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Entry
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- #312080 - PELIZAEUS-MERZBACHER DISEASE; PMD
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- OMIM
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<p>
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<span class="h4">#312080</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/312080"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS312080"> <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="#diagnosis">Diagnosis</a>
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<a href="#mapping">Mapping</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#history">History</a>
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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-cell;">External Links</div>
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</a>
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</h4>
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div><a href="https://clinicaltrials.gov/search?cond=PELIZAEUS-MERZBACHER DISEASE" 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://decipher.sanger.ac.uk/syndrome/38" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=20438&Typ=Pat" title="Pelizaeus-Merzbacher disease, connatal form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pelizaeus-Merzbacher disea… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=20439&Typ=Pat" title="Pelizaeus-Merzbacher disease, classic form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pelizaeus-Merzbacher disea… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=20440&Typ=Pat" title="Pelizaeus-Merzbacher disease, transitional form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pelizaeus-Merzbacher disea… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=20441&Typ=Pat" title="Pelizaeus-Merzbacher disease in female carriers" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pelizaeus-Merzbacher disea… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=20442&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Null syndrome </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=656&Typ=Pat" title="Pelizaeus-Merzbacher disease" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pelizaeus-Merzbacher disea… </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1182/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/5643" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/pelizaeus-merzbacher-disease" 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=312080[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="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=280210" title="Pelizaeus-Merzbacher disease, connatal form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pelizaeus-Merzbacher disea…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=280219" title="Pelizaeus-Merzbacher disease, classic form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pelizaeus-Merzbacher disea…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=280224" title="Pelizaeus-Merzbacher disease, transitional form" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pelizaeus-Merzbacher disea…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=280229" title="Pelizaeus-Merzbacher disease in female carriers" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pelizaeus-Merzbacher disea…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=280234" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Null syndrome</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=702" title="Pelizaeus-Merzbacher disease" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pelizaeus-Merzbacher disea…</a></div>
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</div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/6423a354-2812-4797-9a34-00bdfedb1bf2/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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</div>
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</a>
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</span>
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</span>
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</div>
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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:3210" 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/312080" 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/results?search_type=advanced&omia_id=000770,000903" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:3210" 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>
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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="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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</div>
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</a>
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</span>
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</span>
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</div>
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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:312080" 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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</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>
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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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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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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> 64855000<br />
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<strong>ICD10CM:</strong> E75.27<br />
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<strong>ORPHA:</strong> 280210, 280219, 280224, 280229, 280234, 702<br />
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<strong>DO:</strong> 3210<br />
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">ICD+</a>
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</div>
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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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312080
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</span>
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</span>
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</div>
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</div>
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<div>
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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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PELIZAEUS-MERZBACHER DISEASE; PMD
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</span>
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</h3>
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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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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</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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LEUKODYSTROPHY, HYPOMYELINATING, 1; HLD1
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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>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
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<th>
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|
Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
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<th>
|
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Gene/Locus
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</th>
|
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<th>
|
|
Gene/Locus <br /> MIM number
|
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</th>
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</tr>
|
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</thead>
|
|
<tbody>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/532?start=-3&limit=10&highlight=532">
|
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Xq22.2
|
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</a>
|
|
</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Pelizaeus-Merzbacher disease
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/312080"> 312080 </a>
|
|
</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 recessive">XLR</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">
|
|
PLP1
|
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/300401"> 300401 </a>
|
|
</span>
|
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</td>
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/312080" 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>
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<div class="btn-group">
|
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|
|
<a href="/phenotypicSeries/PS312080" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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|
|
<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>
|
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</div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/312080" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/312080" 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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<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- X-linked recessive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845977</a>, <a href="https://bioportal.bioontology.org/search?q=C1279481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279481</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GROWTH </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<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 />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Head </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Microcephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1148757008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1148757008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/742.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">742.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551563&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551563</a>, <a href="https://bioportal.bioontology.org/search?q=C0025958&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025958</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Microcephaly-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Ears </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Decreased or absent brainstem auditory evoked potentials (BAEP) of waves III-V <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275641&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275641</a>]</span><br /> -
|
|
Hearing impairment (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103276001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103276001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15188001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15188001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H91.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1384666&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1384666</a>, <a href="https://bioportal.bioontology.org/search?q=C1550444&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1550444</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
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<span class="mim-font">
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- Rotary nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44526006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44526006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95783006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95783006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240595&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240595</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001583" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001583</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001583" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001583</a>]</span><br /> -
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Optic atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/76976005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">76976005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/377.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/377.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029124&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029124</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</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">
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<strong> RESPIRATORY </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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<div>
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<span class="h5 mim-font">
|
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<em> Larynx </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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|
- Stridor <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/70407001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">70407001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R06.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R06.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/786.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">786.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038450&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038450</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010307" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010307</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010307" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010307</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> NEUROLOGIC </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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<div>
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<span class="h5 mim-font">
|
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<em> Central 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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|
- Rotary head movements ('rolling,' 'tremor') <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839442&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839442</a>]</span><br /> -
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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 /> -
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Hyporeflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/835279003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">835279003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405946002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405946002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700078</a>, <a href="https://bioportal.bioontology.org/search?q=C0151888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151888</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001315</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>]</span><br /> -
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|
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 /> -
|
|
Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
|
|
Progressive pyramidal signs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5232557&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5232557</a>]</span><br /> -
|
|
Progressive cerebellar signs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5232558&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5232558</a>]</span><br /> -
|
|
Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
|
|
Choreoathetosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43105007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43105007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085583&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085583</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001266" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001266</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001266" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001266</a>]</span><br /> -
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|
Psychomotor delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1144814003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1144814003</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">[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=C5441816&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5441816</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 /> -
|
|
Lack of psychomotor development (severe connatal form) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839444&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839444</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <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">[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 /> -
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|
Psychomotor deterioration (classical form) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839445&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839445</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002361" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002361</a>]</span><br /> -
|
|
Scanning speech <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/77420001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">77420001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240952&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240952</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002168" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002168</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002168" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002168</a>]</span><br /> -
|
|
Dysarthria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8011004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8011004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.13</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/784.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span><br /> -
|
|
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 /> -
|
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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 /> -
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Dysmyelination of the brain, myelin is not formed properly <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839446&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839446</a>]</span><br /> -
|
|
Absent myelination of the brain (severe connatal form) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839447&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839447</a>]</span><br /> -
|
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Diffuse white matter hyperintensities seen on T2-weighed imaging <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5232559&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5232559</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">
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<strong> MISCELLANEOUS </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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- Onset in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848924</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span><br /> -
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Slowly progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854494&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854494</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span><br /> -
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Nystagmus may disappear by mid-childhood<br /> -
|
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Hearing impairment may improve with age<br /> -
|
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Connatal form (type II), most severe with death in first decade<br /> -
|
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Classical form (type I), less severe with survival into adulthood<br /> -
|
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Spastic paraplegia 2 (SPG2, <a href="/entry/312920">312920</a>) is an allelic disorder<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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<div>
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<span class="mim-font">
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- Caused by mutation in the proteolipid protein 1 gene (PLP1, <a href="/entry/300401#0001">300401.0001</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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Leukodystrophy, hypomyelinating
