3212 lines
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Entry
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- #203450 - ALEXANDER DISEASE; ALXDRD
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- OMIM
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<p>
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<span class="h4">#203450</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/203450"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<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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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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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=ALEXANDER 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="#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=22344&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Alexander disease type I </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22345&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Alexander disease type II </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=2&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Alexander disease </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1172/" 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://medlineplus.gov/genetics/condition/alexander-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=203450[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=363717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Alexander disease type I</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=363722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Alexander disease type II</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=58" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Alexander disease</a></div>
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</div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/8c06df06-3961-420c-ae1d-9bfeff40a4ae/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 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:4252" 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/203450" 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/OMIA001208/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:4252" 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 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:203450" 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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<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> 81854007<br />
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<strong>ICD10CM:</strong> G31.86<br />
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<strong>ORPHA:</strong> 363717, 363722, 58<br />
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<strong>DO:</strong> 4252<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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203450
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</span>
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</span>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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ALEXANDER DISEASE; ALXDRD
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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="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<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>
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<tr class="active">
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<th>
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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>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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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/17/649?start=-3&limit=10&highlight=649">
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17q21.31
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</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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Alexander disease
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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/203450"> 203450 </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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GFAP
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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/137780"> 137780 </a>
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</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 ">
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<a href="/clinicalSynopsis/203450" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<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')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/203450" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/203450" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
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<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>
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<p />
|
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </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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- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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|
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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">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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|
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|
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Head </em>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Progressive macrocephaly <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859896&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859896</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004481" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004481</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004481" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004481</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
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</div>
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</div>
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</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Psychomotor regression <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855019&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855019</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002376</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002376</a>]</span><br /> -
|
|
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 /> -
|
|
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 /> -
|
|
Diffuse demyelination (increased signal intensity in T2-weighted images, especially frontal lobes) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859893&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859893</a>]</span><br /> -
|
|
Coarsened pattern of sulci and gyri <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859894&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859894</a>]</span><br /> -
|
|
Presence of Rosenthal fibers (eosinophilic bodies near astrocyte filaments) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859895&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859895</a>]</span><br /> -
|
|
Hydrocephalus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230745008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230745008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G91</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G91.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020255&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020255</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000238" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000238</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000238" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000238</a>]</span><br />
|
|
|
|
</span>
|
|
</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>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Presence of Rosenthal fibers (cytoplasmic inclusions) in astrocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859897&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859897</a>]</span><br /> -
|
|
Presence of glial fibrillary acidic proteins (GFAP) in astrocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859898&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859898</a>]</span><br /> -
|
|
Elevated CSF protein <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1806780&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1806780</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002922" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002922</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002922" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002922</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
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|
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</div>
|
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|
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</div>
|
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|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Average age of onset 6 months (range birth - 2 years)<br /> -
|
|
Death by age 5 (infantile form)<br /> -
|
|
Three variants distinguished by age of onset - infantile (onset before age 2), juvenile (onset in childhood), and adult<br /> -
|
|
Juvenile patients have slower clinical course with preserved intellect, bulbar signs, ataxia, and spasticity<br /> -
|
|
Adult patients have heterogeneous symptoms including some with relapsing-remitting symptoms similar to multiple sclerosis<br />
|
|
|
|
</span>
|
|
</div>
|
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|
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</div>
|
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|
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</div>
|
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|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutations in the glial fibrillary acidic protein gene (GFAP, <a href="/entry/137780#0001">137780.0001</a>)<br />
|
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|
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</span>
|
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</div>
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</div>
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</div>
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|
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<div class="text-right">
|
|
<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>
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<div>
|
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<br />
|
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</div>
