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Entry
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- #256600 - NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2A; NBIA2A
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- OMIM
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<p>
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<span class="h4">#256600</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/256600"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS234200"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#heterogeneity">Heterogeneity</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-row">
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=NEURODEGENERATION WITH BRAIN IRON ACCUMULATION" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=10365&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="#mimGeneReviewsFold" id="mimGeneReviewsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling."><span id="mimGeneReviewsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Gene Reviews</div>
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<div id="mimGeneReviewsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK121988/" title="Neurodegeneration with Brain Iron Accumulation Disorders Overview" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Neurodegeneration with Bra…</a></div><div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1675/" title="PLA2G6-Associated Neurodegeneration" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">PLA2G6-Associated Neurodeg…</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/infantile-neuroaxonal-dystrophy" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=256600[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=35069" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/f4d8b8a9-74b3-45f3-8f2d-9d76f251d4a0/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0110735" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/256600" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/OMIA002105/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0110735" 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">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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</span>
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</span>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:256600" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 52713000<br />
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<strong>ORPHA:</strong> 35069<br />
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<strong>DO:</strong> 0110735<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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256600
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</span>
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</span>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2A; NBIA2A
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</h3>
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</div>
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<div>
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|
<br />
|
|
</div>
|
|
|
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|
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<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">
|
|
NEURODEGENERATION, PLA2G6-ASSOCIATED; PLAN<br />
|
|
NEUROAXONAL DYSTROPHY, INFANTILE; INAD; INAD1<br />
|
|
SEITELBERGER DISEASE
|
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</span>
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<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/22/268?start=-3&limit=10&highlight=268">
|
|
22q13.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Infantile neuroaxonal dystrophy 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/256600"> 256600 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
PLA2G6
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603604"> 603604 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/256600" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS234200" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/256600" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/256600" 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>
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|
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<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>
|
|
|
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|
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|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Developmental delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
|
|
Psychomotor regression, progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850493&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850493</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002376</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002376</a>]</span><br /> -
|
|
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
|
|
Generalized weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13791008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13791008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M62.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M62.81</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R53.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R53.81</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R53.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R53.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.3</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/728.87" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">728.87</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0746674&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0746674</a>, <a href="https://bioportal.bioontology.org/search?q=C3714552&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714552</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003324</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003324</a>]</span><br /> -
|
|
Gait instability <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22631008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22631008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0231686&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0231686</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002317" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002317</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002317" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002317</a>]</span><br /> -
|
|
Ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20262006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20262006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39384006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39384006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.84</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004134</a>, <a href="https://bioportal.bioontology.org/search?q=C1135207&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1135207</a>, <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0010867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010867</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br /> -
|
|
Pyramidal tract signs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14648003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14648003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234132&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234132</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span><br /> -
|
|
Spastic tetraplegia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/192965001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">192965001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0426970&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0426970</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002510</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002510</a>]</span><br /> -
|
|
Hyperreflexia (70%) <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">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151889</a> 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> <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 /> -
|
|
Areflexia (30%) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/37280007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">37280007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234146</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001284" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001284</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001284" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001284</a>]</span><br /> -
|
|
Mental retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a>, <a href="https://bioportal.bioontology.org/search?q=C0025362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
|
|
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
|
|
Autonomic involvement may occur <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850495&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850495</a>]</span><br /> -
|
|
Cerebral atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/278849000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">278849000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235946&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235946</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span><br /> -
|
|
Cerebellar atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0740279&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0740279</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001272" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001272</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001272" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001272</a>]</span><br /> -
|
|
Neuronal loss <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850496&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850496</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002529" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002529</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002529" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002529</a>]</span><br /> -
|
|
Gliosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/359580009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">359580009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81415000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81415000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3887640&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887640</a>, <a href="https://bioportal.bioontology.org/search?q=C0017639&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017639</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002171" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002171</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002446" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002446</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002171" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002171</a>]</span><br /> -
|
|
Axonal dystrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230365004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230365004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0338473&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0338473</a>]</span><br /> -
|
|
Axonal swelling or thickening <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850498&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850498</a>]</span><br /> -
|
|
Axonal 'spheroid' inclusions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850499&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850499</a>]</span><br /> -
|
|
High voltage, fast rhythms seen on EEG <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806475&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806475</a>]</span><br /> -
|
|
Cerebellar atrophy with signal hyperintensity in the cerebellar cortex seen on T2-weighted MRI <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806476&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806476</a>]</span><br /> -
|
|
Increased iron deposition in the basal ganglia (40%) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675364&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675364</a>]</span><br /> -