|
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- <a href="/phenotypicSeries/PS312080">PS312080</a>
|
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- 28 Entries
|
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</h5>
|
|
</div>
|
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</div>
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|
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
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<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>
|
|
<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>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/539?start=-3&limit=10&highlight=539"> 1p34.1 </a>
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619688"> Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619688"> 619688 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616136"> RNF220 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616136"> 616136 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1715?start=-3&limit=10&highlight=1715"> 1q41 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617951"> Leukodystrophy, hypomyelinating, 15 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617951"> 617951 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/138295"> EPRS </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/138295"> 138295 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1743?start=-3&limit=10&highlight=1743"> 1q42.11 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618404"> Leukodystrophy, hypomyelinating, 18 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618404"> 618404 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615843"> DEGS1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615843"> 615843 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1752?start=-3&limit=10&highlight=1752"> 1q42.12 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618688"> Leukodystrophy, hypomyelinating, 19, transient infantile </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618688"> 618688 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618685"> TMEM63A </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618685"> 618685 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1754?start=-3&limit=10&highlight=1754"> 1q42.12 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616420"> Leukodystrophy, hypomyelinating, 10 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616420"> 616420 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616406"> PYCR2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616406"> 616406 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1773?start=-3&limit=10&highlight=1773"> 1q42.13 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608804"> Leukodystrophy, hypomyelinating, 2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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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>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608804"> 608804 </a>
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608803"> GJC2 </a>
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/608803"> 608803 </a>
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</span>
|
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</td>
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/436?start=-3&limit=10&highlight=436"> 2p11.2 </a>
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|
</span>
|
|
</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/620675"> Leukodystrophy, hypomyelinating, 27 </a>
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620675"> 620675 </a>
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616404"> POLR1A </a>
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616404"> 616404 </a>
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</span>
|
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</td>
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/464?start=-3&limit=10&highlight=464"> 2q11.1 </a>
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|
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620978"> ?Leukodystrophy, hypomyelinating, 28 </a>
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620978"> 620978 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188860"> MAL </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188860"> 188860 </a>
|
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</span>
|
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</td>
|
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</tr>
|
|
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|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/654?start=-3&limit=10&highlight=654"> 2q21.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620243"> Leukodystrophy, hypomyelinating, 25 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620243"> 620243 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618978"> TMEM163 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618978"> 618978 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/891?start=-3&limit=10&highlight=891"> 2q33.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612233"> Leukodystrophy, hypomyelinating, 4 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612233"> 612233 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/118190"> HSPD1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/118190"> 118190 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/859?start=-3&limit=10&highlight=859"> 3q26.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619328"> Leukodystrophy, hypomyelinating, 22 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619328"> 619328 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601326"> CLDN11 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601326"> 601326 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/4/465?start=-3&limit=10&highlight=465"> 4q24 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/260600"> Leukodystrophy, hypomyelinating, 3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/260600"> 260600 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603605"> AIMP1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603605"> 603605 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/5/743?start=-3&limit=10&highlight=743"> 5q34 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616140"> Leukodystrophy, hypomyelinating, 9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616140"> 616140 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/107820"> RARS1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/107820"> 107820 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/6/528?start=-3&limit=10&highlight=528"> 6p21.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616494"> Leukodystrophy, hypomyelinating, 11 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616494"> 616494 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610060"> POLR1C </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610060"> 610060 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/6/542?start=-3&limit=10&highlight=542"> 6p21.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620269"> Leukodystrophy, hypomyelinating, 26, with chondrodysplasia </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620269"> 620269 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610788"> SLC35B2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610788"> 610788 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/52?start=-3&limit=10&highlight=52"> 7p22.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618006"> Leukodystrophy, hypomyelinating, 17 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618006"> 618006 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600859"> AIMP2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600859"> 600859 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/74?start=-3&limit=10&highlight=74"> 7p21.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617964"> Leukodystrophy, hypomyelinating, 16 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617964"> 617964 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613413"> TMEM106B </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613413"> 613413 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/110?start=-3&limit=10&highlight=110"> 7p15.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610532"> Leukodystrophy, hypomyelinating, 5 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610532"> 610532 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610531"> HYCC1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610531"> 610531 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/10/327?start=-3&limit=10&highlight=327"> 10q22.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607694"> Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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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 class="mim-font">
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<a href="/entry/607694"> 607694 </a>
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<span class="mim-font">
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<a href="/entry/614258"> POLR3A </a>
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</span>
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<span class="mim-font">
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<a href="/entry/614258"> 614258 </a>
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<span class="mim-font">
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<a href="/geneMap/11/808?start=-3&limit=10&highlight=808"> 11q14.2 </a>
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<span class="mim-font">
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<a href="/entry/616881"> Leukodystrophy, hypomyelinating, 13 </a>
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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 class="mim-font">
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<a href="/entry/616881"> 616881 </a>
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</span>
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<span class="mim-font">
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<a href="/entry/614908"> HIKESHI </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/614908"> 614908 </a>
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</td>
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<span class="mim-font">
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<a href="/geneMap/11/1003?start=-3&limit=10&highlight=1003"> 11q23.3 </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/616683"> Leukodystrophy, hypomyelinating, 12 </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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<span class="mim-font">
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<a href="/entry/616683"> 616683 </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/608549"> VPS11 </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/608549"> 608549 </a>
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<td>
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<span class="mim-font">
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<a href="/geneMap/12/757?start=-3&limit=10&highlight=757"> 12q23.3 </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/614381"> Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism </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/614381"> 614381 </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/614366"> POLR3B </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/614366"> 614366 </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/13/106?start=-3&limit=10&highlight=106"> 13q13.3 </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/617899"> Leukodystrophy, hypomyelinating, 14 </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/617899"> 617899 </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/610553"> UFM1 </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/610553"> 610553 </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/13/319?start=-3&limit=10&highlight=319"> 13q34 </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/619851"> ?Leukodystrophy, hypomyelinating, 24 </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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|
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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/619851"> 619851 </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/605868"> ATP11A </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/605868"> 605868 </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/16/11?start=-3&limit=10&highlight=11"> 16p13.3 </a>
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</span>
|
|
</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/619310"> Leukodystrophy, hypomyelinating, 21 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</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>
|
|
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619310"> 619310 </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/606007"> POLR3K </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/606007"> 606007 </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/17/563?start=-3&limit=10&highlight=563"> 17q21.2 </a>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619071"> ?Leukodystrophy, hypomyelinating, 20 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
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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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</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/619071"> 619071 </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/123830"> CNP </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/123830"> 123830 </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/19/185?start=-3&limit=10&highlight=185"> 19p13.3 </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/612438"> Leukodystrophy, hypomyelinating, 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 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/612438"> 612438 </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/602662"> TUBB4A </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/602662"> 602662 </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/532?start=-3&limit=10&highlight=532"> Xq22.2 </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/312080"> Pelizaeus-Merzbacher disease </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 recessive">XLR</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/312080"> 312080 </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/300401"> PLP1 </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/300401"> 300401 </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 class="text-right small">
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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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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</h4>
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<p>A number sign (#) is used with this entry because Pelizaeus-Merzbacher disease (PMD) is caused by mutation in the PLP1 gene (<a href="/entry/300401">300401</a>), which encodes proteolipid protein-1, on chromosome Xq22.</p><p>Spastic paraplegia-2 (SPG2; <a href="/entry/312920">312920</a>) is an allelic disorder.</p>
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<br />
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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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<p>Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelinating leukodystrophy (HLD1) in which myelin is not formed properly in the central nervous system. PMD is characterized clinically by nystagmus, spastic quadriplegia, ataxia, and developmental delay (summary by <a href="#34" class="mim-tip-reference" title="Inoue, K. <strong>PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2.</strong> Neurogenetics 6: 1-16, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15627202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15627202</a>] [<a href="https://doi.org/10.1007/s10048-004-0207-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15627202">Inoue, 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15627202" 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>Genetic Heterogeneity of Hypomyelinating Leukodystrophy</em></strong></p><p>
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Other forms of hypomyelinating leukodystrophy include HLD2 (<a href="/entry/608804">608804</a>), caused by mutation in the GJC2/GJA12 gene (<a href="/entry/608803">608803</a>) on chromosome 1q41; HLD3 (<a href="/entry/260600">260600</a>), caused by mutation in the AIMP1 gene (<a href="/entry/603605">603605</a>) on chromosome 4q24; HLD4 (<a href="/entry/612233">612233</a>), caused by mutation in the HSPD1 gene (<a href="/entry/118190">118190</a>) on chromosome 2q33.1; HLD5 (<a href="/entry/610532">610532</a>), caused by mutation in the FAM126A gene (<a href="/entry/610531">610531</a>) on chromosome 7p15; HLD6 (<a href="/entry/612438">612438</a>), caused by mutation in the TUBB4A gene (<a href="/entry/602662">602662</a>) on chromosome 19p13; HLD7 (<a href="/entry/607694">607694</a>), caused by mutation in the POLR3A gene (<a href="/entry/614258">614258</a>) on chromosome 10q22; HLD8 (<a href="/entry/614381">614381</a>), caused by mutation in the POLR3B gene (<a href="/entry/614366">614366</a>) on chromosome 12q23; HLD9 (<a href="/entry/616140">616140</a>), caused by mutation in the RARS gene (<a href="/entry/107820">107820</a>) on chromosome 5; HLD10 (<a href="/entry/616420">616420</a>), caused by mutation in the PYCR2 gene (<a href="/entry/616406">616406</a>) on chromosome 1q42; HLD11 (<a href="/entry/616494">616494</a>), caused by mutation in the POLR1C gene (<a href="/entry/610060">610060</a>) on chromosome 6p21; HLD12 (<a href="/entry/616683">616683</a>), caused by mutation in the VPS11 gene (<a href="/entry/608549">608549</a>) on chromosome 11q23; HLD13 (<a href="/entry/616881">616881</a>) caused by mutation in the HIKESHI gene (<a href="/entry/614908">614908</a>) on chromosome 11q14; HLD14 (<a href="/entry/617899">617899</a>), caused by mutation in the UFM1 gene (<a href="/entry/610553">610553</a>) on chromosome 13q13; HLD15 (<a href="/entry/617951">617951</a>), caused by mutation in the EPRS gene (<a href="/entry/138295">138295</a>) on chromosome 1q41; HLD16 (<a href="/entry/617964">617964</a>), caused by mutation in the TMEM106B gene (<a href="/entry/613413">613413</a>) on chromosome 7p21; HLD17 (<a href="/entry/618006">618006</a>), caused by mutation in the AIMP2 gene (<a href="/entry/600859">600859</a>) on chromosome 7p22; HLD18 (<a href="/entry/618404">618404</a>), caused by mutation in the DEGS1 gene (<a href="/entry/615843">615843</a>) on chromosome 1q42; HLD19 (<a href="/entry/618688">618688</a>), caused by mutation in the TMEM63A gene (<a href="/entry/618685">618685</a>) on chromosome 1q42; HLD20 (<a href="/entry/619071">619071</a>), caused by mutation in the CNP gene (<a href="/entry/123830">123830</a>) on chromosome 17q21; HLD21 (<a href="/entry/619310">619310</a>), caused by mutation in the POLR3K gene (<a href="/entry/606007">606007</a>) on chromosome 16p13; HLD22 (<a href="/entry/619328">619328</a>), caused by mutation in the CLDN11 gene (<a href="/entry/601326">601326</a>) on chromosome 3q26; HLD23 (<a href="/entry/619688">619688</a>), caused by mutation in the RNF220 gene (<a href="/entry/616136">616136</a>) on chromosome 1p34; HLD24 (<a href="/entry/619851">619851</a>), caused by mutation in the ATP11A gene (<a href="/entry/605868">605868</a>) on chromosome 13q34; HLD25 (<a href="/entry/620243">620243</a>), caused by mutation in the TMEM163 gene (<a href="/entry/618978">618978</a>) on chromosome 2q21; HLD26 (<a href="/entry/620269">620269</a>), caused by mutation in the SLC35B2 gene (<a href="/entry/610788">610788</a>) on chromosome 6p21; and HLD27 (<a href="/entry/620675">620675</a>), caused by mutation in the POLR1A gene (<a href="/entry/616404">616404</a>) on chromosome 2p11.</p>