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<div>
|
|
<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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|
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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.">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
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<div id="mimTextFold" class="collapse in ">
|
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that Alexander disease (ALXDRD) is caused by heterozygous mutation in the gene encoding glial fibrillary acidic protein (GFAP; <a href="/entry/137780">137780</a>) on chromosome 17q21.</p>
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<p>In decreasing order of frequency, 3 forms of Alexander disease (ALXDRD) are recognized, based on age of onset: infantile, juvenile, and adult. Younger patients typically present with seizures, megalencephaly, developmental delay, and spasticity. In older patients, bulbar or pseudobulbar symptoms predominate, frequently accompanied by spasticity. The disease is progressive, with most patients dying within 10 years of onset. Imaging studies of the brain typically show cerebral white matter abnormalities, preferentially affecting the frontal region (<a href="#6" class="mim-tip-reference" title="Gorospe, J. R., Naidu, S., Johnson, A. B., Puri, V., Raymond, G. V., Jenkins, S. D., Pedersen, R. C., Lewis, D., Knowles, P., Fernandez, R., De Vivo, D., van der Knapp, M. S., Messing, A., Brenner, M., Hoffman, E. P. <strong>Molecular findings in symptomatic and pre-symptomatic Alexander disease patients.</strong> Neurology 58: 1494-1500, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12034785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12034785</a>] [<a href="https://doi.org/10.1212/wnl.58.10.1494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12034785">Gorospe et al., 2002</a>). All 3 forms have been shown to be caused by mutations in the GFAP gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12034785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>This disorder, first described by <a href="#1" class="mim-tip-reference" title="Alexander, W. S. <strong>Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant.</strong> Brain 72: 373-381, 1949.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15409268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15409268</a>] [<a href="https://doi.org/10.1093/brain/72.3.373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15409268">Alexander (1949)</a>, is characterized clinically by development of megalencephaly in infancy accompanied by progressive spasticity and dementia. The features are similar to those of Canavan disease (<a href="/entry/271900">271900</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15409268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Gorospe, J. R., Naidu, S., Johnson, A. B., Puri, V., Raymond, G. V., Jenkins, S. D., Pedersen, R. C., Lewis, D., Knowles, P., Fernandez, R., De Vivo, D., van der Knapp, M. S., Messing, A., Brenner, M., Hoffman, E. P. <strong>Molecular findings in symptomatic and pre-symptomatic Alexander disease patients.</strong> Neurology 58: 1494-1500, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12034785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12034785</a>] [<a href="https://doi.org/10.1212/wnl.58.10.1494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12034785">Gorospe et al. (2002)</a> reported 12 genetically confirmed cases of Alexander disease. Seven of the 12 had onset in infancy (range 2-18 months), with seizures being the most common presenting sign, followed by failure to thrive and delayed motor development. Five patients had juvenile onset (between 5 and 9 years) and presented with variable symptoms ranging from asymptomatic (2 patients) to linear growth failure, excessive sleepiness and vomiting. Patients in both groups showed megalencephaly, bulbar or pseudobulbar signs, spasticity, cognitive deficits and developmental delay. In addition, all patients showed diffuse and symmetric white matter abnormalities in the frontal regions of the brain. <a href="#6" class="mim-tip-reference" title="Gorospe, J. R., Naidu, S., Johnson, A. B., Puri, V., Raymond, G. V., Jenkins, S. D., Pedersen, R. C., Lewis, D., Knowles, P., Fernandez, R., De Vivo, D., van der Knapp, M. S., Messing, A., Brenner, M., Hoffman, E. P. <strong>Molecular findings in symptomatic and pre-symptomatic Alexander disease patients.</strong> Neurology 58: 1494-1500, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12034785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12034785</a>] [<a href="https://doi.org/10.1212/wnl.58.10.1494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12034785">Gorospe et al. (2002)</a> suggested that GFAP gene analysis be included in the diagnostic evaluation of patients presenting with frontal leukoencephalopathy by MRI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12034785" 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="Bassuk, A. G., Joshi, A., Burton, B. K., Larsen, M. B., Burrowes, D. M., Stack, C. <strong>Alexander disease with serial MRS and a new mutation in the glial fibrillary acidic protein gene.</strong> Neurology 61: 1014-1015, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557587</a>] [<a href="https://doi.org/10.1212/01.wnl.0000082440.42354.d0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14557587">Bassuk et al. (2003)</a> reported an infant with Alexander disease who presented with poor feeding on the first day of life, followed by emesis and weight loss. MRI on day 21 of life showed signal abnormalities in the frontal lobes and basal ganglia. Over the next 12 days, the patient became increasingly somnolent and hypotonic, and developed seizures on day 33. Magnetic resonance spectroscopy (MRS) performed 14 days apart demonstrated an interval 2-fold increase in the lipid/lactate peak over the right basal ganglia. Over the course of 25 days, head growth increased from the 50th to the 75th percentile. The child died on day 38 from prolonged seizures and respiratory failure. Mutation analysis detected a heterozygous mutation in the GFAP gene (<a href="/entry/137780#0012">137780.0012</a>). <a href="#2" class="mim-tip-reference" title="Bassuk, A. G., Joshi, A., Burton, B. K., Larsen, M. B., Burrowes, D. M., Stack, C. <strong>Alexander disease with serial MRS and a new mutation in the glial fibrillary acidic protein gene.</strong> Neurology 61: 1014-1015, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557587</a>] [<a href="https://doi.org/10.1212/01.wnl.0000082440.42354.d0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14557587">Bassuk et al. (2003)</a> commented on several unusual aspects of the case, including the rapid clinical decline, the rapid head growth, and the demonstration of progressive lactate elevation in the brain by MRS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14557587" 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="Stumpf, E., Masson, H., Duquette, A., Berthelet, F., McNabb, J., Lortie, A., Lesage, J., Montplaisir, J., Brais, B., Cossette, P. <strong>Adult Alexander disease with autosomal dominant transmission: a distinct entity caused by mutation in the glial fibrillary acid protein gene.</strong> Arch. Neurol. 60: 1307-1312, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12975300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12975300</a>] [<a href="https://doi.org/10.1001/archneur.60.9.1307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12975300">Stumpf et al. (2003)</a> reported a family with an autosomal dominant adult form of Alexander disease. The clinical phenotype varied in severity, but the pattern of evolution was similar in all affected members. Although sleep disturbances and dysautonomia, primarily constipation, began in childhood, the major neurologic features began in the third or fourth decade of life. Features included bulbar signs, ataxia, and pyramidal signs. All patients also had mild dysmorphic features, including progressive kyphosis, arched palate, and short neck. MRI of the older patients showed atrophy of the medulla without signal abnormalities. A mutation in the GFAP gene (<a href="/entry/137780#0013">137780.0013</a>) was identified in all affected members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12975300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Li, R., Johnson, A. B., Salomons, G., Goldman, J. E., Naidu, S., Quinlan, R., Cree, B., Ruyle, S. Z., Banwell, B., D'Hooghe, M., Siebert, J. R., Rolf, C. M., Cox, H., Reddy, A., Gutierrez-Solana, L. G., Collins, A., Weller, R. O., Messing, A., van der Knaap, M. S., Brenner, M. <strong>Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease.</strong> Ann. Neurol. 57: 310-326, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732097</a>] [<a href="https://doi.org/10.1002/ana.20406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732097">Li et al. (2005)</a> reported detailed clinical features of 44 patients with Alexander disease, including 26 with infantile onset, 15 with juvenile onset, and 3 with adult onset. The most common features among the patients with infantile onset included seizures (92%), cognitive defects (82%), macrocephaly (62%), bulbar signs (62%), ataxia (58%), and spasticity (52%). The phenotype of juvenile- and adult-onset cases was less severe. Features of juvenile patients included bulbar signs (73%), cognitive defects (60%), spasticity (53%), ataxia (47%), seizures (27%), and macrocephaly (20%). None of the patients with adult onset had macrocephaly, seizures, or cognitive defects. There was a suggestion of male predominance for the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Sreedharan, J., Shaw, C. E., Jarosz, J., Samuel, M. <strong>Alexander disease with hypothermia, microcoria, and psychiatric and endocrine disturbances.</strong> Neurology 68: 1322-1323, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17438228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17438228</a>] [<a href="https://doi.org/10.1212/01.wnl.0000259543.95222.9d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17438228">Sreedharan et al. (2007)</a> reported an unusual case of a 38-year-old woman with Alexander disease. She presented with a 2-year history of progressive reading difficulty with oscillopsia, slurring dysarthria, choking, and stumbling. Past medical history was significant for endocrine disturbances with an episode of amenorrhea, hypothyroidism, depression, and hypothermic episodes associated with ataxia, facial twitching and drowsiness. Physical examination showed torsional nystagmus and palatal, tongue, and jaw tremor. She had symptomatic microcoria, mild left arm dysmetria, ataxia, and lower limb hyporeflexia. Brain MRI showed brainstem atrophy and symmetric signal changes in the medulla and cerebellum. Her father reportedly had microcoria but refused participation. Genetic analysis identified a heterozygous GFAP mutation in the proband. <a href="#20" class="mim-tip-reference" title="Sreedharan, J., Shaw, C. E., Jarosz, J., Samuel, M. <strong>Alexander disease with hypothermia, microcoria, and psychiatric and endocrine disturbances.