|
|
Thin optic chiasm <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850503&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850503</a>]</span><br />
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</span>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
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<em> Peripheral Nervous System </em>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
|
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|
|
- Decreased nerve conduction velocities (NCV) (30%) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857640&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857640</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000762" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000762</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000762" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000762</a>]</span><br /> -
|
|
Chronic denervation seen on EMG <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3550584&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3550584</a>]</span><br /> -
|
|
Axonal dystrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230365004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230365004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0338473&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0338473</a>]</span><br /> -
|
|
Axonal swelling or thickening <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850498&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850498</a>]</span><br /> -
|
|
Axonal 'spheroid' inclusions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850499&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850499</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<div>
|
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<span class="mim-font">
|
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|
|
- Characteristic spheroids can be found in peripheral tissue, such as skin and conjunctiva <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850505&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850505</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
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<strong> MISCELLANEOUS </strong>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<div>
|
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<span class="mim-font">
|
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|
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- Onset usually in infancy or up to 2 years of age although later onset has been reported ('late-infantile')<br /> -
|
|
Death usually by age 10 years<br /> -
|
|
Allelic disorder to neurodegeneration with brain iron accumulation 2B (NBIA2B, <a href="/entry/610217">610217</a>)<br /> -
|
|
Phenotypic overlap with PKAN neuroaxonal dystrophy (NBIA1, <a href="/entry/234200">234200</a>)<br />
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</span>
|
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
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<strong> MOLECULAR BASIS </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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|
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<div>
|
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<span class="mim-font">
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|
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- Caused by mutation in the phospholipase A2, group VI gene (PLA2G6, <a href="/entry/603604#0001">603604.0001</a>)<br />
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</span>
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</div>
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</div>
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</div>
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<div class="text-right">
|
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
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</div>
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</div>
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small">
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<div class="row">
|
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
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<h5>
|
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Neurodegeneration with brain iron accumulation
|
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- <a href="/phenotypicSeries/PS234200">PS234200</a>
|
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- 10 Entries
|
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</h5>
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</div>
|
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</div>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
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<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
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</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
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<strong>Phenotype</strong>
|
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</th>
|
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
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<strong>Inheritance</strong>
|
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</th>
|
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<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>
|
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</tr>
|
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</thead>
|
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<tbody>
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<span class="mim-font">
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<a href="/geneMap/6/906?start=-3&limit=10&highlight=906"> 6q24.1 </a>
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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/617916"> ?Neurodegeneration with brain iron accumulation 7 </a>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/617916"> 617916 </a>
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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/614825"> REPS1 </a>
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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/614825"> 614825 </a>
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</span>
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<span class="mim-font">
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<a href="/geneMap/9/564?start=-3&limit=10&highlight=564"> 9q34.11 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/617917"> ?Neurodegeneration with brain iron accumulation 8 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/617917"> 617917 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/600184"> CRAT </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/600184"> 600184 </a>
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</span>
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<td>
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<span class="mim-font">
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<a href="/geneMap/11/468?start=-3&limit=10&highlight=468"> 11q12.3 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/620669"> Neurodegeneration with brain iron accumulation 9 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/620669"> 620669 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/134770"> FTH1 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/134770"> 134770 </a>
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/17/581?start=-3&limit=10&highlight=581"> 17q21.2 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/615643"> Neurodegeneration with brain iron accumulation 6 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/615643"> 615643 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/609855"> COASY </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/609855"> 609855 </a>
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/19/526?start=-3&limit=10&highlight=526"> 19q12 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614298"> Neurodegeneration with brain iron accumulation 4 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614298"> 614298 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614297"> C19orf12 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614297"> 614297 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/19/920?start=-3&limit=10&highlight=920"> 19q13.33 </a>
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</span>
|
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</td>
|
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<td>
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<span class="mim-font">
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<a href="/entry/606159"> Neurodegeneration with brain iron accumulation 3 </a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
|
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/606159"> 606159 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/134790"> FTL </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/134790"> 134790 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/20/64?start=-3&limit=10&highlight=64"> 20p13 </a>
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</span>
|
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</td>
|
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<td>
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<span class="mim-font">
|
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<a href="/entry/234200"> Neurodegeneration with brain iron accumulation 1 </a>
|
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</span>
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</td>
|
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/234200"> 234200 </a>
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/606157"> PANK2 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/606157"> 606157 </a>
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/22/268?start=-3&limit=10&highlight=268"> 22q13.1 </a>
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
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<a href="/entry/256600"> Infantile neuroaxonal dystrophy 1 </a>
|
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</span>
|
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</td>
|
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/256600"> 256600 </a>
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</span>
|
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/603604"> PLA2G6 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/603604"> 603604 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/22/268?start=-3&limit=10&highlight=268"> 22q13.1 </a>
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</span>
|
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/610217"> Neurodegeneration with brain iron accumulation 2B </a>
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</span>
|
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/610217"> 610217 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/603604"> PLA2G6 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/603604"> 603604 </a>
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/X/270?start=-3&limit=10&highlight=270"> Xp11.23 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/300894"> Neurodegeneration with brain iron accumulation 5 </a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/300894"> 300894 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/300526"> WDR45 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/300526"> 300526 </a>
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</span>
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</td>
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</tbody>
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</table>
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</div>
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<div class="text-right small">
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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</div>
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<div>
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<br />