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<p><a href="#63" class="mim-tip-reference" title="Tyler, H. R. <strong>Pelizaeus-Merzbacher disease: a clinical study.</strong> AMA Arch. Neurol. Psychiat. 80: 162-169, 1958.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13558772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13558772</a>] [<a href="https://doi.org/10.1001/archneurpsyc.1958.02340080032004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13558772">Tyler (1958)</a> noted that at first, rotary movements of the head and eyes develop but curiously may later disappear. Affected children in these families were sometimes described as 'head nodders' and 'eye waggers.' Spasticity of the legs and later the arms, cerebellar ataxia, dementia, and parkinsonian symptoms are other features developing over the first decade or two of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13558772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Ford, F. R. <strong>Diseases of the Nervous System in Infancy, Childhood and Adolescence. (4th ed.)</strong> Springfield, Ill.: Charles C Thomas (pub.) 1960. Pp. 831-833."None>Ford (1960)</a> referred to Pelizaeus-Merzbacher disease as the chronic infantile type of diffuse cerebral sclerosis. PMD begins in infancy as early as the eighth day and usually no later than the third month and is very slowly progressive so that the victim may survive to middle age. Initial symptoms are pendular eye movements, head shaking, hypotonia, choreoathetosis, and pyramidal signs. The myelin of the peripheral nervous system is not involved in nerve conduction and velocities are normal.</p><p><a href="#53" class="mim-tip-reference" title="Renier, W. O., Gabreels, F. J. M., Hustinx, T. W. J., Jaspar, H. H. J., Geelen, J. A. G., Van Haelst, U. J. G., Lommen, E. J. P., Ter Haar, B. G. A. <strong>Connatal Pelizaeus-Merzbacher disease with congenital stridor in two maternal cousins.</strong> Acta Neuropath. 54: 11-17, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7234326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7234326</a>] [<a href="https://doi.org/10.1007/BF00691328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7234326">Renier et al. (1981)</a> recognized 3 types of Pelizaeus-Merzbacher disease. (1) The classic type, with onset in infancy and death in late adolescence or young adulthood, is characterized by initial signs of nystagmoid eye movement and jerking and rolling head movements or head tremor. Nystagmus disappears and, as the patient matures, ataxia, spasticity, and involuntary movements become manifest, as well as optic atrophy, microcephaly, and subnormal somatic development. (2) The connatal type shows rapid progression and is fatal in infancy or childhood. (3) The transitional form is intermediate. Stridor in early life is a manifestation in some cases of PMD. A possible relation of the X-linked laryngeal abductor paralysis with mental deficiency (<a href="/entry/308850">308850</a>) to the connatal form was proposed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7234326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Kaye, E. M., Doll, R. F., Natowicz, M. R., Smith, F. I. <strong>Pelizaeus-Merzbacher disease presenting as spinal muscular atrophy: clinical and molecular studies.</strong> Ann. Neurol. 36: 916-919, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7998780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7998780</a>] [<a href="https://doi.org/10.1002/ana.410360618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7998780">Kaye et al. (1994)</a> reported 2 brothers who demonstrated neonatal hypotonia and hyporeflexia and were found to have mutations in the PLP1 gene. The authors suggested that peripheral nervous system myelin may be affected in PMD, yielding a clinical picture suggestive of spinal muscular atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7998780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>One of the patients of <a href="#47" class="mim-tip-reference" title="Pelizaeus, F. <strong>Ueber eine eigentumliche Form spastischer Lahmung mit Cerebralerscheinungen auf hereditarer Grundlage (multiple Sklerose).</strong> Arch. Psychiat. Nervenkr. 16: 698, 1885."None>Pelizaeus (1885)</a> lived to 52 years of age, and in the family reported by <a href="#63" class="mim-tip-reference" title="Tyler, H. R. <strong>Pelizaeus-Merzbacher disease: a clinical study.</strong> AMA Arch. Neurol. Psychiat. 80: 162-169, 1958.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13558772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13558772</a>] [<a href="https://doi.org/10.1001/archneurpsyc.1958.02340080032004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13558772">Tyler (1958)</a> an affected male was still living at age 51. <a href="#35" class="mim-tip-reference" title="Johnson, V. P., Carpenter, N. J., Kelts, K. A. <strong>Pelizaeus-Merzbacher disease: clinical and DNA-linkage study of an extended family.</strong> Am. J. Med. Genet. 41: 355-361, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1789292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1789292</a>] [<a href="https://doi.org/10.1002/ajmg.1320410318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1789292">Johnson et al. (1991)</a> studied a 5-generation family in which 6 persons had PMD type I. One patient was 45 years old at the time of report. 'Wavering eyes' and 'floppy head' were noted at the age of a few weeks as the first sign. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1789292+13558772" 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="Hanefeld, F. A., Brockmann, K., Pouwels, P. J. W., Wilken, B., Frahm, J., Dechent, P. <strong>Quantitative proton MRS of Pelizaeus-Merzbacher disease: evidence of dys- and hypomyelination.</strong> Neurology 65: 701-706, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16157902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16157902</a>] [<a href="https://doi.org/10.1212/01.wnl.0000174642.32187.20" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16157902">Hanefeld et al. (2005)</a> performed quantitative proton magnetic resonance spectroscopy (MRS) on 5 children with genetically confirmed PMD. Compared to age-matched controls, affected white matter in PMD patients resembled the metabolite pattern of cortical gray matter, as indicated by increased concentrations of N-acetylaspartate and N-acetylaspartylglutamate, glutamine, myoinositol, and creatine and phosphocreatine. The concentration of choline-containing compounds was reduced. The findings were consistent with enhanced neuroaxonal density, astrogliosis, and reduction of oligodendroglia, suggestive of dys- and hypomyelination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16157902" 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="#60" class="mim-tip-reference" title="Stevenson, R. E., Tarpey, P., May, M. M., Stratton, M. R., Schwartz, C. E. <strong>Arena syndrome is caused by a missense mutation in PLP1. (Letter)</strong> Am. J. Med. Genet. 149A: 1081 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396823</a>] [<a href="https://doi.org/10.1002/ajmg.a.32795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396823">Stevenson et al. (2009)</a> reported follow-up of a 2-generation African American family with X-linked spastic paraplegia, originally reported by <a href="#1" class="mim-tip-reference" title="Arena, J. F., Schwartz, C., Stevenson, R., Lawrence, L., Carpenter, A., Duara, R., Ledbetter, D., Huang, T., Lehner, T., Ott, J., Lubs, H. A. <strong>Spastic paraplegia with iron deposits in the basal ganglia: a new X-linked mental retardation syndrome.</strong> Am. J. Med. Genet. 43: 479-490, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1605230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1605230</a>] [<a href="https://doi.org/10.1002/ajmg.1320430172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1605230">Arena et al. (1992)</a>. <a href="#1" class="mim-tip-reference" title="Arena, J. F., Schwartz, C., Stevenson, R., Lawrence, L., Carpenter, A., Duara, R., Ledbetter, D., Huang, T., Lehner, T., Ott, J., Lubs, H. A. <strong>Spastic paraplegia with iron deposits in the basal ganglia: a new X-linked mental retardation syndrome.</strong> Am. J. Med. Genet. 43: 479-490, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1605230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1605230</a>] [<a href="https://doi.org/10.1002/ajmg.1320430172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1605230">Arena et al. (1992)</a> described 5 affected males who had severe mental retardation, lower limb spasticity and atrophy, absent or dysarthric speech, and impaired ambulation requiring wheelchairs from childhood. Other features included nystagmus, dystonic posturing, and ataxia. Brain imaging studies showed macrogyria, lack of myelination, and increased paramagnetic signal suggestive of iron deposition. <a href="#60" class="mim-tip-reference" title="Stevenson, R. E., Tarpey, P., May, M. M., Stratton, M. R., Schwartz, C. E. <strong>Arena syndrome is caused by a missense mutation in PLP1. (Letter)</strong> Am. J. Med. Genet. 149A: 1081 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396823</a>] [<a href="https://doi.org/10.1002/ajmg.a.32795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396823">Stevenson et al. (2009)</a> identified a hemizygous mutation in the PLP1 gene (D58Y; <a href="/entry/300401#0027">300401.0027</a>) in all affected individuals, confirming that the disorder was in fact PMD. <a href="#60" class="mim-tip-reference" title="Stevenson, R. E., Tarpey, P., May, M. M., Stratton, M. R., Schwartz, C. E. <strong>Arena syndrome is caused by a missense mutation in PLP1. (Letter)</strong> Am. J. Med. Genet. 149A: 1081 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396823</a>] [<a href="https://doi.org/10.1002/ajmg.a.32795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396823">Stevenson et al. (2009)</a> noted that, although altered signals in the basal ganglia and thalamus are not specific for iron deposition, MRI findings suggestive of iron deposition in the basal ganglia have been reported in other patients with PMD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1605230+19396823" 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>Carrier Females</em></strong></p><p>
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Some heterozygous females have manifestations of the disorder. The brain of such a female in the family reported by <a href="#41" class="mim-tip-reference" title="Merzbacher, L. <strong>Gesetzmaessigkeiten in der Vererbung und Verbreitung verschiedener hereditaer-familiaerer Erkrankungen.</strong> Arch. Rass. Ges. Biol. 6: 172-198, 1909."None>Merzbacher (1909)</a> was studied by Spielmeyer (cited by <a href="#63" class="mim-tip-reference" title="Tyler, H. R. <strong>Pelizaeus-Merzbacher disease: a clinical study.</strong> AMA Arch. Neurol. Psychiat. 80: 162-169, 1958.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13558772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13558772</a>] [<a href="https://doi.org/10.1001/archneurpsyc.1958.02340080032004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13558772">Tyler, 1958</a>) with demonstration of changes. In a large family in which PMD was segregating (reported by <a href="#72" class="mim-tip-reference" title="Zeman, W., DeMyer, W. E., Falls, H. F. <strong>Pelizaeus-Merzbacher disease: a study in nosology.</strong> J. Neuropath. Exp. Neurol. 23: 334-354, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14137679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14137679</a>] [<a href="https://doi.org/10.1097/00005072-196404000-00008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14137679">Zeman et al., 1964</a>) and linked to a mutation in PLP by <a href="#62" class="mim-tip-reference" title="Trofatter, J. A., Dlouhy, S. R., DeMyer, W., Conneally, P. M., Hodes, M. E. <strong>Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant.</strong> Proc. Nat. Acad. Sci. 86: 9427-9430, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2480601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2480601</a>] [<a href="https://doi.org/10.1073/pnas.86.23.9427" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2480601">Trofatter et al. (1989)</a>, <a href="#27" class="mim-tip-reference" title="Hodes, M. E., DeMyer, W. E., Pratt, V. M., Edwards, M. K., Dlouhy, S. R. <strong>Girl with signs of Pelizaeus-Merzbacher disease heterozygous for a mutation in exon 2 of the proteolipid protein gene.</strong> Am. J. Med. Genet. 55: 397-401, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7539211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7539211</a>] [<a href="https://doi.org/10.1002/ajmg.1320550402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7539211">Hodes et al. (1995)</a> observed a heterozygous female infant with typical neurologic signs and with magnetic resonance imaging (MRI) of the brain and brain auditory evoked response consistent with the diagnosis of PMD. The mother and grandmother, who were likewise heterozygous for the leu14-to-pro mutation (<a href="/entry/300401#0003">300401.0003</a>), were neurologically normal and showed normal MRIs of the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7539211+14137679+13558772+2480601" 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="#65" class="mim-tip-reference" title="Warshawsky, I., Rudick, R. A., Staugaitis, S. M., Natowicz, M. R. <strong>Primary progressive multiple sclerosis as a phenotype of PLP1 gene mutation.</strong> Ann. Neurol. 58: 470-473, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130097</a>] [<a href="https://doi.org/10.1002/ana.20601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130097">Warshawsky et al. (2005)</a> reported a 49-year-old woman with a history of progressive gait disturbance, white matter disease, and CSF immunoglobulin abnormalities who met criteria for primary progressive multiple sclerosis (MS; <a href="/entry/126200">126200</a>). She and her son, who died at age 10 years of an unknown congenital neurodevelopmental disorder, were found to have a mutation in the PLP1 gene, confirming a diagnosis of Pelizaeus-Merzbacher disease. <a href="#65" class="mim-tip-reference" title="Warshawsky, I., Rudick, R. A., Staugaitis, S. M., Natowicz, M. R. <strong>Primary progressive multiple sclerosis as a phenotype of PLP1 gene mutation.</strong> Ann. Neurol. 58: 470-473, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130097</a>] [<a href="https://doi.org/10.1002/ana.20601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130097">Warshawsky et al. (2005)</a> noted that the finding of an affected mother of a severely affected boy with PMD was contrary to the current belief that mothers of severely affected sons are asymptomatic as adults. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16130097" 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>Carrier females with the submicroscopic duplication in the PLP gene that causes PMD are usually asymptomatic. <a href="#33" class="mim-tip-reference" title="Inoue, K., Tanaka, H., Scaglia, F., Araki, A., Shaffer, L. G., Lupski, J. R. <strong>Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement.</strong> Ann. Neurol. 50: 747-754, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11761472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11761472</a>] [<a href="https://doi.org/10.1002/ana.10036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11761472">Inoue et al. (2001)</a> described 2 unrelated female patients who presented with mild PMD or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results improved dramatically over a 10-year period. The other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, also showed clinical improvement. Interphase fluorescence in situ hybridization analyses identified a PLP gene duplication in both patients. The same analyses in family members indicated that the duplication in both patients occurred as a de novo event. Neither skewing of X inactivation in the peripheral lymphocytes nor PLP gene coding alterations were identified in either patient. These findings indicated that females with a PLP gene duplication can occasionally manifest an early-onset neurologic phenotype. <a href="#33" class="mim-tip-reference" title="Inoue, K., Tanaka, H., Scaglia, F., Araki, A., Shaffer, L. G., Lupski, J. R. <strong>Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement.</strong> Ann. Neurol. 50: 747-754, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11761472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11761472</a>] [<a href="https://doi.org/10.1002/ana.10036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11761472">Inoue et al. (2001)</a> hypothesized that the remarkable clinical improvement was a result of myelin compensation by oligodendrocytes expressing 1 copy of the PLP gene secondary to selection for a favorable X-inactivation pattern. These findings indicated plasticity of oligodendrocytes in the formation of central nervous system myelin and suggested a potential role for stem cell transplantation therapies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11761472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using clinical data compiled from a chart review at Wayne State University comprising 40 pedigrees with PMD including 55 males and 56 carrier females, <a href="#31" class="mim-tip-reference" title="Hurst, S., Garbern, J., Trepanier, A., Gow, A. <strong>Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease.</strong> Genet. Med. 8: 371-378, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16778599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16778599</a>] [<a href="https://doi.org/10.1097/01.gim.0000223551.95862.c3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16778599">Hurst et al. (2006)</a> investigated neurologic symptoms in carrier females. They categorized patients according to disease severity and type of genetic lesion within the PLP1 gene and then analyzed the clinical data using nonparametric t tests and analyses of variance. <a href="#31" class="mim-tip-reference" title="Hurst, S., Garbern, J., Trepanier, A., Gow, A. <strong>Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease.</strong> Genet. Med. 8: 371-378, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16778599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16778599</a>] [<a href="https://doi.org/10.1097/01.gim.0000223551.95862.c3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16778599">Hurst et al. (2006)</a> concluded that their analyses formally demonstrated the link between mild disease in males and symptoms in carrier female relatives. Conversely, mutations causing severe disease in males rarely caused clinical signs in carrier females. The greatest risk of disease in females was found for nonsense/indel or null mutations. Missense mutations carried moderate risk. The lowest risk, which represents the bulk of families with PMD, was associated with PLP1 gene duplications. <a href="#31" class="mim-tip-reference" title="Hurst, S., Garbern, J., Trepanier, A., Gow, A. <strong>Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease.</strong> Genet. Med. 8: 371-378, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16778599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16778599</a>] [<a href="https://doi.org/10.1097/01.gim.0000223551.95862.c3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16778599">Hurst et al. (2006)</a> concluded that effective genetic counseling of PMD and spastic paraplegia carrier females must include an assessment of disease severity in affected male relatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16778599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Marble, M., Voeller, K. S., May, M. M., Stevenson, R. E., Schwartz, C. E., Simensen, R. J. <strong>Pelizaeus-Merzbacher syndrome: neurocognitive function in a family with carrier manifestations.</strong> Am. J. Med. Genet. 143A: 1442-1447, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17568416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17568416</a>] [<a href="https://doi.org/10.1002/ajmg.a.31804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17568416">Marble et al. (2007)</a> reported 2 brothers with classic PMD resulting from a truncating mutation in the PLP1 gene. Three carrier females in the family developed clumsiness, excessive falling, and gait disturbances in the fourth decade of life. Other clinical findings included hyperreflexia, wide-based gait, tremor, and extensor plantar responses. There was also mild cognitive deterioration. X-inactivation studies showed mild skewing (85:15) only in 1 of the carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17568416" 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="#54" class="mim-tip-reference" title="Schinzel, A., Boltshauser, E., Wichmann, W., Haller, D., Valavanis, A. <strong>Pelizaeus-Merzbacher disease: magnetic resonance imaging as a potential tool for carrier detection. (Abstract)</strong> J. Med. Genet. 25: 276-277, 1988."None>Schinzel et al. (1988)</a> and <a href="#6" class="mim-tip-reference" title="Boltshauser, E., Schinzel, A., Wichmann, W., Haller, D., Valavanis, A. <strong>Pelizaeus-Merzbacher disease: identification of heterozygotes with magnetic resonance imaging?