</strong> Neurology 68: 1322-1323, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17438228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17438228</a>] [<a href="https://doi.org/10.1212/01.wnl.0000259543.95222.9d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17438228">Sreedharan et al. (2007)</a> commented that this case represented an unusually slowly progressive form of adult-onset Alexander disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17438228" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Mura, E., Nicita, F., Masnada, S., Battini, R., Ticci, C., Montomoli, M., Berardinelli, A., Pantaleoni, C., Ardissone, A., Foiadelli, T., Tartara, E., Salsano, E., Veggiotti, P., Ceccherini, I., Moroni, I., Bertini, E., Tonduti, D. <strong>Alexander disease evolution over time: data from an Italian cohort of pediatric-onset patients.</strong> Molec. Genet. Metab. 134: 353-358, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34865968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34865968</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.11.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34865968">Mura et al. (2021)</a> described clinical features of 21 Italian patients with pediatric-onset Alexander disease and classified the disease based on clinical features and evolution of the disease. Seventeen patients were classified as having type I disease, including 1 patient with neonatal-onset and 16 patients with infantile-onset. These patients were further categorized into 4 groups: 1 patient with neonatal onset with rapidly evolving disease and death at 8 months of age was classified with type Ia; 5 patients who presented with developmental delay and experienced clinical deterioration by 5 years of age were classified with type Ib; 2 patients who presented with developmental delay and experienced clinical deterioration after 6 years of age were classified with type Ic; 5 patients who presented with developmental delay and remained clinically stable beyond adolescence were categorized with type Id. Four patients could not be categorized as type Ic or Id because they were of a young age and had not yet experienced neurologic decline. Four patients who had juvenile-onset of symptoms with normal development and no or mild cognitive impairment were classified with type II; symptoms in the type II patients included bulbar signs and autonomic dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34865968" 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>From a literature search, <a href="#22" class="mim-tip-reference" title="Vaia, Y., Mura, E., Tonduti, D. <strong>Type I Alexander disease: update and validation of the clinical evolution-based classification.</strong> Molec. Genet. Metab. 138: 107540, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36804850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36804850</a>] [<a href="https://doi.org/10.1016/j.ymgme.2023.107540" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36804850">Vaia et al. (2023)</a> identified 205 patients with pediatric-onset Alexander disease, for whom 65 had enough clinical data for the authors to evaluate the disease evolution classification suggested by <a href="#15" class="mim-tip-reference" title="Mura, E., Nicita, F., Masnada, S., Battini, R., Ticci, C., Montomoli, M., Berardinelli, A., Pantaleoni, C., Ardissone, A., Foiadelli, T., Tartara, E., Salsano, E., Veggiotti, P., Ceccherini, I., Moroni, I., Bertini, E., Tonduti, D. <strong>Alexander disease evolution over time: data from an Italian cohort of pediatric-onset patients.</strong> Molec. Genet. Metab. 134: 353-358, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34865968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34865968</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.11.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34865968">Mura et al. (2021)</a>. They found that 17 patients fulfilled criteria for type Ia (disease onset in the first months of life, absence of postural acquisition, and death by 2 years of age); 15 patients fit into type Ib (disease onset at an average of 5.9 months of age, achieving some head and trunk control); 6 patients fit into type Ic (delayed motor development, achieving ambulation, and deterioration at an average of 6 years of age); 5 patients fit into type Id (delayed motor and speech development but acquisition of ambulation and stable neurologic status into adolescence); 19 patients fit into type II (normal neurodevelopment with neurologic deterioration later in life). Three patients were too young at last evaluation to fit into a definite category. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=34865968+36804850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pathologic Findings</em></strong></p><p>
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Histologically, Alexander disease is characterized by Rosenthal fibers, homogeneous eosinophilic masses which form elongated tapered rods up to 30 microns in length, which are scattered throughout the cortex and white matter and are most numerous in the subpial, perivascular and subependymal regions. These fibers are located in astrocytes, cells that are closely related to blood vessels. Demyelination is present, usually as a prominent feature. A few cases have had hydrocephalus (<a href="#1" class="mim-tip-reference" title="Alexander, W. S. <strong>Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant.</strong> Brain 72: 373-381, 1949.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15409268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15409268</a>] [<a href="https://doi.org/10.1093/brain/72.3.373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15409268">Alexander, 1949</a>). Rosenthal fibers are commonly found in astrocytomas, optic nerve gliomas and states of chronic reactive gliosis, but they are especially conspicuous in Alexander disease. <a href="#8" class="mim-tip-reference" title="Herndon, R. N., Rubinstein, L. J., Freeman, J. N., Mathieson, G. <strong>Light and electron microscopic observations on Rosenthal fibers in Alexander's disease and in multiple sclerosis.</strong> J. Neuropath. Exp. Neurol. 29: 524-551, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5471920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5471920</a>] [<a href="https://doi.org/10.1097/00005072-197010000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5471920">Herndon et al. (1970)</a> expressed the view that Rosenthal fibers found in this situation are the result of degenerative changes in the cytoplasm and cytoplasmic processes of astrocytic glial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5471920+15409268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Iwaki, T., Kume-Iwaki, A., Leim, R. K. H., Goldman, J. E. <strong>Alpha-B-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain.</strong> Cell 57: 71-78, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2539261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2539261</a>] [<a href="https://doi.org/10.1016/0092-8674(89)90173-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2539261">Iwaki et al. (1989)</a> found that alpha-B-crystallin (CRYAB; <a href="/entry/123590">123590</a>) accumulates in the brain in Alexander disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2539261" 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="#23" class="mim-tip-reference" title="van der Knaap, M. S., Naidu, S., Breiter, S. N., Blaser, S., Stroink, H., Springer, S., Begeer, J. C., van Coster, R., Barth, P. G., Thomas, N. H., Valk, J., Powers, J. M. <strong>Alexander disease: diagnosis with MR imaging.</strong> Am. J. Neuroradiol. 22: 541-552, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11237983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11237983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11237983[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="11237983">Van der Knaap et al. (2001)</a> proposed specific MRI criteria for the diagnosis of Alexander disease: extensive, symmetric white matter abnormalities with frontal preponderance; periventricular signal changes; basal ganglia and thalamic signal changes; brainstem lesions; and contrast enhancement of multiple areas throughout the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11237983" 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="van der Knaap, M. S., Salomons, G. S., Li, R., Franzoni, E., Gutierrez-Solana, L. G., Smit, L. M. E., Robinson, R., Ferrie, C. D., Cree, B., Reddy, A., Thomas, N., Banwell, B., Barkhof, F., Jakobs, C., Johnson, A., Messing, A., Brenner, M. <strong>Unusual variants of Alexander's disease.</strong> Ann. Neurol. 57: 327-338, 2005. Note: Erratum: Ann. Neurol. 58: 172 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732098</a>] [<a href="https://doi.org/10.1002/ana.20381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732098">Van der Knaap et al. (2005)</a> reported 9 patients with Alexander disease confirmed by genetic analysis who had atypical MRI features. Alexander disease was not the initial diagnosis for any of the patients, and none of the patients met the MRI-based criteria proposed by <a href="#23" class="mim-tip-reference" title="van der Knaap, M. S., Naidu, S., Breiter, S. N., Blaser, S., Stroink, H., Springer, S., Begeer, J. C., van Coster, R., Barth, P. G., Thomas, N. H., Valk, J., Powers, J. M. <strong>Alexander disease: diagnosis with MR imaging.</strong> Am. J. Neuroradiol. 22: 541-552, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11237983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11237983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11237983[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="11237983">van der Knaap et al. (2001)</a>. MRI in 8 patients showed predominantly posterior fossa lesions, especially multiple tumor-like brainstem lesions. One patient had asymmetric frontal white matter abnormalities and basal ganglia abnormalities. <a href="#25" class="mim-tip-reference" title="van der Knaap, M. S., Salomons, G. S., Li, R., Franzoni, E., Gutierrez-Solana, L. G., Smit, L. M. E., Robinson, R., Ferrie, C. D., Cree, B., Reddy, A., Thomas, N., Banwell, B., Barkhof, F., Jakobs, C., Johnson, A., Messing, A., Brenner, M. <strong>Unusual variants of Alexander's disease.</strong> Ann. Neurol. 57: 327-338, 2005. Note: Erratum: Ann. Neurol. 58: 172 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732098</a>] [<a href="https://doi.org/10.1002/ana.20381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732098">Van der Knaap et al. (2005)</a> concluded that DNA diagnostics is warranted in patients with atypical MRI features that are only suggestive of Alexander disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15732098+11237983" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="van der Knaap, M. S., Ramesh, V., Schiffmann, R., Blaser, S., Kyllerman, M., Gholkar, A., Ellison, D. W., van der Voorn, J. P., van Dooren, S. J. M., Jakobs, C., Barkhof, F., Salomons, G. S. <strong>Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord.</strong> Neurology 66: 494-498, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16505300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16505300</a>] [<a href="https://doi.org/10.1212/01.wnl.0000198770.80743.37" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16505300">Van der Knaap et al. (2006)</a> reported 7 patients with genetically confirmed Alexander disease who had no or inconspicuous cerebral white matter abnormalities and no or minimal contrast enhancement on brain MRI. All had juvenile disease onset with signs of brainstem or spinal cord dysfunction, including bladder and gait disturbances. MRI findings were predominantly signal changes or atrophy of the medulla and spinal cord. Four patients had a kind of 'garland' along the ventricular wall. <a href="#24" class="mim-tip-reference" title="van der Knaap, M. S., Ramesh, V., Schiffmann, R., Blaser, S., Kyllerman, M., Gholkar, A., Ellison, D. W., van der Voorn, J. P., van Dooren, S. J. M., Jakobs, C., Barkhof, F., Salomons, G. S. <strong>Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord.</strong> Neurology 66: 494-498, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16505300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16505300</a>] [<a href="https://doi.org/10.1212/01.wnl.0000198770.80743.37" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16505300">Van der Knaap et al. (2006)</a> concluded that Alexander disease is not invariably a leukoencephalopathy, and that patients with later onset of the disorder may have more unusual phenotypic variation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16505300" 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="#26" class="mim-tip-reference" title="Wohlwill, F. J., Bernstein, J., Yakovlev, P. I. <strong>Dysmyelinogenic leukodystrophy: report of a case of a new, presumably familial type of leukodystrophy with megalobarencephaly.</strong> J. Neuropath. Exp. Neurol. 18: 359-383, 1959.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13665382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13665382</a>] [<a href="https://doi.org/10.1097/00005072-195907000-00001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13665382">Wohlwill et al. (1959)</a> described a sibship of 9, of whom 1 sister and 3 brothers had large heads called hydrocephalic and died at ages 4, 5, 6 and 3, respectively. Alexander disease was proven histologically in the last. Although this sibship suggested possible autosomal recessive inheritance, all the molecular genetic evidence favors autosomal dominant inheritance, i.e., de novo heterozygous mutations as the cause. In vitro studies of one such mutation in the GFAP gene causing Alexander disease (<a href="/entry/137780#0003">137780.0003</a>) found that the mutant protein accumulates into Rosenthal fibers by a pathway that involved filament aggregation and the association of alpha-B-crystallin and HSP27 (<a href="/entry/602195">602195</a>). The data confirmed that the effects of the specific GFAP mutation are dominant; in the heterozygote mutant, the gene product was dominant over wildtype GFAP in coassembly experiments (<a href="#5" class="mim-tip-reference" title="Der Perng, M. D., Su, M., Wen, S. F., Li, R., Gibbon, T., Prescott, A. R., Brenner, M., Quinlan, R. A. <strong>The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alpha-B-crystallin and HSP27.</strong> Am. J. Hum. Genet. 79: 197-213, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16826512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16826512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16826512[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/504411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16826512">Der Perng et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13665382+16826512" 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>Mutations in the GFAP gene were found in the infantile form of Alexander disease by <a href="#3" class="mim-tip-reference" title="Brenner, M., Johnson, A. B., Boespflug-Tanguy, O., Rodriguez, D., Goldman, J. E., Messing, A. <strong>Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.</strong> Nature Genet. 27: 117-120, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11138011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11138011</a>] [<a href="https://doi.org/10.1038/83679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11138011">Brenner et al. (2001)</a>, in the juvenile form by <a href="#18" class="mim-tip-reference" title="Sawaishi, Y., Yano, T., Takaku, I., Takada, G. <strong>Juvenile Alexander disease with a novel mutation in glial fibrillary acidic protein gene.</strong> Neurology 58: 1541-1543, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12034796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12034796</a>] [<a href="https://doi.org/10.1212/wnl.58.10.1541" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12034796">Sawaishi et al. (2002)</a>, and in the adult form by <a href="#16" class="mim-tip-reference" title="Namekawa, M., Takiyama, Y., Aoki, Y., Takayashiki, N., Sakoe, K., Shimazaki, H., Taguci, T., Tanaka, Y., Nishizawa, M., Saito, K., Matsubara, Y., Nakano, I. <strong>Identification of GFAP gene mutation in hereditary adult-onset Alexander's disease.</strong> Ann. Neurol. 52: 779-785, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447932</a>] [<a href="https://doi.org/10.1002/ana.10375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447932">Namekawa et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12034796+11138011+12447932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Brenner, M., Johnson, A. B., Boespflug-Tanguy, O., Rodriguez, D., Goldman, J. E., Messing, A. <strong>Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.</strong> Nature Genet. 27: 117-120, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11138011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11138011</a>] [<a href="https://doi.org/10.1038/83679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11138011">Brenner et al. (2001)</a> identified de novo heterozygous mutations in the GFAP gene in 10 of 11 patients with Alexander disease (<a href="/entry/137780#0001">137780.0001</a>-<a href="/entry/137780#0005">137780.0005</a>). <a href="#17" class="mim-tip-reference" title="Rodriguez, D., Gauthier, F., Bertini, E., Bugiani, M., Brenner, M., N'guyen, S., Goizet, C., Gelot, A., Surtees, R., Pedespan, J.-M., Hernandorena, X., Troncoso, M., Uziel, G., Messing, A., Ponsot, G., Pham-Dinh, D., Dautigny, A., Boespflug-Tanguy, O. <strong>Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 69: 1134-1140, 2001. Note: Erratum: Am. J. Hum. Genet. 69: 1413 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11567214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11567214</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11567214[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/323799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11567214">Rodriguez et al. (2001)</a> likewise identified de novo heterozygous missense GFAP mutations in exon 1 or exon 4 in 14 of 15 patients who were candidates for Alexander disease on the basis of suggestive neuroimaging abnormalities. These included patients without macrocephaly. Affected sibs whose parents were unaffected, including 1 family with neuropathologically proved Alexander disease (<a href="#26" class="mim-tip-reference" title="Wohlwill, F. J., Bernstein, J., Yakovlev, P. I. <strong>Dysmyelinogenic leukodystrophy: report of a case of a new, presumably familial type of leukodystrophy with megalobarencephaly.</strong> J. Neuropath. Exp. Neurol. 18: 359-383, 1959.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13665382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13665382</a>] [<a href="https://doi.org/10.1097/00005072-195907000-00001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13665382">Wohlwill et al., 1959</a>), could represent autosomal recessive transmission or germinal mosaicism for a dominant mutation. Therefore, <a href="#17" class="mim-tip-reference" title="Rodriguez, D., Gauthier, F., Bertini, E., Bugiani, M., Brenner, M., N'guyen, S., Goizet, C., Gelot, A., Surtees, R., Pedespan, J.-M., Hernandorena, X., Troncoso, M., Uziel, G., Messing, A., Ponsot, G., Pham-Dinh, D., Dautigny, A., Boespflug-Tanguy, O. <strong>Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 69: 1134-1140, 2001. Note: Erratum: Am. J. Hum. Genet. 69: 1413 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11567214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11567214</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11567214[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/323799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11567214">Rodriguez et al. (2001)</a> suggested that after the birth of a patient with Alexander disease with a de novo GFAP mutation, prenatal diagnosis should be proposed for all subsequent pregnancies. It remained to be determined whether the heritable dominant forms of Alexander disease described in 2 families, both of which had late onset after age 25 years (<a href="#9" class="mim-tip-reference" title="Howard, R. S., Greenwood, R., Gawler, J., Scaravilli, F., Marsden, C. D., Harding, A. E. <strong>A familial disorder associated with palatal myoclonus, other brainstem signs, tetraparesis, ataxia and Rosenthal fibre formation.</strong> J. Neurol. Neurosurg. Psychiat. 56: 977-981, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8410038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8410038</a>] [<a href="https://doi.org/10.1136/jnnp.56.9.977" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8410038">Howard et al., 1993</a>; <a href="#19" class="mim-tip-reference" title="Schwankhaus, J. D., Parisi, J. E., Gulledge, W. R., Chin, L., Currier, R. D. <strong>Hereditary adult-onset Alexander's disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia.</strong> Neurology 45: 2266-2271, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8848205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8848205</a>] [<a href="https://doi.org/10.1212/wnl.45.12.2266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8848205">Schwankhaus et al., 1995</a>), also had GFAP mutations as the cause. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13665382+8848205+8410038+11567214+11138011" 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>Of 13 patients with MRI white matter abnormalities consistent with Alexander disease, 12 were found by <a href="#6" class="mim-tip-reference" title="Gorospe, J. R., Naidu, S., Johnson, A. B., Puri, V., Raymond, G. V., Jenkins, S. D., Pedersen, R. C., Lewis, D., Knowles, P., Fernandez, R., De Vivo, D., van der Knapp, M. S., Messing, A., Brenner, M., Hoffman, E. P. <strong>Molecular findings in symptomatic and pre-symptomatic Alexander disease patients.