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because this form of neurodegeneration with brain iron accumulation (NBIA), referred to here as 'NBIA2A,' is caused by homozygous or compound heterozygous mutation in the PLA2G6 gene (<a href="/entry/603604">603604</a>) on chromosome 22q13. See NOMENCLATURE section.</p><p>See also NBIA2B (<a href="/entry/610217">610217</a>), an overlapping disorder with later onset.</p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Neurodegeneration with brain iron accumulation-2A (NBIA2A) is an autosomal recessive neurodegenerative disease characterized by onset in the first 2 years of life; it is also referred to as infantile neuroaxonal dystrophy (INAD). Pathologic findings include axonal swelling and spheroid bodies in the central nervous system (review by <a href="#8" class="mim-tip-reference" title="Gregory, A., Polster, B. J., Hayflick, S. J. <strong>Clinical and genetic delineation of neurodegeneration with brain iron accumulation.</strong> J. Med. Genet. 46: 73-80, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18981035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18981035</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18981035[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2008.061929" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18981035">Gregory et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18981035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (<a href="/entry/234200">234200</a>).</p>
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<br />
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<div>
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#24" class="mim-tip-reference" title="Seitelberger, F. <strong>Eine unbekannte Form von infantiler lipoid-Speicher Krankheit des Gehirns. Proc. 1st Int. Cong. of Neuropathology, Rome, Sept. 8-13, 1952. Vol. 3.</strong> Turin: Rosenberg and Sellier (pub.) 1954. Pp. 323-333."None>Seitelberger (1954)</a> first described this infantile form of degenerative encephalopathy characterized pathologically by lipid storage in the brain. Visceral changes were described by <a href="#3" class="mim-tip-reference" title="Cowen, D., Olmstead, E. V. <strong>Infantile neuroaxonal dystrophy.</strong> J. Neuropath. Exp. Neurol. 22: 175-236, 1963.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14023529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14023529</a>] [<a href="https://doi.org/10.1097/00005072-196304000-00001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14023529">Cowen and Olmstead (1963)</a> and by <a href="#22" class="mim-tip-reference" title="Sandbank, U. <strong>Infantile neuroaxonal dystrophy.</strong> Arch. Neurol. 12: 155-159, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14237772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14237772</a>] [<a href="https://doi.org/10.1001/archneur.1965.00460260045005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14237772">Sandbank (1965)</a>. The changes in the brain are widespread focal swelling and degeneration of axons with scattered 'spheroids' (<a href="#3" class="mim-tip-reference" title="Cowen, D., Olmstead, E. V. <strong>Infantile neuroaxonal dystrophy.</strong> J. Neuropath. Exp. Neurol. 22: 175-236, 1963.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14023529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14023529</a>] [<a href="https://doi.org/10.1097/00005072-196304000-00001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14023529">Cowen and Olmstead, 1963</a>). <a href="#4" class="mim-tip-reference" title="Crome, L., Weller, S. D. V. <strong>Infantile neuroaxonal dystrophy.</strong> Arch. Dis. Child. 40: 502-507, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5829994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5829994</a>] [<a href="https://doi.org/10.1136/adc.40.213.502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5829994">Crome and Weller (1965)</a> described a brother and sister, who died at 12 and 18 months, respectively, with mental retardation, paralysis, and epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14237772+5829994+14023529" 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="Scheithauer, B. W., Forno, L. S., Dorfman, L. J., Kane, C. A. <strong>Neuroaxonal dystrophy (Seitelberger's disease) with late onset, protracted course and myoclonic epilepsy.</strong> J. Neurol. Sci. 36: 247-258, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/418153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">418153</a>] [<a href="https://doi.org/10.1016/0022-510x(78)90085-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="418153">Scheithauer et al. (1978)</a> described 2 affected brothers with severe progressive myoclonic epilepsy. One brother had onset at age 10 years and death at age 23 years. Postmortem examination showed widespread and marked neuroaxonal dystrophy, severe cerebellar atrophy, and degeneration of the lateral corticospinal tracts. There was no increased pigmentation in the globus pallidus or substantia nigra, which distinguished the disorder from PKAN (NBIA1; <a href="/entry/234200">234200</a>). The authors suggested that the case was a 'juvenile form' of neuroaxonal dystrophy. The same cases were reported by <a href="#5" class="mim-tip-reference" title="Dorfman, L. J., Pedley, T. A., Thorp, B. R., Scheithauer, B. W. <strong>Juvenile neuroaxonal dystrophy: clinical, electrophysiological, and neuropathological features.</strong> Ann. Neurol. 3: 419-428, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/103487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">103487</a>] [<a href="https://doi.org/10.1002/ana.410030511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="103487">Dorfman et al. (1978)</a>, who noted intellectual deterioration and cerebellar ataxia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=418153+103487" 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="#15" class="mim-tip-reference" title="Malmstrom-Groth, A. G., Kristensson, K. <strong>Neuroaxonal dystrophy in childhood: report of two second cousins with Hallervorden-Spatz disease, and a case of Seitelberger's disease.</strong> Acta Paediat. Scand. 71: 1045-1049, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7158329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7158329</a>] [<a href="https://doi.org/10.1111/j.1651-2227.1982.tb09574.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7158329">Malmstrom-Groth and Kristensson (1982)</a> described the first case to be reported in Scandinavia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7158329" 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="Nagashima, K., Suzuki, S., Ichikawa, E., Uchida, S., Honma, T., Kuroume, T., Hirato, J., Ogawa, A., Ishida, Y. <strong>Infantile neuroaxonal dystrophy: perinatal onset with symptoms of diencephalic syndrome.</strong> Neurology 35: 735-738, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2986047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2986047</a>] [<a href="https://doi.org/10.1212/wnl.35.5.735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2986047">Nagashima et al. (1985)</a> reported a rare neonatal form which probably had its beginnings in utero. Poor sucking, hypotonia, pendulous nystagmus, keratitis sicca with little tearing, and feeble tendon reflexes were noted soon after birth. By age 7 months he had constipation and urinary retention. By 8 months hypothalamic hypothyroidism and diabetes insipidus were demonstrated. Fever suggested a disorder of temperature regulation. At autopsy, spheroid bodies were widely distributed, particularly in the hypothalamus, infundibulum, and neurohypophysis, but also in the myenteric plexus of the colon. <a href="#11" class="mim-tip-reference" title="Hunter, A. G. W., Jimenez, C. L., Carpenter, B. F., MacDonald, I. <strong>Neuroaxonal dystrophy presenting with neonatal dysmorphic features, early onset of peripheral gangrene, and a rapidly lethal course.</strong> Am. J. Med. Genet. 28: 171-180, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3314508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3314508</a>] [<a href="https://doi.org/10.1002/ajmg.1320280124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3314508">Hunter et al. (1987)</a> described 2 brothers who had a remarkably similar history of prenatal onset of neurologic deterioration, gangrene of the distal limbs leading to autoamputation of digits, pathologic changes of axonal dystrophy, and minor anomalies. They died at 9 months and 14.5 months of age. <a href="#11" class="mim-tip-reference" title="Hunter, A. G. W., Jimenez, C. L., Carpenter, B. F., MacDonald, I. <strong>Neuroaxonal dystrophy presenting with neonatal dysmorphic features, early onset of peripheral gangrene, and a rapidly lethal course.</strong> Am. J. Med. Genet. 28: 171-180, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3314508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3314508</a>] [<a href="https://doi.org/10.1002/ajmg.1320280124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3314508">Hunter et al. (1987)</a> concluded that this should be called prenatal or connatal neuroaxonal dystrophy. Four previous cases with clinical signs at birth had all been sporadic. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2986047+3314508" 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="Nardocci, N., Zorzi, G., Farina, L., Binelli, S., Scaioli, W., Ciano, C., Verga, L., Angelini, L., Savoiardo, M., Bugiani, O. <strong>Infantile neuroaxonal dystrophy: clinical spectrum and diagnostic criteria.</strong> Neurology 52: 1472-1478, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10227637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10227637</a>] [<a href="https://doi.org/10.1212/wnl.52.7.1472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10227637">Nardocci et al. (1999)</a> reported 13 patients with INAD. Onset was between 6 months and 2 years of age. Nine patients had rapid motor and mental deterioration, although 4 patients had a slower progression. EMG showed chronic denervation, EEG showed fast rhythms, and all patients had abnormal visual evoked potentials (VEP). T2-weighted MRI showed cerebellar atrophy with signal hyperintensity in the cerebellar cortex. Two patients had hypointensity in the pallida and substantia nigra, as is usually characteristic of NBIA1. <a href="#7" class="mim-tip-reference" title="Farina, L., Nardocci, N., Bruzzone, M. G., D'Incerti, L., Zorzi, G., Verga, L., Morbin, M., Savoiardo, M. <strong>Infantile neuroaxonal dystrophy: neuroradiological studies in 11 patients.</strong> Neuroradiology 41: 376-380, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10379598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10379598</a>] [<a href="https://doi.org/10.1007/s002340050768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10379598">Farina et al. (1999)</a> reported a thin optic chiasm in 4 patients with INAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10379598+10227637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Although brain magnetic resonance imaging (MRI) changes indicating high levels of iron had been reported only rarely in INAD, <a href="#16" class="mim-tip-reference" title="Morgan, N. V., Westaway, S. K., Morton, J. E. V., Gregory, A., Gissen, P., Sonek, S., Cangul, H., Coryell, J., Canham, N., Nardocci, N., Zorzi, G., Pasha, S., and 15 others. <strong>PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.</strong> Nature Genet. 38: 752-754, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783378</a>] [<a href="https://doi.org/10.1038/ng1826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783378">Morgan et al. (2006)</a> found that 8 of 20 INAD kindreds (40%) with mutations in the PLA2G6 gene (<a href="/entry/603604">603604</a>) showed high iron in the globus pallidus. The authors concluded that INAD should clearly be included in the differential diagnosis of neurodegeneration with high brain iron. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16783378" 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="Tonelli, A., Romaniello, R., Grasso, R., Cavallini, A., Righini, A., Bresolin, N., Borgatti, R., Bassi, M. T. <strong>Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy.</strong> Clin. Genet. 78: 432-440, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20584031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20584031</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01417.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20584031">Tonelli et al. (2010)</a> reported a patient with infantile neuroaxonal dystrophy confirmed by genetic analysis (<a href="/entry/603604#0014">603604.0014</a> and <a href="/entry/603604#0015">603604.0015</a>). The child had a severe and rapidly progressive disease course, with onset before age 12 months, hypotonia, severe developmental delay with mental retardation, motor regression, and no eye contact. Tetraparesis developed by age 18 months. Skin biopsy showed axonal spheroids. Although brain iron accumulation was not present, MRI at age 20 months showed hyperintensities on T2-weighted imaging in the caudate and putamen, suggesting an early degeneration process, and cerebellar cortical atrophy. The mutations were predicted to result in an almost complete lack of enzyme activity, although a gain of function could not be excluded. A second unrelated patient with 2 splice site mutations in the PLA2G6 gene showed a similarly rapid disease course; brain MRI showed only cerebellar atrophy at age 19 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20584031" 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>Distinction from Neurodegeneration with Brain Iron Accumulation 2B (Pantothenate Kinase-Associated Neurodegeneration)</em></strong></p><p>