</strong> Hum. Genet. 80: 393-394, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3198119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3198119</a>] [<a href="https://doi.org/10.1007/BF00273659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3198119">Boltshauser et al. (1988)</a> suggested that MRI may be a suitable means for carrier detection. In obligate carriers they demonstrated bilateral multiple areas with signal hyperintensity in the periventricular and subcortical white matter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3198119" 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="#16" class="mim-tip-reference" title="Feldman, J. I., Kearns, D. B., Seid, A. B., Pransky, S. M., Jones, M. C. <strong>The otolaryngologic manifestations of Pelizaeus-Merzbacher disease.</strong> Arch. Otolaryng. Head Neck Surg. 116: 613-616, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2328119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2328119</a>] [<a href="https://doi.org/10.1001/archotol.1990.01870050113019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2328119">Feldman et al. (1990)</a> described stridor and respiratory difficulties at birth as well as polyhydramnios during pregnancy. Tracheomalacia was suspected. Typical abnormalities of the auditory brainstem responses were suggested as a means of early diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2328119" 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="#70" class="mim-tip-reference" title="Woodward, K., Kendall, E., Vetrie, D., Malcolm, S. <strong>Pelizaeus-Merzbacher disease: identification of Xq22 proteolipid-protein duplications and characterization of breakpoints by interphase FISH.</strong> Am. J. Hum. Genet. 63: 207-217, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634530</a>] [<a href="https://doi.org/10.1086/301933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634530">Woodward et al. (1998)</a> confirmed that PLP overdosage is an important genetic abnormality in PMD and showed that interphase fluorescence in situ hybridization is a reliable technique that will facilitate diagnosis and carrier detection. They characterized the duplication breakpoints in 4 families and suggested origin and mechanisms for the rearrangements. The importance of gene dosage in myelin disorders was highlighted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9634530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Bridge, P. J., MacLeod, P. M., Lillicrap, D. P. <strong>Carrier detection and prenatal diagnosis of Pelizaeus-Merzbacher disease using a combination of anonymous DNA polymorphisms and the proteolipid protein (PLP) gene cDNA.</strong> Am. J. Med. Genet. 38: 616-621, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1676565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1676565</a>] [<a href="https://doi.org/10.1002/ajmg.1320380423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1676565">Bridge et al. (1991)</a> performed carrier detection and prenatal diagnosis by means of an intragenic MspI polymorphism of the PLP gene and closely linked DNA markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1676565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Boespflug-Tanguy, O., Mimault, C., Melki, J., Cavagna, A., Giraud, G., Pham Dinh, D., Dastugue, B., Dautigny, A., PMD Clinical Group. <strong>Genetic homogeneity of Pelizaeus-Merzbacher disease: tight linkage to the proteolipoprotein locus in 16 affected families.</strong> Am. J. Hum. Genet. 55: 461-467, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7915877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7915877</a>]" pmid="7915877">Boespflug-Tanguy et al. (1994)</a> suggested that RFLP analysis could be used to improve genetic counseling for the 75 to 90% of affected families in which a PLP exon mutation cannot be demonstrated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7915877" 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="#71" class="mim-tip-reference" title="Woodward, K., Palmer, R., Rao, K., Malcolm, S. <strong>Prenatal diagnosis by FISH in a family with Pelizaeus-Merzbacher disease caused by duplication of the PLP gene.</strong> Prenatal Diag. 19: 266-268, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10210128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10210128</a>] [<a href="https://doi.org/10.1002/(sici)1097-0223(199903)19:3<266::aid-pd515>3.0.co;2-#" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10210128">Woodward et al. (1999)</a> used interphase FISH in lymphocyte preparations for prenatal diagnosis of PMD in a family with the disorder. The fetus was determined to be unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10210128" 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>Differential Diagnosis</em></strong></p><p>
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In a retrospective study of neurophysiologic results from 10 patients with PMD-like disease (PMLD1; <a href="/entry/608804">608804</a>) caused by mutation in the GJC2 gene (<a href="/entry/608803">608803</a>) and 8 with classic PMD, <a href="#26" class="mim-tip-reference" title="Henneke, M., Gegner, S., Hahn, A., Plecko-Startinig, B., Weschke, B., Gartner, J., Brockmann, K. <strong>Clinical neurophysiology in GJA12-related hypomyelination vs Pelizaeus-Merzbacher disease.</strong> Neurology 74: 1785-1789, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513814</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181e0f820" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513814">Henneke et al. (2010)</a> found that brainstem auditory evoked potentials (BAEP) were significantly worse among those with classic PMD. Waves III, IV, and V, which are generated in the pons and midbrain, were absent in all patients with PMD, but were clearly recordable in 11 of 13 investigations in patients with PMLD1. Investigations of auditory acuity were not available. Visual and somatosensory evoked potentials showed conductive delay in both groups of patients, without significant differences. Nerve conduction studies were normal in all patients with PMD and indicated mild peripheral neuropathy in only 2 of 10 patients with PMLD1. <a href="#26" class="mim-tip-reference" title="Henneke, M., Gegner, S., Hahn, A., Plecko-Startinig, B., Weschke, B., Gartner, J., Brockmann, K. <strong>Clinical neurophysiology in GJA12-related hypomyelination vs Pelizaeus-Merzbacher disease.</strong> Neurology 74: 1785-1789, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513814</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181e0f820" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513814">Henneke et al. (2010)</a> concluded that BAEP is a helpful tool to differentiate between these 2 disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20513814" 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>On the basis of comparative mapping of the human and mouse X chromosomes, <a href="#9" class="mim-tip-reference" title="Buckle, V. J., Edwards, J. H., Evans, E. P., Jonasson, J. A., Lyon, M. F., Peters, J., Searle, A. G. <strong>Comparative maps of human and mouse X chromosomes. (Abstract)</strong> Cytogenet. Cell Genet. 40: 594-595, 1985."None>Buckle et al. (1985)</a> predicted that PMD would map to Xq between PGK1 (<a href="/entry/311800">311800</a>) and GLA (<a href="/entry/300644">300644</a>), i.e., somewhere in the segment q13-q22--precisely the region to which <a href="#68" class="mim-tip-reference" title="Willard, H. F., Riordan, J. R. <strong>Assignment of the gene for myelin proteolipid protein to the X chromosome: implications for X-linked myelin disorders.</strong> Science 230: 940-942, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3840606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3840606</a>] [<a href="https://doi.org/10.1126/science.3840606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3840606">Willard and Riordan (1985)</a> assigned the PLP gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3840606" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Boespflug-Tanguy, O., Mimault, C., Melki, J., Cavagna, A., Giraud, G., Pham Dinh, D., Dastugue, B., Dautigny, A., PMD Clinical Group. <strong>Genetic homogeneity of Pelizaeus-Merzbacher disease: tight linkage to the proteolipoprotein locus in 16 affected families.</strong> Am. J. Hum. Genet. 55: 461-467, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7915877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7915877</a>]" pmid="7915877">Boespflug-Tanguy et al. (1994)</a> carried out a linkage analysis with polymorphic markers of the PLP genomic region in 16 families segregating Pelizaeus-Merzbacher disease. Multipoint analysis gave a maximum location score for the PMD locus and the PLP gene in the same interval between DXS94 and DXS287, suggesting that in all families PMD is linked to the PLP locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7915877" 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="#39" class="mim-tip-reference" title="Koeppen, A. H., Ronca, N. A., Greenfield, E. A., Hans, M. B. <strong>Defective biosynthesis of proteolipid protein in Pelizaeus-Merzbacher disease.</strong> Ann. Neurol. 21: 159-170, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3827224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3827224</a>] [<a href="https://doi.org/10.1002/ana.410210208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3827224">Koeppen et al. (1987)</a> demonstrated absence of proteolipid apoprotein (lipophilin) by immunocytochemistry and enzyme-linked immunosorbent assay in the brain from an 18-year-old patient with PMD. On the other hand, despite the lack of myelin-specific lipids, they found residual immunoreactivity for myelin basic protein, myelin-associated glycoprotein, and 2-prime,3-prime-cyclic nucleotide-3-prime-phosphodiesterase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3827224" 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="Gow, A., Lazzarini, R. A. <strong>A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease.</strong> Nature Genet. 13: 422-428, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696336</a>] [<a href="https://doi.org/10.1038/ng0896-422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696336">Gow and Lazzarini (1996)</a> suggested a cellular basis for the difference in disease severity between the classic and connatal forms of PMD, based on protein trafficking of the 2 products of the PLP gene, PLP and DM20. Classic PMD mutations correlated with accumulation of PLP in the endoplasmic reticulum (ER) of transfected COS-7 cells, while the cognate DM20 traversed the secretory pathway to the cell surface. On the other hand, <a href="#23" class="mim-tip-reference" title="Gow, A., Lazzarini, R. A. <strong>A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease.</strong> Nature Genet. 13: 422-428, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696336</a>] [<a href="https://doi.org/10.1038/ng0896-422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696336">Gow and Lazzarini (1996)</a> found that connatal PMD mutations led to the accumulation of both mutant PLP and DM20 proteins in the ER of COS-7 cells with little of either isoform transported to the cell surface. Moreover, they showed that transport-competent mutant DM20s facilitated trafficking of cognate PLPs and hence may influence disease severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8696336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Inoue, K., Osaka, H., Sugiyama, N., Kawanishi, C., Onishi, H., Nezu, A., Kimura, K., Kimura, S., Yamada, Y., Kosaka, K. <strong>A duplicated PLP gene causing Pelizaeus-Merzbacher disease detected by comparative multiplex PCR.</strong> Am. J. Hum. Genet. 59: 32-39, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8659540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8659540</a>]" pmid="8659540">Inoue et al. (1996)</a> identified PLP gene duplications (<a href="/entry/300401#0021">300401.0021</a>) in 4 families with PMD. Thus, PMD may be caused by duplication or deletion of the PLP gene (<a href="#50" class="mim-tip-reference" title="Raskind, W. H., Williams, C. A., Hudson, L. D., Bird, T. D. <strong>Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease.</strong> Am. J. Hum. Genet. 49: 1355-1360, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1720927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1720927</a>]" pmid="1720927">Raskind et al., 1991</a>) as well as by point mutations. This situation is similar to that in Charcot-Marie-Tooth disease type 1a (CMT1A; <a href="/entry/118220">118220</a>), which may be caused by duplication, deletion, or point mutation in the PMP22 gene (<a href="/entry/601097">601097</a>). <a href="#32" class="mim-tip-reference" title="Inoue, K., Osaka, H., Sugiyama, N., Kawanishi, C., Onishi, H., Nezu, A., Kimura, K., Kimura, S., Yamada, Y., Kosaka, K. <strong>A duplicated PLP gene causing Pelizaeus-Merzbacher disease detected by comparative multiplex PCR.</strong> Am. J. Hum. Genet. 59: 32-39, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8659540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8659540</a>]" pmid="8659540">Inoue et al. (1996)</a> suggested that since the homologous myelin protein gene PMP22 is duplicated in the majority of patients with CMT1A, PLP gene overdosage may be an important genetic abnormality in PMD and affect myelin formation. Animal models support PLP duplications as a molecular basis for the disease, since transgenic mice with extra copies of the wildtype PLP gene and overexpression of the mRNA exhibit a similar phenotype of abnormal CNS myelination and premature death. Neurologic symptoms and severity of the disease in transgenic mice correlates with PLP-gene copy number and with the level of overexpression. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8659540+1720927" 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="#59" class="mim-tip-reference" title="Southwood, C. M., Garbern, J., Jiang, W., Gow, A. <strong>The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher disease.</strong> Neuron 36: 585-596, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12441049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12441049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12441049[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/s0896-6273(02)01045-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12441049">Southwood et al. (2002)</a> noted that different mutations in the PLP1 gene cause different disease phenotypes ranging from severe connatal PMD to milder forms characterized by pure spastic paraplegia (SPG2). They presented evidence implicating the unfolded protein response (UPR), a stress-induced signaling cascade that regulates the secretory pathway through the endoplasmic reticulum, as a modulator of disease phenotype. The authors found that oligodendrocytes and microglia from 2 mouse models of PMD with coding mutations in the Plp1 gene, msd (see <a href="/entry/300401#0019">300401.0019</a>) and rsh (see <a href="/entry/300401#0013">300401.0013</a>), in which mutant proteins accumulate in the endoplasmic reticulum, expressed the UPR-associated proteins Chop (<a href="/entry/126337">126337</a>) and Atf3 (<a href="/entry/603148">603148</a>), indicating induction of the UPR. Similarly, postmortem brain tissue from a patient with PMD and mutation in the PLP1 gene (<a href="/entry/300401#0022">300401.0022</a>) showed a 5-fold increase in CHOP expression in the white matter. By contrast, brain and spinal cord tissue from mice with overexpression of Plp1 (see, e.g., <a href="/entry/300401#0021">300401.0021</a>), in which mutant protein does not accumulate in the endoplasmic reticulum, did not show evidence of UPR induction. Transgenic rsh mice who were Chop-deficient showed a more severe phenotype, suggesting that Chop modulated toxic effects of the Plp1 coding mutation. <a href="#59" class="mim-tip-reference" title="Southwood, C. M., Garbern, J., Jiang, W., Gow, A. <strong>The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher disease.</strong> Neuron 36: 585-596, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12441049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12441049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12441049[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/s0896-6273(02)01045-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12441049">Southwood et al. (2002)</a> concluded that variable disease severity associated with different PLP1 mutations results from graded responses to metabolic stress as modulated by the UPR: the greater the accumulation of mutated PLP1 protein in the endoplasmic reticulum, the more intense the UPR and the higher the likelihood of apoptosis and increased disease severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12441049" 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="#46" class="mim-tip-reference" title="Numata, Y., Morimura, T., Nakamura, S., Hirano, E., Kure, S., Goto, Y., Inoue, K. <strong>Depletion of molecular chaperones from the endoplasmic reticulum and fragmentation of the Golgi apparatus associated with pathogenesis in Pelizaeus-Merzbacher disease.</strong> J. Biol. Chem. 288: 7451-7466, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23344956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23344956</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23344956[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/10.1074/jbc.M112.435388" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23344956">Numata et al. (2013)</a> found that expression of the PLP1-A243V mutant (<a href="/entry/300401#0019">300401.0019</a>), which causes severe disease, depleted some ER chaperones with a KDEL (lys-asp-glu-leu) motif in HeLa cells and human oligodendrocytes, and was associated with transfer of the chaperone proteins to the cytoplasm. The same PLP1 mutant also induced fragmentation of the Golgi apparatus. The organelle changes were less prominent in cells with milder disease-associated PLP1 mutants, suggesting a correlation between degree of depletion and phenotypic variability. Similar changes are also observed in cells expressing another disease-causing gene that triggers ER stress, as well as in cells treated with brefeldin A, which induces ER stress and Golgi fragmentation by inhibiting transfer of proteins from the Golgi back to the ER. Mutant PLP1 disturbed localization of the KDEL receptor in the Golgi. The data suggested that PLP1 mutants inhibit Golgi-to-ER retrograde trafficking, which reduces the supply of ER chaperones and induces Golgi fragmentation. <a href="#46" class="mim-tip-reference" title="Numata, Y., Morimura, T., Nakamura, S., Hirano, E., Kure, S., Goto, Y., Inoue, K. <strong>Depletion of molecular chaperones from the endoplasmic reticulum and fragmentation of the Golgi apparatus associated with pathogenesis in Pelizaeus-Merzbacher disease.</strong> J. Biol. Chem. 288: 7451-7466, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23344956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23344956</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23344956[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/10.1074/jbc.M112.435388" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23344956">Numata et al. (2013)</a> proposed that depletion of ER chaperones and Golgi fragmentation induced by mutant misfolded proteins contribute to trafficking defects that underlie the pathogenesis of inherited ER stress-related diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23344956" 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="#12" class="mim-tip-reference" title="Cremers, F. P. M., Pfeiffer, R. A., van de Pol, T. J. R., Hofker, M. H., Kruse, T. A., Wieringa, B., Ropers, H. H. <strong>An interstitial duplication of the X chromosome in a male allows physical fine mapping of probes from the Xq13-q22 region.</strong> Hum. Genet. 77: 23-27, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3476455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3476455</a>] [<a href="https://doi.org/10.1007/BF00284707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3476455">Cremers et al. (1987)</a> found an insertional translocation into the proximal long arm of the X chromosome in a boy who showed findings typical of PMD at autopsy. Duplication of Xq21-q22 was identified using a large number of X-specific and several X-Y-specific probes. There appeared to be 2 intact copies of the PLP gene (<a href="/entry/300401">300401</a>) present. The duplication was apparently due to a de novo mutation, because the mother had a normal female karyotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3476455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with the classic form of PMD, <a href="#20" class="mim-tip-reference" title="Gencic, S., Abuelo, D., Ambler, M., Hudson, L. D. <strong>Pelizaeus-Merzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein.</strong> Am. J. Hum. Genet. 45: 435-442, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2773936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2773936</a>]" pmid="2773936">Gencic et al. (1989)</a> described a missense mutation in exon 5 of the PLP gene (<a href="/entry/300401#0001">300401.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2773936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Hodes, M. E., Pratt, V. M., Dlouhy, S. R. <strong>Genetics of Pelizaeus-Merzbacher disease.</strong> Dev. Neurosci. 15: 383-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7530633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7530633</a>] [<a href="https://doi.org/10.1159/000111361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7530633">Hodes et al. (1993)</a> found that about 30% of patients with the diagnosis of Pelizaeus-Merzbacher disease had a mutation in the coding portion of the proteolipid protein gene. Although the mutations were generally recessive, some mutations were frequently expressed in females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7530633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Mimault, C., Giraud, G., Courtois, V., Cailloux, F., Boire, J. Y., Dastugue, B., Boespflug-Tanguy, O., Clinical European Network on Brain Dysmyelinating Disease. <strong>Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not.</strong> Am. J. Hum. Genet. 65: 360-369, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10417279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10417279</a>] [<a href="https://doi.org/10.1086/302483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10417279">Mimault et al. (1999)</a> investigated 82 strictly selected sporadic cases of PMD and found PLP mutations in 77%. Complete PLP gene duplication was the most frequent abnormality (62%), whereas point mutations in coding or splice site regions of the gene were involved less frequently (38%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10417279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the same report in which they described mutations in the PLP gene in Pelizaeus-Merzbacher disease, <a href="#30" class="mim-tip-reference" title="Hudson, L. D., Puckett, C., Berndt, J., Chan, J., Gencic, S. <strong>Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder.</strong> Proc. Nat. Acad. Sci. 86: 8128-8131, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2479017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2479017</a>] [<a href="https://doi.org/10.1073/pnas.86.20.8128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2479017">Hudson et al. (1989)</a> studied a 6-generation family originally described by <a href="#66" class="mim-tip-reference" title="Watanabe, I., Patel, V., Goebel, H. H., Siakotos, A. N., Zeman, W., DeMyer, W., Dyer, J. S. <strong>Early lesion of Pelizaeus-Merzbacher disease: electron microscopic and biochemical study.</strong> J. Neuropath. Exp. Neurol. 32: 313-333, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4123133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4123133</a>] [<a href="https://doi.org/10.1097/00005072-197304000-00010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4123133">Watanabe et al. (1973)</a> and further characterized by <a href="#67" class="mim-tip-reference" title="Wilkus, R. J., Farrell, D. F. <strong>Electrophysiologic observations in the classical form of Pelizaeus-Merzbacher disease.</strong> Neurology 26: 1042-1045, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/988510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">988510</a>] [<a href="https://doi.org/10.1212/wnl.26.11.1042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="988510">Wilkus and Farrell (1976)</a>. More than 23 males were affected with a disorder fitting the textbook description of Pelizaeus-Merzbacher disease, both clinically and genetically; however, curious pathologic changes had been noted in a 3-month-old affected infant: apparently normal myelin was present but to a considerable extent the myelin sheaths were organized into ball-like structures in the oligodendrocyte perikarya and terminal processes (<a href="#66" class="mim-tip-reference" title="Watanabe, I., Patel, V., Goebel, H. H., Siakotos, A. N., Zeman, W., DeMyer, W., Dyer, J. S. <strong>Early lesion of Pelizaeus-Merzbacher disease: electron microscopic and biochemical study.</strong> J. Neuropath. Exp. Neurol. 32: 313-333, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4123133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4123133</a>] [<a href="https://doi.org/10.1097/00005072-197304000-00010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4123133">Watanabe et al., 1973</a>). <a href="#30" class="mim-tip-reference" title="Hudson, L. D., Puckett, C., Berndt, J., Chan, J., Gencic, S. <strong>Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder.</strong> Proc. Nat. Acad. Sci. 86: 8128-8131, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2479017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2479017</a>] [<a href="https://doi.org/10.1073/pnas.86.20.8128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2479017">Hudson et al. (1989)</a> reported that the PLP gene from this pedigree was unaltered for over 4 kb of coding and noncoding sequence, that Southern blot hybridization failed to reveal any differences from the normal gene, and that a detailed restriction map of a phage lambda genomic clone from 1 patient, containing exons 1-7, also failed to uncover any differences from the normal gene. On the basis of these findings, <a href="#30" class="mim-tip-reference" title="Hudson, L. D., Puckett, C., Berndt, J., Chan, J., Gencic, S. <strong>Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder.</strong> Proc. Nat. Acad. Sci. 86: 8128-8131, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2479017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2479017</a>] [<a href="https://doi.org/10.1073/pnas.86.20.8128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2479017">Hudson et al. (1989)</a> proposed that in addition to the PLP locus another locus on the X chromosome affects myelination. However, <a href="#19" class="mim-tip-reference" title="Garbern, J. <strong>Personal Communication.</strong> Detroit, Mich. 11/2004."None>Garbern (2004)</a> provided information that affected members of the family described by <a href="#66" class="mim-tip-reference" title="Watanabe, I., Patel, V., Goebel, H. H., Siakotos, A. N., Zeman, W., DeMyer, W., Dyer, J. S. <strong>Early lesion of Pelizaeus-Merzbacher disease: electron microscopic and biochemical study.</strong> J. Neuropath. Exp. Neurol. 32: 313-333, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4123133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4123133</a>] [<a href="https://doi.org/10.1097/00005072-197304000-00010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4123133">Watanabe et al. (1973)</a> and by <a href="#67" class="mim-tip-reference" title="Wilkus, R. J., Farrell, D. F. <strong>Electrophysiologic observations in the classical form of Pelizaeus-Merzbacher disease.</strong> Neurology 26: 1042-1045, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/988510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">988510</a>] [<a href="https://doi.org/10.1212/wnl.26.11.1042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="988510">Wilkus and Farrell (1976)</a> were found to have a duplication of the PLP1 (<a href="/entry/300401#0021">300401.0021</a>) gene and therefore represent bona fide cases of Pelizaeus-Merzbacher disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2479017+4123133+988510" 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="#10" class="mim-tip-reference" title="Cailloux, F., Gauthier-Barichard, F., Mimault, C., Isabelle, V., Courtois, V., Giraud, G., Dastugue, B., Boespflug-Tanguy, O., Clinical European Network on Brain Dysmyelinating Disease. <strong>Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations.</strong> Europ. J. Hum. Genet. 8: 837-845, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11093273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11093273</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11093273">Cailloux et al. (2000)</a> investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by PCR amplification and sequencing of the 7 coding regions and splice sites of the PLP1 gene. Abnormalities were identified in 29 (56%) of the PMD and 4 (14%) of the SPG cases. Of the 33 mutations detected, 23 were missense mutations, 3 were deletion/insertions with frameshifts, and 7 were splice site mutations. Clinical severity was found to be correlated with the nature of the mutation. The severe forms of PMD were most frequently associated with missense mutations in exons 2 and 4, leading to amino acid changes at positions highly conserved in other DM proteins. The mild forms of PMD were frequently caused by mutations, resulting in the production of truncated proteins or by missense mutations. The mutations mostly affected exon 5, leading to the substitution of amino acids only partly conserved in the extracytoplasmic C-D loop. SPG was associated with splice site mutations or changes in the PLP-specific B-C loop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11093273" 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="#52" class="mim-tip-reference" title="Regis, S., Biancheri, R., Bertini, E., Burlina, A., Lualdi, S., Bianco, M. G., Devescovi, R., Rossi, A., Uziel, G., Filocamo, M. <strong>Genotype-phenotype correlation in five Pelizaeus-Merzbacher disease patients with PLP1 gene duplications.</strong> Clin. Genet. 73: 279-287, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18190592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18190592</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00961.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18190592">Regis et al. (2008)</a> found no association between clinical disease severity and size of PLP1 duplications among 5 unrelated PMD patients with PLP1 duplications ranging in size from 167-195 kb to 580-700 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18190592" 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="#11" class="mim-tip-reference" title="Carvalho, C. M. B., Bartnik, M., Pehlivan, D., Fang, P., Shen, J., Lupski, J. R. <strong>Evidence for disease penetrance relating to CNV size: Pelizaeus-Merzbacher disease and manifesting carriers with a familial 11 Mb duplication at Xq22.</strong> Clin. Genet. 81: 532-541, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21623770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21623770</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21623770[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/10.1111/j.1399-0004.2011.01716.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21623770">Carvalho et al. (2012)</a> reported a family in which a complex duplication of Xq22 was associated with variable expression of PMD in a boy, 2 of his sisters, and his mother. Array CGH and breakpoint junction sequencing in all patients identified a 56-kb duplication on Xq22 that was inserted in an inverted orientation amid an 11-Mb duplication of Xq22 that included the PLP1 gene. This rearrangement resulted in a copy number gain of PLP1; the 11-Mb duplication also included about 65 protein-coding genes, 18 of which are known to be expressed in the brain. The 3-year-old male proband had classic features of the disorder, including global developmental delay, rotary nystagmus, hypotonia with peripheral hyperreflexia, abnormal white matter signals in the cerebral hemispheres on brain MRI, and small corpus callosum, perhaps suggesting delayed myelination. Two sisters, aged around 5 and 6 years, had mild developmental delay and were in special education classes. One had mild hypotonia and periventricular white matter abnormalities. All 3 children also had a forehead nevus flammeus and deep-set eyes. The mother, who was not formally evaluated, had a history of substance abuse and had lost custody of her 5 children, perhaps consistent with some degree of developmental delay. The 2 girls had a random X-inactivation pattern in blood, but a skewed to moderate pattern favoring the normal allele in buccal cells, whereas the mother had moderate skewing in both blood and buccal cells. These findings suggested tissue-specific expression of the genomic rearrangement in the female carriers. <a href="#11" class="mim-tip-reference" title="Carvalho, C. M. B., Bartnik, M., Pehlivan, D., Fang, P., Shen, J., Lupski, J. R. <strong>Evidence for disease penetrance relating to CNV size: Pelizaeus-Merzbacher disease and manifesting carriers with a familial 11 Mb duplication at Xq22.</strong> Clin. Genet. 81: 532-541, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21623770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21623770</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21623770[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/10.1111/j.1399-0004.2011.01716.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21623770">Carvalho et al. (2012)</a> hypothesized that the large size of the rearrangement was responsible for increased penetrance in these females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21623770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bahrambeigi, V., Song, X., Sperle, K., Beck, C. R., Hijazi, H., Grochowski, C. M., Gu, S., Seeman, P., Woodward, K. J., Carvalho, C. M. B., Hobson, G. M., Lupski, J. R. <strong>Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants.</strong> Genome Med. 11: 80, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31818324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31818324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31818324[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/10.1186/s13073-019-0676-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31818324">Bahrambeigi et al. (2019)</a> analyzed genomic rearrangements in 50 unrelated male patients with Pelizaeus-Merzbacher disease and PLP1 copy number gains. Analysis with a high-density customized array showed that 33 patients had single duplications, ranging from 122 kb to approximately 4.5 Mb, and 17 patients had complex genomic rearrangements (CGR). Of the CGR patients, 9 had a pattern of interspersed duplications separated by a copy neutral region, 3 had a triplication flanked by duplications, and rearrangements with other complexities were identified in the other 5 individuals. In 40 of the 50 patients, the authors ascertained at least one breakpoint junction via PCR amplification. Microhomology was found in 26% of sequenced join-points, ranging from 2 to 9 bp, and evidence for microhomeology was observed in approximately 33% of join-points. <a href="#2" class="mim-tip-reference" title="Bahrambeigi, V., Song, X., Sperle, K., Beck, C. R., Hijazi, H., Grochowski, C. M., Gu, S., Seeman, P., Woodward, K. J., Carvalho, C. M. B., Hobson, G. M., Lupski, J. R. <strong>Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants.</strong> Genome Med. 11: 80, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31818324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31818324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31818324[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/10.1186/s13073-019-0676-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31818324">Bahrambeigi et al. (2019)</a> also performed a metaanalysis of published PLP1 rearrangements, including 159 join-points from 124 unrelated individuals. They found single duplications in 55% of individuals and a triplication flanked by duplications as the most common CGR in 20% of individuals. In approximately 32% of join-points, there was evidence for microhomeology, and in 22% of cases of join-points, there was evidence for microhomology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31818324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a retrospective hospital- and clinic-based study involving 122 children with an inherited leukodystrophy, <a href="#7" class="mim-tip-reference" title="Bonkowsky, J. L., Nelson, C., Kingston, J. L., Filloux, F. M., Mundorff, M. B., Srivastava, R. <strong>The burden of inherited leukodystrophies in children.</strong> Neurology 75: 718-725, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20660364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20660364</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181eee46b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20660364">Bonkowsky et al. (2010)</a> found that the most common diagnoses were metachromatic leukodystrophy (<a href="/entry/250100">250100</a>) (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (<a href="/entry/300100">300100</a>) (4.1%). No final diagnosis was reported in 51% of patients. The disorder was severe: epilepsy was found in 49%, mortality was 34%, and the average age at death was 8.2 years. The population incidence of leukodystrophy in general was found to be 1 in 7,663 live births. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20660364" 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="#58" class="mim-tip-reference" title="Sidman, R. L., Dickie, M. M., Appel, S. H. <strong>Mutant mice (quaking and jimpy) with deficient myelination in the central nervous system.</strong> Science 144: 309-311, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14169723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14169723</a>] [<a href="https://doi.org/10.1126/science.144.3616.309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14169723">Sidman et al. (1964)</a> described 'jimpy,' an X-linked demyelination disorder in mice, which is similar to Pelizaeus-Merzbacher disease in man. The jimpy mutation was shown by <a href="#44" class="mim-tip-reference" title="Nave, K.-A., Lai, C., Bloom, F. E., Milner, R. J. <strong>Jimpy mutant mouse: a 74-base deletion in the mRNA for myelin proteolipid protein and evidence for a primary defect in RNA splicing.</strong> Proc. Nat. Acad. Sci. 83: 9264-9268, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3466187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3466187</a>] [<a href="https://doi.org/10.1073/pnas.83.23.9264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3466187">Nave et al. (1986)</a> to reside in the gene for PLP and to be of such a nature that it leads to an incorrectly spliced RNA transcript. They observed a 74-base deletion in the mRNA for PLP. Also see <a href="#13" class="mim-tip-reference" title="Dautigny, A., Mattei, M.-G., Morello, D., Alliel, P. M., Pham-Dinh, D., Amar, L., Arnaud, D., Simon, D., Mattei, J.-F., Guenet, J.-L., Avner, P. <strong>The structural gene coding for myelin-associated proteolipid protein is mutated in jimpy mice.</strong> Nature 321: 867-869, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2425262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2425262</a>] [<a href="https://doi.org/10.1038/321867a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2425262">Dautigny et al. (1986)</a>. <a href="#29" class="mim-tip-reference" title="Hudson, L. D., Berndt, J. A., Puckett, C., Kozak, C. A., Lazzarini, R. A. <strong>Aberrant splicing of proteolipid protein mRNA in the dysmyelinating jimpy mutant mouse.</strong> Proc. Nat. Acad. Sci. 84: 1454-1458, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3469678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3469678</a>] [<a href="https://doi.org/10.1073/pnas.84.5.1454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3469678">Hudson et al. (1987)</a> found that PLP in jimpy mice lacks amino acids 208-232; however, the region is present in the jimpy PLP-encoding gene. The authors proposed that the jimpy mutant has a point mutation or a deletion of a few bases that alters the normal splicing pattern and generates partially deleted PLP transcripts. <a href="#30" class="mim-tip-reference" title="Hudson, L. D., Puckett, C., Berndt, J., Chan, J., Gencic, S. <strong>Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder.</strong> Proc. Nat. Acad. Sci. 86: 8128-8131, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2479017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2479017</a>] [<a href="https://doi.org/10.1073/pnas.86.20.8128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2479017">Hudson et al. (1989)</a> pointed out that absence of PLP produces more devastating effects than those of dysmyelination; a block in oligodendrocyte maturation is evident in jimpy mutant mice, and mature oligodendrocytes are absent from both jimpy and Pelizaeus-Merzbacher brains. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3469678+2425262+2479017+14169723+3466187" 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="Feutz, A.-C., Bellomi, I., Allinquant, B., Schladenhaufen, Y., Ghandour, M. S. <strong>Isolation and characterization of defective jimpy oligodendrocytes in culture.</strong> J. Neurocytol. 24: 865-877, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8576715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8576715</a>] [<a href="https://doi.org/10.1007/BF01179985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8576715">Feutz et al. (1995)</a> demonstrated that jimpy oligodendrocytes in tissue culture were unresponsive to basic fibroblast growth factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8576715" 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="Gencic, S., Hudson, L. D. <strong>Conservative amino acid substitution in the myelin proteolipid protein of jimpy-msd mice.</strong> J. Neurosci. 10: 117-124, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1688931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1688931</a>] [<a href="https://doi.org/10.1523/JNEUROSCI.10-01-00117.1990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1688931">Gencic and Hudson (1990)</a> demonstrated that the jimpy-msd (myelin synthesis deficient) mouse has an ala242-to-val (A242V; <a href="/entry/300401#0019">300401.0019</a>) mutation in the Plp1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1688931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate the pathogenetic mechanism of the PLP mutation in the jimpy mouse, <a href="#56" class="mim-tip-reference" title="Schneider, A., Griffiths, I. R., Readhead, C., Nave, K.-A. <strong>Dominant-negative action of the jimpy mutation in mice complemented with an autosomal transgene for myelin proteolipid protein.</strong> Proc. Nat. Acad. Sci. 92: 4447-4451, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7538670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7538670</a>] [<a href="https://doi.org/10.1073/pnas.92.10.4447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7538670">Schneider et al. (1995)</a> took advantage of the X-linkage of the gene and complemented jimpy with a wildtype PLP transgene. In this artificial heterozygous situation, the jimpy mutation emerged as genetically dominant. At the cellular level, oligodendrocytes showed little increase in survival although PLP gene and the autosomal transgene were coexpressed. In surviving oligodendrocytes, wildtype PLP was functional and immunodetectable in myelin. Moreover, compacted myelin sheaths regained their normal periodicity. This suggested that, despite the presence of functional wildtype PLP, misfolded jimpy PLP is by itself the primary cause of abnormal oligodendrocyte death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7538670" 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="#38" class="mim-tip-reference" title="Koeppen, A. H., Barron, K. D., Csiza, C. K., Greenfield, E. A. <strong>Comparative immunocytochemistry of Pelizaeus-Merzbacher disease, the jimpy mouse, and the myelin-deficient rat.</strong> J. Neurol. Sci. 84: 315-327, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2454299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2454299</a>] [<a href="https://doi.org/10.1016/0022-510x(88)90135-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2454299">Koeppen et al. (1988)</a> and <a href="#5" class="mim-tip-reference" title="Boison, D., Stoffel, W. <strong>Myelin-deficient rat: a point mutation in exon III (A-to-C, thr75-to-pro) of the myelin proteolipid protein causes dysmyelination and oligodendrocyte death.</strong> EMBO J. 8: 3295-3302, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2479544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2479544</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1989.tb08490.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2479544">Boison and Stoffel (1989)</a> showed that the X-linked 'myelin deficiency' mutation (md) in the rat is homologous to PMD. <a href="#14" class="mim-tip-reference" title="Duncan, I. D., Hammang, J. P., Trapp, B. D. <strong>Abnormal compact myelin in the myelin-deficient rat: absence of proteolipid protein correlates with a defect in the intraperiod line.</strong> Proc. Nat. Acad. Sci. 84: 6287-6291, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3476944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3476944</a>] [<a href="https://doi.org/10.1073/pnas.84.17.6287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3476944">Duncan et al. (1987)</a> presented evidence that a defect in the PLP gene is responsible for the hypomyelination. The myelinated fibers were found to be positive for myelin basic protein (<a href="/entry/159430">159430</a>) but negative for PLP. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2479544+2454299+3476944" 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="#57" class="mim-tip-reference" title="Schneider, A., Montague, P., Griffiths, I., Fanarraga, M., Kennedy, P., Brophy, P., Nave, K.-A. <strong>Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene.</strong> Nature 358: 758-761, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1380672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1380672</a>] [<a href="https://doi.org/10.1038/358758a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1380672">Schneider et al. (1992)</a> demonstrated that the mouse mutant 'rumpshaker' (rsh) has an ile186-to-thr (I186T; <a href="/entry/300401#0013">300401.0013</a>) mutation in a membrane-embedded domain of PLP. Surprisingly, 'rumpshaker' mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes. Hypomyelination can thus be genetically separated from PLP-dependent oligodendrocyte degeneration. <a href="#57" class="mim-tip-reference" title="Schneider, A., Montague, P., Griffiths, I., Fanarraga, M., Kennedy, P., Brophy, P., Nave, K.-A. <strong>Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene.</strong> Nature 358: 758-761, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1380672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1380672</a>] [<a href="https://doi.org/10.1038/358758a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1380672">Schneider et al. (1992)</a> suggested that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1380672" 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>Paralytic tremor (pt) is a sex-linked disorder in chinchilla rabbits that causes body tremor and limb paralysis in association with hypomyelination in the central nervous system but normal myelin in the peripheral nervous system. The number of oligodendrocytes is not reduced nor is there premature death of oligodendrocytes, although the myelin is 30% of normal. In pt rabbits, <a href="#61" class="mim-tip-reference" title="Tosic, M., Dolivo, M., Domanska-Janik, K., Matthieu, J.-M. <strong>Paralytic tremor (pt): a new allele of the proteolipid protein gene in rabbits.</strong> J. Neurochem. 63: 2210-2216, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7525875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7525875</a>] [<a href="https://doi.org/10.1046/j.1471-4159.1994.63062210.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7525875">Tosic et al. (1994)</a> demonstrated a T-to-A transversion in exon 2 of the proteolipid protein gene which would cause a substitution of histidine by glutamine at the end of the first potential transmembrane domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7525875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Klugmann, M., Schwab, M. H., Puhlhofer, A., Schneider, A., Zimmermann, F., Griffiths, I. R., Nave, K.-A. <strong>Assembly of CNS myelin in the absence of proteolipid protein.</strong> Neuron 18: 59-70, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9010205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9010205</a>] [<a href="https://doi.org/10.1016/s0896-6273(01)80046-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9010205">Klugmann et al. (1997)</a> generated mice deficient in PLP and DM20 by targeted disruption. Mutant mice that lacked expression of the Plp gene failed to exhibit the known dysmyelinated phenotype. Unable to encode PLP/DM20 or PLP-related polypeptides, oligodendrocytes were still competent to myelinate CNS axons of all calibers and to assemble compact myelin sheaths. Ultrastructurally, however, the electron-dense intraperiod lines in myelin remained condensed, correlating with its reduced physical stability. <a href="#37" class="mim-tip-reference" title="Klugmann, M., Schwab, M. H., Puhlhofer, A., Schneider, A., Zimmermann, F., Griffiths, I. R., Nave, K.-A. <strong>Assembly of CNS myelin in the absence of proteolipid protein.</strong> Neuron 18: 59-70, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9010205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9010205</a>] [<a href="https://doi.org/10.1016/s0896-6273(01)80046-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9010205">Klugmann et al. (1997)</a> concluded that after myelin compaction, PLP forms a stabilizing membrane junction, similar to a zipper. They stated that dysmyelination and oligodendrocyte death emerge as an epiphenomenon of other PLP mutations and have been uncoupled in the PLP null allele from the risk of premature myelin breakdown. <a href="#24" class="mim-tip-reference" title="Griffiths, I., Klugmann, M., Anderson, T., Yool, D., Thomson, C., Schwab, M. H., Schneider, A., Zimmermann, F., McCulloch, M., Nadon, N., Nave, K.-A. <strong>Axonal swellings and degeneration in mice lacking the major proteolipid of myelin.</strong> Science 280: 1610-1613, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9616125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9616125</a>] [<a href="https://doi.org/10.1126/science.280.5369.1610" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9616125">Griffiths et al. (1998)</a> showed that Plp-Dm20 -/- mice assembled compact myelin sheaths but subsequently developed widespread axonal swellings and degeneration, associated predominantly with small-caliber nerve fibers. Similar swellings were absent in dysmyelinated shiverer mice, which lack myelin basic protein (MBP), but recurred in MBP/Plp double mutants. <a href="#24" class="mim-tip-reference" title="Griffiths, I., Klugmann, M., Anderson, T., Yool, D., Thomson, C., Schwab, M. H., Schneider, A., Zimmermann, F., McCulloch, M., Nadon, N., Nave, K.-A. <strong>Axonal swellings and degeneration in mice lacking the major proteolipid of myelin.</strong> Science 280: 1610-1613, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9616125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9616125</a>] [<a href="https://doi.org/10.1126/science.280.5369.1610" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9616125">Griffiths et al. (1998)</a> concluded that fiber degeneration, which was probably secondary to impaired axonal transport, could indicate that myelinated axons require local oligodendroglial support. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9616125+9010205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The 'shaking pup' (<a href="#43" class="mim-tip-reference" title="Nadon, N. L., Duncan, I. D., Hudson, L. D. <strong>A point mutation in the proteolipid protein gene of the 'shaking pup' interrupts oligodendrocyte development.</strong> Development 110: 529-537, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1723945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1723945</a>] [<a href="https://doi.org/10.1242/dev.110.2.529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1723945">Nadon et al., 1990</a>) is a PLP mutation in the dog. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1723945" 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="#51" class="mim-tip-reference" title="Readhead, C., Schneider, A., Griffiths, I., Nave, K.-A. <strong>Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage.</strong> Neuron 12: 583-595, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7512350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7512350</a>] [<a href="https://doi.org/10.1016/0896-6273(94)90214-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7512350">Readhead et al. (1994)</a> generated normal mouse lines expressing autosomal copies of the wildtype Plp gene and found that a 2-fold increase in Plp gene dosage resulted in hypomyelination, astrocytosis, seizures, and premature death. They concluded that the myelination process is exquisitely sensitive to the accurate level of PLP gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7512350" 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="#49" class="mim-tip-reference" title="Prukop, T., Epplen, D. B., Nientiedt, T., Wichert, S. P., Fledrich, R., Stassart, R. M., Rossner, M. J., Edgar, J. M., Werner, H. B., Nave, K.-A., Sereda, M. W. <strong>Progesterone antagonist therapy in a Pelizaeus-Merzbacher mouse model.</strong> Am. J. Hum. Genet. 94: 533-546, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24680886/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24680886</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24680886[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.2014.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24680886">Prukop et al. (2014)</a> studied the transgenic mouse strain developed by <a href="#51" class="mim-tip-reference" title="Readhead, C., Schneider, A., Griffiths, I., Nave, K.-A. <strong>Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage.</strong> Neuron 12: 583-595, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7512350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7512350</a>] [<a href="https://doi.org/10.1016/0896-6273(94)90214-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7512350">Readhead et al. (1994)</a> with a 2-fold increase in Plp1 gene dosage. Treatment with the nuclear progesterone receptor (PGR; <a href="/entry/607311">607311</a>) antagonist Lonaprisan reduced Plp1 mRNA in the central nervous system of treated transgenic mice compared to controls. After 10 weeks of therapy, treated mice showed less progression of neurologic signs compared to controls, suggesting a dosage effect of Plp1 on the motor phenotype. Lonaprisan also increased the number of myelinated axons in the corticospinal tract of mutant mice compared to untreated mice. However, Lonaprisan did not influence the extent of hypomyelination and did not alter the number of unmyelinated axons. The findings suggested that overexpression of Plp1 in oligodendrocytes leads to the loss of myelinated axons via a gain of function. Microarray and RT-PCR analysis of mouse brain indicated that Lonaprisan downregulated genes involved in apoptosis, including Bax (<a href="/entry/600040">600040</a>) and Casp7 (<a href="/entry/601761">601761</a>). Lonaprisan also prevented oligodendrocyte loss and reduced astrogliosis in mutant mouse brains. The study offered a proof of principle that pharmacologic targeting of the nuclear progesterone receptor, which is a transcription factor, can inhibit Plp1 expression in animals with increased Plp1 dosage, resulting in an amelioration of axonal loss and slowing of disease progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24680886+7512350" 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 family reported by Wolfslast (1943), with what he termed spastic diplegia, is an example of X-linked spastic paraplegia. One affected male was living at age 50 years and a second at age 20 years. Nystagmus was described in a female carrier. However, <a href="#3" class="mim-tip-reference" title="Becker, P. E. <strong>Personal Communication.</strong> Goettingen, Germany 1961."None>Becker (1961)</a> expressed the opinion that Wolfslast's family suffered from the Pelizaeus-Merzbacher syndrome, and <a href="#64" class="mim-tip-reference" title="Verschuer, O. <strong>Lehrbuch der Humangenetik.</strong> Munich: Urban und Schwarzenberg (pub.) 1958."None>Verschuer (1958)</a> stated the same opinion.</p>
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<strong>Pelizaeus-Merzbacher disease: a study in nosology.</strong>
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J. Neuropath. Exp. Neurol. 23: 334-354, 1964.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14137679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14137679</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14137679" 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/10.1097/00005072-196404000-00008" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 10/20/2020
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Cassandra L. Kniffin - updated : 4/28/2014<br>Cassandra L. Kniffin - updated : 5/20/2013<br>Cassandra L. Kniffin - updated : 6/28/2012<br>Cassandra L. Kniffin - updated : 10/20/2010<br>Cassandra L. Kniffin - updated : 6/25/2010<br>Cassandra L. Kniffin - updated : 10/16/2009<br>Cassandra L. Kniffin - updated : 9/8/2008<br>Cassandra L. Kniffin - updated : 5/6/2008<br>Ada Hamosh - updated : 7/25/2007<br>Cassandra L. Kniffin - updated : 5/4/2006<br>Cassandra L. Kniffin - updated : 11/29/2005<br>Cassandra L. Kniffin - updated : 11/4/2005<br>Victor A. McKusick - updated : 1/19/2005<br>Cassandra L. Kniffin - updated : 11/9/2004<br>Cassandra L. Kniffin - reorganized : 8/28/2002<br>Victor A. McKusick - updated : 1/14/2002<br>Victor A. McKusick - updated : 3/15/2001<br>Michael B. Petersen - updated : 2/12/2001<br>Victor A. McKusick - updated : 9/11/2000<br>George E. Tiller - updated : 5/2/2000<br>Stylianos E. Antonarakis - updated : 5/1/2000<br>Victor A. McKusick - updated : 1/11/2000<br>Victor A. McKusick - updated : 6/18/1999<br>Victor A. McKusick - updated : 2/14/1999<br>Victor A. McKusick - updated : 7/22/1998<br>Victor A. McKusick - updated : 2/25/1998<br>Victor A. McKusick - updated : 2/19/1998<br>Victor A. McKusick - updated : 5/15/1997<br>Iosif W. Lurie - updated : 7/4/1996<br>Orest Hurko - updated : 4/1/1996<br>Orest Hurko - updated : 2/22/1996<br>Orest Hurko - updated : 9/8/1995
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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alopez : 01/17/2024
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ckniffin : 01/17/2024<br>carol : 03/02/2023<br>carol : 02/28/2023<br>alopez : 02/14/2023<br>ckniffin : 02/13/2023<br>alopez : 01/10/2022<br>ckniffin : 12/30/2021<br>alopez : 05/20/2021<br>ckniffin : 05/17/2021<br>alopez : 05/04/2021<br>ckniffin : 04/30/2021<br>carol : 11/10/2020<br>ckniffin : 10/22/2020<br>carol : 10/20/2020<br>alopez : 12/09/2019<br>ckniffin : 12/03/2019<br>alopez : 04/30/2019<br>ckniffin : 04/29/2019<br>alopez : 06/05/2018<br>ckniffin : 06/04/2018<br>carol : 05/08/2018<br>ckniffin : 05/07/2018<br>carol : 05/02/2018<br>ckniffin : 05/01/2018<br>carol : 03/05/2018<br>ckniffin : 03/05/2018<br>carol : 08/09/2017<br>carol : 06/15/2017<br>alopez : 10/17/2016<br>carol : 07/09/2016<br>carol : 4/4/2016<br>alopez : 4/1/2016<br>ckniffin : 3/24/2016<br>carol : 1/12/2016<br>ckniffin : 12/8/2015<br>carol : 7/29/2015<br>ckniffin : 7/29/2015<br>carol : 6/18/2015<br>ckniffin : 6/15/2015<br>alopez : 12/18/2014<br>ckniffin : 12/16/2014<br>carol : 4/30/2014<br>mcolton : 4/29/2014<br>ckniffin : 4/28/2014<br>carol : 6/20/2013<br>ckniffin : 6/10/2013<br>carol : 5/30/2013<br>ckniffin : 5/20/2013<br>carol : 7/2/2012<br>ckniffin : 6/28/2012<br>carol : 12/8/2011<br>ckniffin : 12/7/2011<br>terry : 10/10/2011<br>wwang : 2/10/2011<br>ckniffin : 2/4/2011<br>ckniffin : 2/4/2011<br>wwang : 10/29/2010<br>ckniffin : 10/20/2010<br>carol : 7/30/2010<br>wwang : 7/6/2010<br>ckniffin : 6/25/2010<br>wwang : 11/6/2009<br>ckniffin : 10/16/2009<br>ckniffin : 7/14/2009<br>wwang : 1/13/2009<br>wwang : 12/2/2008<br>ckniffin : 11/26/2008<br>wwang : 9/12/2008<br>ckniffin : 9/8/2008<br>wwang : 5/12/2008<br>ckniffin : 5/6/2008<br>alopez : 8/2/2007<br>alopez : 8/2/2007<br>terry : 7/25/2007<br>carol : 3/28/2007<br>carol : 11/28/2006<br>carol : 5/10/2006<br>ckniffin : 5/4/2006<br>wwang : 12/5/2005<br>ckniffin : 11/29/2005<br>wwang : 11/15/2005<br>ckniffin : 11/4/2005<br>terry : 3/3/2005<br>carol : 1/19/2005<br>carol : 11/10/2004<br>ckniffin : 11/9/2004<br>cwells : 11/5/2003<br>carol : 5/28/2003<br>carol : 11/15/2002<br>ckniffin : 11/14/2002<br>carol : 8/28/2002<br>ckniffin : 8/28/2002<br>ckniffin : 7/16/2002<br>ckniffin : 7/16/2002<br>carol : 7/9/2002<br>mcapotos : 1/15/2002<br>terry : 1/14/2002<br>mcapotos : 3/26/2001<br>mcapotos : 3/22/2001<br>terry : 3/15/2001<br>cwells : 2/13/2001<br>cwells : 2/12/2001<br>cwells : 1/18/2001<br>terry : 1/10/2001<br>carol : 11/9/2000<br>mcapotos : 9/27/2000<br>mcapotos : 9/18/2000<br>terry : 9/11/2000<br>alopez : 5/2/2000<br>mgross : 5/1/2000<br>mgross : 5/1/2000<br>alopez : 2/23/2000<br>mgross : 2/3/2000<br>terry : 1/11/2000<br>alopez : 11/29/1999<br>jlewis : 6/25/1999<br>terry : 6/18/1999<br>carol : 4/21/1999<br>carol : 2/14/1999<br>terry : 7/22/1998<br>terry : 7/22/1998<br>carol : 3/30/1998<br>terry : 3/18/1998<br>mark : 2/25/1998<br>terry : 2/19/1998<br>mark : 7/8/1997<br>jenny : 5/15/1997<br>terry : 5/12/1997<br>jamie : 1/21/1997<br>terry : 1/15/1997<br>mark : 8/10/1996<br>terry : 8/9/1996<br>terry : 8/1/1996<br>carol : 7/21/1996<br>carol : 7/4/1996<br>mark : 6/7/1996<br>mark : 6/7/1996<br>mark : 6/7/1996<br>mark : 6/7/1996<br>terry : 6/7/1996<br>terry : 5/30/1996<br>terry : 4/15/1996<br>terry : 4/1/1996<br>terry : 4/1/1996<br>terry : 3/22/1996<br>mark : 3/5/1996<br>mark : 3/4/1996<br>mark : 2/22/1996<br>terry : 2/20/1996<br>mark : 11/6/1995<br>terry : 3/29/1995<br>davew : 8/22/1994<br>jason : 7/20/1994<br>pfoster : 4/25/1994