</strong> Neurology 58: 1494-1500, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12034785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12034785</a>] [<a href="https://doi.org/10.1212/wnl.58.10.1494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12034785">Gorospe et al. (2002)</a> to have GFAP mutations. Four of the 9 changes identified were novel mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12034785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Li, R., Johnson, A. B., Salomons, G. S., van der Knapp, M. S., Rodriguez, D., Boespflug-Tanguy, O., Gorospe, J. R., Goldman, J. E., Messing, A., Brenner, M. <strong>Propensity for paternal inheritance of de novo mutations in Alexander disease.</strong> Hum. Genet. 119: 137-144, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16365765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16365765</a>] [<a href="https://doi.org/10.1007/s00439-005-0116-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16365765">Li et al. (2006)</a> determined that the paternal chromosome carried the GFAP mutation in 24 of 28 unrelated cases of Alexander disease analyzed, suggesting that most mutations occur during spermatogenesis rather than in the embryo. No effect of paternal age was observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16365765" 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 13 unrelated Italian patients with Alexander disease, including 8 with the infantile, 2 with the juvenile, and 3 with the adult form, <a href="#4" class="mim-tip-reference" title="Caroli, F., Biancheri, R., Seri, M., Rossi, A., Pessagno, A., Bugiani, M., Corsolini, F., Savasta, S., Romano, S., Antonelli, C., Romano, A., Pareyson, D., Gambero, P., Uziel, G., Ravazzolo, R., Ceccherini, I., Filocamo, M. <strong>GFAP mutations and polymorphisms in 13 unrelated Italian patients affected by Alexander disease.</strong> Clin. Genet. 72: 427-433, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17894839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17894839</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00869.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17894839">Caroli et al. (2007)</a> identified 11 different mutations in the GFAP gene (see, e.g., <a href="/entry/137780#0005">137780.0005</a>), including 4 novel mutations. Ten mutations occurred in the rod domains and 1 in the tail domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17894839" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Karp, N., Lee, D., Shickh, S., Jenkins, M. D. <strong>c.1289G-A (p.Arg430His) variant in the epsilon isoform of the GFAP gene in a patient with adult onset Alexander disease.</strong> Europ. J. Med. Genet. 62: 235-238, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30048824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30048824</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30048824">Karp et al. (2019)</a> reported a patient with adult-onset Alexander disease in whom, after excluding mutation in the GFAP-alpha isoform, they identified heterozygosity for a missense mutation (c.1289G-A, R430H) in exon 7A of the GFAP-epsilon isoform. The authors noted that the same mutation in GFAP-epsilon had been identified by <a href="#14" class="mim-tip-reference" title="Melchionda, L., Fang, M., Wang, H., Fugnanesi, V., Morbin, M., Liu, X., Li, W., Ceccherini, I., Farina, L., Savoiardo, M., D'Adamo, P., Zhang, J., Costa, A., Ravaglia, S., Ghezzi, D., Zeviani, M. <strong>Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant.</strong> Orphanet J. Rare Dis. 8: 66, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23634874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23634874</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23634874[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/10.1186/1750-1172-8-66" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23634874">Melchionda et al. (2013)</a> in a brother and sister half-sib pair with adult onset of the disorder in whom mutation in GFAP-alpha had been excluded. The brother also had a mutation (c.2566C-T, P856S) in the HDAC6 gene (<a href="/entry/300272">300272</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30048824+23634874" 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="#7" class="mim-tip-reference" title="Hagemann, T. L., Boelens, W. C., Wawrousek, E. F., Messing, A. <strong>Suppression of GFAP toxicity by alpha-B-crystallin in mouse models of Alexander disease.</strong> Hum. Molec. Genet. 18: 1190-1199, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19129171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19129171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19129171[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/10.1093/hmg/ddp013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19129171">Hagemann et al. (2009)</a> noted that Rosenthal fibers in the complex astrocytic inclusions characteristic of Alexander disease contain GFAP, vimentin (VIM; <a href="/entry/193060">193060</a>), plectin (PLEC1; <a href="/entry/601282">601282</a>), ubiquitin (UBB; <a href="/entry/191339">191339</a>), HSP27, and alpha-B-crystallin. CRYAB regulates GFAP assembly, and elevation of CRYAB is a consistent feature of Alexander disease; however, its role in Rosenthal fibers and disease pathology is not known. In a mouse model of Alexander disease, <a href="#7" class="mim-tip-reference" title="Hagemann, T. L., Boelens, W. C., Wawrousek, E. F., Messing, A. <strong>Suppression of GFAP toxicity by alpha-B-crystallin in mouse models of Alexander disease.</strong> Hum. Molec. Genet. 18: 1190-1199, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19129171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19129171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19129171[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/10.1093/hmg/ddp013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19129171">Hagemann et al. (2009)</a> showed that loss of Cryab resulted in increased mortality, whereas elevation of Cryab rescued animals from terminal seizures. When mice with Rosenthal fibers induced by overexpression of GFAP were crossed into a Cryab-null background, over half died at 1 month of age. Restoration of Cryab expression through the GFAP promoter reversed this outcome, showing the effect was astrocyte-specific. Conversely, in mice carrying an Alexander disease-associated mutation and in mice overexpressing wildtype GFAP, which, despite natural induction of Cryab also died at 1 month, transgenic overexpression of Cryab resulted in a markedly reduced CNS stress response, restored expression of the glutamate transporter Glt1 (SLC1A2; <a href="/entry/600300">600300</a>), and protected these animals from death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19129171" 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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Alexander, W. S.
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<strong>Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant.</strong>
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Brain 72: 373-381, 1949.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15409268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15409268</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15409268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/72.3.373" target="_blank">Full Text</a>]
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Bassuk, A. G., Joshi, A., Burton, B. K., Larsen, M. B., Burrowes, D. M., Stack, C.
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<strong>Alexander disease with serial MRS and a new mutation in the glial fibrillary acidic protein gene.</strong>
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Neurology 61: 1014-1015, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557587</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14557587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000082440.42354.d0" target="_blank">Full Text</a>]
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Brenner, M., Johnson, A. B., Boespflug-Tanguy, O., Rodriguez, D., Goldman, J. E., Messing, A.
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<strong>Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.</strong>
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Nature Genet. 27: 117-120, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11138011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11138011</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11138011" 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/10.1038/83679" target="_blank">Full Text</a>]
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Caroli, F., Biancheri, R., Seri, M., Rossi, A., Pessagno, A., Bugiani, M., Corsolini, F., Savasta, S., Romano, S., Antonelli, C., Romano, A., Pareyson, D., Gambero, P., Uziel, G., Ravazzolo, R., Ceccherini, I., Filocamo, M.
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<strong>GFAP mutations and polymorphisms in 13 unrelated Italian patients affected by Alexander disease.</strong>
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Clin. Genet. 72: 427-433, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17894839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17894839</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17894839" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2007.00869.x" target="_blank">Full Text</a>]
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Der Perng, M. D., Su, M., Wen, S. F., Li, R., Gibbon, T., Prescott, A. R., Brenner, M., Quinlan, R. A.
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<strong>The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alpha-B-crystallin and HSP27.</strong>
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Am. J. Hum. Genet. 79: 197-213, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16826512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16826512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16826512[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16826512" 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/10.1086/504411" target="_blank">Full Text</a>]
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Gorospe, J. R., Naidu, S., Johnson, A. B., Puri, V., Raymond, G. V., Jenkins, S. D., Pedersen, R. C., Lewis, D., Knowles, P., Fernandez, R., De Vivo, D., van der Knapp, M. S., Messing, A., Brenner, M., Hoffman, E. P.
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<strong>Molecular findings in symptomatic and pre-symptomatic Alexander disease patients.</strong>
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Neurology 58: 1494-1500, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12034785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12034785</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12034785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.58.10.1494" target="_blank">Full Text</a>]
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Hagemann, T. L., Boelens, W. C., Wawrousek, E. F., Messing, A.