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<a href="#26" class="mim-tip-reference" title="Williamson, K., Sima, A. A. F., Curry, B., Ludwin, S. K. <strong>Neuroaxonal dystrophy in young adults: a clinicopathological study of two unrelated cases.</strong> Ann. Neurol. 11: 335-343, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7103414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7103414</a>] [<a href="https://doi.org/10.1002/ana.410110403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7103414">Williamson et al. (1982)</a> described 2 unrelated sporadic cases of neuroaxonal dystrophy in young adults and suggested that the disorder represented a transitional form between Seitelberger disease and Hallervorden-Spatz disease. Initial clinical manifestations in both patients were psychiatric, followed by extrapyramidal symptoms, dementia, cerebellar ataxia, and corticospinal dysfunction. Myoclonic seizures were not present. Pathologic examination of both patients showed generalized distribution of spheroids within the central nervous system and, in 1 patient, in peripheral nerves as well. Both patients had Lewy bodies in the pigmented brainstem nuclei, and 1 patient had Lewy bodies in the cerebral cortex. <a href="#26" class="mim-tip-reference" title="Williamson, K., Sima, A. A. F., Curry, B., Ludwin, S. K. <strong>Neuroaxonal dystrophy in young adults: a clinicopathological study of two unrelated cases.</strong> Ann. Neurol. 11: 335-343, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7103414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7103414</a>] [<a href="https://doi.org/10.1002/ana.410110403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7103414">Williamson et al. (1982)</a> noted that the 2 cases could be examples of 'juvenile' neuroaxonal dystrophy, but also noted the similarities to Hallervorden-Spatz disease and suggested that the 2 disorders could be fundamentally the same entity, possibly due to homozygosity for different alleles at the same locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7103414" 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="#10" class="mim-tip-reference" title="Hortnagel, K., Nardocci, N., Zorzi, G., Garavaglia, B., Botz, E., Meitinger, T., Klopstock, T. <strong>Infantile neuroaxonal dystrophy and pantothenate kinase-associated neurodegeneration: locus heterogeneity.</strong> Neurology 63: 922-924, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15365152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15365152</a>] [<a href="https://doi.org/10.1212/01.wnl.0000137046.28085.b2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15365152">Hortnagel et al. (2004)</a> delineated some of the phenotypic differences between INAD (NBIA2A) and PKAN (NBIA1). INAD usually begins within the first 2 years of life and leads to death before age 10 years, whereas PKAN has a late-infantile or juvenile onset, and patients may survive into their third decade. However, there are reports of early-infantile PKAN and late-onset INAD. INAD is characterized mainly by a pyramidal syndrome with spastic tetraplegia, hyperreflexia, and visual impairment, whereas PKAN is more of an extrapyramidal syndrome with dystonia, parkinsonism, and choreoathetosis. Both disorders have axonal swellings and spheroids throughout the central nervous system, but patients with INAD may also have spheroids in peripheral tissues. PKAD is associated with iron accumulation in the basal ganglia, leading to the characteristic 'eye of the tiger' sign on brain MRI. INAD shows cerebellar atrophy with hyperintensity in the cerebellar cortex. However, both imaging and pathologic features can show overlap in both diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15365152" 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="#10" class="mim-tip-reference" title="Hortnagel, K., Nardocci, N., Zorzi, G., Garavaglia, B., Botz, E., Meitinger, T., Klopstock, T. <strong>Infantile neuroaxonal dystrophy and pantothenate kinase-associated neurodegeneration: locus heterogeneity.</strong> Neurology 63: 922-924, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15365152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15365152</a>] [<a href="https://doi.org/10.1212/01.wnl.0000137046.28085.b2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15365152">Hortnagel et al. (2004)</a> used linkage analysis and molecular analysis to exclude the PANK2 gene as causative in 8 INAD patients from 7 families previously reported by <a href="#19" class="mim-tip-reference" title="Nardocci, N., Zorzi, G., Farina, L., Binelli, S., Scaioli, W., Ciano, C., Verga, L., Angelini, L., Savoiardo, M., Bugiani, O. <strong>Infantile neuroaxonal dystrophy: clinical spectrum and diagnostic criteria.</strong> Neurology 52: 1472-1478, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10227637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10227637</a>] [<a href="https://doi.org/10.1212/wnl.52.7.1472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10227637">Nardocci et al. (1999)</a> and <a href="#7" class="mim-tip-reference" title="Farina, L., Nardocci, N., Bruzzone, M. G., D'Incerti, L., Zorzi, G., Verga, L., Morbin, M., Savoiardo, M. <strong>Infantile neuroaxonal dystrophy: neuroradiological studies in 11 patients.</strong> Neuroradiology 41: 376-380, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10379598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10379598</a>] [<a href="https://doi.org/10.1007/s002340050768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10379598">Farina et al. (1999)</a>. The findings indicated that infantile neuroaxonal dystrophy and PKAN are genetically distinct disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10379598+10227637+15365152" 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="Kurian, M. A., Morgan, N. V., MacPherson, L., Foster, K., Peake, D., Gupta, R., Philip, S. G., Hendriksz, C., Morton, J. E. V., Kingston, H. M., Rosser, E. M., Wassmer, E., Gissen, P., Maher, E. R. <strong>Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN).</strong> Neurology 70: 1623-1629, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18443314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18443314</a>] [<a href="https://doi.org/10.1212/01.wnl.0000310986.48286.8e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18443314">Kurian et al. (2008)</a> reported 14 children from 9 families with neurodegeneration associated with mutations in the PLA2G6 gene. Eleven patients from 6 families were of Pakistani origin. The mean age at symptom onset was 14 months (range, 12 to 22 months), and onset was characterized by regression of psychomotor development and onset of global developmental delay. There was rapid disease progression with 5 children dying at a mean age of 9 years. The main features included bulbar dysfunction, axial hypotonia, spasticity, contractures, spinal deformities, dystonia, cerebellar features. and optic atrophy. Dysmorphic features were not readily apparent. Brain imaging of 13 patients showed cerebellar atrophy, cerebellar gliosis, white matter abnormalities, and atrophy of the corpus callosum. Ten children had evidence of increased iron deposition in the globus pallidus. Seven children had axonal sensorimotor neuropathy with spheroid body formation. <a href="#13" class="mim-tip-reference" title="Kurian, M. A., Morgan, N. V., MacPherson, L., Foster, K., Peake, D., Gupta, R., Philip, S. G., Hendriksz, C., Morton, J. E. V., Kingston, H. M., Rosser, E. M., Wassmer, E., Gissen, P., Maher, E. R. <strong>Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN).</strong> Neurology 70: 1623-1629, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18443314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18443314</a>] [<a href="https://doi.org/10.1212/01.wnl.0000310986.48286.8e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18443314">Kurian et al. (2008)</a> noted that the phenotype was very homogeneous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18443314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Morgan, N. V., Westaway, S. K., Morton, J. E. V., Gregory, A., Gissen, P., Sonek, S., Cangul, H., Coryell, J., Canham, N., Nardocci, N., Zorzi, G., Pasha, S., and 15 others. <strong>PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.</strong> Nature Genet. 38: 752-754, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783378</a>] [<a href="https://doi.org/10.1038/ng1826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783378">Morgan et al. (2006)</a> performed genomewide linkage studies in 12 families with INAD. Using polymorphic microsatellite markers, they mapped an INAD locus to a 6.0-Mb region of chromosome 22q12.3-q13.2 (lod score of 4.78 at D22S692), with evidence of locus heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16783378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Aicardi, J., Castelein, P. <strong>Infantile neuroaxonal dystrophy.</strong> Brain 102: 727-748, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/509195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">509195</a>] [<a href="https://doi.org/10.1093/brain/102.4.727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="509195">Aicardi and Castelein (1979)</a> reported 8 cases of late infantile neuroaxonal dystrophy and reviewed 76 previously reported cases. Most patients showed a progressive disorder starting within the first 2 years of life with motor and mental deterioration, bilateral pyramidal tract signs, marked hypotonia, and early visual disturbances. Seizures were not reported. EEG showed high voltage, fast rhythms, and EMG results were consistent with chronic denervation. Axonal endings consistently showed spheroid bodies, which could also be detected in skin and conjunctiva. <a href="#1" class="mim-tip-reference" title="Aicardi, J., Castelein, P. <strong>Infantile neuroaxonal dystrophy.</strong> Brain 102: 727-748, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/509195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">509195</a>] [<a href="https://doi.org/10.1093/brain/102.4.727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="509195">Aicardi and Castelein (1979)</a> noted that both clinical and pathologic features were necessary for diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=509195" 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="#21" class="mim-tip-reference" title="Ramaekers, V. T., Lake, B. D., Harding, B., Boyd, S., Harden, A., Brett, E. M., Wilson, J. <strong>Diagnostic difficulties in infantile neuroaxonal dystrophy: a clinicopathological study of eight cases.</strong> Neuropediatrics 18: 170-175, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3683759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3683759</a>] [<a href="https://doi.org/10.1055/s-2008-1052474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3683759">Ramaekers et al. (1987)</a> outlined the diagnostic difficulties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3683759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Ozmen, M., Caliskan, M., Goebel, H. H., Apak, S. <strong>Infantile neuroaxonal dystrophy: diagnosis by skin biopsy.