK2 mutations. Patients who were compound heterozygous had earlier onset than those with heterozygous mutations. Pramstaller et al. (2005) concluded that heterozygous mutations in the PARK2 gene contribute to idiopathic PD. Postmortem analysis of 1 of the patients reported by Pramstaller et al. (2005) with both PARK2 mutations showed SNCA-positive Lewy bodies. </p><p>Zhu et al. (2022) compared phenotypes among patients with idiopathic Parkinson disease, patients with heterozygous PRKN variants, and patients with biallelic PRKN variants consistent with PARK2. Age of onset was significantly younger and standardized testing of olfaction was better among patients with biallelic mutations than for patients with idiopathic Parkinson disease and heterozygous PRKN groups. Age of onset of PRKN biallelic patients was 38 years of age or younger. In contrast, standard cognitive assessment and an assessment of disease severity were not significantly different among the groups. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Kitada et al. (1998) suggested that parkin may function similarly to ubiquitin family members, and its defect in PDJ may interfere with the ubiquitin-mediated proteolytic pathway leading to the death of nigral neurons. </p><p>Shimura et al. (2001) hypothesized that alpha-synuclein and parkin interact functionally, namely, that parkin ubiquitinates alpha-synuclein normally and that this process is altered in autosomal recessive Parkinson disease. Shimura et al. (2001) identified a protein complex in normal human brain that includes parkin as the E3 ubiquitin ligase, UBCH7 (603721) as its associated E2 ubiquitin-conjugating enzyme, and a novel 22-kD glycosylated form of alpha-synuclein (alpha-Sp22) as its substrate. In contrast to normal parkin, mutant parkin associated with autosomal recessive Parkinson disease failed to bind alpha-Sp22. In an in vitro ubiquitination assay, alpha-Sp22 was modified by normal, but not mutant, parkin into polyubiquitinated, high molecular weight species. Accordingly, alpha-Sp22 accumulated in a nonubiquitinated form in parkin-deficient Parkinson disease brains. Shimura et al. (2001) concluded that alpha-Sp22 is a substrate for parkin's ubiquitin ligase activity in normal human brain and that loss of parkin function causes pathologic accumulation of alpha-Sp22. These findings demonstrated a critical biochemical reaction between the 2 Parkinson disease-linked gene products and suggested that this reaction underlies the accumulation of ubiquitinated alpha-synuclein in conventional Parkinson disease. </p><p>Mortiboys et al. (2008) found that fibroblasts derived from PD patients with biallelic mutations in the PARK2 gene had significantly decreased mitochondrial complex I activity and ATP production compared to controls. Patient fibroblasts also showed altered morphology, including a greater degree of mitochondrial branching, as well as increased susceptibility to mitochondrial toxins. Complete knockdown of parkin using siRNA in control fibroblasts confirmed that the effects were due to parkin deficiency. In contrast, 50% knockdown of parkin, mimicking haploinsufficiency in humans, did not result in impaired mitochondrial function or morphology. Treatment with experimental neuroprotective glutathione replacement compounds resulted in restoration of the mitochondrial membrane potential. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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</p>
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<p class="mim-text-font">
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Portman, A. T., Giladi, N., Leenders, K. L., Maguire, P., Veenma-van der Duin, L., Swart, J., Pruim, J., Simon, E. S., Hassin-Baer, S., Korczyn, A. D.
<strong>The nigrostriatal dopaminergic system in familial early onset parkinsonism with parkin mutations.</strong>
Neurology 56: 1759-1762, 2001.
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Pramstaller, P. P., Schlossmacher, M. G., Jacques, T. S., Scaravilli, F., Eskelson, C., Pepivani, I., Hedrich, K., Adel, S., Gonzales-McNeal, M., Hilker, R., Kramer, P. L., Klein, C.
<strong>Lewy body Parkinson&#x27;s disease in a large pedigree with 77 parkin mutation carriers.</strong>
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Saito, M., Matsumine, H., Tanaka, H., Ishikawa, A., Shimoda-Matsubayashi, S., Schaffer, A. A., Mizuno, Y., Tsuji, S.
<strong>Refinement of the gene locus for autosomal recessive juvenile parkinsonism (AR-JP) on chromosome 6q25.2-27 and identification of markers exhibiting linkage disequilibrium.</strong>
J. Hum. Genet. 43: 22-31, 1998.
[PubMed: 9609994]
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Sasaki, S., Shirata, A., Yamane, K., Iwata, M.
<strong>Parkin-positive autosomal recessive juvenile parkinsonism with alpha-synuclein-positive inclusions.</strong>
Neurology 63: 678-682, 2004.
[PubMed: 15326242]
[Full Text: https://doi.org/10.1212/01.wnl.0000134657.25904.0b]
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Shimura, H., Schlossmacher, M. G., Hattori, N., Frosch, M. P., Trockenbacher, A., Schneider, R., Mizuno, Y., Kosik, K. S., Selkoe, D. J.
<strong>Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson&#x27;s disease.</strong>
Science 293: 263-269, 2001.
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Takahashi, H., Ohama, E., Suzuki, S., Horikawa, Y., Ishikawa, A., Morita, T., Tsuji, S., Ikuta, F.
<strong>Familial juvenile parkinsonism: clinical and pathologic study in a family.</strong>
Neurology 44: 437-441, 1994.
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Tassin, J., Durr, A., de Broucker, T., Abbas, N., Bonifati, V., De Michele, G., Bonnet, A.-M., Broussolle, E., Pollak, P., Vidailhet, M., De Mari, M., Marconi, R., Medjbeur, S., Filla, A., Meco, G., Agid, Y., Brice, A., French Parkinson's Disease Genetics Study Group, European Consortium on Genetic Susceptibility in Parkinson's Disease.
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<strong>Paralysis agitans of early onset with marked diurnal fluctuation of symptoms.</strong>
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Sonja A. Rasmussen - updated : 01/31/2023<br>Cassandra L. Kniffin - updated : 11/14/2011<br>Cassandra L. Kniffin - updated : 6/23/2011<br>Cassandra L. Kniffin - updated : 3/24/2011<br>Cassandra L. Kniffin - updated : 10/14/2009<br>Cassandra L. Kniffin - updated : 1/14/2009<br>Cassandra L. Kniffin - updated : 3/19/2008<br>Cassandra L. Kniffin - updated : 5/17/2006<br>Cassandra L. Kniffin - updated : 4/21/2006<br>Cassandra L. Kniffin - updated : 11/4/2005<br>Cassandra L. Kniffin - updated : 7/5/2005<br>Cassandra L. Kniffin - updated : 4/5/2005<br>Victor A. McKusick - updated : 1/19/2005<br>Cassandra L. Kniffin - updated : 1/5/2004<br>Cassandra L. Kniffin - reorganized : 9/11/2003<br>Cassandra L. Kniffin - updated : 11/8/2002<br>Victor A. McKusick - updated : 9/17/2002<br>Victor A. McKusick - updated : 1/22/1999<br>Orest Hurko - updated : 11/9/1998<br>Victor A. McKusick - updated : 7/17/1998<br>Victor A. McKusick - updated : 4/22/1998<br>Victor A. McKusick - updated : 4/6/1998<br>Victor A. McKusick - updated : 3/12/1997<br>Orest Hurko - updated : 11/24/1996
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Victor A. McKusick : 9/15/1994
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