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<strong>Suppression of GFAP toxicity by alpha-B-crystallin in mouse models of Alexander disease.</strong>
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Hum. Molec. Genet. 18: 1190-1199, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19129171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19129171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19129171[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19129171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp013" target="_blank">Full Text</a>]
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Herndon, R. N., Rubinstein, L. J., Freeman, J. N., Mathieson, G.
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<strong>Light and electron microscopic observations on Rosenthal fibers in Alexander's disease and in multiple sclerosis.</strong>
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J. Neuropath. Exp. Neurol. 29: 524-551, 1970.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5471920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5471920</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5471920" 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/10.1097/00005072-197010000-00002" target="_blank">Full Text</a>]
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Howard, R. S., Greenwood, R., Gawler, J., Scaravilli, F., Marsden, C. D., Harding, A. E.
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<strong>A familial disorder associated with palatal myoclonus, other brainstem signs, tetraparesis, ataxia and Rosenthal fibre formation.</strong>
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J. Neurol. Neurosurg. Psychiat. 56: 977-981, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8410038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8410038</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8410038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jnnp.56.9.977" target="_blank">Full Text</a>]
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Iwaki, T., Kume-Iwaki, A., Leim, R. K. H., Goldman, J. E.
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[<a href="https://doi.org/10.1016/0092-8674(89)90173-6" target="_blank">Full Text</a>]
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<strong>c.1289G-A (p.Arg430His) variant in the epsilon isoform of the GFAP gene in a patient with adult onset Alexander disease.</strong>
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[<a href="https://doi.org/10.1016/j.ejmg.2018.07.020" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20406" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-005-0116-7" target="_blank">Full Text</a>]
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<strong>Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant.</strong>
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[<a href="https://doi.org/10.1186/1750-1172-8-66" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2021.11.009" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.10375" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/323799" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.58.10.1541" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.45.12.2266" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000259543.95222.9d" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.60.9.1307" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2023.107540" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000198770.80743.37" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20381" target="_blank">Full Text</a>]
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Wohlwill, F. J., Bernstein, J., Yakovlev, P. I.
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<strong>Dysmyelinogenic leukodystrophy: report of a case of a new, presumably familial type of leukodystrophy with megalobarencephaly.</strong>
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J. Neuropath. Exp. Neurol. 18: 359-383, 1959.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13665382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13665382</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13665382" 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/10.1097/00005072-195907000-00001" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 06/09/2023
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Hilary J. Vernon - updated : 03/17/2022<br>Carol A. Bocchini - updated : 04/15/2019<br>George E. Tiller - updated : 10/27/2009<br>Cassandra L. Kniffin - updated : 12/4/2008<br>Cassandra L. Kniffin - updated : 8/21/2008<br>Cassandra L. Kniffin - updated : 12/4/2007<br>Victor A. McKusick - updated : 7/7/2006<br>Cassandra L. Kniffin - updated : 5/16/2006<br>Cassandra L. Kniffin - updated : 5/24/2005<br>Cassandra L. Kniffin - updated : 1/21/2004<br>Victor A. McKusick - updated : 1/30/2003<br>Cassandra L. Kniffin - updated : 11/27/2002<br>Victor A. McKusick - updated : 11/27/2001<br>Victor A. McKusick - updated : 1/2/2001
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Victor A. McKusick : 6/2/1986
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carol : 06/09/2023
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carol : 03/19/2022<br>carol : 03/18/2022<br>carol : 03/17/2022<br>carol : 04/16/2019<br>carol : 04/15/2019<br>carol : 03/12/2015<br>terry : 3/15/2013<br>terry : 10/2/2012<br>carol : 3/21/2011<br>wwang : 11/10/2009<br>terry : 10/27/2009<br>wwang : 12/4/2008<br>ckniffin : 12/4/2008<br>wwang : 9/2/2008<br>ckniffin : 8/21/2008<br>wwang : 12/10/2007<br>ckniffin : 12/4/2007<br>alopez : 7/14/2006<br>terry : 7/7/2006<br>wwang : 5/18/2006<br>ckniffin : 5/16/2006<br>wwang : 6/16/2005<br>wwang : 6/2/2005<br>ckniffin : 5/24/2005<br>tkritzer : 1/23/2004<br>ckniffin : 1/21/2004<br>tkritzer : 1/14/2004<br>ckniffin : 1/7/2004<br>cwells : 1/30/2003<br>ckniffin : 12/4/2002<br>carol : 12/4/2002<br>ckniffin : 11/27/2002<br>carol : 5/8/2002<br>alopez : 12/3/2001<br>terry : 11/27/2001<br>mgross : 1/2/2001<br>mgross : 3/24/1999<br>alopez : 2/26/1999<br>mimadm : 11/12/1995<br>warfield : 4/14/1994<br>carol : 11/20/1992<br>carol : 4/1/1992<br>supermim : 3/16/1992<br>carol : 8/22/1990
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<strong>#</strong> 203450
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ALEXANDER DISEASE; ALXDRD
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<strong>SNOMEDCT:</strong> 81854007;
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<strong>ICD10CM:</strong> G31.86;
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<strong>ORPHA:</strong> 363717, 363722, 58;
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<strong>DO:</strong> 4252;
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17q21.31
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Alexander disease
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Autosomal dominant
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GFAP
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<span class="mim-font">
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137780
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<p>A number sign (#) is used with this entry because of evidence that Alexander disease (ALXDRD) is caused by heterozygous mutation in the gene encoding glial fibrillary acidic protein (GFAP; 137780) on chromosome 17q21.</p>
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<strong>Description</strong>
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<p>In decreasing order of frequency, 3 forms of Alexander disease (ALXDRD) are recognized, based on age of onset: infantile, juvenile, and adult. Younger patients typically present with seizures, megalencephaly, developmental delay, and spasticity. In older patients, bulbar or pseudobulbar symptoms predominate, frequently accompanied by spasticity. The disease is progressive, with most patients dying within 10 years of onset. Imaging studies of the brain typically show cerebral white matter abnormalities, preferentially affecting the frontal region (Gorospe et al., 2002). All 3 forms have been shown to be caused by mutations in the GFAP gene. </p>