</strong> Brain Dev. 13: 256-259, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1659791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1659791</a>] [<a href="https://doi.org/10.1016/s0387-7604(12)80059-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1659791">Ozmen et al. (1991)</a> demonstrated in 4 patients that the diagnosis can be made by ultrastructural examination of biopsied skin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1659791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of NBIA2A in the families reported by <a href="#16" class="mim-tip-reference" title="Morgan, N. V., Westaway, S. K., Morton, J. E. V., Gregory, A., Gissen, P., Sonek, S., Cangul, H., Coryell, J., Canham, N., Nardocci, N., Zorzi, G., Pasha, S., and 15 others. <strong>PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.</strong> Nature Genet. 38: 752-754, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783378</a>] [<a href="https://doi.org/10.1038/ng1826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783378">Morgan et al. (2006)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16783378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Morgan, N. V., Westaway, S. K., Morton, J. E. V., Gregory, A., Gissen, P., Sonek, S., Cangul, H., Coryell, J., Canham, N., Nardocci, N., Zorzi, G., Pasha, S., and 15 others. <strong>PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.</strong> Nature Genet. 38: 752-754, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783378</a>] [<a href="https://doi.org/10.1038/ng1826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783378">Morgan et al. (2006)</a> identified mutations in the PLA2G6 gene (<a href="/entry/603604">603604</a>) in 31 families with INAD and in the original family with Karak syndrome. They identified a total of 44 unique mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16783378" 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="#12" class="mim-tip-reference" title="Khateeb, S., Flusser, H., Ofir, R., Shelef, I., Narkis, G., Vardi, G., Shorer, Z., Levy, R., Galil, A., Elbedour, K., Birk, O. S. <strong>PLA2G6 mutation underlies infantile neuroaxonal dystrophy.</strong> Am. J. Hum. Genet. 79: 942-948, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033970</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17033970[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17033970">Khateeb et al. (2006)</a> studied affected individuals from 2 unrelated Bedouin Israeli kindreds. Brain imaging demonstrated diffuse cerebellar atrophy and abnormal iron deposition in the medial and lateral globus pallidus. Progressive white-matter disease and reduction of the N-acetyl aspartate:chromium ratio were evident on magnetic resonance spectroscopy, suggesting loss of myelination. The clinical and radiologic diagnosis of INAD was verified by sural nerve biopsy. The disease gene was mapped to a 1.17-Mb locus on chromosome 22q13.1, and an underlying mutation common to both affected families was identified in PLA2G6 (<a href="/entry/603604#0004">603604.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17033970" 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="Gregory, A., Westaway, S. K., Holm, I. E., Kotzbauer, P. T., Hogarth, P., Sonek, S., Coryell, J. C., Nguyen, T. M., Nardocci, N., Zorzi, G., Rodriguez, D., Desguerre, I., and 10 others. <strong>Neurodegeneration associated with genetic defects in phospholipase A(2).</strong> Neurology 71: 1402-1409, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18799783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18799783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18799783[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/01.wnl.0000327094.67726.28" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18799783">Gregory et al. (2008)</a> found PLA2G6 mutations in 45 (79%) of 56 patients with INAD1 and in 6 (20%) of 23 patients with idiopathic NBIA (see, e.g., <a href="/entry/603604#0006">603604.0006</a>-<a href="/entry/603604#0008">603604.0008</a>). No PLA2G6 mutations were found in 11 patients with clinical evidence of INAD, including 5 in whom spheroids were reported on peripheral nerve biopsy. All 28 patients with 2 null mutations or homozygous for any mutation had early onset and rapidly progressive disease, consistent with INAD. Patients with the less severe phenotype of NBIA tended to have compound heterozygous missense mutations, consistent with residual protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18799783" 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>Historically, the diagnosis of INAD has required histopathologic evidence of dystrophic axons. However, <a href="#16" class="mim-tip-reference" title="Morgan, N. V., Westaway, S. K., Morton, J. E. V., Gregory, A., Gissen, P., Sonek, S., Cangul, H., Coryell, J., Canham, N., Nardocci, N., Zorzi, G., Pasha, S., and 15 others. <strong>PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.</strong> Nature Genet. 38: 752-754, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783378</a>] [<a href="https://doi.org/10.1038/ng1826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783378">Morgan et al. (2006)</a> found that the presence of spheroids on biopsy did not absolutely correlate with mutations in PLA2G6. Five individuals with clinical and pathologic features of INAD were negative for PLA2G6 mutations. Linkage data supported the existence of 1 additional INAD locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16783378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Drecourt, A., Babdor, J., Dussiot, M., Petit, F., Goudin, N., Garfa-Traore, M., Habarou, F., Bole-Feysot, C., Nitschke, P., Ottolenghi, C., Metodiev, M. D., Serre, V., Desguerre, I., Boddaert, N., Hermine, O., Munnich, A., Rotig, A. <strong>Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 102: 266-277, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395073</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395073[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395073">Drecourt et al. (2018)</a> found that cells derived from NBIA patients with PLA2G6 mutations showed a significant increase (10- to 30-fold change) in cellular iron content when incubated with iron compared to controls. In response to high iron, patient cells showed a normal and appropriate decrease in transferrin receptor (TFRC; <a href="/entry/190010">190010</a>) mRNA levels, but the amount of TFRC did not decrease in patient cells, suggesting impaired posttranslational lysosomal-based degradation of TFRC. Patient cells showed impaired transferrin (<a href="/entry/190000">190000</a>) and TFRC trafficking and recycling compared to controls, with clustering at the surface and in the perinuclear region, as well as abnormally enlarged lysosomes. Patient cells also showed decreased palmitoylation of TFRC, which is necessary for regulating TFRC endocytosis. Addition of the antimalarial agent artesunate rescued abnormal TFRC palmitoylation and decreased iron content in cultured patient fibroblasts. Similar findings were observed in studies of cells from NBIA patients due to mutations in other NBIA-associated genes. <a href="#6" class="mim-tip-reference" title="Drecourt, A., Babdor, J., Dussiot, M., Petit, F., Goudin, N., Garfa-Traore, M., Habarou, F., Bole-Feysot, C., Nitschke, P., Ottolenghi, C., Metodiev, M. D., Serre, V., Desguerre, I., Boddaert, N., Hermine, O., Munnich, A., Rotig, A. <strong>Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation.</strong> Am. J. Hum. Genet. 102: 266-277, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395073</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395073[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395073">Drecourt et al. (2018)</a> concluded that NBIA results from defective endosomal recycling and should be regarded as a disorder of cellular trafficking, whatever the original genetic defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29395073" 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>This disorder, caused by mutation in the PLA2G6 gene, is referred to in OMIM as NBIA2A because the original phenotype was described as a form of neurodegeneration with brain iron accumulation (NBIA; <a href="#16" class="mim-tip-reference" title="Morgan, N. V., Westaway, S. K., Morton, J. E. V., Gregory, A., Gissen, P., Sonek, S., Cangul, H., Coryell, J., Canham, N., Nardocci, N., Zorzi, G., Pasha, S., and 15 others. <strong>PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.</strong> Nature Genet. 38: 752-754, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783378</a>] [<a href="https://doi.org/10.1038/ng1826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783378">Morgan et al., 2006</a>). Some references in the literature (see, e.g., <a href="#2" class="mim-tip-reference" title="Chinnery, P. F., Crompton, D. E., Birchall, D., Jackson, M. J., Coulthard, A., Lombes, A., Quinn, N., Wills, A., Fletcher, N., Mottershead, J. P., Cooper, P., Kellett, M., Bates, D., Burn, J. <strong>Clinical features and natural history of neuroferritinopathy caused by the FTL1 460insA mutation.</strong> Brain 130: 110-119, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17142829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17142829</a>] [<a href="https://doi.org/10.1093/brain/awl319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17142829">Chinnery et al., 2007</a>) use the designation 'NBIA2' to refer to a similar disorder caused by mutation in the FTL gene (<a href="/entry/134790">134790</a>). OMIM refers to NBIA caused by mutation in the FTL gene as NBIA3 (<a href="/entry/606159">606159</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16783378+17142829" 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="Kurian, M. A., Morgan, N. V., MacPherson, L., Foster, K., Peake, D., Gupta, R., Philip, S. G., Hendriksz, C., Morton, J. E. V., Kingston, H. M., Rosser, E. M., Wassmer, E., Gissen, P., Maher, E. R. <strong>Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN).</strong> Neurology 70: 1623-1629, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18443314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18443314</a>] [<a href="https://doi.org/10.1212/01.wnl.0000310986.48286.8e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18443314">Kurian et al. (2008)</a> proposed that disorders due to PLA2G6 mutations be referred to as 'PLA2G6-associated neurodegeneration (PLAN).' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18443314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#14" class="mim-tip-reference" title="Malik, I., Turk, J., Mancuso, D. J., Montier, L., Wohltmann, M., Wozniak, D. F., Schmidt, R. E., Gross, R. W., Kotzbauer, P. T. <strong>Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations.</strong> Am. J. Path. 172: 406-416, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18202189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18202189</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18202189[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.2353/ajpath.2008.070823" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18202189">Malik et al. (2008)</a> found that Pla2g6-null mice developed age-dependent neurologic impairment that was evident in rotarod, balance, and climbing tests by 13 months of age. Neuropathologic analysis showed numerous spheroids in the brain similar to those observed in human INAD. Spheroids contained tubulovesicular membranes and stained strongly with anti-ubiquitin antibodies. Onset of motor impairment correlated with increased spheroids throughout the neuropil in nearly all brain regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18202189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Nakai1960" class="mim-tip-reference" title="Nakai, H., Landing, B. H., Schubert, W. K. <strong>Seitelberger's spastic amaurotic axonal idiocy. Report of a case in a 9-year-old boy with comment on visceral manifestation.</strong> Pediatrics 25: 441-449, 1960.">Nakai et al. (1960)</a>
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Aicardi, J., Castelein, P.