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<span class="mim-font">
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<strong>#</strong> 312080
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<span class="mim-font">
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PELIZAEUS-MERZBACHER DISEASE; PMD
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<em>Alternative titles; symbols</em>
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LEUKODYSTROPHY, HYPOMYELINATING, 1; HLD1
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<strong>SNOMEDCT:</strong> 64855000;
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<strong>ICD10CM:</strong> E75.27;
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<strong>ORPHA:</strong> 280210, 280219, 280224, 280229, 280234, 702;
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<strong>DO:</strong> 3210;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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<span class="mim-font">
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Xq22.2
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<span class="mim-font">
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Pelizaeus-Merzbacher disease
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<span class="mim-font">
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312080
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<span class="mim-font">
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X-linked recessive
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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PLP1
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<span class="mim-font">
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300401
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because Pelizaeus-Merzbacher disease (PMD) is caused by mutation in the PLP1 gene (300401), which encodes proteolipid protein-1, on chromosome Xq22.</p><p>Spastic paraplegia-2 (SPG2; 312920) is an allelic disorder.</p>
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<span class="mim-font">
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<strong>Description</strong>
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<p>Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelinating leukodystrophy (HLD1) in which myelin is not formed properly in the central nervous system. PMD is characterized clinically by nystagmus, spastic quadriplegia, ataxia, and developmental delay (summary by Inoue, 2005). </p><p><strong><em>Genetic Heterogeneity of Hypomyelinating Leukodystrophy</em></strong></p><p>
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Other forms of hypomyelinating leukodystrophy include HLD2 (608804), caused by mutation in the GJC2/GJA12 gene (608803) on chromosome 1q41; HLD3 (260600), caused by mutation in the AIMP1 gene (603605) on chromosome 4q24; HLD4 (612233), caused by mutation in the HSPD1 gene (118190) on chromosome 2q33.1; HLD5 (610532), caused by mutation in the FAM126A gene (610531) on chromosome 7p15; HLD6 (612438), caused by mutation in the TUBB4A gene (602662) on chromosome 19p13; HLD7 (607694), caused by mutation in the POLR3A gene (614258) on chromosome 10q22; HLD8 (614381), caused by mutation in the POLR3B gene (614366) on chromosome 12q23; HLD9 (616140), caused by mutation in the RARS gene (107820) on chromosome 5; HLD10 (616420), caused by mutation in the PYCR2 gene (616406) on chromosome 1q42; HLD11 (616494), caused by mutation in the POLR1C gene (610060) on chromosome 6p21; HLD12 (616683), caused by mutation in the VPS11 gene (608549) on chromosome 11q23; HLD13 (616881) caused by mutation in the HIKESHI gene (614908) on chromosome 11q14; HLD14 (617899), caused by mutation in the UFM1 gene (610553) on chromosome 13q13; HLD15 (617951), caused by mutation in the EPRS gene (138295) on chromosome 1q41; HLD16 (617964), caused by mutation in the TMEM106B gene (613413) on chromosome 7p21; HLD17 (618006), caused by mutation in the AIMP2 gene (600859) on chromosome 7p22; HLD18 (618404), caused by mutation in the DEGS1 gene (615843) on chromosome 1q42; HLD19 (618688), caused by mutation in the TMEM63A gene (618685) on chromosome 1q42; HLD20 (619071), caused by mutation in the CNP gene (123830) on chromosome 17q21; HLD21 (619310), caused by mutation in the POLR3K gene (606007) on chromosome 16p13; HLD22 (619328), caused by mutation in the CLDN11 gene (601326) on chromosome 3q26; HLD23 (619688), caused by mutation in the RNF220 gene (616136) on chromosome 1p34; HLD24 (619851), caused by mutation in the ATP11A gene (605868) on chromosome 13q34; HLD25 (620243), caused by mutation in the TMEM163 gene (618978) on chromosome 2q21; HLD26 (620269), caused by mutation in the SLC35B2 gene (610788) on chromosome 6p21; and HLD27 (620675), caused by mutation in the POLR1A gene (616404) on chromosome 2p11.</p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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<p>Tyler (1958) noted that at first, rotary movements of the head and eyes develop but curiously may later disappear. Affected children in these families were sometimes described as 'head nodders' and 'eye waggers.' Spasticity of the legs and later the arms, cerebellar ataxia, dementia, and parkinsonian symptoms are other features developing over the first decade or two of life. </p><p>Ford (1960) referred to Pelizaeus-Merzbacher disease as the chronic infantile type of diffuse cerebral sclerosis. PMD begins in infancy as early as the eighth day and usually no later than the third month and is very slowly progressive so that the victim may survive to middle age. Initial symptoms are pendular eye movements, head shaking, hypotonia, choreoathetosis, and pyramidal signs. The myelin of the peripheral nervous system is not involved in nerve conduction and velocities are normal.</p><p>Renier et al. (1981) recognized 3 types of Pelizaeus-Merzbacher disease. (1) The classic type, with onset in infancy and death in late adolescence or young adulthood, is characterized by initial signs of nystagmoid eye movement and jerking and rolling head movements or head tremor. Nystagmus disappears and, as the patient matures, ataxia, spasticity, and involuntary movements become manifest, as well as optic atrophy, microcephaly, and subnormal somatic development. (2) The connatal type shows rapid progression and is fatal in infancy or childhood. (3) The transitional form is intermediate. Stridor in early life is a manifestation in some cases of PMD. A possible relation of the X-linked laryngeal abductor paralysis with mental deficiency (308850) to the connatal form was proposed. </p><p>Kaye et al. (1994) reported 2 brothers who demonstrated neonatal hypotonia and hyporeflexia and were found to have mutations in the PLP1 gene. The authors suggested that peripheral nervous system myelin may be affected in PMD, yielding a clinical picture suggestive of spinal muscular atrophy. </p><p>One of the patients of Pelizaeus (1885) lived to 52 years of age, and in the family reported by Tyler (1958) an affected male was still living at age 51. Johnson et al. (1991) studied a 5-generation family in which 6 persons had PMD type I. One patient was 45 years old at the time of report. 'Wavering eyes' and 'floppy head' were noted at the age of a few weeks as the first sign. </p><p>Hanefeld et al. (2005) performed quantitative proton magnetic resonance spectroscopy (MRS) on 5 children with genetically confirmed PMD. Compared to age-matched controls, affected white matter in PMD patients resembled the metabolite pattern of cortical gray matter, as indicated by increased concentrations of N-acetylaspartate and N-acetylaspartylglutamate, glutamine, myoinositol, and creatine and phosphocreatine. The concentration of choline-containing compounds was reduced. The findings were consistent with enhanced neuroaxonal density, astrogliosis, and reduction of oligodendroglia, suggestive of dys- and hypomyelination. </p><p>Stevenson et al. (2009) reported follow-up of a 2-generation African American family with X-linked spastic paraplegia, originally reported by Arena et al. (1992). Arena et al. (1992) described 5 affected males who had severe mental retardation, lower limb spasticity and atrophy, absent or dysarthric speech, and impaired ambulation requiring wheelchairs from childhood. Other features included nystagmus, dystonic posturing, and ataxia. Brain imaging studies showed macrogyria, lack of myelination, and increased paramagnetic signal suggestive of iron deposition. Stevenson et al. (2009) identified a hemizygous mutation in the PLP1 gene (D58Y; 300401.0027) in all affected individuals, confirming that the disorder was in fact PMD. Stevenson et al. (2009) noted that, although altered signals in the basal ganglia and thalamus are not specific for iron deposition, MRI findings suggestive of iron deposition in the basal ganglia have been reported in other patients with PMD. </p><p><strong><em>Carrier Females</em></strong></p><p>
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Some heterozygous females have manifestations of the disorder. The brain of such a female in the family reported by Merzbacher (1909) was studied by Spielmeyer (cited by Tyler, 1958) with demonstration of changes. In a large family in which PMD was segregating (reported by Zeman et al., 1964) and linked to a mutation in PLP by Trofatter et al. (1989), Hodes et al. (1995) observed a heterozygous female infant with typical neurologic signs and with magnetic resonance imaging (MRI) of the brain and brain auditory evoked response consistent with the diagnosis of PMD. The mother and grandmother, who were likewise heterozygous for the leu14-to-pro mutation (300401.0003), were neurologically normal and showed normal MRIs of the brain. </p><p>Warshawsky et al. (2005) reported a 49-year-old woman with a history of progressive gait disturbance, white matter disease, and CSF immunoglobulin abnormalities who met criteria for primary progressive multiple sclerosis (MS; 126200). She and her son, who died at age 10 years of an unknown congenital neurodevelopmental disorder, were found to have a mutation in the PLP1 gene, confirming a diagnosis of Pelizaeus-Merzbacher disease. Warshawsky et al. (2005) noted that the finding of an affected mother of a severely affected boy with PMD was contrary to the current belief that mothers of severely affected sons are asymptomatic as adults. </p><p>Carrier females with the submicroscopic duplication in the PLP gene that causes PMD are usually asymptomatic. Inoue et al. (2001) described 2 unrelated female patients who presented with mild PMD or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results improved dramatically over a 10-year period. The other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, also showed clinical improvement. Interphase fluorescence in situ hybridization analyses identified a PLP gene duplication in both patients. The same analyses in family members indicated that the duplication in both patients occurred as a de novo event. Neither skewing of X inactivation in the peripheral lymphocytes nor PLP gene coding alterations were identified in either patient. These findings indicated that females with a PLP gene duplication can occasionally manifest an early-onset neurologic phenotype. Inoue et al. (2001) hypothesized that the remarkable clinical improvement was a result of myelin compensation by oligodendrocytes expressing 1 copy of the PLP gene secondary to selection for a favorable X-inactivation pattern. These findings indicated plasticity of oligodendrocytes in the formation of central nervous system myelin and suggested a potential role for stem cell transplantation therapies. </p><p>Using clinical data compiled from a chart review at Wayne State University comprising 40 pedigrees with PMD including 55 males and 56 carrier females, Hurst et al. (2006) investigated neurologic symptoms in carrier females. They categorized patients according to disease severity and type of genetic lesion within the PLP1 gene and then analyzed the clinical data using nonparametric t tests and analyses of variance. Hurst et al. (2006) concluded that their analyses formally demonstrated the link between mild disease in males and symptoms in carrier female relatives. Conversely, mutations causing severe disease in males rarely caused clinical signs in carrier females. The greatest risk of disease in females was found for nonsense/indel or null mutations. Missense mutations carried moderate risk. The lowest risk, which represents the bulk of families with PMD, was associated with PLP1 gene duplications. Hurst et al. (2006) concluded that effective genetic counseling of PMD and spastic paraplegia carrier females must include an assessment of disease severity in affected male relatives. </p><p>Marble et al. (2007) reported 2 brothers with classic PMD resulting from a truncating mutation in the PLP1 gene. Three carrier females in the family developed clumsiness, excessive falling, and gait disturbances in the fourth decade of life. Other clinical findings included hyperreflexia, wide-based gait, tremor, and extensor plantar responses. There was also mild cognitive deterioration. X-inactivation studies showed mild skewing (85:15) only in 1 of the carriers. </p>
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<span class="mim-font">
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<strong>Diagnosis</strong>
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<p>Schinzel et al. (1988) and Boltshauser et al. (1988) suggested that MRI may be a suitable means for carrier detection. In obligate carriers they demonstrated bilateral multiple areas with signal hyperintensity in the periventricular and subcortical white matter. </p><p>Feldman et al. (1990) described stridor and respiratory difficulties at birth as well as polyhydramnios during pregnancy. Tracheomalacia was suspected. Typical abnormalities of the auditory brainstem responses were suggested as a means of early diagnosis. </p><p>Woodward et al. (1998) confirmed that PLP overdosage is an important genetic abnormality in PMD and showed that interphase fluorescence in situ hybridization is a reliable technique that will facilitate diagnosis and carrier detection. They characterized the duplication breakpoints in 4 families and suggested origin and mechanisms for the rearrangements. The importance of gene dosage in myelin disorders was highlighted. </p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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Bridge et al. (1991) performed carrier detection and prenatal diagnosis by means of an intragenic MspI polymorphism of the PLP gene and closely linked DNA markers. </p><p>Boespflug-Tanguy et al. (1994) suggested that RFLP analysis could be used to improve genetic counseling for the 75 to 90% of affected families in which a PLP exon mutation cannot be demonstrated. </p><p>Woodward et al. (1999) used interphase FISH in lymphocyte preparations for prenatal diagnosis of PMD in a family with the disorder. The fetus was determined to be unaffected. </p><p><strong><em>Differential Diagnosis</em></strong></p><p>
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In a retrospective study of neurophysiologic results from 10 patients with PMD-like disease (PMLD1; 608804) caused by mutation in the GJC2 gene (608803) and 8 with classic PMD, Henneke et al. (2010) found that brainstem auditory evoked potentials (BAEP) were significantly worse among those with classic PMD. Waves III, IV, and V, which are generated in the pons and midbrain, were absent in all patients with PMD, but were clearly recordable in 11 of 13 investigations in patients with PMLD1. Investigations of auditory acuity were not available. Visual and somatosensory evoked potentials showed conductive delay in both groups of patients, without significant differences. Nerve conduction studies were normal in all patients with PMD and indicated mild peripheral neuropathy in only 2 of 10 patients with PMLD1. Henneke et al. (2010) concluded that BAEP is a helpful tool to differentiate between these 2 disorders. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>On the basis of comparative mapping of the human and mouse X chromosomes, Buckle et al. (1985) predicted that PMD would map to Xq between PGK1 (311800) and GLA (300644), i.e., somewhere in the segment q13-q22--precisely the region to which Willard and Riordan (1985) assigned the PLP gene. </p><p>Boespflug-Tanguy et al. (1994) carried out a linkage analysis with polymorphic markers of the PLP genomic region in 16 families segregating Pelizaeus-Merzbacher disease. Multipoint analysis gave a maximum location score for the PMD locus and the PLP gene in the same interval between DXS94 and DXS287, suggesting that in all families PMD is linked to the PLP locus. </p>
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<span class="mim-font">
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<strong>Pathogenesis</strong>
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<p>Koeppen et al. (1987) demonstrated absence of proteolipid apoprotein (lipophilin) by immunocytochemistry and enzyme-linked immunosorbent assay in the brain from an 18-year-old patient with PMD. On the other hand, despite the lack of myelin-specific lipids, they found residual immunoreactivity for myelin basic protein, myelin-associated glycoprotein, and 2-prime,3-prime-cyclic nucleotide-3-prime-phosphodiesterase. </p><p>Gow and Lazzarini (1996) suggested a cellular basis for the difference in disease severity between the classic and connatal forms of PMD, based on protein trafficking of the 2 products of the PLP gene, PLP and DM20. Classic PMD mutations correlated with accumulation of PLP in the endoplasmic reticulum (ER) of transfected COS-7 cells, while the cognate DM20 traversed the secretory pathway to the cell surface. On the other hand, Gow and Lazzarini (1996) found that connatal PMD mutations led to the accumulation of both mutant PLP and DM20 proteins in the ER of COS-7 cells with little of either isoform transported to the cell surface. Moreover, they showed that transport-competent mutant DM20s facilitated trafficking of cognate PLPs and hence may influence disease severity. </p><p>Inoue et al. (1996) identified PLP gene duplications (300401.0021) in 4 families with PMD. Thus, PMD may be caused by duplication or deletion of the PLP gene (Raskind et al., 1991) as well as by point mutations. This situation is similar to that in Charcot-Marie-Tooth disease type 1a (CMT1A; 118220), which may be caused by duplication, deletion, or point mutation in the PMP22 gene (601097). Inoue et al. (1996) suggested that since the homologous myelin protein gene PMP22 is duplicated in the majority of patients with CMT1A, PLP gene overdosage may be an important genetic abnormality in PMD and affect myelin formation. Animal models support PLP duplications as a molecular basis for the disease, since transgenic mice with extra copies of the wildtype PLP gene and overexpression of the mRNA exhibit a similar phenotype of abnormal CNS myelination and premature death. Neurologic symptoms and severity of the disease in transgenic mice correlates with PLP-gene copy number and with the level of overexpression. </p><p>Southwood et al. (2002) noted that different mutations in the PLP1 gene cause different disease phenotypes ranging from severe connatal PMD to milder forms characterized by pure spastic paraplegia (SPG2). They presented evidence implicating the unfolded protein response (UPR), a stress-induced signaling cascade that regulates the secretory pathway through the endoplasmic reticulum, as a modulator of disease phenotype. The authors found that oligodendrocytes and microglia from 2 mouse models of PMD with coding mutations in the Plp1 gene, msd (see 300401.0019) and rsh (see 300401.0013), in which mutant proteins accumulate in the endoplasmic reticulum, expressed the UPR-associated proteins Chop (126337) and Atf3 (603148), indicating induction of the UPR. Similarly, postmortem brain tissue from a patient with PMD and mutation in the PLP1 gene (300401.0022) showed a 5-fold increase in CHOP expression in the white matter. By contrast, brain and spinal cord tissue from mice with overexpression of Plp1 (see, e.g., 300401.0021), in which mutant protein does not accumulate in the endoplasmic reticulum, did not show evidence of UPR induction. Transgenic rsh mice who were Chop-deficient showed a more severe phenotype, suggesting that Chop modulated toxic effects of the Plp1 coding mutation. Southwood et al. (2002) concluded that variable disease severity associated with different PLP1 mutations results from graded responses to metabolic stress as modulated by the UPR: the greater the accumulation of mutated PLP1 protein in the endoplasmic reticulum, the more intense the UPR and the higher the likelihood of apoptosis and increased disease severity. </p><p>Numata et al. (2013) found that expression of the PLP1-A243V mutant (300401.0019), which causes severe disease, depleted some ER chaperones with a KDEL (lys-asp-glu-leu) motif in HeLa cells and human oligodendrocytes, and was associated with transfer of the chaperone proteins to the cytoplasm. The same PLP1 mutant also induced fragmentation of the Golgi apparatus. The organelle changes were less prominent in cells with milder disease-associated PLP1 mutants, suggesting a correlation between degree of depletion and phenotypic variability. Similar changes are also observed in cells expressing another disease-causing gene that triggers ER stress, as well as in cells treated with brefeldin A, which induces ER stress and Golgi fragmentation by inhibiting transfer of proteins from the Golgi back to the ER. Mutant PLP1 disturbed localization of the KDEL receptor in the Golgi. The data suggested that PLP1 mutants inhibit Golgi-to-ER retrograde trafficking, which reduces the supply of ER chaperones and induces Golgi fragmentation. Numata et al. (2013) proposed that depletion of ER chaperones and Golgi fragmentation induced by mutant misfolded proteins contribute to trafficking defects that underlie the pathogenesis of inherited ER stress-related diseases. </p>