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<p>This disorder, first described by Alexander (1949), is characterized clinically by development of megalencephaly in infancy accompanied by progressive spasticity and dementia. The features are similar to those of Canavan disease (271900). </p><p>Gorospe et al. (2002) reported 12 genetically confirmed cases of Alexander disease. Seven of the 12 had onset in infancy (range 2-18 months), with seizures being the most common presenting sign, followed by failure to thrive and delayed motor development. Five patients had juvenile onset (between 5 and 9 years) and presented with variable symptoms ranging from asymptomatic (2 patients) to linear growth failure, excessive sleepiness and vomiting. Patients in both groups showed megalencephaly, bulbar or pseudobulbar signs, spasticity, cognitive deficits and developmental delay. In addition, all patients showed diffuse and symmetric white matter abnormalities in the frontal regions of the brain. Gorospe et al. (2002) suggested that GFAP gene analysis be included in the diagnostic evaluation of patients presenting with frontal leukoencephalopathy by MRI. </p><p>Bassuk et al. (2003) reported an infant with Alexander disease who presented with poor feeding on the first day of life, followed by emesis and weight loss. MRI on day 21 of life showed signal abnormalities in the frontal lobes and basal ganglia. Over the next 12 days, the patient became increasingly somnolent and hypotonic, and developed seizures on day 33. Magnetic resonance spectroscopy (MRS) performed 14 days apart demonstrated an interval 2-fold increase in the lipid/lactate peak over the right basal ganglia. Over the course of 25 days, head growth increased from the 50th to the 75th percentile. The child died on day 38 from prolonged seizures and respiratory failure. Mutation analysis detected a heterozygous mutation in the GFAP gene (137780.0012). Bassuk et al. (2003) commented on several unusual aspects of the case, including the rapid clinical decline, the rapid head growth, and the demonstration of progressive lactate elevation in the brain by MRS. </p><p>Stumpf et al. (2003) reported a family with an autosomal dominant adult form of Alexander disease. The clinical phenotype varied in severity, but the pattern of evolution was similar in all affected members. Although sleep disturbances and dysautonomia, primarily constipation, began in childhood, the major neurologic features began in the third or fourth decade of life. Features included bulbar signs, ataxia, and pyramidal signs. All patients also had mild dysmorphic features, including progressive kyphosis, arched palate, and short neck. MRI of the older patients showed atrophy of the medulla without signal abnormalities. A mutation in the GFAP gene (137780.0013) was identified in all affected members. </p><p>Li et al. (2005) reported detailed clinical features of 44 patients with Alexander disease, including 26 with infantile onset, 15 with juvenile onset, and 3 with adult onset. The most common features among the patients with infantile onset included seizures (92%), cognitive defects (82%), macrocephaly (62%), bulbar signs (62%), ataxia (58%), and spasticity (52%). The phenotype of juvenile- and adult-onset cases was less severe. Features of juvenile patients included bulbar signs (73%), cognitive defects (60%), spasticity (53%), ataxia (47%), seizures (27%), and macrocephaly (20%). None of the patients with adult onset had macrocephaly, seizures, or cognitive defects. There was a suggestion of male predominance for the disorder. </p><p>Sreedharan et al. (2007) reported an unusual case of a 38-year-old woman with Alexander disease. She presented with a 2-year history of progressive reading difficulty with oscillopsia, slurring dysarthria, choking, and stumbling. Past medical history was significant for endocrine disturbances with an episode of amenorrhea, hypothyroidism, depression, and hypothermic episodes associated with ataxia, facial twitching and drowsiness. Physical examination showed torsional nystagmus and palatal, tongue, and jaw tremor. She had symptomatic microcoria, mild left arm dysmetria, ataxia, and lower limb hyporeflexia. Brain MRI showed brainstem atrophy and symmetric signal changes in the medulla and cerebellum. Her father reportedly had microcoria but refused participation. Genetic analysis identified a heterozygous GFAP mutation in the proband. Sreedharan et al. (2007) commented that this case represented an unusually slowly progressive form of adult-onset Alexander disease. </p><p>Mura et al. (2021) described clinical features of 21 Italian patients with pediatric-onset Alexander disease and classified the disease based on clinical features and evolution of the disease. Seventeen patients were classified as having type I disease, including 1 patient with neonatal-onset and 16 patients with infantile-onset. These patients were further categorized into 4 groups: 1 patient with neonatal onset with rapidly evolving disease and death at 8 months of age was classified with type Ia; 5 patients who presented with developmental delay and experienced clinical deterioration by 5 years of age were classified with type Ib; 2 patients who presented with developmental delay and experienced clinical deterioration after 6 years of age were classified with type Ic; 5 patients who presented with developmental delay and remained clinically stable beyond adolescence were categorized with type Id. Four patients could not be categorized as type Ic or Id because they were of a young age and had not yet experienced neurologic decline. Four patients who had juvenile-onset of symptoms with normal development and no or mild cognitive impairment were classified with type II; symptoms in the type II patients included bulbar signs and autonomic dysfunction. </p><p>From a literature search, Vaia et al. (2023) identified 205 patients with pediatric-onset Alexander disease, for whom 65 had enough clinical data for the authors to evaluate the disease evolution classification suggested by Mura et al. (2021). They found that 17 patients fulfilled criteria for type Ia (disease onset in the first months of life, absence of postural acquisition, and death by 2 years of age); 15 patients fit into type Ib (disease onset at an average of 5.9 months of age, achieving some head and trunk control); 6 patients fit into type Ic (delayed motor development, achieving ambulation, and deterioration at an average of 6 years of age); 5 patients fit into type Id (delayed motor and speech development but acquisition of ambulation and stable neurologic status into adolescence); 19 patients fit into type II (normal neurodevelopment with neurologic deterioration later in life). Three patients were too young at last evaluation to fit into a definite category. </p><p><strong><em>Pathologic Findings</em></strong></p><p>
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Histologically, Alexander disease is characterized by Rosenthal fibers, homogeneous eosinophilic masses which form elongated tapered rods up to 30 microns in length, which are scattered throughout the cortex and white matter and are most numerous in the subpial, perivascular and subependymal regions. These fibers are located in astrocytes, cells that are closely related to blood vessels. Demyelination is present, usually as a prominent feature. A few cases have had hydrocephalus (Alexander, 1949). Rosenthal fibers are commonly found in astrocytomas, optic nerve gliomas and states of chronic reactive gliosis, but they are especially conspicuous in Alexander disease. Herndon et al. (1970) expressed the view that Rosenthal fibers found in this situation are the result of degenerative changes in the cytoplasm and cytoplasmic processes of astrocytic glial cells. </p><p>Iwaki et al. (1989) found that alpha-B-crystallin (CRYAB; 123590) accumulates in the brain in Alexander disease. </p>
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<strong>Diagnosis</strong>
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<p>Van der Knaap et al. (2001) proposed specific MRI criteria for the diagnosis of Alexander disease: extensive, symmetric white matter abnormalities with frontal preponderance; periventricular signal changes; basal ganglia and thalamic signal changes; brainstem lesions; and contrast enhancement of multiple areas throughout the brain. </p><p>Van der Knaap et al. (2005) reported 9 patients with Alexander disease confirmed by genetic analysis who had atypical MRI features. Alexander disease was not the initial diagnosis for any of the patients, and none of the patients met the MRI-based criteria proposed by van der Knaap et al. (2001). MRI in 8 patients showed predominantly posterior fossa lesions, especially multiple tumor-like brainstem lesions. One patient had asymmetric frontal white matter abnormalities and basal ganglia abnormalities. Van der Knaap et al. (2005) concluded that DNA diagnostics is warranted in patients with atypical MRI features that are only suggestive of Alexander disease. </p><p>Van der Knaap et al. (2006) reported 7 patients with genetically confirmed Alexander disease who had no or inconspicuous cerebral white matter abnormalities and no or minimal contrast enhancement on brain MRI. All had juvenile disease onset with signs of brainstem or spinal cord dysfunction, including bladder and gait disturbances. MRI findings were predominantly signal changes or atrophy of the medulla and spinal cord. Four patients had a kind of 'garland' along the ventricular wall. Van der Knaap et al. (2006) concluded that Alexander disease is not invariably a leukoencephalopathy, and that patients with later onset of the disorder may have more unusual phenotypic variation. </p>
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<p>Wohlwill et al. (1959) described a sibship of 9, of whom 1 sister and 3 brothers had large heads called hydrocephalic and died at ages 4, 5, 6 and 3, respectively. Alexander disease was proven histologically in the last. Although this sibship suggested possible autosomal recessive inheritance, all the molecular genetic evidence favors autosomal dominant inheritance, i.e., de novo heterozygous mutations as the cause. In vitro studies of one such mutation in the GFAP gene causing Alexander disease (137780.0003) found that the mutant protein accumulates into Rosenthal fibers by a pathway that involved filament aggregation and the association of alpha-B-crystallin and HSP27 (602195). The data confirmed that the effects of the specific GFAP mutation are dominant; in the heterozygote mutant, the gene product was dominant over wildtype GFAP in coassembly experiments (Der Perng et al., 2006). </p>
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<strong>Molecular Genetics</strong>