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<strong>Infantile neuroaxonal dystrophy.</strong>
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Brain 102: 727-748, 1979.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/509195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">509195</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=509195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/102.4.727" target="_blank">Full Text</a>]
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Chinnery, P. F., Crompton, D. E., Birchall, D., Jackson, M. J., Coulthard, A., Lombes, A., Quinn, N., Wills, A., Fletcher, N., Mottershead, J. P., Cooper, P., Kellett, M., Bates, D., Burn, J.
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<strong>Clinical features and natural history of neuroferritinopathy caused by the FTL1 460insA mutation.</strong>
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Brain 130: 110-119, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17142829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17142829</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17142829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awl319" target="_blank">Full Text</a>]
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Cowen, D., Olmstead, E. V.
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<strong>Infantile neuroaxonal dystrophy.</strong>
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J. Neuropath. Exp. Neurol. 22: 175-236, 1963.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14023529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14023529</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14023529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1097/00005072-196304000-00001" target="_blank">Full Text</a>]
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Crome, L., Weller, S. D. V.
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<strong>Infantile neuroaxonal dystrophy.</strong>
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Arch. Dis. Child. 40: 502-507, 1965.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5829994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5829994</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5829994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/adc.40.213.502" target="_blank">Full Text</a>]
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Dorfman, L. J., Pedley, T. A., Thorp, B. R., Scheithauer, B. W.
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<strong>Juvenile neuroaxonal dystrophy: clinical, electrophysiological, and neuropathological features.</strong>
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Ann. Neurol. 3: 419-428, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/103487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">103487</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=103487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.410030511" target="_blank">Full Text</a>]
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Drecourt, A., Babdor, J., Dussiot, M., Petit, F., Goudin, N., Garfa-Traore, M., Habarou, F., Bole-Feysot, C., Nitschke, P., Ottolenghi, C., Metodiev, M. D., Serre, V., Desguerre, I., Boddaert, N., Hermine, O., Munnich, A., Rotig, A.
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<strong>Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation.</strong>
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Am. J. Hum. Genet. 102: 266-277, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395073</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395073[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=29395073" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2018.01.003" target="_blank">Full Text</a>]
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Farina, L., Nardocci, N., Bruzzone, M. G., D'Incerti, L., Zorzi, G., Verga, L., Morbin, M., Savoiardo, M.
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<strong>Infantile neuroaxonal dystrophy: neuroradiological studies in 11 patients.</strong>
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Neuroradiology 41: 376-380, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10379598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10379598</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10379598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s002340050768" target="_blank">Full Text</a>]
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Gregory, A., Polster, B. J., Hayflick, S. J.
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<strong>Clinical and genetic delineation of neurodegeneration with brain iron accumulation.</strong>
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J. Med. Genet. 46: 73-80, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18981035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18981035</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18981035[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=18981035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.061929" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000327094.67726.28" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000137046.28085.b2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320280124" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/508572" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000310986.48286.8e" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.2353/ajpath.2008.070823" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1651-2227.1982.tb09574.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1826" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.35.5.735" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1055/s-2008-1052474" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1965.00460260045005" target="_blank">Full Text</a>]
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Tonelli, A., Romaniello, R., Grasso, R., Cavallini, A., Righini, A., Bresolin, N., Borgatti, R., Bassi, M. T.
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<strong>Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy.</strong>
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Clin. Genet. 78: 432-440, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20584031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20584031</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20584031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2010.01417.x" target="_blank">Full Text</a>]
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Williamson, K., Sima, A. A. F., Curry, B., Ludwin, S. K.
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<strong>Neuroaxonal dystrophy in young adults: a clinicopathological study of two unrelated cases.</strong>
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Ann. Neurol. 11: 335-343, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7103414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7103414</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7103414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.410110403" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 03/23/2018
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Cassandra L. Kniffin - updated : 9/28/2011<br>Cassandra L. Kniffin - updated : 2/18/2010<br>Cassandra L. Kniffin - updated : 3/27/2009<br>Cassandra L. Kniffin - updated : 2/23/2009<br>Victor A. McKusick - updated : 10/10/2006<br>Victor A. McKusick - updated : 6/27/2006<br>Cassandra L. Kniffin - reorganized : 2/25/2005<br>Cassandra L. Kniffin - updated : 2/22/2005<br>Victor A. McKusick - updated : 3/3/2003<br>Victor A. McKusick - updated : 12/9/1998
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Creation Date:
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Victor A. McKusick : 6/4/1986
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alopez : 01/10/2024
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carol : 09/27/2023<br>carol : 02/22/2022<br>carol : 03/28/2018<br>alopez : 03/27/2018<br>ckniffin : 03/23/2018<br>carol : 07/12/2016<br>carol : 5/27/2016<br>carol : 2/17/2014<br>carol : 9/20/2013<br>ckniffin : 9/19/2013<br>carol : 5/23/2013<br>carol : 10/12/2011<br>ckniffin : 9/28/2011<br>ckniffin : 3/12/2010<br>carol : 3/1/2010<br>ckniffin : 2/18/2010<br>terry : 12/17/2009<br>wwang : 4/14/2009<br>ckniffin : 3/27/2009<br>wwang : 2/25/2009<br>ckniffin : 2/23/2009<br>ckniffin : 3/16/2007<br>alopez : 10/11/2006<br>alopez : 10/11/2006<br>terry : 10/10/2006<br>alopez : 6/28/2006<br>terry : 6/27/2006<br>tkritzer : 2/25/2005<br>ckniffin : 2/22/2005<br>alopez : 3/17/2004<br>cwells : 11/10/2003<br>carol : 3/5/2003<br>tkritzer : 3/4/2003<br>tkritzer : 3/3/2003<br>carol : 2/24/1999<br>dkim : 12/14/1998<br>terry : 12/9/1998<br>psherman : 10/26/1998<br>mimadm : 4/29/1994<br>warfield : 3/30/1994<br>supermim : 3/17/1992<br>carol : 11/26/1991<br>carol : 5/10/1991<br>supermim : 3/20/1990
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<strong>#</strong> 256600
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NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2A; NBIA2A
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NEURODEGENERATION, PLA2G6-ASSOCIATED; PLAN<br />
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NEUROAXONAL DYSTROPHY, INFANTILE; INAD; INAD1<br />
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SEITELBERGER DISEASE
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<strong>SNOMEDCT:</strong> 52713000;
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<strong>ORPHA:</strong> 35069;
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<strong>DO:</strong> 0110735;
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Inheritance
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22q13.1
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Infantile neuroaxonal dystrophy 1
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256600