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<strong>Molecular Genetics</strong>
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<p>Cremers et al. (1987) found an insertional translocation into the proximal long arm of the X chromosome in a boy who showed findings typical of PMD at autopsy. Duplication of Xq21-q22 was identified using a large number of X-specific and several X-Y-specific probes. There appeared to be 2 intact copies of the PLP gene (300401) present. The duplication was apparently due to a de novo mutation, because the mother had a normal female karyotype. </p><p>In a patient with the classic form of PMD, Gencic et al. (1989) described a missense mutation in exon 5 of the PLP gene (300401.0001). </p><p>Hodes et al. (1993) found that about 30% of patients with the diagnosis of Pelizaeus-Merzbacher disease had a mutation in the coding portion of the proteolipid protein gene. Although the mutations were generally recessive, some mutations were frequently expressed in females. </p><p>Mimault et al. (1999) investigated 82 strictly selected sporadic cases of PMD and found PLP mutations in 77%. Complete PLP gene duplication was the most frequent abnormality (62%), whereas point mutations in coding or splice site regions of the gene were involved less frequently (38%). </p><p>In the same report in which they described mutations in the PLP gene in Pelizaeus-Merzbacher disease, Hudson et al. (1989) studied a 6-generation family originally described by Watanabe et al. (1973) and further characterized by Wilkus and Farrell (1976). More than 23 males were affected with a disorder fitting the textbook description of Pelizaeus-Merzbacher disease, both clinically and genetically; however, curious pathologic changes had been noted in a 3-month-old affected infant: apparently normal myelin was present but to a considerable extent the myelin sheaths were organized into ball-like structures in the oligodendrocyte perikarya and terminal processes (Watanabe et al., 1973). Hudson et al. (1989) reported that the PLP gene from this pedigree was unaltered for over 4 kb of coding and noncoding sequence, that Southern blot hybridization failed to reveal any differences from the normal gene, and that a detailed restriction map of a phage lambda genomic clone from 1 patient, containing exons 1-7, also failed to uncover any differences from the normal gene. On the basis of these findings, Hudson et al. (1989) proposed that in addition to the PLP locus another locus on the X chromosome affects myelination. However, Garbern (2004) provided information that affected members of the family described by Watanabe et al. (1973) and by Wilkus and Farrell (1976) were found to have a duplication of the PLP1 (300401.0021) gene and therefore represent bona fide cases of Pelizaeus-Merzbacher disease. </p>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Cailloux et al. (2000) investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by PCR amplification and sequencing of the 7 coding regions and splice sites of the PLP1 gene. Abnormalities were identified in 29 (56%) of the PMD and 4 (14%) of the SPG cases. Of the 33 mutations detected, 23 were missense mutations, 3 were deletion/insertions with frameshifts, and 7 were splice site mutations. Clinical severity was found to be correlated with the nature of the mutation. The severe forms of PMD were most frequently associated with missense mutations in exons 2 and 4, leading to amino acid changes at positions highly conserved in other DM proteins. The mild forms of PMD were frequently caused by mutations, resulting in the production of truncated proteins or by missense mutations. The mutations mostly affected exon 5, leading to the substitution of amino acids only partly conserved in the extracytoplasmic C-D loop. SPG was associated with splice site mutations or changes in the PLP-specific B-C loop. </p><p>Regis et al. (2008) found no association between clinical disease severity and size of PLP1 duplications among 5 unrelated PMD patients with PLP1 duplications ranging in size from 167-195 kb to 580-700 kb. </p>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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<p>Carvalho et al. (2012) reported a family in which a complex duplication of Xq22 was associated with variable expression of PMD in a boy, 2 of his sisters, and his mother. Array CGH and breakpoint junction sequencing in all patients identified a 56-kb duplication on Xq22 that was inserted in an inverted orientation amid an 11-Mb duplication of Xq22 that included the PLP1 gene. This rearrangement resulted in a copy number gain of PLP1; the 11-Mb duplication also included about 65 protein-coding genes, 18 of which are known to be expressed in the brain. The 3-year-old male proband had classic features of the disorder, including global developmental delay, rotary nystagmus, hypotonia with peripheral hyperreflexia, abnormal white matter signals in the cerebral hemispheres on brain MRI, and small corpus callosum, perhaps suggesting delayed myelination. Two sisters, aged around 5 and 6 years, had mild developmental delay and were in special education classes. One had mild hypotonia and periventricular white matter abnormalities. All 3 children also had a forehead nevus flammeus and deep-set eyes. The mother, who was not formally evaluated, had a history of substance abuse and had lost custody of her 5 children, perhaps consistent with some degree of developmental delay. The 2 girls had a random X-inactivation pattern in blood, but a skewed to moderate pattern favoring the normal allele in buccal cells, whereas the mother had moderate skewing in both blood and buccal cells. These findings suggested tissue-specific expression of the genomic rearrangement in the female carriers. Carvalho et al. (2012) hypothesized that the large size of the rearrangement was responsible for increased penetrance in these females. </p><p>Bahrambeigi et al. (2019) analyzed genomic rearrangements in 50 unrelated male patients with Pelizaeus-Merzbacher disease and PLP1 copy number gains. Analysis with a high-density customized array showed that 33 patients had single duplications, ranging from 122 kb to approximately 4.5 Mb, and 17 patients had complex genomic rearrangements (CGR). Of the CGR patients, 9 had a pattern of interspersed duplications separated by a copy neutral region, 3 had a triplication flanked by duplications, and rearrangements with other complexities were identified in the other 5 individuals. In 40 of the 50 patients, the authors ascertained at least one breakpoint junction via PCR amplification. Microhomology was found in 26% of sequenced join-points, ranging from 2 to 9 bp, and evidence for microhomeology was observed in approximately 33% of join-points. Bahrambeigi et al. (2019) also performed a metaanalysis of published PLP1 rearrangements, including 159 join-points from 124 unrelated individuals. They found single duplications in 55% of individuals and a triplication flanked by duplications as the most common CGR in 20% of individuals. In approximately 32% of join-points, there was evidence for microhomeology, and in 22% of cases of join-points, there was evidence for microhomology. </p>
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<strong>Population Genetics</strong>
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<p>In a retrospective hospital- and clinic-based study involving 122 children with an inherited leukodystrophy, Bonkowsky et al. (2010) found that the most common diagnoses were metachromatic leukodystrophy (250100) (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (300100) (4.1%). No final diagnosis was reported in 51% of patients. The disorder was severe: epilepsy was found in 49%, mortality was 34%, and the average age at death was 8.2 years. The population incidence of leukodystrophy in general was found to be 1 in 7,663 live births. </p>
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<strong>Animal Model</strong>
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<p>Sidman et al. (1964) described 'jimpy,' an X-linked demyelination disorder in mice, which is similar to Pelizaeus-Merzbacher disease in man. The jimpy mutation was shown by Nave et al. (1986) to reside in the gene for PLP and to be of such a nature that it leads to an incorrectly spliced RNA transcript. They observed a 74-base deletion in the mRNA for PLP. Also see Dautigny et al. (1986). Hudson et al. (1987) found that PLP in jimpy mice lacks amino acids 208-232; however, the region is present in the jimpy PLP-encoding gene. The authors proposed that the jimpy mutant has a point mutation or a deletion of a few bases that alters the normal splicing pattern and generates partially deleted PLP transcripts. Hudson et al. (1989) pointed out that absence of PLP produces more devastating effects than those of dysmyelination; a block in oligodendrocyte maturation is evident in jimpy mutant mice, and mature oligodendrocytes are absent from both jimpy and Pelizaeus-Merzbacher brains. </p><p>Feutz et al. (1995) demonstrated that jimpy oligodendrocytes in tissue culture were unresponsive to basic fibroblast growth factor. </p><p>Gencic and Hudson (1990) demonstrated that the jimpy-msd (myelin synthesis deficient) mouse has an ala242-to-val (A242V; 300401.0019) mutation in the Plp1 gene. </p><p>To investigate the pathogenetic mechanism of the PLP mutation in the jimpy mouse, Schneider et al. (1995) took advantage of the X-linkage of the gene and complemented jimpy with a wildtype PLP transgene. In this artificial heterozygous situation, the jimpy mutation emerged as genetically dominant. At the cellular level, oligodendrocytes showed little increase in survival although PLP gene and the autosomal transgene were coexpressed. In surviving oligodendrocytes, wildtype PLP was functional and immunodetectable in myelin. Moreover, compacted myelin sheaths regained their normal periodicity. This suggested that, despite the presence of functional wildtype PLP, misfolded jimpy PLP is by itself the primary cause of abnormal oligodendrocyte death. </p><p>Koeppen et al. (1988) and Boison and Stoffel (1989) showed that the X-linked 'myelin deficiency' mutation (md) in the rat is homologous to PMD. Duncan et al. (1987) presented evidence that a defect in the PLP gene is responsible for the hypomyelination. The myelinated fibers were found to be positive for myelin basic protein (159430) but negative for PLP. </p><p>Schneider et al. (1992) demonstrated that the mouse mutant 'rumpshaker' (rsh) has an ile186-to-thr (I186T; 300401.0013) mutation in a membrane-embedded domain of PLP. Surprisingly, 'rumpshaker' mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes. Hypomyelination can thus be genetically separated from PLP-dependent oligodendrocyte degeneration. Schneider et al. (1992) suggested that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease. </p><p>Paralytic tremor (pt) is a sex-linked disorder in chinchilla rabbits that causes body tremor and limb paralysis in association with hypomyelination in the central nervous system but normal myelin in the peripheral nervous system. The number of oligodendrocytes is not reduced nor is there premature death of oligodendrocytes, although the myelin is 30% of normal. In pt rabbits, Tosic et al. (1994) demonstrated a T-to-A transversion in exon 2 of the proteolipid protein gene which would cause a substitution of histidine by glutamine at the end of the first potential transmembrane domain. </p><p>Klugmann et al. (1997) generated mice deficient in PLP and DM20 by targeted disruption. Mutant mice that lacked expression of the Plp gene failed to exhibit the known dysmyelinated phenotype. Unable to encode PLP/DM20 or PLP-related polypeptides, oligodendrocytes were still competent to myelinate CNS axons of all calibers and to assemble compact myelin sheaths. Ultrastructurally, however, the electron-dense intraperiod lines in myelin remained condensed, correlating with its reduced physical stability. Klugmann et al. (1997) concluded that after myelin compaction, PLP forms a stabilizing membrane junction, similar to a zipper. They stated that dysmyelination and oligodendrocyte death emerge as an epiphenomenon of other PLP mutations and have been uncoupled in the PLP null allele from the risk of premature myelin breakdown. Griffiths et al. (1998) showed that Plp-Dm20 -/- mice assembled compact myelin sheaths but subsequently developed widespread axonal swellings and degeneration, associated predominantly with small-caliber nerve fibers. Similar swellings were absent in dysmyelinated shiverer mice, which lack myelin basic protein (MBP), but recurred in MBP/Plp double mutants. Griffiths et al. (1998) concluded that fiber degeneration, which was probably secondary to impaired axonal transport, could indicate that myelinated axons require local oligodendroglial support. </p><p>The 'shaking pup' (Nadon et al., 1990) is a PLP mutation in the dog. </p><p>Readhead et al. (1994) generated normal mouse lines expressing autosomal copies of the wildtype Plp gene and found that a 2-fold increase in Plp gene dosage resulted in hypomyelination, astrocytosis, seizures, and premature death. They concluded that the myelination process is exquisitely sensitive to the accurate level of PLP gene expression. </p><p>Prukop et al. (2014) studied the transgenic mouse strain developed by Readhead et al. (1994) with a 2-fold increase in Plp1 gene dosage. Treatment with the nuclear progesterone receptor (PGR; 607311) antagonist Lonaprisan reduced Plp1 mRNA in the central nervous system of treated transgenic mice compared to controls. After 10 weeks of therapy, treated mice showed less progression of neurologic signs compared to controls, suggesting a dosage effect of Plp1 on the motor phenotype. Lonaprisan also increased the number of myelinated axons in the corticospinal tract of mutant mice compared to untreated mice. However, Lonaprisan did not influence the extent of hypomyelination and did not alter the number of unmyelinated axons. The findings suggested that overexpression of Plp1 in oligodendrocytes leads to the loss of myelinated axons via a gain of function. Microarray and RT-PCR analysis of mouse brain indicated that Lonaprisan downregulated genes involved in apoptosis, including Bax (600040) and Casp7 (601761). Lonaprisan also prevented oligodendrocyte loss and reduced astrogliosis in mutant mouse brains. The study offered a proof of principle that pharmacologic targeting of the nuclear progesterone receptor, which is a transcription factor, can inhibit Plp1 expression in animals with increased Plp1 dosage, resulting in an amelioration of axonal loss and slowing of disease progression. </p>
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<span class="mim-font">
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<strong>History</strong>
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<span class="mim-text-font">
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<p>A family reported by Wolfslast (1943), with what he termed spastic diplegia, is an example of X-linked spastic paraplegia. One affected male was living at age 50 years and a second at age 20 years. Nystagmus was described in a female carrier. However, Becker (1961) expressed the opinion that Wolfslast's family suffered from the Pelizaeus-Merzbacher syndrome, and Verschuer (1958) stated the same opinion.</p>
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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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Eicher and Hoppe (1973); Gertner et al. (1970); Niakan et al. (1979);
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Penrose (1954); Schneck et al. (1971); Wolfslast (1943)
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</span>
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<div>
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<br />
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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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Warshawsky, I., Rudick, R. A., Staugaitis, S. M., Natowicz, M. R.
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<strong>Electrophysiologic observations in the classical form of Pelizaeus-Merzbacher disease.</strong>
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Willard, H. F., Riordan, J. R.
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<strong>Assignment of the gene for myelin proteolipid protein to the X chromosome: implications for X-linked myelin disorders.</strong>
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Wolfslast, W.
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<strong>Eine Sippe mit recessiver geschlechtsgebundener spastischer Diplegie.</strong>
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Z. Menschl. Vererb. Konstitutionsl. 27: 189-198, 1943.
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Woodward, K., Palmer, R., Rao, K., Malcolm, S.
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Zeman, W., DeMyer, W. E., Falls, H. F.
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Hilary J. Vernon - updated : 10/20/2020<br>Cassandra L. Kniffin - updated : 4/28/2014<br>Cassandra L. Kniffin - updated : 5/20/2013<br>Cassandra L. Kniffin - updated : 6/28/2012<br>Cassandra L. Kniffin - updated : 10/20/2010<br>Cassandra L. Kniffin - updated : 6/25/2010<br>Cassandra L. Kniffin - updated : 10/16/2009<br>Cassandra L. Kniffin - updated : 9/8/2008<br>Cassandra L. Kniffin - updated : 5/6/2008<br>Ada Hamosh - updated : 7/25/2007<br>Cassandra L. Kniffin - updated : 5/4/2006<br>Cassandra L. Kniffin - updated : 11/29/2005<br>Cassandra L. Kniffin - updated : 11/4/2005<br>Victor A. McKusick - updated : 1/19/2005<br>Cassandra L. Kniffin - updated : 11/9/2004<br>Cassandra L. Kniffin - reorganized : 8/28/2002<br>Victor A. McKusick - updated : 1/14/2002<br>Victor A. McKusick - updated : 3/15/2001<br>Michael B. Petersen - updated : 2/12/2001<br>Victor A. McKusick - updated : 9/11/2000<br>George E. Tiller - updated : 5/2/2000<br>Stylianos E. Antonarakis - updated : 5/1/2000<br>Victor A. McKusick - updated : 1/11/2000<br>Victor A. McKusick - updated : 6/18/1999<br>Victor A. McKusick - updated : 2/14/1999<br>Victor A. McKusick - updated : 7/22/1998<br>Victor A. McKusick - updated : 2/25/1998<br>Victor A. McKusick - updated : 2/19/1998<br>Victor A. McKusick - updated : 5/15/1997<br>Iosif W. Lurie - updated : 7/4/1996<br>Orest Hurko - updated : 4/1/1996<br>Orest Hurko - updated : 2/22/1996<br>Orest Hurko - updated : 9/8/1995
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Victor A. McKusick : 6/4/1986
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