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<p>Mutations in the GFAP gene were found in the infantile form of Alexander disease by Brenner et al. (2001), in the juvenile form by Sawaishi et al. (2002), and in the adult form by Namekawa et al. (2002). </p><p>Brenner et al. (2001) identified de novo heterozygous mutations in the GFAP gene in 10 of 11 patients with Alexander disease (137780.0001-137780.0005). Rodriguez et al. (2001) likewise identified de novo heterozygous missense GFAP mutations in exon 1 or exon 4 in 14 of 15 patients who were candidates for Alexander disease on the basis of suggestive neuroimaging abnormalities. These included patients without macrocephaly. Affected sibs whose parents were unaffected, including 1 family with neuropathologically proved Alexander disease (Wohlwill et al., 1959), could represent autosomal recessive transmission or germinal mosaicism for a dominant mutation. Therefore, Rodriguez et al. (2001) suggested that after the birth of a patient with Alexander disease with a de novo GFAP mutation, prenatal diagnosis should be proposed for all subsequent pregnancies. It remained to be determined whether the heritable dominant forms of Alexander disease described in 2 families, both of which had late onset after age 25 years (Howard et al., 1993; Schwankhaus et al., 1995), also had GFAP mutations as the cause. </p><p>Of 13 patients with MRI white matter abnormalities consistent with Alexander disease, 12 were found by Gorospe et al. (2002) to have GFAP mutations. Four of the 9 changes identified were novel mutations. </p><p>Li et al. (2006) determined that the paternal chromosome carried the GFAP mutation in 24 of 28 unrelated cases of Alexander disease analyzed, suggesting that most mutations occur during spermatogenesis rather than in the embryo. No effect of paternal age was observed. </p><p>In 13 unrelated Italian patients with Alexander disease, including 8 with the infantile, 2 with the juvenile, and 3 with the adult form, Caroli et al. (2007) identified 11 different mutations in the GFAP gene (see, e.g., 137780.0005), including 4 novel mutations. Ten mutations occurred in the rod domains and 1 in the tail domain. </p><p>Karp et al. (2019) reported a patient with adult-onset Alexander disease in whom, after excluding mutation in the GFAP-alpha isoform, they identified heterozygosity for a missense mutation (c.1289G-A, R430H) in exon 7A of the GFAP-epsilon isoform. The authors noted that the same mutation in GFAP-epsilon had been identified by Melchionda et al. (2013) in a brother and sister half-sib pair with adult onset of the disorder in whom mutation in GFAP-alpha had been excluded. The brother also had a mutation (c.2566C-T, P856S) in the HDAC6 gene (300272). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hagemann et al. (2009) noted that Rosenthal fibers in the complex astrocytic inclusions characteristic of Alexander disease contain GFAP, vimentin (VIM; 193060), plectin (PLEC1; 601282), ubiquitin (UBB; 191339), HSP27, and alpha-B-crystallin. CRYAB regulates GFAP assembly, and elevation of CRYAB is a consistent feature of Alexander disease; however, its role in Rosenthal fibers and disease pathology is not known. In a mouse model of Alexander disease, Hagemann et al. (2009) showed that loss of Cryab resulted in increased mortality, whereas elevation of Cryab rescued animals from terminal seizures. When mice with Rosenthal fibers induced by overexpression of GFAP were crossed into a Cryab-null background, over half died at 1 month of age. Restoration of Cryab expression through the GFAP promoter reversed this outcome, showing the effect was astrocyte-specific. Conversely, in mice carrying an Alexander disease-associated mutation and in mice overexpressing wildtype GFAP, which, despite natural induction of Cryab also died at 1 month, transgenic overexpression of Cryab resulted in a markedly reduced CNS stress response, restored expression of the glutamate transporter Glt1 (SLC1A2; 600300), and protected these animals from death. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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Mura, E., Nicita, F., Masnada, S., Battini, R., Ticci, C., Montomoli, M., Berardinelli, A., Pantaleoni, C., Ardissone, A., Foiadelli, T., Tartara, E., Salsano, E., Veggiotti, P., Ceccherini, I., Moroni, I., Bertini, E., Tonduti, D.
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<strong>Hereditary adult-onset Alexander's disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia.</strong>
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<p class="mim-text-font">
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Stumpf, E., Masson, H., Duquette, A., Berthelet, F., McNabb, J., Lortie, A., Lesage, J., Montplaisir, J., Brais, B., Cossette, P.
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<strong>Adult Alexander disease with autosomal dominant transmission: a distinct entity caused by mutation in the glial fibrillary acid protein gene.</strong>
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<p class="mim-text-font">
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Vaia, Y., Mura, E., Tonduti, D.
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<strong>Type I Alexander disease: update and validation of the clinical evolution-based classification.</strong>
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Molec. Genet. Metab. 138: 107540, 2023.
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[PubMed: 36804850]
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[Full Text: https://doi.org/10.1016/j.ymgme.2023.107540]
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</p>
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<li>
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<p class="mim-text-font">
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van der Knaap, M. S., Naidu, S., Breiter, S. N., Blaser, S., Stroink, H., Springer, S., Begeer, J. C., van Coster, R., Barth, P. G., Thomas, N. H., Valk, J., Powers, J. M.
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<strong>Alexander disease: diagnosis with MR imaging.</strong>
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Am. J. Neuroradiol. 22: 541-552, 2001.
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[PubMed: 11237983]
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<li>
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<p class="mim-text-font">
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van der Knaap, M. S., Ramesh, V., Schiffmann, R., Blaser, S., Kyllerman, M., Gholkar, A., Ellison, D. W., van der Voorn, J. P., van Dooren, S. J. M., Jakobs, C., Barkhof, F., Salomons, G. S.
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<strong>Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord.</strong>
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Neurology 66: 494-498, 2006.
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[PubMed: 16505300]
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[Full Text: https://doi.org/10.1212/01.wnl.0000198770.80743.37]
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<li>
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<p class="mim-text-font">
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van der Knaap, M. S., Salomons, G. S., Li, R., Franzoni, E., Gutierrez-Solana, L. G., Smit, L. M. E., Robinson, R., Ferrie, C. D., Cree, B., Reddy, A., Thomas, N., Banwell, B., Barkhof, F., Jakobs, C., Johnson, A., Messing, A., Brenner, M.
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<strong>Unusual variants of Alexander's disease.</strong>
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|
Ann. Neurol. 57: 327-338, 2005. Note: Erratum: Ann. Neurol. 58: 172 only, 2005.
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[PubMed: 15732098]
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[Full Text: https://doi.org/10.1002/ana.20381]
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</p>
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<p class="mim-text-font">
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Wohlwill, F. J., Bernstein, J., Yakovlev, P. I.
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<strong>Dysmyelinogenic leukodystrophy: report of a case of a new, presumably familial type of leukodystrophy with megalobarencephaly.</strong>
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J. Neuropath. Exp. Neurol. 18: 359-383, 1959.
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[PubMed: 13665382]
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[Full Text: https://doi.org/10.1097/00005072-195907000-00001]
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Hilary J. Vernon - updated : 06/09/2023<br>Hilary J. Vernon - updated : 03/17/2022<br>Carol A. Bocchini - updated : 04/15/2019<br>George E. Tiller - updated : 10/27/2009<br>Cassandra L. Kniffin - updated : 12/4/2008<br>Cassandra L. Kniffin - updated : 8/21/2008<br>Cassandra L. Kniffin - updated : 12/4/2007<br>Victor A. McKusick - updated : 7/7/2006<br>Cassandra L. Kniffin - updated : 5/16/2006<br>Cassandra L. Kniffin - updated : 5/24/2005<br>Cassandra L. Kniffin - updated : 1/21/2004<br>Victor A. McKusick - updated : 1/30/2003<br>Cassandra L. Kniffin - updated : 11/27/2002<br>Victor A. McKusick - updated : 11/27/2001<br>Victor A. McKusick - updated : 1/2/2001
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Victor A. McKusick : 6/2/1986
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