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Autosomal recessive
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3
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PLA2G6
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603604
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<p>A number sign (#) is used with this entry because this form of neurodegeneration with brain iron accumulation (NBIA), referred to here as 'NBIA2A,' is caused by homozygous or compound heterozygous mutation in the PLA2G6 gene (603604) on chromosome 22q13. See NOMENCLATURE section.</p><p>See also NBIA2B (610217), an overlapping disorder with later onset.</p>
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<p>Neurodegeneration with brain iron accumulation-2A (NBIA2A) is an autosomal recessive neurodegenerative disease characterized by onset in the first 2 years of life; it is also referred to as infantile neuroaxonal dystrophy (INAD). Pathologic findings include axonal swelling and spheroid bodies in the central nervous system (review by Gregory et al., 2009). </p><p>For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).</p>
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<p>Seitelberger (1954) first described this infantile form of degenerative encephalopathy characterized pathologically by lipid storage in the brain. Visceral changes were described by Cowen and Olmstead (1963) and by Sandbank (1965). The changes in the brain are widespread focal swelling and degeneration of axons with scattered 'spheroids' (Cowen and Olmstead, 1963). Crome and Weller (1965) described a brother and sister, who died at 12 and 18 months, respectively, with mental retardation, paralysis, and epilepsy. </p><p>Scheithauer et al. (1978) described 2 affected brothers with severe progressive myoclonic epilepsy. One brother had onset at age 10 years and death at age 23 years. Postmortem examination showed widespread and marked neuroaxonal dystrophy, severe cerebellar atrophy, and degeneration of the lateral corticospinal tracts. There was no increased pigmentation in the globus pallidus or substantia nigra, which distinguished the disorder from PKAN (NBIA1; 234200). The authors suggested that the case was a 'juvenile form' of neuroaxonal dystrophy. The same cases were reported by Dorfman et al. (1978), who noted intellectual deterioration and cerebellar ataxia. </p><p>Malmstrom-Groth and Kristensson (1982) described the first case to be reported in Scandinavia. </p><p>Nagashima et al. (1985) reported a rare neonatal form which probably had its beginnings in utero. Poor sucking, hypotonia, pendulous nystagmus, keratitis sicca with little tearing, and feeble tendon reflexes were noted soon after birth. By age 7 months he had constipation and urinary retention. By 8 months hypothalamic hypothyroidism and diabetes insipidus were demonstrated. Fever suggested a disorder of temperature regulation. At autopsy, spheroid bodies were widely distributed, particularly in the hypothalamus, infundibulum, and neurohypophysis, but also in the myenteric plexus of the colon. Hunter et al. (1987) described 2 brothers who had a remarkably similar history of prenatal onset of neurologic deterioration, gangrene of the distal limbs leading to autoamputation of digits, pathologic changes of axonal dystrophy, and minor anomalies. They died at 9 months and 14.5 months of age. Hunter et al. (1987) concluded that this should be called prenatal or connatal neuroaxonal dystrophy. Four previous cases with clinical signs at birth had all been sporadic. </p><p>Nardocci et al. (1999) reported 13 patients with INAD. Onset was between 6 months and 2 years of age. Nine patients had rapid motor and mental deterioration, although 4 patients had a slower progression. EMG showed chronic denervation, EEG showed fast rhythms, and all patients had abnormal visual evoked potentials (VEP). T2-weighted MRI showed cerebellar atrophy with signal hyperintensity in the cerebellar cortex. Two patients had hypointensity in the pallida and substantia nigra, as is usually characteristic of NBIA1. Farina et al. (1999) reported a thin optic chiasm in 4 patients with INAD. </p><p>Although brain magnetic resonance imaging (MRI) changes indicating high levels of iron had been reported only rarely in INAD, Morgan et al. (2006) found that 8 of 20 INAD kindreds (40%) with mutations in the PLA2G6 gene (603604) showed high iron in the globus pallidus. The authors concluded that INAD should clearly be included in the differential diagnosis of neurodegeneration with high brain iron. </p><p>Tonelli et al. (2010) reported a patient with infantile neuroaxonal dystrophy confirmed by genetic analysis (603604.0014 and 603604.0015). The child had a severe and rapidly progressive disease course, with onset before age 12 months, hypotonia, severe developmental delay with mental retardation, motor regression, and no eye contact. Tetraparesis developed by age 18 months. Skin biopsy showed axonal spheroids. Although brain iron accumulation was not present, MRI at age 20 months showed hyperintensities on T2-weighted imaging in the caudate and putamen, suggesting an early degeneration process, and cerebellar cortical atrophy. The mutations were predicted to result in an almost complete lack of enzyme activity, although a gain of function could not be excluded. A second unrelated patient with 2 splice site mutations in the PLA2G6 gene showed a similarly rapid disease course; brain MRI showed only cerebellar atrophy at age 19 months. </p><p><strong><em>Distinction from Neurodegeneration with Brain Iron Accumulation 2B (Pantothenate Kinase-Associated Neurodegeneration)</em></strong></p><p>
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Williamson et al. (1982) described 2 unrelated sporadic cases of neuroaxonal dystrophy in young adults and suggested that the disorder represented a transitional form between Seitelberger disease and Hallervorden-Spatz disease. Initial clinical manifestations in both patients were psychiatric, followed by extrapyramidal symptoms, dementia, cerebellar ataxia, and corticospinal dysfunction. Myoclonic seizures were not present. Pathologic examination of both patients showed generalized distribution of spheroids within the central nervous system and, in 1 patient, in peripheral nerves as well. Both patients had Lewy bodies in the pigmented brainstem nuclei, and 1 patient had Lewy bodies in the cerebral cortex. Williamson et al. (1982) noted that the 2 cases could be examples of 'juvenile' neuroaxonal dystrophy, but also noted the similarities to Hallervorden-Spatz disease and suggested that the 2 disorders could be fundamentally the same entity, possibly due to homozygosity for different alleles at the same locus. </p><p>Hortnagel et al. (2004) delineated some of the phenotypic differences between INAD (NBIA2A) and PKAN (NBIA1). INAD usually begins within the first 2 years of life and leads to death before age 10 years, whereas PKAN has a late-infantile or juvenile onset, and patients may survive into their third decade. However, there are reports of early-infantile PKAN and late-onset INAD. INAD is characterized mainly by a pyramidal syndrome with spastic tetraplegia, hyperreflexia, and visual impairment, whereas PKAN is more of an extrapyramidal syndrome with dystonia, parkinsonism, and choreoathetosis. Both disorders have axonal swellings and spheroids throughout the central nervous system, but patients with INAD may also have spheroids in peripheral tissues. PKAD is associated with iron accumulation in the basal ganglia, leading to the characteristic 'eye of the tiger' sign on brain MRI. INAD shows cerebellar atrophy with hyperintensity in the cerebellar cortex. However, both imaging and pathologic features can show overlap in both diseases. </p><p>Hortnagel et al. (2004) used linkage analysis and molecular analysis to exclude the PANK2 gene as causative in 8 INAD patients from 7 families previously reported by Nardocci et al. (1999) and Farina et al. (1999). The findings indicated that infantile neuroaxonal dystrophy and PKAN are genetically distinct disorders. </p><p>Kurian et al. (2008) reported 14 children from 9 families with neurodegeneration associated with mutations in the PLA2G6 gene. Eleven patients from 6 families were of Pakistani origin. The mean age at symptom onset was 14 months (range, 12 to 22 months), and onset was characterized by regression of psychomotor development and onset of global developmental delay. There was rapid disease progression with 5 children dying at a mean age of 9 years. The main features included bulbar dysfunction, axial hypotonia, spasticity, contractures, spinal deformities, dystonia, cerebellar features. and optic atrophy. Dysmorphic features were not readily apparent. Brain imaging of 13 patients showed cerebellar atrophy, cerebellar gliosis, white matter abnormalities, and atrophy of the corpus callosum. Ten children had evidence of increased iron deposition in the globus pallidus. Seven children had axonal sensorimotor neuropathy with spheroid body formation. Kurian et al. (2008) noted that the phenotype was very homogeneous. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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</div>
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<span class="mim-text-font">
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<p>Morgan et al. (2006) performed genomewide linkage studies in 12 families with INAD. Using polymorphic microsatellite markers, they mapped an INAD locus to a 6.0-Mb region of chromosome 22q12.3-q13.2 (lod score of 4.78 at D22S692), with evidence of locus heterogeneity. </p>
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<span class="mim-font">
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<strong>Diagnosis</strong>
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<span class="mim-text-font">
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<p>Aicardi and Castelein (1979) reported 8 cases of late infantile neuroaxonal dystrophy and reviewed 76 previously reported cases. Most patients showed a progressive disorder starting within the first 2 years of life with motor and mental deterioration, bilateral pyramidal tract signs, marked hypotonia, and early visual disturbances. Seizures were not reported. EEG showed high voltage, fast rhythms, and EMG results were consistent with chronic denervation. Axonal endings consistently showed spheroid bodies, which could also be detected in skin and conjunctiva. Aicardi and Castelein (1979) noted that both clinical and pathologic features were necessary for diagnosis. </p><p>Ramaekers et al. (1987) outlined the diagnostic difficulties. </p><p>Ozmen et al. (1991) demonstrated in 4 patients that the diagnosis can be made by ultrastructural examination of biopsied skin. </p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Inheritance</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The transmission pattern of NBIA2A in the families reported by Morgan et al. (2006) was consistent with autosomal recessive inheritance. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Morgan et al. (2006) identified mutations in the PLA2G6 gene (603604) in 31 families with INAD and in the original family with Karak syndrome. They identified a total of 44 unique mutations. </p><p>Khateeb et al. (2006) studied affected individuals from 2 unrelated Bedouin Israeli kindreds. Brain imaging demonstrated diffuse cerebellar atrophy and abnormal iron deposition in the medial and lateral globus pallidus. Progressive white-matter disease and reduction of the N-acetyl aspartate:chromium ratio were evident on magnetic resonance spectroscopy, suggesting loss of myelination. The clinical and radiologic diagnosis of INAD was verified by sural nerve biopsy. The disease gene was mapped to a 1.17-Mb locus on chromosome 22q13.1, and an underlying mutation common to both affected families was identified in PLA2G6 (603604.0004). </p><p>Gregory et al. (2008) found PLA2G6 mutations in 45 (79%) of 56 patients with INAD1 and in 6 (20%) of 23 patients with idiopathic NBIA (see, e.g., 603604.0006-603604.0008). No PLA2G6 mutations were found in 11 patients with clinical evidence of INAD, including 5 in whom spheroids were reported on peripheral nerve biopsy. All 28 patients with 2 null mutations or homozygous for any mutation had early onset and rapidly progressive disease, consistent with INAD. Patients with the less severe phenotype of NBIA tended to have compound heterozygous missense mutations, consistent with residual protein function. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Heterogeneity</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Historically, the diagnosis of INAD has required histopathologic evidence of dystrophic axons. However, Morgan et al. (2006) found that the presence of spheroids on biopsy did not absolutely correlate with mutations in PLA2G6. Five individuals with clinical and pathologic features of INAD were negative for PLA2G6 mutations. Linkage data supported the existence of 1 additional INAD locus. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Pathogenesis</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Drecourt et al. (2018) found that cells derived from NBIA patients with PLA2G6 mutations showed a significant increase (10- to 30-fold change) in cellular iron content when incubated with iron compared to controls. In response to high iron, patient cells showed a normal and appropriate decrease in transferrin receptor (TFRC; 190010) mRNA levels, but the amount of TFRC did not decrease in patient cells, suggesting impaired posttranslational lysosomal-based degradation of TFRC. Patient cells showed impaired transferrin (190000) and TFRC trafficking and recycling compared to controls, with clustering at the surface and in the perinuclear region, as well as abnormally enlarged lysosomes. Patient cells also showed decreased palmitoylation of TFRC, which is necessary for regulating TFRC endocytosis. Addition of the antimalarial agent artesunate rescued abnormal TFRC palmitoylation and decreased iron content in cultured patient fibroblasts. Similar findings were observed in studies of cells from NBIA patients due to mutations in other NBIA-associated genes. Drecourt et al. (2018) concluded that NBIA results from defective endosomal recycling and should be regarded as a disorder of cellular trafficking, whatever the original genetic defect. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>This disorder, caused by mutation in the PLA2G6 gene, is referred to in OMIM as NBIA2A because the original phenotype was described as a form of neurodegeneration with brain iron accumulation (NBIA; Morgan et al., 2006). Some references in the literature (see, e.g., Chinnery et al., 2007) use the designation 'NBIA2' to refer to a similar disorder caused by mutation in the FTL gene (134790). OMIM refers to NBIA caused by mutation in the FTL gene as NBIA3 (606159). </p><p>Kurian et al. (2008) proposed that disorders due to PLA2G6 mutations be referred to as 'PLA2G6-associated neurodegeneration (PLAN).' </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Malik et al. (2008) found that Pla2g6-null mice developed age-dependent neurologic impairment that was evident in rotarod, balance, and climbing tests by 13 months of age. Neuropathologic analysis showed numerous spheroids in the brain similar to those observed in human INAD. Spheroids contained tubulovesicular membranes and stained strongly with anti-ubiquitin antibodies. Onset of motor impairment correlated with increased spheroids throughout the neuropil in nearly all brain regions. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Nakai et al. (1960)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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Khateeb, S., Flusser, H., Ofir, R., Shelef, I., Narkis, G., Vardi, G., Shorer, Z., Levy, R., Galil, A., Elbedour, K., Birk, O. S.
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Morgan, N. V., Westaway, S. K., Morton, J. E. V., Gregory, A., Gissen, P., Sonek, S., Cangul, H., Coryell, J., Canham, N., Nardocci, N., Zorzi, G., Pasha, S., and 15 others.
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<strong>PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.</strong>
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Nakai, H., Landing, B. H., Schubert, W. K.
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Nardocci, N., Zorzi, G., Farina, L., Binelli, S., Scaioli, W., Ciano, C., Verga, L., Angelini, L., Savoiardo, M., Bugiani, O.
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<strong>Infantile neuroaxonal dystrophy: clinical spectrum and diagnostic criteria.</strong>
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<strong>Infantile neuroaxonal dystrophy: diagnosis by skin biopsy.</strong>
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<strong>Diagnostic difficulties in infantile neuroaxonal dystrophy: a clinicopathological study of eight cases.</strong>
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<strong>Infantile neuroaxonal dystrophy.</strong>
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Arch. Neurol. 12: 155-159, 1965.
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[PubMed: 14237772]
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[Full Text: https://doi.org/10.1001/archneur.1965.00460260045005]
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<p class="mim-text-font">
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Scheithauer, B. W., Forno, L. S., Dorfman, L. J., Kane, C. A.
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<strong>Neuroaxonal dystrophy (Seitelberger's disease) with late onset, protracted course and myoclonic epilepsy.</strong>
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[Full Text: https://doi.org/10.1016/0022-510x(78)90085-0]
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Seitelberger, F.
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<strong>Eine unbekannte Form von infantiler lipoid-Speicher Krankheit des Gehirns. Proc. 1st Int. Cong. of Neuropathology, Rome, Sept. 8-13, 1952. Vol. 3.</strong>
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Turin: Rosenberg and Sellier (pub.) 1954. Pp. 323-333.
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Tonelli, A., Romaniello, R., Grasso, R., Cavallini, A., Righini, A., Bresolin, N., Borgatti, R., Bassi, M. T.
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<strong>Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy.</strong>
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[PubMed: 20584031]
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Williamson, K., Sima, A. A. F., Curry, B., Ludwin, S. K.
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<strong>Neuroaxonal dystrophy in young adults: a clinicopathological study of two unrelated cases.</strong>
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[PubMed: 7103414]
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[Full Text: https://doi.org/10.1002/ana.410110403]
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Cassandra L. Kniffin - updated : 03/23/2018<br>Cassandra L. Kniffin - updated : 9/28/2011<br>Cassandra L. Kniffin - updated : 2/18/2010<br>Cassandra L. Kniffin - updated : 3/27/2009<br>Cassandra L. Kniffin - updated : 2/23/2009<br>Victor A. McKusick - updated : 10/10/2006<br>Victor A. McKusick - updated : 6/27/2006<br>Cassandra L. Kniffin - reorganized : 2/25/2005<br>Cassandra L. Kniffin - updated : 2/22/2005<br>Victor A. McKusick - updated : 3/3/2003<br>Victor A. McKusick - updated : 12/9/1998
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Victor A. McKusick : 6/4/1986
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